e. Several carcinogens from cigarette smoke should be studied for
synergistic, additive, or antagonistic effects on carcinogenesis
because tobacco constituents are inhaled or swallowed as a
mixture, not individually.

f. Further investigations of promoters, cocarcinogens, and initia-
tors of eancer in cigarette smoke are necessary.

g.New models for carcinogenicity should be developed with
emphasis on in vitro or short-term experiments.

h. Nicotine itself should be investigated for carcinogenic or
cocarcinogenic action in animals even though it is a very toxic
chemical. Similarly, acrolein should be tested for carcinogenic
and cocarcinogenic action.

. Anti-carcinogens or preventive compounds, such as vitamin A,
retinoids, or other chemicals that may prevent carcinogenesis
deserve further investigation.

j. There should be a registry for listing all the different chemicals
identified in cigarette smoke, along with known properties of
those chemicals.

5. Cooperative international epidemiologic studies should examine
different tobaccos, ethnic groups, diets, and smoking habits. Such
studies would describe the differences in development of tobacco-
related cancers and elucidate the etiologic roles of differing
cigarettes.

6. Genetic markers such as HLA or other indices should be sought to
identify high-risk groups prone to tobacco-related diseases if they
smoke. Genetically susceptible individuals should be counseled
about their high-risk status.

me

Summary

1. Today’s filter-tipped, lower “tar” and nicotine cigarettes produce
lower rates of lung cancer than do their higher “tar” and nicotine
predecessors. Nonetheless, smokers of lower “tar” and nicotine
cigarettes have much higher lung cancer incidence and mortality
than do nonsmokers.

2. Smokers of lower “tar” and nicotine cigarettes may tend to
smoke larger numbers of cigarettes, to inhale more deeply, to
have relatively higher amounts of carboxyhemoglobin than
predicted from machine measurements of carbon monoxide yield,
and to have higher than predicted carbon monoxide in exhaled
air.

3. In attempting to develop a “less hazardous” cigarette, singular
emphasis has been placed on reducing the “tar” yield of cigarette
smoke because of the early demonstration of a causal relationship
between “tar” and lung cancer. Comparable data on changes in

101
yield of constituents in the gas phase of smoke are not publicly
available.

4.The occurrence of laryngeal cancer has been reported to be
reduced among smokers who use filtered cigarettes, compared
with those who use nonfiltered cigarettes.

5. There is no epidemiologic evidence to prove or to disprove a
decreased occurrence of cancers of other sites in humans who
smoke lower “tar” and nicotine cigarettes.

6. In evaluating the effect of smoking lower “tar” and nicotine
cigarettes on histologic changes in the bronchial epithelium, it
was determined in one autopsy study that male smokers who died
between 1970 and 1977 had fewer histological changes than those
smokers who died between 1950 and 1955.

7. Even among those who do not develop cancer, histologic changes
in the tracheobronchial tree are more advanced at autopsy in
smokers of cigarettes with higher “tar” and nicotine than among
smokers of cigarettes with lower yields.

8. The “tar” content of smoke condensate of today’s cigarettes is
less tumorigenic to mouse skin than that of cigarettes of 30 years
ago. Levels of the known carcinogen benzo{a}pyrene are lower in
the smoke of today’s cigarettes than in that of cigarettes of 30
years ago. Flavor additives used in lower “tar” and nicotine
cigarettes produce traces of mutagenic compounds.

9. Although studies point to polycyclic aromatic hydrocarbons in the
“tar” of inhaled cigarette smoke as potential carcinogens for
humans, additional work is needed to determine whether nicotine
plays a major role as a carcinogen. Definition of the role of
nicotine in carcinogenesis is necessary prior to advocacy of
cigarettes yielding less “tar” but more nicotine.

10. Animal studies have shown that a significant reduction of “tar”
and a selective reduction of tumor initiators and cocarcinogens
can markedly reduce the tumorigenic potency of cigarette smoke.

102
References

(1)
(2)

(3)

(4)

(5)

(6)

(7)

(8)
(9)

(10)
(12)

(12)

(18)

(14)

(15)

(16)

(17)

(18)

AMES, B.N., SIMS, P., GROVER, P.I. Epoxides of carcinogenic polycyclic
hydrocarbons are frameshift mutagens. Science 176(4030): 47-49, April 7, 1972.

ARNOTT, M.S., YAMAUCHI, T., JOHNSTON, D.A. In: Griffin, A.C., and
Shaw, C.R. (Editors). Careinogens: Identification and Mechanisms of Action.
New York, Raven Press, 1979, pp. 145-156.

AUERBACH, 0., HAMMOND, E.C., GARFINKEL, L. Changes in bronchial
epithelium in relation to cigarette smoking, 1955-1960 vs. 1970-1977. New
England Journal of Medicine 300(8): 381-886, February 22, 1979.

AUERBACH, O., STOUT, A.P., HAMMOND, E.C., GARFINKEL, L. Changes
in bronchial epithelium in relation to cigarette smoking and in relation to lung
cancer. New England Journal of Medicine 265(6): 253, August 10, 1961.

AUERBACH, O., STOUT, A.P., HAMMOND, E.C., GARFINKEL, L. Bronchial
epithelium in former smokers. New England Journal of Medicine 267(3): 119,
July 19, 1962.

AUERBACH, O., STOUT, A.P., HAMMOND, EC., GARFINKEL, L. Changes
in bronchial epithelium in relation to sex, age, residence, smoking and
pneumonia. New England Journal of Medicine 267(3): 111, July 19, 1962.

BANERJEE, S., VAN DUUREN, B.L. Covalent binding of the carcinogen
trichloroethylene to hepatic microsomal proteins and to exogenous DNA in
vitro. Cancer Research 38(3): 776-780, March 1978.

BARRY, E.J., GUTMANN, H.R. Protein modifications by activated carcinogens.
Journal of Biological Chemistry 248(7): 2730-2737, April 10, 1973.

BARRY, EJ., OVECHKA, C.A.. GUTMANN, H.R. Journal of Biological
Chemistry 243: 51-60, 1968.

BELAND, F.A. National Cancer Institute Monograph , in press.

BERMAN, J.J., RICE, J.M., WENK, M.L., ROLLER, P.P. Intestinal tumors
induced by a single intraperitoneal injection of methyl (acetoxymethyl)
nitrosamine in three strains of rats. Cancer Research 39(5): 1462-1465, May
1979.

BERNFELD, P., HOMBURGER, F., RUSSFIELD, A.B. Cigarette smoke-
induced cancer of the larynx in hamsters (CINCH): A method to assay the
carcinogenicity of cigarette smoke. Progress in Experimental Tumor Research
2A: 315-319, 1979.

BERNFELD, P., HOMBURGER, F., SOTO, E., PAI, KJ. Cigarette smoke
inhalation studies in inbred Syrian golden hamsters. Journal of the National
Cancer Institute 63(3): 675-689, September 1979.

BOCK, F.G. Cocarcinogenic properties of nicotine. In: Gori, G.B., Bock, F.G.
(Editors). Banbury Report 8—A Safe Cigarette? Cold Spring Harbor, New
York, Cold Spring Harbor Laboratory, 1980, pp. 129-139.

BOTELHO, L.H., RYAN, D.E., LEVIN, W. Amino acid compositions and partial
amino acid sequences of three highly purified forms of liver microsomal
cytochrome P-450 from rats treated with polychlorinated biphenyls, phenobar-
bital, or 3-methylcholanthrene. Journal of Biological Chemistry 254(13): 5635-
5640, July 10, 1979.

BOYLAND, E. The biological significance of metabolism of polycyclic com-
pounds. In: Williams, R.T. (Editor). Biological Oxidation of Aromatic Rings.
Biochemical Society Symposia No. 5, 1950, pp. 40-54.

BRUNNEMANN, K.D., YU, L., HOFFMANN, D. Assessment of carcinogenic
volatile N-nitrosamines in tobacco and in mainstream and sidestream smoke
from cigarettes. Cancer Research 37(9): 3218-3222, September 1977.

CHANG, S.-K., HARRINGTON, G.W., ROTHSTEIN, M., SHERGALIS, W.A.,
SWERN, D., VOHRA, S.K. Accelerating effect of ascorbic acid on N-
nitrosamine formation and nitrosation by oxyhyponitrite. Cancer Research
39(10): 3871-3874, October 1979.

108
(19)

(20)

(22)

(22)

(23)

(24)

(25)

(26)

(27)

(28)
(29)

(0)

($1)

(82)

104

CHEN, C.B., HECHT, S.S., HOFFMANN, D. Metabolic alpha-hydroxylation of
the tobacco-specific carcinogen, N-nitrosonornicotine. Cancer Research 38(11):
3639-3645, November 1978.

DAVIS, B.R., WHITEHEAD, J.K., GILL, ME, LEE, P.N., BUTTERWORTH,
A.D., ROE, J.F.C. Response of rat lung to tobacco smoke condensate or
fractions derived from it administered repeatedly by intratracheal instillation,
British Journal of Cancer 31(4): 458-461, 1975.

DEUTSCH, J., LEUTZ, J.C., YANG, SK., GELBOIN, H. V., CHANG, Y.L.,
VATSIS, K.P., COON, M.J. Regio- and stereoselectivity of various forms of
purified cytochrome P-450 in the metabolism of benzo[a]pyrene and (-)trans-
7,8-dihydroxy-7,8-dihydrobenzo{a]pyrene as shown by product formation and
binding to DNA. Proceedings of the National Academy of Sciences of the United
States of America 77): 3123-3127, July 1978.

DOLL, R. Cancers Related to Smoking. Proceedings of the Second World
Conference on Smoking and Health, London, Pitman Medical, 1971, pp. 10-23.

DONTENWILL, W.P. Tumorigenic effect of chronic cigarette smoke inhalation
on Syrian golden hamsters. In: Karbe, E., Park, J.F. (Editors). International
Symposium, Seattle, June 23-26, 1974. Experimental Lung Cancer: Carcino-
genesis and Bioassays. New York, Springer-Verlag, 1974, pp. 382-359.

DONTENWILL, W., CHEVALIER, H.-J., HARKE, H.-P., KLIMISCH, H.-J.,
RECKZEH, G., FLEISHMANN, B., KELLER, W. Experimentelle Untersu-
chungen uber die tumorerzeugende Wirkung von Zigarettenrauch-Kondensa-
ten an der Mausehaut. VII. Mitteilung Einzelverleiche von Kondensaten
verschiedener modifizierter Zigaretten. [Experimental investigations on the
tumorigenic activity of cigarette smoke condensate on mouse skin. VII.
Comparative studies of condensates from different modified cigarettes.]
Zeitschrift fur Krebsforschung und Kliniache Onkologie 89(2): 145-151, 1977.

EVERSON, R.B. Hypothesis: Individuals transplacentally exposed to maternal
smoking may be at increased cancer risk in adult life. Lancet 2(8186): 123-126,
July 19, 1980,

FAN, T.Y., VITA, R. FINE, D.H. C-Nitro compounds: A new class of
nitrosating agents. Toricology Letters 2(1): 5-10, May 1978.

FERON, V.J., KRUYSSE, J. Effects of exposure to acrolein vapor in hamsters
simultaneously treated with benzo[a]pyrene or dimethylnitrosamine. Journal
of Toxicology and Environmental Health 3(3): 379-394, October 1977.

FUCHS, R.P.P. Analytical Biochemistry 91: 663-678, 1978.

GORI, G.B. (Editor). Toward Less Hazardous Cigarettes. The First Set of
Experimental Cigarettes. U.S. Department of Health, Education, and Welfare,
Public Health Service, National Institutes of Health, National Cancer
Institute, Smoking and Health Program, Report No. 1, DHEW Publication No.
(NIH) 76-905, 1976, 148 pp.

GORI, G.B. (Editor). Teward Less Hazardous Cigarettes. The Second Set of
Experimental Cigarettes. U.S. Department of Health, Education, and Welfare,
Public Health Service, National Institutes of Health, National Cancer
Institute, Smoking and Health Program, Report No. 2, DHEW Publication No.
(NIH) 76-1111, 1976, 153 pp.

GORI, G.B. (Editor). Toward Less Hazardous Cigarettes. The Third Set of
Experimental Cigarettes. U.S. Department of Health, Education, and Welfare,
Public Health Service, National Institutes of Health, National Cancer
Institute, Smoking and Health Program, Report No. 3, DHEW Publication No.
(NTH) 77-1280, 1977, 152 pp.

GORI, G.B. (Editor). Toward Less Hazardous Cigarettes. The Fourth Set of
Experimental Cigarettes. U.S. Department of Health, Education, and Welfare,
Public Health Service, National Institutes of Health, National Cancer
Institute, Office of Cancer Communications, March 1980, 210 pp.
($3)

(34)

($5)

(6)

(37)

(88)

(89)

(40)

(4D

(42)

(43)

(44)

(45)

(48)

4%)

(48)

GUENGERICH, FP. Separation and purification of multiple forms of micro-
somal cytochrome P-450. Activities of different forms of cytochrome P-450
towards several compounds of environmental interest. Journal of Biological
Chemistry 252(11): 3970-3979, June 10, 1977.

HAENSZEL, W. (Editor). Epidemiological Approaches to the Study of Cancer
and Other Chronic Diseases. U.S. Department of Health, Education, and
Welfare, Public Health Service, National Institutes of Health, National Cancer
Institute Monograph No. 19, January 1966, 465 pp.

HAMMOND, E.C., GARFINKEL, L., SEIDMAN, H., LEW, E.A. “Tar” and
nicotine content of cigarette smoke in relation to death rates. Environmental
Research 12(3): 263-274, December 1976.

HAMMOND, E.C., GARFINKEL, L., SEIDMAN, H., LEW, E.A. Some recent
findings concerning cigarette smoking. In: Hiatt, H.H., Watson, J .D., Winsten,
J.A. (Editors). Origins of Human Cancer. Book A. Incidence of Cancer in
Humans. Cold Spring Harbor Conferences on Cell Proliferation, Volume 4,
New York, Cold Spring Harbor Laboratory, 1977, pp. 101-112.

HAMMOND, E.C., HORN, D. Smoking and death rates—Report on forty-four
months of follow-up of 187,783 men. I. Total mortality. Journal of the
American Medical Association 166(10): 1159-1178, March 8, 1958.

HAMMOND, E.C., HORN, D. Smoking and death rates—Report on forty-four
months of follow-up of 187,783 men. II. Death rates by cause. Journal of the
American Medical Association 166(11): 1294-1308, March 15, 1958.

HARLEY, N.H., COHEN, B.S., TSO, T.C. Polonium-210: A questionable risk
factor in smoking-related carcinogenesis. In: Gori, G.B., Bock, F.G. (Editors).
Banbury Report 8—A Safe Cigarette? Cold Spring Harbor, New York, Cold
Spring Harbor Laboratory, 1980, pp. 93-104.

HAWKSWORTH, G., HILL, MJ. The in vivo formation of N-nitrosamines in
the rat bladder and their subsequent absorption. British Journal of Cancer
29(5): 358-358, May 1974.

HECHT, S.S., ORNAF, R.M., HOFFMANN, D. Chemical studies on tobacco
smoke. XXXIII. N’-nitrosonornicotine in tobacco: Analysis of possible contrib-
uting factors and biologic implications. Journal of the National Cancer
Institute 54(5): 1237-1244, May 1975.

HECHT, S.S., YOUNG, R., CHEN, C.B. Metabolism in the F-344 rat of 4(N-
methyl-N-nitrosamine)-1-(3-pyridyl)-1-butanone, a tobacco specific carcinogen.
Cancer Research 40(11): 4144-4150, November 1980.

HENSCHLER, D., BONSE, G. Advances in Pharmacology and Therapeutics 9:
123-130, 1979.

HILL, P., MARQUARDT, H. Plasma and urine changes after smoking different
brands of cigarettes. Clinical Pharmacology and Therapeutics 27(5): 652-658,
May 1980.

HILL, D.L., SHIH, T.W., JOHNSTON, T.P., STRUCK, R.F. Macromolecular
binding and metabolism of the carcinogen 1,2-dibromoethane. Cancer Research
$8(8): 2438-2442, August 1978.

HOFFMANN, D., ADAMS, J.D., BRUNNEMANJ, K.D., HECHT, S.S. Assess-
ment of tobacco-specific N-nitrosamines in tobacco products. Cancer Research
39(7): 2505-2509, 1979.

HOFFMANN, D., CHEN, C.B., HECHT, S.S. The role of volatile and nonvolatile
N-nitrosamines in tobacco carcinogenesis. In: Gori, G.B., Bock, F.G. (Editors).
Banbury Report 8—A Safe Cigarette? Cold Spring Harbor, New York, Cold
Spring Harbor Laboratory, 1980, pp. 118-127.

HOFFMANN, D., SCHMELTZ, I., HECHT, S.S., WYNDER, ELL. Tobacco
carcinogenesis. In: Gelboin, H.V., Tso, P.O. (Editors). Polycyclic Hydrocarbons
and Cancer. New York, Academic Press, 1978, pp. 85-117.

105
(49)

(50)

(51)

(52)

(58)

(54)

(55)
(56)

(57)

(58)
(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

106

HOFFMANN, D., TSO, T.C., GORI, G.B. The less harmful cigarette. Preventive
Medicine 9(2): 287-296, March 1980.

ILNITSKY, A.P., MISCHENKO, V.S., SHABAD, L.M. New data on voleanoes
as natural sources of carcinogenic substances. Cancer Letters 3(5/6): 227-230,
November 1977,

ILNITSKY, A.P., VINOGRADOV, V.N., RIABCHUN, V.K., MISCHENKO,
V.S., GVILDIS, V.Y., BELITSKY, G.A., SHABAD, L.M. Cancer Letters &(1):
51-58, November 1979.

ILNITSKY, A.P., VINOGRADOV, V.N., RIABCHUN, V.K., MISCHENKO,
V.S., GVILDIS, V.I., CHERNENKY, V.L, BELITSKY, G.A., SHABAD, LM.
Doklady Akademii Nauk SSSR 245: 254-257, 1979.

INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. N-Nitrosonor-
nicotine. IARC Monographs on the Evaluation of the Carcinogenic Risk of
Chemicals to Humans: Some N-nitroso Compounds. International Agency for
Research on Cancer Monograph 11: 281-286, May 1978.

JAFFE, J.H., KANZLER, M., FRIEDMAN, L. Studies of switching to low tar
and nicotine cigarettes. In: Gori, G.B., Bock, F.G. (Editors). Banbury Report 3-
A Safe Cigarette? Cold Spring Harbor, New York, Cold Spring Harbor
Laboratory, 1980, p. 311.

KADLUBAR, F-F. National Cancer Institute Monograph, in press.

KADLUBAR, F.F., MILLER, J.A., MILLER, E.C. Guanyl O*-arylamination and
O%arylation of DNA by the carcinogen N-hydroxy-1-naphthylamine. Cancer
Research 38(11): 3628-3688, November 1978.

KAPITULNIK, J., LEVIN, W., CONNEY, A.H., YAGI, H., JERINA, D.M.
Benzofa]pyrene 7,8-dihydrodiol is more carcinogenic than benzo[a]pyrene in
newborn mice. Nature 266(5600): 378-380, March 24, 1977.

KING, C.M., TRAUB, N.R., LORTZ, Z.M., THISSEN, M.R. Cancer Research 39:
3359-3372, 1979.

KING, H.W., OSBORNE, M.R., BROOKES, P. Chemico-Biological Interactions
24: 345-358, 1979.

KOESTNER, A., SWENBERG, J.A., WECHSLER, W. Experimental tumors of
the nervous system induced by resorptive N-nitrosourea compounds. Progress
in Experimental Tumor Research 17: 9-30, 1972.

KOREEDA, M., MOORE, P.D., YAGI, H., YEH, HJ.C., JERINA, DM.
Alkylation of polyguanylic acid at the 2-amino group and phosphate by the
potent mutagen ( +} 7B,8a-dihydroxy-98,106-epoxy-7,8,9,10-tetrahydroben-
zofa]pyrene. Journal of the American Chemical Society 98(21): 6720-6722,
October 13, 1976.

KOZLOWSKI, L.T., FRECKER, R.C., KHOUW, V., POPE, M.A. The misuse of
“less-hazardous” cigarettes and its detection: Hole-blocking of ventilated
filters. American Journal of Public Health 70(11): 1202-1208, November 1980.

KUNZE, M., VUTUC, C. Threshold of tar exposure: Analysis of smoking history
of male lung cancer cases and controls. In: Gori, G.B., Bock, F.G. (Editors).
Banbury Report 8—A Safe Cigarette? Cold Spring Harbor, New York, Cold
Spring Harbor Laboratory, 1980, pp. 29-36.

LAVOIE, E.J., HECHT, S.S., HOFFMANN, D., WYNDER, ELL. The less
harmful cigarette and tobacco smoke flavors, In: Gori, G.B., Bock, F.G.
(Editors). Banbury Report 3—A Safe Cigarette? Cold Spring Harbor, New
York, Cold Spring Harbor Laboratory, 1980, pp. 251-260.

LEFFINGWELL, J.C., YOUNG, H.J., BERNASEK, E. Tobacco Flavoring for
Smoking Products. Winston-Salem, North Carolina, RJ. Reynolds Co., 1972.

LIJINSKY, W., REUBER, M.D. Carcinogenicity in rats of nitrosomethylethyla-
mines labeled with deuterium in several Positions. Cancer Research 40(1): 19-
21, January 1980.
(67)

(68)

(69)

(70)

(71)

(72)
(78)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

(88)

LITWACK, G., CAKE, M.H., FILLER, R., TAYLOR, K. Physical measurements
of the liver glucocorticoid receptor. Biochemical Journal 169(2): 445-448,
February 1978.

LITWACK, G., KETTERER, B., ARIAS, IM. Ligandin: A hepatic protein which
binds steroids, bilirubin, carcinogens and a number of exogenous organic
anions. Natwre 234(5329): 466-467, December 17, 1971.

LLOYD, J.W. Long-term mortality study of steelworkers. V. Respiratory cancer
in coke plant workers. Journal of Occupational Medicine 13(2): 53-68,
February 1971.

MAXWELL, J.C., JR. Trends in cigarette consumption. In: Gori, G.B., Bock,
F.G. (Editors). Banbury Report 8—A Safe Cigarette? Cold Spring Harbor, New
York, Cold Spring Harbor Laboratory, 1980, pp. 325-332.

MILLER, E.C., MILLER, J.A. The presence and significance of bound aminoa-
zodyes in the livers of rats fed p-dimethylaminoazobenzene. Cancer Research
7: 468-480, 1947.

MILLER, E.C., MILLER, J.A. In: Searle, C.E. (Editor). Chemical Carcinogens.
American Chemical Society Monograph 178, 1976, pp. 737-762.

MILLER, J.A., MILLER, E.C. Advances in Pharmacology and Therapeutics 9:
3-12, 1979.

MOSCHEL, RC., BAIRD, W.M., DIPPLE, A. Metabolic activation of the
carcinogen 7,12-dimethylbenz{aJanthracene for DNA binding. Biochemical and
Biephysical Research Communications T6(4): 1092-1098, June 20, 1977.

MOSS, A.J. Changes in Cigarette Smoking and Current Smoking Practices
Among Adults: United States, 1978. U.S. Department of Health, Education,
and Welfare, Public Health Service, National Center for Health Statistics.
Advance Data from Vital and Health Statistics, Publication No. 52, September
19, 1979, 15 pp.

NAKANISHI, K., KASAI, H., CHO, H., HARVEY, RG., JEFFREY, A.M,
JENNETTE, K.W., WEINSTEIN, LB. Absolute configuration of a ribonucleic
acid adduct formed by metabolism benzo[a]pyrene. Journal of the American
Chemical Society 99(1): 258-260, January 5, 1977.

NEBERT, D.W. Genetic control of carcinogen metabolism leading to individual
differences in cancer risk. Biochimie 60(9): 1019-1029, December 1978.

NEBERT, D.W., JENSEN, N.M. The Ah locus: Genetic regulation of the
metabolism of carcinogens, drugs, and other environmental chemicals by
cytochrome P-450-mediated monooxygenases. CRC Critical Reviews in Bio-
chemistry 6(1): 401-437, June 1979.

NEBERT, D.W., LEVITT, 2.C., PELKONEN, O. In: Griffin, AC., Shaw, C.R.
(Editors). Carcinogens: Identification and Mechanisms of Action. New York,
Raven Press, 1979, pp. 157-185.

NICOLOV, I.G., CHERNOZEMSKY, I.N. Tumors and hyperplastic lesions in
Syrian hamsters following transplacental and neonatal treatment with
cigarette smoke condensate. Journal of Cancer Research and Clinical Oncology
94(12): 249-256, 1979.

NORMAN, R.L., MULLER-EBERHARD, U., JOHNSON, E.F. The role of
cytochrome P-450 forms in 2-aminoanthracene and benzofa]pyrene mutagene-
sis. Biochemical and Biophysical Research Communications 89(1): 195-201,
July 12, 1979.

NORMAN, V. The effect of perforated tipping paper on the yield of various
smoke components. Beitrage zur Tabakforschung 7(5): 282-287, September
1974.

PARKES, H.G. The epidemiology of the aromatic amine cancers. In: Searle, C.E.
(Editor). Chemical Carcinogens. American Chemical Society Monograph 173:
462-480, 1976.

107
(84)

(85)

(86)

(87)

(88)
(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(100)

(101)

108

PATRIANAKOS, C., HOFFMANN, D. Chemical studies on tobacco smoke.
LXIV. On the analysis of aromatic amines in cigarette smoke. Journal of
Analytical Toxicology 3(4): 150-154, J uly/August 1979.

RADFORD, E.P., HUNT, V.R., LITTLE, J.B., WYNDER, E.L., HOFFMANN,
D. Carcinogenicity of tobacco-smoke constituents. Science 165(3890): 312-818,
July 18, 1969.

REDMOND, C.K., CIOCCO, A., LLOYD, J.W., RUSH, H.W. Long term
mortality of steelworkers. VI. Mortality from malignant neoplasms among
coke oven workers. Journal of Occupational Medicine 14(8): 621-628, August
1972,

RICE, J.M. Prenatal effects of chemical carcinogens and methods for their
detection. In: Kimmel, C.A., Buelke-Sam, J. (Editors). Developmental Toxicity.
1980.

ROE, F.C., WALTERS, M.A. Some unsolved problems in lung cancer etiology.
Progress in Experimental Tumor Research 6: 126-227, 1965.

ROWLAND, LR., GRASSO, P. Degradation of N-nitrosamines by intestinal
bacteria. Applied Microbiology 29(1): 7-12, January 1975.

RUSSELL, M.A.H. The case for medium-nicotine, low-tar, low-carbon monoxide
cigarettes. In: Gori, G.B., Bock, F.G. (Editors). Banbury Report $—A Safe
Cigarette? Cold Spring Harbor, New York, Cold Spring Harbor Laboratory,
1980, pp. 297-310.

SATO, R., OMURA, T. (Editors). Cytochrome P-450. Tokyo, Kodansha Ltd., 1978,
233 pp.

SCHMELTZ, I., HOFFMANN, D. Nitrogen-containing compounds in tobacco
and tobacco smoke. Chemical Reviews TU): 295-811, June 1977.

SHIFFMAN, S.M. Diminished smoking, withdrawal symptoms, and cessation: A
cautionary note. In: Gori, G.B., Bock, F.G. (Editors). Banbury Report $—A
Safe Cigarette? Cold Spring Harbor, New York, Cold Spring Harbor Laborato-
ry, 1980, pp. 283-296.

SINGER, B. N-nitroso alkylating agents: Formation and persistence of alkyl
derivatives in mammalian nucleic acids aa contributing factors in carcinogene-
sis. Journal of the National Cancer Institute 62(6): 1829-1839, June 1979.

SINGER, S.S. Kinetics and mechanism of aliphatic transnitrosation. Journal of
Organic Chemistry 48(24): 4612-4616, November 24, 1978,

SLAGA, T.J., GLEASON, G.L., DIGIOVANNI, J.. SUKUMARAN, K.B.,
HARVEY, R.G. Potent tumor-initiating activity of the 8,4-dihydrodiol of 7,12-
dimethylbenz{aJanthracene in mouse skin. Cancer Research 89(6): 1984-1936,
June 1979.

SOROF, S., YOUNG, E.M., MCBRIDE, R.A., COFFEY, C.B. Cancer Research
30(7): 2029-2084, July 1970.

SUTTON, S.R., FEYERABEND, C., COLE, P.V., RUSSELL, M.A.H. Adjust-
ment of smokers to dilution of tobacco smoke by ventilated cigarette holders.
Clinical Pharmacology and Therapeutics 2A(4): 395-405, October 1978.

THOMAS, P.E., LU, A.Y.H., RYAN, D., WEST, 8.B., KAWALEK, J., LEVIN,
W. Immunochemical evidence for six forms of rat liver cytochrome P450
obtained using antibodies against purified rat liver cytochromes P450 and
P448. Molecular Pharmacology 12(5): 746-758, September 1976.

TSO, T.C. Modification through agricultural techniques for developing a safer
tobacco. In: Gori, G.B., Bock, F.G. (Editors). Banbury Report 3—A Safe
cigarette? Cold Spring Harbor, New York, Cold Spring Harbor Laboratory,
1980, pp. 181-190.

U.S. DEPARTMENT OF AGRICULTURE, Economic Research Service. Tobacco
Situation 171, 1980.
(102)

(103)

(104)

(105)

(106)

(107)
(108)

(109)

(110)

(112)

(112)

(113)

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Smoking
and Health: A Report of the Surgeon General. U.S. Department of Health,
Education, and Welfare, Public Health Service, Office of the Assistant
Secretary for Health, Office on Smoking and Health, DHEW Publication No.
(PHS) 79-50066, 1979, 1136 pp.

U.S. PUBLIC HEALTH SERVICE. Smoking and Health, Report of the Advisory
Committee to the Surgeon General of the Public Health Service. U.S. Depart-
ment of Health, Education, and Welfare, Public Health Service, Center for
Disease Control, PHS Publication No. 1103, 1964, 387 pp.

U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A
Report to the Surgeon General: 1971. U.S, Department of Health, Education,
and Welfare, Health Services and Mental Health Administration, DHEW
Publication No. (HSM) 71-7513, 1971, 458 pp.

WALD, N. Mortality from lung cancer and coronary heart-disease in relation to
changes in smoking habits. Lancet 1(7951): 1386-138, January 1976.

WALD, NJ., IDLE, M., BOREHAM, J. Inhaling habits among smokers of
different types of cigarettes. Thoraz, in press.

WEISBURGER, E.K., Cancer Research, in press.

WOOD, A.W., LEVIN, W., LU, A.Y.H., RYAN, D., WEST, S.B., LEHR, R.E.,
SCHAEFER-RIDDER, M., JERINA, D.M., CONNEY, A.H. Mutagenicity of
metabolically activated benzo{aJanthracene 3,4-dihydrodiol: Evidence for bay
region activation of carcinogenic polycyclic hydrocarbons. Biochemical and
Biophysical Research Communications 7X2): 680-686, September 20, 1976.

WYNDER, E.L., HOFFMANN, D. Tobacco and Tobacco Smoke. Studies in
Experimental Carcinogenesis. New York, Academic Press, 1967, 730 pp.

WYNDER, E.L., HOFFMANN, D. (Editors). Toward a Less Harmful Cigarette.
U.S. Department of Health, Education, and Welfare, Public Health Service,
National Institutes of Health, National Cancer Institute Monograph No. 28,
June 1968, 282 pp.

WYNDER, E.L., STELLMAN, S.D. Impact of long-term filter cigarette usage
on lung and larynx cancer risk: A case-control study. Journal of the National
Cancer Institute 62(3): 471, March 1979.

YANG, S.K., ROLLER, P.P., FU, P.P., HARVEY, R.G., GELBOIN, H.V.
Evidence for a 2,3-epoxide as an intermediate in the microsomal metabolism of
benzo[a]pyrene to 3-hydroxybenzo[a]pyrene. Biochemical and Biophysical
Research Communications T7(4): 1176-1182, August 22, 1977.

ZAJDELA, F., CROISY, A., BARBIN, A., MALAVEILLE, C., TOMATIS, L.,
BARTSCH, H. Carcinogenicity of chloroethylene oxide, an ultimate reactive
metabolite of vinyl chloride, and bis(chloromethyl)ether after subcutaneous
administration and in initiation-promotion experiments in mice. Cancer
Research 40(2): 352-356, February 1980.

109
Section 4. CARDIOVASCULAR
DISEASES
CONTENTS

Introduction

 

 

The Relation of Cigarette Smoking to Cardiovascular Risk

 

Factors in Cigarette Smoke Related to Cardiovascular
Function
Nicotine
Carbon Monoxide
Other Components

 

Studies of the Impact of Lower “Tar” and Nicotine
Cigarettes on Coronary Heart Disease

 

The Challenge of Future Research

 

Proposed Future Research
Descriptive Studies
Cohort Studies

Observational Studies

Clinical Trials

Case-Control Studies
Studies of Mechanisms
Animal Experimentation
Technical Resource Center
Bekavioral Ramifications

 

Summary

 

References

LIST OF TABLES

Table 1.—Coronary heart disease—mortality ratios

 

 

Table 2.—The effect of the cessation of cigarette smoking

118
on the incidence of coronary heart disease (CHD)—
morbidity ratios in males

Table 3.—Filter cigarettes and risk of

coronary heart
disease in men

114
introduction

The expectation that a lower “tar” and nicotine cigarette would be
associated with less cardiovascular disease is based on two well-known
epidemiological findings: (1) the strong dose-related association be-
tween cigarette use and coronary heart disease (CHD)—the largest
component of cardiovascular disease; and (2) the evidence that if one
quits smoking, the vascular consequences of smoking diminish. Table 1
shows that the more people smoke per day, the greater their risk of
coronary heart disease. Table 2 summarizes several studies indicating
that persons who quit have a lower risk of CHD.

These findings have been challenged (41) because the sample of
smokers who have voluntarily quit may be biased through self-
selection. Indeed, even prior to quitting, persons who stop smoking
differ from those who continue smoking (15); however, their major
cardiovascular risk factors do not differ (18).

A multivariate analysis of the impact of smoking on CHD that takes
into account all the major possible confounders shows smoking’s
independent effect on CHD risk (3). In some studies (18), the quitters
were more sick than those who continued to smoke, but none of the
known major factors involved in CHD risk (disregarding cigarette
smoking) explains the difference in CHD rates between smokers and
nonsmokers. None of the factors distinguishing quitters from continu-

TABLE 1.—Coronary heart disease—mortality ratios

 

 

Number of cigarettes smoked
Reference NS 10 10-20 <20 2 > 20-40 >40
Hammond and 1.00 129 1.89 220 241
Horn (28)
Doyle et al. (14) 1.00 2.00 1.70 3.50
Doll and Peto 1.00 1.29 127 143
(18)
Pooling Project 1.00 1.65 1.70 3.00
(38)
Kahn (29) 1.00 1.89 L8 184 2.00

 

NOTE: NS = Nonsmokers.

TABLE 2.—The effect of the cessation of cigarette smoking on
the incidence of coronary heart disease (CHD)—
morbidity ratios in males

 

 

Never Former
Reference smoked smokers Smokers
Hammond and Garfinkel (21) 1.00 1.16 1.62
Jenkins et al. (27) 1.00 2.15 236
Shapiro et al. (42) 1.00 0.76 1.87

Kannel et al. (30) 1.00 0.80 1.70

 

115
ing smokers clarifies why the risk of cardiovascular disease declines
rapidly following smoking cessation.

The effect of smoking on CHD risk fulfills many epidemiological
criteria for a causal association: powerful, independent, dose related,
and reversible. When the association of smoking with CHD is adjusted
by the other major risk factors, the coefficients are strengthened,
rather than weakened (19).

At present only a few of the several thousand substances found in
cigarette smoke have been implicated in cardiovascular risk; others
have yet to be fully assessed. In order to facilitate a complete analysis,
a study would have to measure the impact of each substance in
cigarette smoke and establish its independent contribution. However,
testing large fractions of cigarette smoke for cardiovascular risk might
allow the elimination of specific constituents.

Currently, one can define only part of the impact of smoking on
cardiovascular risk. What factors isolated in cigarette smoke are
known to have cardiovascular consequences? What. is already known of
the cardiovascular impact of smoking cigarettes with some of these
factors removed? In view of the rapidly changing variety of cigarettes
found in the market, how can one keep pace with studying the
cardiovascular impact of each new lower “tar,” lower nicotine, lower
carbon monoxide cigarette?

The Relation of Cigarette Smoking to Cardiovascular Risk

Many exhaustive reviews of this issue exist, and only a brief account
of the essential findings is presented here. The chapter on cardiovascu-
lar disease in the 1979 Surgeon General’s Report on Smoking and
Health amply documents that cigarette smoking is a major, indepen-
dent coronary heart disease risk factor in Western countries (46). There
is substantial evidence from autopsies that more atherosclerosis is
found in smokers than in nonsmokers (44). Hyaline thickening of
arterioles in the heart is more prevalent in smokers (6). Experiments
on atherosclerosis in animals, however, have not produced uniform
results.

In those parts of the world where serum cholesterol levels are low,
especially below 160 mg%, smoking is not as strong a risk factor as it is
in the United States (33). After the age of 65, smoking poses less of a
cardiovascular risk than it does in younger age groups ($1). Study
results differ on whether smoking is a risk factor in coronary heart
disease following a myocardial infarction (46). The relationship of
smoking to angina pectoris is uncertain (27, 31).

It is essential to emphasize these points because one could plan a
study of lower “tar” and nicotine cigarettes in developing countries,
with older subjects or with people who have already had a myocardial
infarction or angina pectoris and find that the excess risk of CHD

116
among smokers had disappeared. To establish that lower “tar” and
nicotine cigarettes cause less risk of CHD than higher yield cigarettes,
there should be studies of randomly selected American men, 40 to 60
years of age, for the development of sudden death, first myocardial
infarction, or peripheral vascular disease—endpoints with which
cigarettes are associated at more than double the normal risk.

All the other factors associated with CHD risk should be measured
simultaneously in a multivariate analysis so that any differences
caused by quitter self-selection can be eliminated as the explanation of
reduced risk. In this way, independent change in risk caused by the
change in smoking behavior could be accurately assessed.

In addition to its effect on coronary heart disease, smoking increases
the risk of arteriosclerotic peripheral vascular disease. Its impact on
cerebrovascular disease is less uniform (46).

Factors In Cigarette Smoke Related to Cardiovascular Function

Most of the studies on cardiovascular endpoints associated with
cigarette smoke have focused on nicotine and carbon monoxide rather
than on “tar,” which has not been demonstrated to have a major acute
cardiovascular effect. Less is known about the effects of cadmium,
zinc, chromium, carbon disulfide, carbon dioxide, tobacco antigens,
hydrogen cyanide, nitrous oxide, or polonium-210, among other
constituents of cigarette smoke.

Nicotine

Many studies have documented a dose effect of nicotine on
cardiovascular function (2, 45). Acute studies in humans indicate a rise
in heart rate, an elevation of systolic blood pressure, and cutaneous
vasoconstriction. Cardiac output generally rises, but not always. Since
stroke volume is generally not affected, or may fall, in patients with
angina pectoris (2), the observed rise in cardiac output has been
attributed to an increased heart rate.

Such changes have been attributed to a stimulation of sympathetic
ganglia by nicotine. This stimulation results in a rise in catecholamines,
which in turn produces variable degrees of positive chronotropic and
inotropic cardiac actions. Other effects include generalized peripheral
vasoconstriction and transient systemic (primarily systolic) hyperten-
sion (7).

Levels of free fatty acids rise in nicotine-treated subjects, possibly as
another consequence of the catecholamine release ($2). Whether free
fatty acids affect cardiac function adversely, as some researchers have
proposed (37), or aid in fatty deposition as others have suggested (10)
has not yet been fully established.

Nicotine increases the diurnal secretion of cortisol (26). Plasma
cortisol levels have been found to be elevated during myocardial

117
infarction, but the increase may be an effect rather than a cause of this
condition. On the other hand, the cortisol rise has been implicated as a
precursor of ventricular arrhythmias (36).

Nicotine-stimulated release of catecholamines has also been suggest-
ed as a cause of increased platelet stickiness and aggregation (24); this
and other smoking-related hemostatic effects are potential mecha-
nisms by which smoking may contribute to increased cardiovascular
disease.

Although the evidence is meager, some of the acute effects of
nicotine on cardiovascular function, such as elevation of heart rate and
blood pressure, are dose related and apparently diminish in some
lower-nicotine varieties of cigarettes (2, 45).

Carbon Monoxide

Carbon monoxide is inhaled in the form of a gas in cigarette smoke.
Its affinity for hemoglobin is approximately 210 times greater than
that of oxygen. The availability of oxygen to the myocardium is
further decreased by the tighter binding of oxygen to hemoglobin in
the presence of carboxyhemoglobin. Carbon monoxide also combines
with myoglobin, impairing the availability of oxygen to the mitochond-
ria. In addition, carbon monoxide can combine directly with cyto-
chrome oxidase to slow the oxidation of reduced nicotinamide-adenine-
dinucleotide (55).

Carbon monoxide has a direct impact on cardiac function in patients
with angina pectoris, including a negative inotropic effect on the
myocardium. Aronow (1) demonstrated an increase in left ventricular
end-diastolic pressure, with a significant decrease in left ventricular
dp/dt and stroke index. Anginal patients with increased carboxyhemo-
globin levels also experience significantly shortened exercise time until
the onset of angina pectoris (3). DeBias and co-workers (12) have also
shown in monkeys that exposure to carboxyhemoglobin lowers the
threshold for ventricular fibrillation.

Myocardial ultrastructural changes have been described in rabbits
exposed to carbon monoxide. Among the changes are myofibrillar
necrosis and mitochondrial degeneration (5).

Astrup (4) has proposed that carboxyhemoglobin increases hypoxia
of vessel walls. Because this condition may increase the permeability to
lipids, including cholesterol-laden lipoproteins, it may promote the
process of atherosclerosis. It has been shown that exposure of humans
to carbon monoxide increases the rate of disappearance of radio-
iodinated serum albumin (43). Wald and Howard (49) have shown that
the carboxyhemoglobin level is more closely related to the prevalence
of coronary heart disease than is smoking history. They emphasize that
smokers who are physically active enhance their mechanisms for
releasing carboxyhemoglobin and have a much better CHD prognosis
than do sedentary smokers.

118
Other Components

MeMillan (35) has reviewed studies on a variety of other factors in
cigarette smoke and has concluded that much more data are needed.
He noted a possible association of cadmium with hypertension.
Smoking generally results in an acute rise in blood pressure, but has
not been proved to cause chronic hypertension. Whether tobacco
antigens play a role in increased endothelial cell damage is conjectural.
Finally, McMillan considered the hypothesis proposed by Benditt and
Benditt (18) that atherosclerosis is really caused by monoclonal smooth
muscle cellular proliferation. If so, one may be persuaded that “tar,”
which is mutagenic, is atherogenic after all.

Studies of the Impact of Lower “Tar’ and Nicotine Cigarettes
on Coronary Heart Disease

Not all cigarettes that produce a lower yield of one substance
necessarily provide a lower yield of other substances. Indeed, research
suggests that cigarettes with unperforated filters (“unventilated”),
which yield lower “tar” and nicotine levels than do nonfiltered
cigarettes, may increase exposure to carbon monoxide (58) and lead to
higher levels of carboxyhemoglobin (52). Cigarettes with perforated
(“ventilated”) filters may produce lower carbon monoxide yields (52).

People who smoke lower “tar” and _ nicotine cigarettes do not
generally smoke substantially more cigarettes per day than smokers of
higher yield cigarettes (16, 40, 51); however, their intake of “tar,”
nicotine, and carbon monoxide is higher than would be predicted by
data from machine-smoked cigarettes. This suggests that these
cigarettes are smoked more intensively than higher yield cigarettes
(40, 51).

There is evidence from four studies of the association between
cardiovascular disease and the use of lower “tar” and nicotine
cigarettes. Hammond et al. (22), in their prospective study of
volunteers of the American Cancer Society, have shown reductions of
10 to 20 percent in observed coronary deaths among persons smoking
lower “tar” and nicotine cigarettes when compared with those who
reported smoking similar numbers of regular cigarettes per day.
Hawthorne and Fry (25), in three prospective surveys of over 18,000
persons in west-central Scotland, showed a slightly increased relative
coronary mortality in persons who smoked filtered cigarettes com-
pared with persons who smoked unfiltered cigarettes. Dean et al. (12),
in a retrospective mortality study in northeast England published by
the Tobacco Research Council, showed relative risks of about 0.6 for
coronary heart disease and 0.4 for cerebrovascular disease in filter
cigarette users versus smokers of unfiltered cigarettes. Unfortunately,
smoking habits of cases and controls were obtained from different
sources and at different times, confounding the study design. Recent

119
TABLE 3.—Filter cigarettes and risk of coronary heart disease

 

 

in men

Reference Plain Filter
Hawthorne and Fry (25) 100 104

Hammond et al. (22)
«4.» , Period 1 1.00 0.98
Low “tar” { period 2 1.00 0.82
qm , Period 1 1.00 0.91
Medium “tar” { period 2 1.00 1.08
Dean et al. (11) 1.00 0.66

Castelli et al. (9)

< 55 1.00 1.02
55+ 100 0.85

 

unpublished data from Framingham (9) have failed to show a lower
CHD risk among smokers of filter cigarettes, and in younger men
there was actually a slightly higher rate of coronary disease among
smokers of filtered cigarettes (Table 3).

This study took into account the other major CHD risk factors
(cholesterol, blood pressure, and age); the increased risk in filter
smokers is independent of effects attributed to these other factors.
Overall, use of lower “tar” and nicotine cigarettes has not produced a
consistent decrease in risk for cardiovascular disease; indeed, in some
studies a slight increase in risk has been seen. Additional studies will be
needed to assess the actual impact of any changes in the composition of
cigarettes on subsequent CHD rates. Terms like “lower yield” may
describe only part of the change; other additives and the overall use of
the cigarette might actually increase risk. Wald (54) has shown that, in
the United Kingdom, while lung cancer mortality fell in men from
1956-60 to 1969-78, with the change to filter cigarettes, CHD mortality
increased. The author wondered whether the decrease in “tar”
accounted for the lower lung cancer death rates, and whether
unchanged levels of carbon monoxide might have contributed to the
observed continuing rise in CHD death rates.

The Challenge of Future Research

In the United States, virtually no filtered cigarettes were smoked
before 1950; now 90 percent of the cigarettes sold are filtered. The
sales-weighted average “tar” composition per cigarette has decreased
from over 35 mg of “tar” per cigarette in the early 1950s to under 15
mg in 1979. Currently, nicotine has decreased from over 2.5 mg per
cigarette to about 1.0 mg per cigarette. Ultra low nicotine and “tar”
cigarettes are now increasingly available, with levels of under 1.0 mg
“tar” and 0.1 mg nicotine. Unfortunately, the amount of carbon
monoxide delivered by cigarettes has not been studied as intensively as
the “tar” and nicotine levels, although a recent United Kingdom

120
survey of old and current cigarettes indicates that carbon monoxide
yields have changed much less than “tar” or nicotine yields. This may
be the case in the United States as well. Linking cigarette carbon
monoxide yields to possible toxicity is further complicated by the fact
that patterns of smoke inhalation for lower “tar” and nicotine
cigarettes may differ from patterns for higher “tar” and nicotine
cigarettes (51).

A technique should be developed to monitor the effect of changes in
cigarette composition, particularly in nicotine and carbon monoxide
content, on cardiovascular risk.

Proposed Future Research
Descriptive Studies

Continued research into the changes in cigarette smoking is needed.
Surveys such as the National Health and Nutrition Examination
Survey (NHANES), prospective epidemiological field studies, and
prepaid hospital insurance group studies are needed to provide
comprehensive information on cardiovascular disease caused by
smoking. Such studies should include worldwide data surveillance.

Cohort Studies
Observational Studies

Observational studies are studies of large populations in which a
variety of factors related to cardiovascular disease are measured and
followed, permitting an independent analysis of variables such as a
given cigarette brand.

There are now a number of studies that follow a given population
over a period of time to assess prospectively the impact of smoking.
Some of these are traditional single-town studies in which a random
sample of a given population is followed over varying time intervals,
often every 2 to 5 years. Examples of such studies are those in
Framingham, Tecumseh, Puerto Rico, Evans County (Georgia), Hono-
lulu, and Goteborg and Stockholm, Sweden, where whole populations
or samples thereof are followed on a more or less continuous basis. In
addition, there are worksite studies, such as the Albany civil servants,
People’s Gas Company of Chicago employees, Western Electrie work-
ers (Chicago), Minneapolis business executives, California longshore-
men, and British doctors, which call for repeated observations.
Questionnaire studies, such as the American Cancer Society’s 25-State
Study or the 9-State Study, the U.S. Veterans Study, the Canadian
Veterans Study, the Swedish Study, the Japanese 29 Health Districts
Study, and the Study of California Males, can observe as many as a
million subjects.

121
In addition to measuring the risk for cardiovascular disease, most of
these studies also assess other consequences of smoking. They allow,
better than any other studies, the calculation of the independent effect
of smoking.

The shortcoming of these prospective studies has been that the
average turnaround time has been approximately 10 years. Occasional-
ly, a 4-year interval produces enough data for a meaningful analysis,
but with the rate of change in the composition of cigarettes, the
information could be outdated by the time the data are collected and
analyzed.

Clinical Trials

Several clinical trials of the effect of smoking intervention on
coronary heart disease are in progress. Perhaps the most promising of
these is the Multiple Risk Factor Intervention Trial (MRFIT) (28), in
which high-risk men were randomly assigned to a special-intervention
group and a usual-care group. The study, now in its 6th year, avoids
self-selection bias by contrasting the overall disease experience of the
two randomly assigned groups. Unfortunately, the inferences that may
be drawn about lower “tar” and nicotine cigarettes per se (which is
only a part of the intervention program) are somewhat limited and do
involve self-selection. Another problem is that this study directs its
intervention to serum cholesterol and blood pressure control as well as
to smoking cessation. Nevertheless, long-term studies like the MRFIT
are recommended because the followup of cohorts may provide
findings that differ qualitatively from those available in strictly
observational studies and because the measurement of other major risk
factors permits the estimation of the independent effect of smoking
behavior changes. All such clinical trials should incorporate the
conviction of the medical and public health communities that current
smokers ought to quit and that nonsmokers should not begin to smoke.

Case-Control Studies

Case-control studies have the advantage of relatively short turn-
around times and usually are less expensive than other studies.
Unfortunately, unless very carefully designed, they can suffer from a
partial and therefore less accurate assessment of the disease under
study. For example, in studying cigarettes, one must assess the death
endpoints of coronary disease. The problem in studies of this kind is
how to compile an objective smoking history of the deceased.
Obtaining information from a spouse or close associate introduces a
certain amount of error, but this error may be controlled somewhat by
interviewing close associates of the members of the control group.

122
In studies of nonfatal myocardial infarction, the survival of both the
cases and the controls allows more precise measures of the variables
under study.

Despite shortcomings, case-control studies represent the major
means for assessment of the relative cardiovascular risk of varying
cigarettes. Further, serial case-control studies, similarly designed,
performed, and analyzed, could provide information on changes in risk
over time. In such studies care must be taken to select appropriate
controls, to treat cases and controls alike, to avoid hospital-based
rosters, and to study well-defined and documented endpoints.

Studies of Mechanisms

In view of the difficulties involved in doing large population-based
studies and the need to know more about the mechanisms whereby
cigarettes cause damage, more studies are needed on the components
in cigarettes that affect cardiovascular risk. It may be that nicotine
and carbon monoxide are the chief toxic agents, but until more is
learned of the other constituents, judgements are based on scanty
information.

Perhaps the main reason to pursue the study of disease mechanisms
is to shorten the turnaround time for assessing any new brand of
cigarette; studies could be designed to measure particular constituents
of the cigarette smoke and characteristics of the subject at risk.

With better noninvasive cardiovascular techniques, studies of how a
particular cigarette affects cardiac function could be performed in
greater depth. Such studies would provide better measurement of the
biological effect of the cigarette smoke components in individual
smokers. Measurement of expired carbon monoxide, serum carboxy-
hemoglobin, thiocyanate, and cotinine would help resolve not only
differences in the composition of cigarettes, but also major differences
in the ways individuals smoke (47, 48). These more precise measure-
ments of smoke exposure and dosage of smoke constituents could be
correlated with a host of biochemical and physiological parameters.

The number of biochemical factors found to be affected by smoking
continues to grow. Lower HDL cholesterol levels are found in smokers
than in nonsmokers, an effect that is associated with an increased CHD
risk (17).

A variety of effects could be weighed to produce a multifactorial
analysis of how cigarettes produce atherosclerosis, sudden death, and
other cardiovascular problems.

Physiological studies using treadmill performance, scintillation
scanning—including gated pool studies—and Holter monitoring could
provide better clues to the action of cigarettes on cardiovascular
function. If such alterations in function could be more certainly tied to
later events, they might prove invaluable predictors of smoking-
related risk for a given individual.

123
Animal Experimentation

Most of the animal models used in studies of the effects of cigarette
smoke have been designed to test its carcinogenicity on the bronchial
epithelium or the skin of small animals, usually rodents. A few models
have been developed to examine the effects of inhalation on the
respiratory and cardiovascular systems of rodents, dogs, or nonhuman
primates (20). Very few animal studies have attempted to assess the
effects of different cigarette smokes in inhalation studies of experi-
mental atherosclerosis or on the styles of inhalation that may be
intervening variables in the pathogenesis of atherosclerosis. It is
feasible to induce nonhuman primates to inhale cigarette smoke (34).
Such primates frequently develop many of the physiologic changes
related to the atherosclerosis found in human smokers ($9). The
further utilization of such animal models would permit a comparison of
the effects of proposed lower “tar” and nicotine cigarettes with the
effects of conventional higher yield cigarettes under controlled
conditions. Subjects could be assigned randomly to different types of
cigarettes to eliminate the self-selection bias.

The primates could be examined for effects of smoke from different
cigarettes on response variables such as serum lipids and lipoproteins.
At this time, the augmentation of experimental atherosclerosis by
exposure to cigarette smoke has not yet been demonstrated; further
development of an animal model must occur before definitive studies
in atherogenesis will be practical.

Technical Resource Center

In addition to monitoring research evidence on the impact of
smoking on health, further activities should focus on developing tools
for the conduct of studies on the impact of smoking on health in
several areas. A standard questionnaire on smoking should be refined
for use by the various studies in the United States and in foreign
countries.

In addition, techniques for measuring actual exposures to carbon
monoxide, cotinine, nicotine, and many other substances could be
evaluated to determine the most effective analytic techniques. Where
debate continues on the merits of one test versus another, studies
should be designed to resolve the issue. Control of test quality should
be instituted and could be ascertained, even from widely disparate
groups. Not only could a hierarchy of useful tests be provided, but a
quality-control mechanism should be developed to ensure continued
high performance.

Finally, frequent updated ratings of “tar,” nicotine, and particularly
carbon monoxide yields would permit others to conduct better studies
of the impact of cigarette smoke components on cardiovascular
functions.

124
Behavioral Ramifications

It is important to determine the effect of lower “tar” and nicotine
cigarettes on cardiovascular disease risk reduction. A key unknown is
whether efforts to persuade people to switch to lower “tar” and
nicotine cigarettes interfere with other efforts to persuade people not
to begin smoking or to quit. Activities to provide a less hazardous
cigarette should not interfere with efforts to eliminate cigarette
smoking.

Finally, given the limitation in research funds, priorities for research
must be drawn. The research proposals outlined above are of high
priority. The combination of results from a variety of studies can
provide a consensus on the impact of a given innovation in lower “tar”
and nicotine cigarette composition. Ultimately, the effect of lower
“tar” and nicotine cigarettes will be measured in terms of smoker
morbidity and mortality.

Summary

1. Epidemiological studies show that the incidence of coronary
heart disease (CHD) increases as the daily number of cigarettes
smoked increases and that the incidence of CHD decreases among
those who quit smoking. These dose-related effects suggest that
lower “tar” and nicotine cigarettes might be associated with
lower risks of CHD. However, the overall changes in the
composition of cigarettes that have occurred during the last 10 to
15 years have not produced a clearly demonstrated effect on
cardiovascular disease, and some studies suggest that a decreased
risk of CHD may not have occurred.

2. Of the several thousand substances found in cigarette smoke,
only a few have been implicated in cardiovascular risk. A number
of substances have not yet been adequately assessed. Further, the
changes in smoke constituents that have resulted from changes in
the cigarette product have not been documented.

3. Linking cigarette smoke yields to cardiovascular disease is
complicated by the evidence that smokers of lower “tar” and
nicotine cigarettes may smoke more “intensively,” although they
may not smoke a substantially greater number of cigarettes daily
than do smokers of higher “tar” and nicotine cigarettes. The net
result could be to decrease the actual intake of “tar,” nicotine,
and carbon monoxide less than that expected on the basis of
machine measurements.

4, Nicotine stimulates the sympathetic nervous system, producing a
rise in catecholamines that in turn increases heart rate, elevates
systolic blood pressure, constricts cutaneous blood vessels, and
increases levels of free fatty acids. The nicotine-stimulated
release of catecholamines has been suggested as the cause of

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