Tobaccoand Health John H. Holbrook, M.D.
Prior to 1900, most tobacco was con
United States remains high (exceeding
sumed in the form of cigars, pipe to bacco, chewing tobacco, and snuff; cigarettes were only popularized just prior to World War I. However, over the next several decades, cigarette pro duction in the United States climbed from four billion cigarettes in 1910' to approximately 600 billion cigarettes in
4100 cigarettes per year for those over
1974.2
The
tremendous
increase
in cig
arette production dramatically illus trates the growth of a major public health problem: the widespread in halation of tobacco smoke. During the past 25 years, numerous epidemio logical, clinical, pathological, and ex perimental studies have shown that cigarette smolqng is causally related to premature disability, disease, and death.3'5 Legislative bodies have re sponded to these data by supporting public education programs, prohibiting cigarette advertising, requiring health warnings on packaged tobacco prod ucts, encouraging the production of cigarettes containing less tar and nico tine, and enacting laws to prevent smok ing in public places. In spite of these efforts to discourage smoking, per capita consumption of cigarettes in the @ Dr. Holbrook is Assistant Professor of Internal Medicine, Department of InternalMedicine, Divisionof General InternalMedicine,Univer sity of Utah, Salt Lake City, Utah. 344
18 years of age2), and young women are taking up cigarette smoking in increas ing numbers. Physicochemical Properties Tobacco smoke is produced by incom plete combustion of the tobacco leaf. Mainstream smoke is generated when air is drawn through the cigarette, at which time the temperature of the burn ing zone may reach 880°C; sidestream smoke is generated when the cigarette is burning at rest, at which time the temperature may reach 835°C.6In the burning process, organic matter is frac tionated into smaller molecules (pyrol ysis). Some of the newly formed mole cules are unstable and recombine to form compounds not originally present in tobacco (pyrosynthesis).7 Some com ponents of mainstream smoke are fil tered by unburnt tobacco only to be come partly revaporized when reached by the ember; hence, many of the con stituents of cigarette smoke become more concentrated as smoking con tinues. Mainstream smoke contains from lx l0@to 5x l0@particles per ml., with the mean particle size ranging from 0.2 to 1.1 There are approximately 500 mg. of mainstream smoke in a ciga rette, of which more than 85 percent is
composed of nitrogen,
oxygen, and
CA—A CANCER JOURNAL FOR CLINICIANS
carbon dioxide. About eight percent of the mainstream smoke consists of par ticulate kmatter and the remainder is made up of a vapor phase and other gases.7 After smoke is drawn into the mouth, nose, and throat, some con stituents are absorbed directly through the oral mucosa;9 other constituents are inhaled into the bronchopulmonary tree where they are either absorbed or retained.'0 Pharmacology Approximately 1000 different sub stances have been identified in tobacco smoke,8― some of which are found in concentrations that represent a definite health hazard.4 A number of substances occur in borderline concentrations, while other chemical constituents may be hazardous only when they interact with the different components of to bacco smoke.4 Substances of acknowl edged significance are carcinogens, carbon monoxide, nicotine, and ir ritant gases. VOL. 27, NO.6 NOVEMBER/DECEMBER 1977
The carcinogens in tobacco smoke have also been classified as: (1) com plete carcinogens; (2) cocarcinogens, including tumor initiators and promot ers; and (3) tumor accelerators.'2 Most of the known carcinogens in cigarette smoke are found in tobacco “¿tar,― a name given to the aggregate of particu late matter in cigarette smoke after subtracting nicotine and moisture. Application of tobacco “¿tar― to the tissues of experimental animals readily induces malignant changes,7 and dogs trained to inhale cigarette smoke through tracheostomae have developed lung cancer.'3 A substantial part of the carcinogenic activity of “¿tar― is due to a group of compounds known as poly nuclear aromatic hydrocarbons (PAH). Benzo(a)-pyrene is a PAH occurring in high concentrations in tobacco smoke.@ N-nitrosamines are well-known animal carcinogens which have been identified recently in both tobacco'4 and cigarette smoke condensate.'5 In addition, very low concentrations of beta-naphthyl 345
amine, a potent human bladder car cinogen, have also been found in ciga rette smoke.16 Other constituents of tobacco smoke which may play a role in carcinogenesis are radioactive ele ments such as polonium-210, free radi cals, and metals such as nickel.7 Carbon monoxide is a major air pol lutant, and cigarette smoking is the most important source of this pollutant for smokers.'7 Carbon monoxide is present in mainstream cigarette smoke in significant amounts, accounting for from 2.9 to 5.1 percent of its weight.7
“¿Cigaretteproduction in the U.S. climbed from four billion cigarettes in 1910 to 600 billion cigarettes in 1974.― Carboxyhemoglobin levels of moderate cigarette smokers average around six percent, while those of non-smokers are usually near one percent.'8 Heavy smokers and those who inhale show the highest carboxyhemoglobin levels. Oxygen carrying capacity is diminished in cigarette smokers because elevated carboxyhemoglobin levels reduce the amount of available hemoglobin and shift the oxygen-hemoglobin dissocia tion curve to the left. Elevated carboxy hemoglobin levels impair maximal exercise performance,'9 aggravate is chemic vascular disease and chronic pulmonary disease,20-23 and may con tribute to the pathogenesis of coronary heart disease and arteriosclerotic pe ripheral vascular disease.24 Small eleva tions in carboxyhemoglobin may exert subtle influences on the central nervous system as measured by impaired time interval discrimination and perfor mance on psychomotor tests.4'25 Nicotine is a highly toxic alkaloid which is a ganglionic stimulator. Most cigarettes currently sold in the United
States deliver about 1.3 mg. of nico
tine.26 Since nicotine has both stimulant and depressant actions, its effects in man are often complex and unpredict able. In addition to stimulating the cardiovascular system and central ner vous system, nicotine causes the release of norepinephrine, epinephrine, and antidiuretic hormone.27 Catecholamine release may also account for an in crease in serum-free fatty acids28 and in platelet aggregation produced by nico tine.29 The cardiovascular responses to nicotine include increases in heart rate, systemic arterial pressure, cardiac out put, stroke volume, velocity of myo cardial contraction, and peripheral vasoconstriction. The net effect is to increase myocardial tissue oxygen demand. In normal individuals, this increased oxygen demand is generally followed by an increase in coronary blood flow; however, patients with coronary artery disease may not be ca pable of increasing coronary flow and myocardial hypoxia may result. Bellet demonstrated that cigarette smoke in halation decreases the ventricular fi brillation threshold in normal dogs and in dogs with acute myocardial infarc tion.3°The peripheral vasoconstriction caused by nicotine aggravates ischemia in patients with arteriosclerotic periph eral vascular disease. Cigarette smoke contains several irritant gases including: acrolein, nitro gen dioxide, formaldehyde, hydrogen sulfide, and ammonia. These substances produce coughing, bronchospasm, increased mucus secretion, and cili astasis. Some of the irritant gases such as acrolein and phenol are also cocar cinogens.7 Hydrocyanic acid, a respira tory enzyme poison, is also present in cigarette smoke. Smoking and Total Mortality An increase in the incidence of cancer of the lung was noted in the United States in 1930, and studies linking smok ing to excess morbidity and mortality CA—A CANCER JOURNAL FOR CLINICIANS
@
soon followed. The early, retrospective studies dealt largely with lung cancer while the later prospective studies showed that cigarette smokers experi enced greater overall morbidity and mortality from a number of conditions than non-smokers. Approximately 75 percent of the excess mortality experi enced by cigarette smokers was due to coronary artery disease, cancer of the lung and other sites, and chronic ob structive pulmonary disease.3' Data taken from four large prospec tive studies involving more than 1.4 million British doctors, U.S. veterans, Canadian pensioners and U.S. men and women demonstrated that male ciga rette smokers, taken as a whole, had a 30 to 80 percent greater mortality than non-smokers (Table 1).32.35 The evi dence suggested a dose-response rela tionship because the excess mortality rose with increasing cigarette consump tion and was greater in those who start ed smoking at an early age and who inhaled. It was also noted that the ex VOL. 27, NO.6 NOVEMBER/DECEMBER 1977
cess mortality decreased with smoking cessation (Table The findings for women were similar to those for men, but the excess mortality was somewhat less than in men. The total number of excess deaths in cigarette smokers was greater in older people because of the generally higher death rates at older ages; however, the mortality excess of cigarette smokers was proportionately greater at ages 45 to 54 than at younger or older ages. In order to emphasize the risk to the individual cigarette smoker, Hammond calculated the amount by which a cigarette 3moker's life is short ened at various ages according to the number of cigarettes he smokes. For example, according to this estimate, an average 30-year-old male who smokes 15 cigarettes per day may expect to lose about five and one-half years of life (Fig. l).36 Clinical Correlations Coronary Heart Disease (CHD) The relationship
between smoking and 347
Figure 1 LIFE EXPECTANCY AT AGE 25 (MALE) Cigarettesper day 73.6
never smoked
1-9
69.0
10-19
68.1
20-39
67.4
40+
65.3
25
35
CHD is important because CHD ac counts for more than 50 percent of the excess mortality due to smoking33 and because many coronary deaths occur suddenly and prematurely in those un der 65 years of age. Cigarette smoking, hypertension,
and hypercholesterolemia are alterable “¿majorrisk-factors― contributing to the development of CHD.37,38 Cigarette smoking is an independent risk-factor which also acts synergistically with the other two major risk-factors. Male cigarette smokers have approximately a two-fold greater risk of dying from CHD than non-smokers. In men, a dose-response relationship exists be tween cigarette smoking and CHD morbidity and mortality. Women cig arette smokers also experience increased
mortality from CHD, but it is less than that of men.33 Application of the risk-factor con cept in clinical medicine constitutes an important preventiveapproach to CHD, 348
45
55
65
75
which may favorably alter the course of the disease before it becomes far advanced.39. @° Cessation of cigarette smoking decreases the risk of death from CHD.33'374' This decrease is mea surable within one year after stopping smoking; after ten years, the risk ap proaches that of the non-smoker. As part of a comprehensive approach to managing CHD risk-factors, physi cians should actively advise and assist patients to stop smoking. Patients who have an acute myocardial infarction are especially motivated to accept such advice, and in this situation, 50 percent cessation rates have been reported.42
In autopsy studies, cigarette smokers have been shown to have a greater fre quency and severity of coronary athero sclerosis4r and greater myocardial arte riolarwallthicknessthan non-smokers .@ Cerebral and Peripheral Occlusive Vascular Disease Cigarette
smoking
is associated
with
CA—A CANCER JOURNAL FOR CLINICIANS
@
increased mortality from cerebrovas cular disease,3' 31 and is also a risk factor for the development of arterio sclerosis obliterans. In addition, it ag gravates established peripheral vascular
disease.45 The patency of peripheral bypass
grafts
may also be adversely
affected by cigarette smoking.@ Thromboangitis
obliterans(Buerger's
disease), an uncommon obliterative and inflammatory process which affects peripheral arteries and veins in a seg mental fashion, characteristically at tacks young male cigarette smokers between. the ages of 20 and 45 years.
Controversy
continiies over whether
this is adistinct disease entity, or whether
it is an unusual subgroup of arterio sclerosis obliterans. Cessation of tobac co usage is the only effective therapy.3
Certain occupations are associated with an increased risk of developing
“¿A 30-year-old male who smokes 15 cigarettes per day may expect to lose five and one-half years of life.― lung cancer that is enhanced by ciga rette smoking.3 In the uranium mining50 and asbestos industries,5' cigarette smoking workers have much higher lung cancer rates than those which would result from the industrial ex posure alone or from smoking alone. Other Cancer Sites
The smoking of cigarettes, pipes, and Lung Cancer
@
In the United State in 1977 lung cancer will account for more cancer deaths (an estimated 89,000), than any other can cer site.47 Cogent epidemiological data, coupled with experimental and patho logical evidence, -establish cigarette smoking as the most important cause of lung cancer.3'5 The average male cig arette smoker's risk of developing lung cancer is ten times greater than that of the non-smoker. In heavy smokers, the risk is 15 to 30 times as great as that of non-smokers. (Fig. 2)32.35Lung cancer death rates for women are lower than for men, but in recent years, they have increased proportionately more rapidly than those for men.47 For both men and women the risk of developing lung cancer is directly related to total cig arette smoke exposure, as measured by the number of cigarettes smoked per day, the duration of smoking, the age at initiation of smoking, the depth of inhalation, and the “¿tar― and nicotine levels in the cigarette smoked.3 The risk of developing lung cancer diminshes with cessation of smoking.33'49 VOL. 27, NO.6 NOVEMBER/DECEMBER 1977
cigars is a significant factor in the de velopment of cancer of the oral cavity, pharynx, larynx, and esophagus.3'5
Pipe-smoking appears to be causally related to cancer of the lip.5 The com bined exposure to alcohol and cigà rettes is associated with especially high esophageal, oral, and pharyngeal can
cer rates.3. 52 Carcinoma of the pan creas and bladder is also more common in cigarette smokers than in non smokers.3'53
Chronic Obstructive Pulmonary Disease (COPD) In the United States, cigarette smoking is the most important factor contribut ing to the development of COPD,3'5 which was responsible for more than 25,000 deaths in l974.@@Male cigarette smokers experience from four to 25 times higher death rates from emphy sema and bronchitis than non-smok ers.32'35 Dose-response relationships exist between cigarette smoking and these increased mortality rates. COPD is also one of the most im portant causes of chronic disability in 349
@
the United States,55 and disabling pul monary symptoms and impaired pul monary function are more frequent in men and women who smoke than in non-smokers.3'4 Even young cigarette smokers of high school age have im paired ventilatory function compared to non-smoking peers.56@57Small airway dysfunction is more common in asymp tomatic cigarette smokers than non smokers.58 Ex-cigarette smokers have lower death rates from COPD than do continuing smokers.3'4 Cessation is also associated with some improvement in ventilatory function and a decrease in prevalence of pulmonary symp toms.3
On the average, the cigarette smoking mother has nearly twice the risk of de livering a stillborn child as does the non-smoking mother.5 This risk may be even greater in women who for other reasons have a high-risk pregnancy. There is a strong association between maternal cigarette smoking and higher late fetal and neonatal death rates. The fetus of a smoking mother is exposed
For most of the American popula tion, cigarette smoking is a more im portant cause of COPD than air pollu tion or occupational exposure; cigarette smoking may also act conjointly with occupational and environmental ex posures to produce greater COPD mor bidity and mortality.3'5 Cigarette smok ing exerts an adverse effect on the pul monary clearance mechanism.3'5'58 Res piratory infections are more prevalent and severe among cigarette smokers than among non-smokers,3'6° and ciga rette smokers appear to develop post operative respiratory complications more frequently than non-smokers.3'6' Recent autopsy studies confirm that emphysema is much more frequent and severe in cigarette smokers than in non smokers.3'4'62' 63
to carbon monoxide and nicotine which
Pregnancy An estimated one-third of American women of childbearing age are cigarette smokers.5 It is well known that drugs, rubella, and radiation may endanger the unborn child; it is less well known that maternal smoking during preg nancy may be harmful to the fetus. Infants of mothers who smoke dur ing pregnancy have a mean birth weight of approximately 6 ounces less than infants born to non-smoking mothers.4 350
“¿Cessationof cigarette smoking decreases the risk of death from coronary heart disease.―
may mediate the noted adverse effects. Gastrointestinal Disorders Cigarette smoking males have an in creased prevalence of peptic ulcer di sease.3 They also have a three- to four fold increase in death rates from peptic ulcer disease compared to non-smokers. These relationships are stronger for gastric than for duodenal ulcer. Smok ing appears to reduce the effectiveness of standard peptic ulcer therapy and to slow the rate of ulcer healing.64 Recent experimental studies suggest that smok ing may mediate this effect by inhibit ing pancreatic bicarbonate secretion.65 Cigarette smoke inhalation is followed by a rapid decrease in lower espohageal sphincter pressure, an effect which may encourage gastro-esophageal reflux.@ Allergy Tobacco smoke inhalation may result in complex pharmacologic, irritative, and allergic effects which may be dif ficult to distinguish from one another.4 Although allergy to tobacco smoke appears to be unusual, exposure to smoke may produce exacerbation of allergic symptoms in both smokers and non-smokers who are suffering from CA—A CANCER JOURNAL FOR CLINICIANS
Figure2
.c a, 0
a,
C.) C
a,
x20
C
0 0 a, >.
a,
t
0
0
10
20
30
40
50
Current number of cigarettessmokedper day British doctors
Canadian veterans
U. S. veterans
U. S. men
allergies of diverse causes. Asthmatics should be instructed to avoid cigarette
those of cigarette smokers. Death rates from cancer of the lung, pancreas, and
smoke inhalation.
bladder, as well as CHD and COPD,
Pipes and Cigars In the United States, pipe and cigar smokers as a group experience overall death rates that are substantially lower than those of cigarette smokers and only slightly higher than those of non smokers.5 This appears to be due to the
relatively low total exposure to tobacco smoke that a pipe or cigar smoker re ceives, as most pipe and cigar smokers
report that they do not inhale. How ever, at those sites directly exposed to
cigar and pipe smoke, such as the oral cavity, larynx, pharynx, and esophagus, cancer death rates of pipe and cigar smokers are approximately equal to VOL. 27, NO.6 NOVEMBER/DECEMBER 1977
are not greatly
elevated
in cigar and
pipe smokers above the rates of non smokers. Involuntary Smoking
Attention has been focused on the pos sible hazards of breathing
in a cigarette
smoke-filled environment.67 The to bacco smoke in such an environment differs qualitatively and quantitatively from that inhaled directly from the cigarette; this is because smoke in the
environment arises from both main stream and sidestream sources. In addition to contributing to the dis comfort of many individuals, cigarette
smoke is a significant atmospheric pol 351
lutant.25 For example, under conditions of heavy smoking and poor ventilation, the maximum limit for an eight-hour work exposure to carbon monoxide (50 ppm) may be exceeded. Even in cases where ventilation is adequate, the upper limit for carbon monoxide in ambient air (9 ppm) may be exceeded.
Exposure to air contaminated by cigarette smoke may be especially harm ful for those already suffering from CHD and COPD.@ 25Enough carbon monoxide may be present in smoke filled rooms
to diminish
the exercise
tolerance of patients with angina pec tons.20 25.68
References
ityof condensatefractions. Cancer 27:848-864, 1971. 13. Auerbach, 0. et al.: Effects of cigarette 1. U.S. Department of Health, Education, and smoking on dogs. II. Pulmonary neoplasms. Welfare,Rublic Health Service:Smoking, To Arch.Environ.Health21:754-768, 1970. bacco,and Health.U.S. PublicHealth Service 14. Hoffmann, D. et al.:N'-nitrosonornicotine Publication No. 1931, Washington, D.C., Super intobacco.Science186:265-267, 1974. intendent of Documents, 1969. 15. Rhoades, J.W., and Johnson, D.E.: Method 2. U.S. Department of Agriculture: Agricultural for the determinationof N-nitrosaminesin to Statistics 1975. Washington, D.C., Superinten bacco-smoke condensate. i. Natl. Cancer Inst. dent of Documents, 1975, P. 106. 48:1841-1843, 1972. 3. U.S. Department of Health, Education, and 16. Hoffmann, D.; Masuda, Y., and Wynder, Welfare, Public Health Service: The Health Con E.L.: Alpha-naphthylamine and beta-naphthy sequences of Smoking; A Report of the Surgeon lamine in cigarette smoke. Nature 221:254-256, General 1971. DHEW Publication No. (HSM) 1961. 71-7513. Washington, D.C., U.S. Superintendent 17. Stewart, R.D.; Baretta, E.D., and Platte, of Documents, 1971. L.R.: Carboxyhemoglobin levels in American 4. U.S. Department of Health, Education, and blood donors. JAMA 229:1187-1195, 1974. Welfare, Public Health Service: The Health Con 18. Goldsmith, J.R.: Contribution of motor ve sequences of Smoking; A Report of the Surgeon hicle exhaust, industry, and cigarette smoking General 1972. DHEW Publication No. (HSM) to community carbon monoxide exposures. Ann. 72-7516. Washington, D.C., U.S. Superintendent N.Y. Acad. Sci. 174:122-134, 1970. of Documents, 1972. 19. Aronow, W.S., and Cassidy, J.: Effect of carbon monoxide on maximal treadmill exercise: 5. U.S. Department of Health, Education, and a study in normal persons. Ann. Intern. Med. 83: Welfare, Public Health Service: The Health Con 496-499, 1975. sequences of Smoking 1973. DHEW Publication 20. Anderson, E.W.; Andelman, R.i., and No. (HSM) 734704. Washington, D.C., U.S. Strauch, J.M.: Effect of low-level carbon mo Superintendent of Documents, 1973. noxide exposure on onset and duration of angina 6. Touey, G.P.: Measurement of the combustion pectoris. Ann. Intern. Med. 79:46-50, 1973. zone temperature of cigarettes. Tobacco 144: 21. Aronow, W.S. et al.: Effect of cigarette 18-22, 1957. smoking and breathingcarbonmonoxide on car 7. Wynder, E.L., and Hoffmann, D.: Tobacco diovascular hemodynamics in anginalpatients. and Tobacco Smoke. Studies in Experimental Carcinogenesis. New York:Academic Press,1967. Circulation 50:340-347, 1974. 22. Aronow, W.S.; Stemmer, E.A., and Isbell, 8. Stedman, R.L.: The chemical composition of MW.: Effect of carbon monoxide exposure on tobacco and tobacco smoke. Chemical Reviews intermittent claudication. Circulation 49:415-417, 68:153-207, 1968. 1974. .9. Dalhamm, T.; Edfors, M.L., and Rylander, 23. Brody, iS., and Coburn, R.F.: Carbon mo R.: Mouth absorption of various compounds in noxide-induced arterial hypoxemia. Science 164: cigarette smoke. Arch. Environ. Health 16:8311297-1298, 1969. 835,1968. 24. Astrup, P., and Kjeldsen, K.: Carbon mo 10. Dalhamm, T.; Edfors, M.L., and Rylander, noxide, smoking, and atherosclerosis. Med. Clin. R.: Retention of cigarette smoke components in North Am. 58:323-350, 1974. human lungs. Arch. Environ. Health 17:746-748, 1968. 25. U.S. Department of Health, Education, and Welfare, Public Health Service: The Health Con 11. Smoking and Health'Now.Royal Collegeof Physicians. London: Pitman Medicaland Scien sequences of Smoking 1975. DHEW Publication No. (CDC) 76-8704. Washington, D.C., U.S. tific Publishing Company, 1971. 12. Hoffmann, D., and Wynder, E.L.:A study Superintendent of Documents, 1975. of tobaccocarcinogenesis. XI. Tumor initiators,26. Report of “¿tar― and nicotine content of the tumor accelerators, and tumor promotingactiv smoke of ‘¿135 ‘¿varietiesof cigarettes. Federal 352
CA—A CANCER JOURNAL FOR CLINICIANS
Trade Commission, September, 1975. 27. Goodman, L.S., and Gilman, A.: The Phar macological Basis of Therapeutics. New York: Macmillan Publishing Company, 1975, Pp. 567-570. 28. Kershbaum, A.; Khorsandian, R.; Caplan, R.F. et al.: The roleof catecholamines in the free fatty acid response of cigarette smoking. Circula tion 28:52-57, 1963. 29. Levine, P.H.: An acute effect of cigarette smoking on platelet function. Circulation 48:619623, 1973. 30. Bellet, S.; DeGuzman, N.T.; Kostis, J.B. et al.: The effect of inhalation of cigarette smoke on ventricular fibrillation threshold in normal dogs and dogs with acute myocardial infarction. Am. Heart J. 83 :67-76, 1972. 31. Hammond, E.C., and Horn, D.: Smoking and death rates —¿report on 44 months of follow up of 187,783 men. JAMA. 166:1159-1172, 1958. 32. Doll, R., and Hill, A.B.: Mortality in rela tion to smoking: ten years' observations of British doctors. Brit. Med. J. 5395:1399-1410, 1460-1467, 1964. 33. Hammond, E.C.: Smoking in relation to the death rates of one million men and women. Natl. Cancer Inst. Monogr. No. 19, 1966. 34. Kahn, H.A.: The Dorn study of smoking and mortality among U.S. veterans: report on eight and one-half years of observation. Natl. Cancer Inst. Monogr. No. 19, 1966. 35. Best, E.W.R.: A Canadian study of smoking and health. Department of National Health and Welfare, Ottawa, Canada, 1969. 36. Hammond, E.C.: The scientific background. World Conference on Smoking and Health, American Cancer Society, 1967. 37. Inter@s@xiety Commission forHeart Disease Resources. Primary prevention of the athero sclerotic diseases. Circulation 42:A-54-A-95, 1970. 38. Stamler, J., and Epstein, F.H.: Coronary heart disease: risk factors as guides to preventive action. Prey. Med. 1:27-48, 1972. 39. Ross, R.S.: The case for prevention of coro nary heart disease. Circulation 51:1-6, 1975. 40. Stamler, J.: Primary prevention of sudden coronary death. Supplement III to Circulation 52:258-279, 1975. 41. Gordon, T.; Kannel, W.B., and McGee, D.: Death and coronaryattacksin men aftergiving up cigarette smoking. Lancet 2:1345-1348, 1974. 42. Burt, A. et al.: Stopping smoking after myo cardial infarction. Lancet 1:304-306, 1974. 43. Auerbach, 0.; Hammond, E.C., and Gar finkel, L.: Smoking in relation to atherosclerosis of the coronary arteries. N. EngI. J. Med. 273: 775-779, 1965. 44. Auerbach, 0. et al.: Thickness of walls of myocardial arterioles in relation to smoking and age. Arch. Environ. Health 22:20-27, 1971. 45. Gordon, T., and Kannel, W.B.: Predisposi tion to atherosclerosis in the head, heart, and legs. JAMA 221:661-666, 1972. 46. Robicsek, F. et al.: The effect of continued cigarette smoking on the patency of synthetic vascular grafts in Leriche syndrome. J. Thorac. Cardiovasc. Surg. 70:107-112, 1975. 47. Cancer' Facts and'Figures,.American Cancer VOL. 27, NO.6 NOVEMBER/DECEMBER 1977
Society, New York,1977. 48. Schneiderman, M.A., and Levin, D.L.: Trends in lung cancer. Cancer 30:1320-1325, 1972. 49. Doll, R., and Pike, M.C.: Trends in mortal ity among British doctors in relation to their smoking habits. J. Royal Coil. Phy. Lond. 6:216222, 1972. 50. Lundin, F.E., Jr. etal.: Mortality of uranium miners in relation to radiation exposure, hard rock mining, and cigarette smoking. Health Phys. 16:571-578, 1969. 51. Selikoff, U.; Hammond, E.C., and Churg, J.: Asbestos exposure, smoking, and neoplasia. JAMA 204:106-112, 1968. 52. Rothman, K., and Keller, A.: The effect of jointexposureto alcoholand tobaccoon riskof cancer of. the mouth and pharynx. J. Chronic Dis. 25 :711-716, 1972. 53. Hoover, R., and Cole, P.: Population trends in cigarette smoking and bladder cancer. Am. J. Epidemiol. 94:409-418, 1971. 54. U.S. Department of Health, Education, and Welfare: Monthly Vital Statistics Report. (An nual Summary for the U.S. 1974) 23:21 (HRA) 76-1120, 1975. 55. Ferris, B., Jr.: Chronic bronchitis and em physema.Med. Clin.North Am. 57:637-649, 1973. 56. Seely, J.E.; Zuskin, E., and Bouhuys, A.: Cigarette smoking: objective evidence for lung damage in teen-agers. Science 172:741-743, 1971. 57. Lim, T.P.K.: Airway obstruction among high school students. Am. Rev. Respir. Dis. 108:985988, 1973. 58. U.S. Department of Health, Education, and Welfare, Public Health Service: The Health Con sequences of Smoking 1974. DHEW Publication No. (CDC) 74-8704. Washington, D.C., U.S. Superintendent of Documents, 1974. 59. Bode, F.R. et al.: Reversibility of pulmonary function abnormalities in smokers. Am.J. Med. 59:43-52, 1975. 60. Fridy, W.W., Jr. et al.: Airways function during mild viral respiratory illnesses. Ann. In tern. Med. 80:150-155, 1974. 61. Laszlo, G. et al.: The diagnosis and prophy laxis of pulmonary complications of surgical operation. Br.J.Surg.60:129-134, 1973. 62. Niewoehner, D.E.;Kleinerman, J., and Rice, D.B.: Pathologic changes in the peripheral air ways of young cigarette smokers. N. Engl. J. Med..291:755-758, 1973. 63. Spain, D.M.; Siegel, H., and Bradess, V.A.: Emphysema in apparently healthy adults. Smok ing, age, and sex. JAMA 224:322-325, 1973. 64. Doll, R.; Jones, F.A., and Pygott, F.: Effect of smoking on theproductionand maintenance of gastric and duodenal ulcers. Lancet 1:657-662, 1958. 65. Solomon, T.E.,and Jacobson,ED: Cigar ette smoking and duodenal-ulcer disease. N. Engl. J. Med. 286:1212-1213, 1972. 66. Salter, R.H.: Lower oesophageal sphincter therapeutic implications. Lancet 1:347-349, 1974. 67. Huber, G.L.: Smoking and nonsmokers —¿ what is the issue? N. EngI. J. Med. 292:858-859, 1975. 68. Aronow, W.S.; and Isbell, M.W.: Carbon monoxide effect on exercise-induced angina pec tons. Ann. Intern. Med. 79:392-395, 1973. 353
Prior to 1900, most tobacco was con
United States remains high (exceeding
sumed in the form of cigars, pipe to bacco, chewing tobacco, and snuff; cigarettes were only popularized just prior to World War I. However, over the next several decades, cigarette pro duction in the United States climbed from four billion cigarettes in 1910' to approximately 600 billion cigarettes in
4100 cigarettes per year for those over
1974.2
The
tremendous
increase
in cig
arette production dramatically illus trates the growth of a major public health problem: the widespread in halation of tobacco smoke. During the past 25 years, numerous epidemio logical, clinical, pathological, and ex perimental studies have shown that cigarette smolqng is causally related to premature disability, disease, and death.3'5 Legislative bodies have re sponded to these data by supporting public education programs, prohibiting cigarette advertising, requiring health warnings on packaged tobacco prod ucts, encouraging the production of cigarettes containing less tar and nico tine, and enacting laws to prevent smok ing in public places. In spite of these efforts to discourage smoking, per capita consumption of cigarettes in the @ Dr. Holbrook is Assistant Professor of Internal Medicine, Department of InternalMedicine, Divisionof General InternalMedicine,Univer sity of Utah, Salt Lake City, Utah. 344
18 years of age2), and young women are taking up cigarette smoking in increas ing numbers. Physicochemical Properties Tobacco smoke is produced by incom plete combustion of the tobacco leaf. Mainstream smoke is generated when air is drawn through the cigarette, at which time the temperature of the burn ing zone may reach 880°C; sidestream smoke is generated when the cigarette is burning at rest, at which time the temperature may reach 835°C.6In the burning process, organic matter is frac tionated into smaller molecules (pyrol ysis). Some of the newly formed mole cules are unstable and recombine to form compounds not originally present in tobacco (pyrosynthesis).7 Some com ponents of mainstream smoke are fil tered by unburnt tobacco only to be come partly revaporized when reached by the ember; hence, many of the con stituents of cigarette smoke become more concentrated as smoking con tinues. Mainstream smoke contains from lx l0@to 5x l0@particles per ml., with the mean particle size ranging from 0.2 to 1.1 There are approximately 500 mg. of mainstream smoke in a ciga rette, of which more than 85 percent is
composed of nitrogen,
oxygen, and
CA—A CANCER JOURNAL FOR CLINICIANS
carbon dioxide. About eight percent of the mainstream smoke consists of par ticulate kmatter and the remainder is made up of a vapor phase and other gases.7 After smoke is drawn into the mouth, nose, and throat, some con stituents are absorbed directly through the oral mucosa;9 other constituents are inhaled into the bronchopulmonary tree where they are either absorbed or retained.'0 Pharmacology Approximately 1000 different sub stances have been identified in tobacco smoke,8― some of which are found in concentrations that represent a definite health hazard.4 A number of substances occur in borderline concentrations, while other chemical constituents may be hazardous only when they interact with the different components of to bacco smoke.4 Substances of acknowl edged significance are carcinogens, carbon monoxide, nicotine, and ir ritant gases. VOL. 27, NO.6 NOVEMBER/DECEMBER 1977
The carcinogens in tobacco smoke have also been classified as: (1) com plete carcinogens; (2) cocarcinogens, including tumor initiators and promot ers; and (3) tumor accelerators.'2 Most of the known carcinogens in cigarette smoke are found in tobacco “¿tar,― a name given to the aggregate of particu late matter in cigarette smoke after subtracting nicotine and moisture. Application of tobacco “¿tar― to the tissues of experimental animals readily induces malignant changes,7 and dogs trained to inhale cigarette smoke through tracheostomae have developed lung cancer.'3 A substantial part of the carcinogenic activity of “¿tar― is due to a group of compounds known as poly nuclear aromatic hydrocarbons (PAH). Benzo(a)-pyrene is a PAH occurring in high concentrations in tobacco smoke.@ N-nitrosamines are well-known animal carcinogens which have been identified recently in both tobacco'4 and cigarette smoke condensate.'5 In addition, very low concentrations of beta-naphthyl 345
amine, a potent human bladder car cinogen, have also been found in ciga rette smoke.16 Other constituents of tobacco smoke which may play a role in carcinogenesis are radioactive ele ments such as polonium-210, free radi cals, and metals such as nickel.7 Carbon monoxide is a major air pol lutant, and cigarette smoking is the most important source of this pollutant for smokers.'7 Carbon monoxide is present in mainstream cigarette smoke in significant amounts, accounting for from 2.9 to 5.1 percent of its weight.7
“¿Cigaretteproduction in the U.S. climbed from four billion cigarettes in 1910 to 600 billion cigarettes in 1974.― Carboxyhemoglobin levels of moderate cigarette smokers average around six percent, while those of non-smokers are usually near one percent.'8 Heavy smokers and those who inhale show the highest carboxyhemoglobin levels. Oxygen carrying capacity is diminished in cigarette smokers because elevated carboxyhemoglobin levels reduce the amount of available hemoglobin and shift the oxygen-hemoglobin dissocia tion curve to the left. Elevated carboxy hemoglobin levels impair maximal exercise performance,'9 aggravate is chemic vascular disease and chronic pulmonary disease,20-23 and may con tribute to the pathogenesis of coronary heart disease and arteriosclerotic pe ripheral vascular disease.24 Small eleva tions in carboxyhemoglobin may exert subtle influences on the central nervous system as measured by impaired time interval discrimination and perfor mance on psychomotor tests.4'25 Nicotine is a highly toxic alkaloid which is a ganglionic stimulator. Most cigarettes currently sold in the United
States deliver about 1.3 mg. of nico
tine.26 Since nicotine has both stimulant and depressant actions, its effects in man are often complex and unpredict able. In addition to stimulating the cardiovascular system and central ner vous system, nicotine causes the release of norepinephrine, epinephrine, and antidiuretic hormone.27 Catecholamine release may also account for an in crease in serum-free fatty acids28 and in platelet aggregation produced by nico tine.29 The cardiovascular responses to nicotine include increases in heart rate, systemic arterial pressure, cardiac out put, stroke volume, velocity of myo cardial contraction, and peripheral vasoconstriction. The net effect is to increase myocardial tissue oxygen demand. In normal individuals, this increased oxygen demand is generally followed by an increase in coronary blood flow; however, patients with coronary artery disease may not be ca pable of increasing coronary flow and myocardial hypoxia may result. Bellet demonstrated that cigarette smoke in halation decreases the ventricular fi brillation threshold in normal dogs and in dogs with acute myocardial infarc tion.3°The peripheral vasoconstriction caused by nicotine aggravates ischemia in patients with arteriosclerotic periph eral vascular disease. Cigarette smoke contains several irritant gases including: acrolein, nitro gen dioxide, formaldehyde, hydrogen sulfide, and ammonia. These substances produce coughing, bronchospasm, increased mucus secretion, and cili astasis. Some of the irritant gases such as acrolein and phenol are also cocar cinogens.7 Hydrocyanic acid, a respira tory enzyme poison, is also present in cigarette smoke. Smoking and Total Mortality An increase in the incidence of cancer of the lung was noted in the United States in 1930, and studies linking smok ing to excess morbidity and mortality CA—A CANCER JOURNAL FOR CLINICIANS
@
soon followed. The early, retrospective studies dealt largely with lung cancer while the later prospective studies showed that cigarette smokers experi enced greater overall morbidity and mortality from a number of conditions than non-smokers. Approximately 75 percent of the excess mortality experi enced by cigarette smokers was due to coronary artery disease, cancer of the lung and other sites, and chronic ob structive pulmonary disease.3' Data taken from four large prospec tive studies involving more than 1.4 million British doctors, U.S. veterans, Canadian pensioners and U.S. men and women demonstrated that male ciga rette smokers, taken as a whole, had a 30 to 80 percent greater mortality than non-smokers (Table 1).32.35 The evi dence suggested a dose-response rela tionship because the excess mortality rose with increasing cigarette consump tion and was greater in those who start ed smoking at an early age and who inhaled. It was also noted that the ex VOL. 27, NO.6 NOVEMBER/DECEMBER 1977
cess mortality decreased with smoking cessation (Table The findings for women were similar to those for men, but the excess mortality was somewhat less than in men. The total number of excess deaths in cigarette smokers was greater in older people because of the generally higher death rates at older ages; however, the mortality excess of cigarette smokers was proportionately greater at ages 45 to 54 than at younger or older ages. In order to emphasize the risk to the individual cigarette smoker, Hammond calculated the amount by which a cigarette 3moker's life is short ened at various ages according to the number of cigarettes he smokes. For example, according to this estimate, an average 30-year-old male who smokes 15 cigarettes per day may expect to lose about five and one-half years of life (Fig. l).36 Clinical Correlations Coronary Heart Disease (CHD) The relationship
between smoking and 347
Figure 1 LIFE EXPECTANCY AT AGE 25 (MALE) Cigarettesper day 73.6
never smoked
1-9
69.0
10-19
68.1
20-39
67.4
40+
65.3
25
35
CHD is important because CHD ac counts for more than 50 percent of the excess mortality due to smoking33 and because many coronary deaths occur suddenly and prematurely in those un der 65 years of age. Cigarette smoking, hypertension,
and hypercholesterolemia are alterable “¿majorrisk-factors― contributing to the development of CHD.37,38 Cigarette smoking is an independent risk-factor which also acts synergistically with the other two major risk-factors. Male cigarette smokers have approximately a two-fold greater risk of dying from CHD than non-smokers. In men, a dose-response relationship exists be tween cigarette smoking and CHD morbidity and mortality. Women cig arette smokers also experience increased
mortality from CHD, but it is less than that of men.33 Application of the risk-factor con cept in clinical medicine constitutes an important preventiveapproach to CHD, 348
45
55
65
75
which may favorably alter the course of the disease before it becomes far advanced.39. @° Cessation of cigarette smoking decreases the risk of death from CHD.33'374' This decrease is mea surable within one year after stopping smoking; after ten years, the risk ap proaches that of the non-smoker. As part of a comprehensive approach to managing CHD risk-factors, physi cians should actively advise and assist patients to stop smoking. Patients who have an acute myocardial infarction are especially motivated to accept such advice, and in this situation, 50 percent cessation rates have been reported.42
In autopsy studies, cigarette smokers have been shown to have a greater fre quency and severity of coronary athero sclerosis4r and greater myocardial arte riolarwallthicknessthan non-smokers .@ Cerebral and Peripheral Occlusive Vascular Disease Cigarette
smoking
is associated
with
CA—A CANCER JOURNAL FOR CLINICIANS
@
increased mortality from cerebrovas cular disease,3' 31 and is also a risk factor for the development of arterio sclerosis obliterans. In addition, it ag gravates established peripheral vascular
disease.45 The patency of peripheral bypass
grafts
may also be adversely
affected by cigarette smoking.@ Thromboangitis
obliterans(Buerger's
disease), an uncommon obliterative and inflammatory process which affects peripheral arteries and veins in a seg mental fashion, characteristically at tacks young male cigarette smokers between. the ages of 20 and 45 years.
Controversy
continiies over whether
this is adistinct disease entity, or whether
it is an unusual subgroup of arterio sclerosis obliterans. Cessation of tobac co usage is the only effective therapy.3
Certain occupations are associated with an increased risk of developing
“¿A 30-year-old male who smokes 15 cigarettes per day may expect to lose five and one-half years of life.― lung cancer that is enhanced by ciga rette smoking.3 In the uranium mining50 and asbestos industries,5' cigarette smoking workers have much higher lung cancer rates than those which would result from the industrial ex posure alone or from smoking alone. Other Cancer Sites
The smoking of cigarettes, pipes, and Lung Cancer
@
In the United State in 1977 lung cancer will account for more cancer deaths (an estimated 89,000), than any other can cer site.47 Cogent epidemiological data, coupled with experimental and patho logical evidence, -establish cigarette smoking as the most important cause of lung cancer.3'5 The average male cig arette smoker's risk of developing lung cancer is ten times greater than that of the non-smoker. In heavy smokers, the risk is 15 to 30 times as great as that of non-smokers. (Fig. 2)32.35Lung cancer death rates for women are lower than for men, but in recent years, they have increased proportionately more rapidly than those for men.47 For both men and women the risk of developing lung cancer is directly related to total cig arette smoke exposure, as measured by the number of cigarettes smoked per day, the duration of smoking, the age at initiation of smoking, the depth of inhalation, and the “¿tar― and nicotine levels in the cigarette smoked.3 The risk of developing lung cancer diminshes with cessation of smoking.33'49 VOL. 27, NO.6 NOVEMBER/DECEMBER 1977
cigars is a significant factor in the de velopment of cancer of the oral cavity, pharynx, larynx, and esophagus.3'5
Pipe-smoking appears to be causally related to cancer of the lip.5 The com bined exposure to alcohol and cigà rettes is associated with especially high esophageal, oral, and pharyngeal can
cer rates.3. 52 Carcinoma of the pan creas and bladder is also more common in cigarette smokers than in non smokers.3'53
Chronic Obstructive Pulmonary Disease (COPD) In the United States, cigarette smoking is the most important factor contribut ing to the development of COPD,3'5 which was responsible for more than 25,000 deaths in l974.@@Male cigarette smokers experience from four to 25 times higher death rates from emphy sema and bronchitis than non-smok ers.32'35 Dose-response relationships exist between cigarette smoking and these increased mortality rates. COPD is also one of the most im portant causes of chronic disability in 349
@
the United States,55 and disabling pul monary symptoms and impaired pul monary function are more frequent in men and women who smoke than in non-smokers.3'4 Even young cigarette smokers of high school age have im paired ventilatory function compared to non-smoking peers.56@57Small airway dysfunction is more common in asymp tomatic cigarette smokers than non smokers.58 Ex-cigarette smokers have lower death rates from COPD than do continuing smokers.3'4 Cessation is also associated with some improvement in ventilatory function and a decrease in prevalence of pulmonary symp toms.3
On the average, the cigarette smoking mother has nearly twice the risk of de livering a stillborn child as does the non-smoking mother.5 This risk may be even greater in women who for other reasons have a high-risk pregnancy. There is a strong association between maternal cigarette smoking and higher late fetal and neonatal death rates. The fetus of a smoking mother is exposed
For most of the American popula tion, cigarette smoking is a more im portant cause of COPD than air pollu tion or occupational exposure; cigarette smoking may also act conjointly with occupational and environmental ex posures to produce greater COPD mor bidity and mortality.3'5 Cigarette smok ing exerts an adverse effect on the pul monary clearance mechanism.3'5'58 Res piratory infections are more prevalent and severe among cigarette smokers than among non-smokers,3'6° and ciga rette smokers appear to develop post operative respiratory complications more frequently than non-smokers.3'6' Recent autopsy studies confirm that emphysema is much more frequent and severe in cigarette smokers than in non smokers.3'4'62' 63
to carbon monoxide and nicotine which
Pregnancy An estimated one-third of American women of childbearing age are cigarette smokers.5 It is well known that drugs, rubella, and radiation may endanger the unborn child; it is less well known that maternal smoking during preg nancy may be harmful to the fetus. Infants of mothers who smoke dur ing pregnancy have a mean birth weight of approximately 6 ounces less than infants born to non-smoking mothers.4 350
“¿Cessationof cigarette smoking decreases the risk of death from coronary heart disease.―
may mediate the noted adverse effects. Gastrointestinal Disorders Cigarette smoking males have an in creased prevalence of peptic ulcer di sease.3 They also have a three- to four fold increase in death rates from peptic ulcer disease compared to non-smokers. These relationships are stronger for gastric than for duodenal ulcer. Smok ing appears to reduce the effectiveness of standard peptic ulcer therapy and to slow the rate of ulcer healing.64 Recent experimental studies suggest that smok ing may mediate this effect by inhibit ing pancreatic bicarbonate secretion.65 Cigarette smoke inhalation is followed by a rapid decrease in lower espohageal sphincter pressure, an effect which may encourage gastro-esophageal reflux.@ Allergy Tobacco smoke inhalation may result in complex pharmacologic, irritative, and allergic effects which may be dif ficult to distinguish from one another.4 Although allergy to tobacco smoke appears to be unusual, exposure to smoke may produce exacerbation of allergic symptoms in both smokers and non-smokers who are suffering from CA—A CANCER JOURNAL FOR CLINICIANS
Figure2
.c a, 0
a,
C.) C
a,
x20
C
0 0 a, >.
a,
t
0
0
10
20
30
40
50
Current number of cigarettessmokedper day British doctors
Canadian veterans
U. S. veterans
U. S. men
allergies of diverse causes. Asthmatics should be instructed to avoid cigarette
those of cigarette smokers. Death rates from cancer of the lung, pancreas, and
smoke inhalation.
bladder, as well as CHD and COPD,
Pipes and Cigars In the United States, pipe and cigar smokers as a group experience overall death rates that are substantially lower than those of cigarette smokers and only slightly higher than those of non smokers.5 This appears to be due to the
relatively low total exposure to tobacco smoke that a pipe or cigar smoker re ceives, as most pipe and cigar smokers
report that they do not inhale. How ever, at those sites directly exposed to
cigar and pipe smoke, such as the oral cavity, larynx, pharynx, and esophagus, cancer death rates of pipe and cigar smokers are approximately equal to VOL. 27, NO.6 NOVEMBER/DECEMBER 1977
are not greatly
elevated
in cigar and
pipe smokers above the rates of non smokers. Involuntary Smoking
Attention has been focused on the pos sible hazards of breathing
in a cigarette
smoke-filled environment.67 The to bacco smoke in such an environment differs qualitatively and quantitatively from that inhaled directly from the cigarette; this is because smoke in the
environment arises from both main stream and sidestream sources. In addition to contributing to the dis comfort of many individuals, cigarette
smoke is a significant atmospheric pol 351
lutant.25 For example, under conditions of heavy smoking and poor ventilation, the maximum limit for an eight-hour work exposure to carbon monoxide (50 ppm) may be exceeded. Even in cases where ventilation is adequate, the upper limit for carbon monoxide in ambient air (9 ppm) may be exceeded.
Exposure to air contaminated by cigarette smoke may be especially harm ful for those already suffering from CHD and COPD.@ 25Enough carbon monoxide may be present in smoke filled rooms
to diminish
the exercise
tolerance of patients with angina pec tons.20 25.68
References
ityof condensatefractions. Cancer 27:848-864, 1971. 13. Auerbach, 0. et al.: Effects of cigarette 1. U.S. Department of Health, Education, and smoking on dogs. II. Pulmonary neoplasms. Welfare,Rublic Health Service:Smoking, To Arch.Environ.Health21:754-768, 1970. bacco,and Health.U.S. PublicHealth Service 14. Hoffmann, D. et al.:N'-nitrosonornicotine Publication No. 1931, Washington, D.C., Super intobacco.Science186:265-267, 1974. intendent of Documents, 1969. 15. Rhoades, J.W., and Johnson, D.E.: Method 2. U.S. Department of Agriculture: Agricultural for the determinationof N-nitrosaminesin to Statistics 1975. Washington, D.C., Superinten bacco-smoke condensate. i. Natl. Cancer Inst. dent of Documents, 1975, P. 106. 48:1841-1843, 1972. 3. U.S. Department of Health, Education, and 16. Hoffmann, D.; Masuda, Y., and Wynder, Welfare, Public Health Service: The Health Con E.L.: Alpha-naphthylamine and beta-naphthy sequences of Smoking; A Report of the Surgeon lamine in cigarette smoke. Nature 221:254-256, General 1971. DHEW Publication No. (HSM) 1961. 71-7513. Washington, D.C., U.S. Superintendent 17. Stewart, R.D.; Baretta, E.D., and Platte, of Documents, 1971. L.R.: Carboxyhemoglobin levels in American 4. U.S. Department of Health, Education, and blood donors. JAMA 229:1187-1195, 1974. Welfare, Public Health Service: The Health Con 18. Goldsmith, J.R.: Contribution of motor ve sequences of Smoking; A Report of the Surgeon hicle exhaust, industry, and cigarette smoking General 1972. DHEW Publication No. (HSM) to community carbon monoxide exposures. Ann. 72-7516. Washington, D.C., U.S. Superintendent N.Y. Acad. Sci. 174:122-134, 1970. of Documents, 1972. 19. Aronow, W.S., and Cassidy, J.: Effect of carbon monoxide on maximal treadmill exercise: 5. U.S. Department of Health, Education, and a study in normal persons. Ann. Intern. Med. 83: Welfare, Public Health Service: The Health Con 496-499, 1975. sequences of Smoking 1973. DHEW Publication 20. Anderson, E.W.; Andelman, R.i., and No. (HSM) 734704. Washington, D.C., U.S. Strauch, J.M.: Effect of low-level carbon mo Superintendent of Documents, 1973. noxide exposure on onset and duration of angina 6. Touey, G.P.: Measurement of the combustion pectoris. Ann. Intern. Med. 79:46-50, 1973. zone temperature of cigarettes. Tobacco 144: 21. Aronow, W.S. et al.: Effect of cigarette 18-22, 1957. smoking and breathingcarbonmonoxide on car 7. Wynder, E.L., and Hoffmann, D.: Tobacco diovascular hemodynamics in anginalpatients. and Tobacco Smoke. Studies in Experimental Carcinogenesis. New York:Academic Press,1967. Circulation 50:340-347, 1974. 22. Aronow, W.S.; Stemmer, E.A., and Isbell, 8. Stedman, R.L.: The chemical composition of MW.: Effect of carbon monoxide exposure on tobacco and tobacco smoke. Chemical Reviews intermittent claudication. Circulation 49:415-417, 68:153-207, 1968. 1974. .9. Dalhamm, T.; Edfors, M.L., and Rylander, 23. Brody, iS., and Coburn, R.F.: Carbon mo R.: Mouth absorption of various compounds in noxide-induced arterial hypoxemia. Science 164: cigarette smoke. Arch. Environ. Health 16:8311297-1298, 1969. 835,1968. 24. Astrup, P., and Kjeldsen, K.: Carbon mo 10. Dalhamm, T.; Edfors, M.L., and Rylander, noxide, smoking, and atherosclerosis. Med. Clin. R.: Retention of cigarette smoke components in North Am. 58:323-350, 1974. human lungs. Arch. Environ. Health 17:746-748, 1968. 25. U.S. Department of Health, Education, and Welfare, Public Health Service: The Health Con 11. Smoking and Health'Now.Royal Collegeof Physicians. London: Pitman Medicaland Scien sequences of Smoking 1975. DHEW Publication No. (CDC) 76-8704. Washington, D.C., U.S. tific Publishing Company, 1971. 12. Hoffmann, D., and Wynder, E.L.:A study Superintendent of Documents, 1975. of tobaccocarcinogenesis. XI. Tumor initiators,26. Report of “¿tar― and nicotine content of the tumor accelerators, and tumor promotingactiv smoke of ‘¿135 ‘¿varietiesof cigarettes. Federal 352
CA—A CANCER JOURNAL FOR CLINICIANS
Trade Commission, September, 1975. 27. Goodman, L.S., and Gilman, A.: The Phar macological Basis of Therapeutics. New York: Macmillan Publishing Company, 1975, Pp. 567-570. 28. Kershbaum, A.; Khorsandian, R.; Caplan, R.F. et al.: The roleof catecholamines in the free fatty acid response of cigarette smoking. Circula tion 28:52-57, 1963. 29. Levine, P.H.: An acute effect of cigarette smoking on platelet function. Circulation 48:619623, 1973. 30. Bellet, S.; DeGuzman, N.T.; Kostis, J.B. et al.: The effect of inhalation of cigarette smoke on ventricular fibrillation threshold in normal dogs and dogs with acute myocardial infarction. Am. Heart J. 83 :67-76, 1972. 31. Hammond, E.C., and Horn, D.: Smoking and death rates —¿report on 44 months of follow up of 187,783 men. JAMA. 166:1159-1172, 1958. 32. Doll, R., and Hill, A.B.: Mortality in rela tion to smoking: ten years' observations of British doctors. Brit. Med. J. 5395:1399-1410, 1460-1467, 1964. 33. Hammond, E.C.: Smoking in relation to the death rates of one million men and women. Natl. Cancer Inst. Monogr. No. 19, 1966. 34. Kahn, H.A.: The Dorn study of smoking and mortality among U.S. veterans: report on eight and one-half years of observation. Natl. Cancer Inst. Monogr. No. 19, 1966. 35. Best, E.W.R.: A Canadian study of smoking and health. Department of National Health and Welfare, Ottawa, Canada, 1969. 36. Hammond, E.C.: The scientific background. World Conference on Smoking and Health, American Cancer Society, 1967. 37. Inter@s@xiety Commission forHeart Disease Resources. Primary prevention of the athero sclerotic diseases. Circulation 42:A-54-A-95, 1970. 38. Stamler, J., and Epstein, F.H.: Coronary heart disease: risk factors as guides to preventive action. Prey. Med. 1:27-48, 1972. 39. Ross, R.S.: The case for prevention of coro nary heart disease. Circulation 51:1-6, 1975. 40. Stamler, J.: Primary prevention of sudden coronary death. Supplement III to Circulation 52:258-279, 1975. 41. Gordon, T.; Kannel, W.B., and McGee, D.: Death and coronaryattacksin men aftergiving up cigarette smoking. Lancet 2:1345-1348, 1974. 42. Burt, A. et al.: Stopping smoking after myo cardial infarction. Lancet 1:304-306, 1974. 43. Auerbach, 0.; Hammond, E.C., and Gar finkel, L.: Smoking in relation to atherosclerosis of the coronary arteries. N. EngI. J. Med. 273: 775-779, 1965. 44. Auerbach, 0. et al.: Thickness of walls of myocardial arterioles in relation to smoking and age. Arch. Environ. Health 22:20-27, 1971. 45. Gordon, T., and Kannel, W.B.: Predisposi tion to atherosclerosis in the head, heart, and legs. JAMA 221:661-666, 1972. 46. Robicsek, F. et al.: The effect of continued cigarette smoking on the patency of synthetic vascular grafts in Leriche syndrome. J. Thorac. Cardiovasc. Surg. 70:107-112, 1975. 47. Cancer' Facts and'Figures,.American Cancer VOL. 27, NO.6 NOVEMBER/DECEMBER 1977
Society, New York,1977. 48. Schneiderman, M.A., and Levin, D.L.: Trends in lung cancer. Cancer 30:1320-1325, 1972. 49. Doll, R., and Pike, M.C.: Trends in mortal ity among British doctors in relation to their smoking habits. J. Royal Coil. Phy. Lond. 6:216222, 1972. 50. Lundin, F.E., Jr. etal.: Mortality of uranium miners in relation to radiation exposure, hard rock mining, and cigarette smoking. Health Phys. 16:571-578, 1969. 51. Selikoff, U.; Hammond, E.C., and Churg, J.: Asbestos exposure, smoking, and neoplasia. JAMA 204:106-112, 1968. 52. Rothman, K., and Keller, A.: The effect of jointexposureto alcoholand tobaccoon riskof cancer of. the mouth and pharynx. J. Chronic Dis. 25 :711-716, 1972. 53. Hoover, R., and Cole, P.: Population trends in cigarette smoking and bladder cancer. Am. J. Epidemiol. 94:409-418, 1971. 54. U.S. Department of Health, Education, and Welfare: Monthly Vital Statistics Report. (An nual Summary for the U.S. 1974) 23:21 (HRA) 76-1120, 1975. 55. Ferris, B., Jr.: Chronic bronchitis and em physema.Med. Clin.North Am. 57:637-649, 1973. 56. Seely, J.E.; Zuskin, E., and Bouhuys, A.: Cigarette smoking: objective evidence for lung damage in teen-agers. Science 172:741-743, 1971. 57. Lim, T.P.K.: Airway obstruction among high school students. Am. Rev. Respir. Dis. 108:985988, 1973. 58. U.S. Department of Health, Education, and Welfare, Public Health Service: The Health Con sequences of Smoking 1974. DHEW Publication No. (CDC) 74-8704. Washington, D.C., U.S. Superintendent of Documents, 1974. 59. Bode, F.R. et al.: Reversibility of pulmonary function abnormalities in smokers. Am.J. Med. 59:43-52, 1975. 60. Fridy, W.W., Jr. et al.: Airways function during mild viral respiratory illnesses. Ann. In tern. Med. 80:150-155, 1974. 61. Laszlo, G. et al.: The diagnosis and prophy laxis of pulmonary complications of surgical operation. Br.J.Surg.60:129-134, 1973. 62. Niewoehner, D.E.;Kleinerman, J., and Rice, D.B.: Pathologic changes in the peripheral air ways of young cigarette smokers. N. Engl. J. Med..291:755-758, 1973. 63. Spain, D.M.; Siegel, H., and Bradess, V.A.: Emphysema in apparently healthy adults. Smok ing, age, and sex. JAMA 224:322-325, 1973. 64. Doll, R.; Jones, F.A., and Pygott, F.: Effect of smoking on theproductionand maintenance of gastric and duodenal ulcers. Lancet 1:657-662, 1958. 65. Solomon, T.E.,and Jacobson,ED: Cigar ette smoking and duodenal-ulcer disease. N. Engl. J. Med. 286:1212-1213, 1972. 66. Salter, R.H.: Lower oesophageal sphincter therapeutic implications. Lancet 1:347-349, 1974. 67. Huber, G.L.: Smoking and nonsmokers —¿ what is the issue? N. EngI. J. Med. 292:858-859, 1975. 68. Aronow, W.S.; and Isbell, M.W.: Carbon monoxide effect on exercise-induced angina pec tons. Ann. Intern. Med. 79:392-395, 1973. 353
