It has been reported (100) that diabetic males who smoke have a 50% greater incidence of clinically detectable arteriosclerosis obliterans in the legs than those who do not smoke. In general, however, there is little information about the relation of smoking to peripheral arteriosclerosis. Most experienced clinicians advise patients with obliterative peripheral arte- rial disease to stop smoking (45). Buerger's disease, or thromhoangiitis obliterans, has been traditionally associated with smoking. and the literature contains numerous clinical re- ports describing the arrest of Buerger's disease when smoking is stopped and its reactivation on resumption of smoking. The existence of Buerger's disease as an entity separate from arteriosclerosis obliterans has been re- centlv challenged ( 1011, but well defended (61). It -is apparent that much mere work will have to be done to determine what relationship may exist bet\\-een non-coronary occlusive vascular dis- ease, aneurysmal disease, and smoking. CHARA4CTERISTICS OF CIGARETTE SMOKERS If it could be shown that cig;arette smokers and non-smokers had signifi- cant constitutional differences apart from any differences that might be caused by smoking itself, then a possibility w-ould exist that some predisposition of smokers to a particular disease might also be of constitutional origin and not caused by smoking. Cigarette smokers have, in fact, been found to differ as a group from non-smokers, but the differences, such as serum cholesterol concentration and resting heart rate, could have resulted from the smoking habit itself, so far as present knowledge indicates. The concentration of serum cholesterol has been found to be slightly higher in smokers than in non-smokers by a number of investigators (6, 18, 49, 63, 95)) but others have found no relationship (1, 54). Dawber (19) found not only that serum cholesterol was higher in smokers than in non-smokers but also that it remained higher in those who stopped smoking. Smokers tend to be leaner than non-smokers, but to gain when they stop smoking (3, 18,491. A few personality differences have been reported between cigarette smokers and non-smokers. F rle man's type A men i the coronary type) tended to be ' d heavy smokers (33 j. Smokers are said to be more easily angered and to eat more when under stress (94). They have been reported to marry oftener. to change jobs more frequently. to be more often hospitalized, and to par- ticipate more actively in sports; than non-smokers (60). Thomas I 94. 95 I hai rel)or ted that the parents of medical students \vho smoke have a significantl!- higher incidence of arteriosclerotic and hyper- tensive cardiovascular disease than parents of non-smokers. Clearl!-. this finding is open to more than c,ne interpretation. Smokers tend to have a higher heart rate than non-smokers (3. 94 1. The matter of constitutional predisposition to smoking has been inves- tipated in twins. It has been found I 27. 2X. 32 I that the smoking hahits of monozygotic twins are siynifirantly morr alike than those of diz\-gotic tGne. even when memhers of a tw-in pair are brought up separately. 326 In spite of some bits of suggestive evidence the existence of basic consti- tutional differences between smokers and non-smokers is not presently established. The constitutional hypothesis, which links smoking and predis- position to disease, is discussed in detail in Chapter 9, Cancer. PSYCHO-SOCIAL FACTORS OF SMOKING IN RELATION TO CARDIOVASCULAR DISEASE Even less conclusve information is available on the role of psycho-social factors of smoking in relation to cardiovascular disease. Studies which have focussed on this are limited in number according to Heinzelmann (44 1. Even fewer. he found, are those which have specifically examined the relative weight of these variables or their interaction. Reviewing those available, he observes that the evidence is highly fragmentary and uncertain. The findings suggest that the relationship between smoking behavior and coronary heart disease may reflect the influence of stress factors and/or personality mechanisms. However, they permit no definitive statements with respect to the relative role of pyscho-social factors and smoking in relation to etiology of the disease. SUMMARY Smoking and nicotine administration cause acute cardiovascular effects similar to those induced by stimulation of the autonomic nervous system, but these effects do not account well for the observed association between cigarette smoking and coronary disease. It is established that male ciga- rette smokers have a higher death rate from coronary disease than non- smoking males. The association of smoking with other cardiovascular disorders is less well established. If cigarette smoking actually caused the higher death rate from coronary disease, it would on this account be responsible for many deaths of middle-aged and elderly males in the United States. Other factors such as high blood pressure, high serum cholesterol, and excessive obesity are also known to be associated with an unusually high death rate from coronary disease., The causative role of these other factors in coronary disease, though not proven, is suspected strongly enough to be a major reason for taking countermeasures against them. It is also more prudent to assume that the established association between ciga- rette smoking and coronary disease has causative meaning than to suspend judgment until no uncertainty remains. CONCLUSION Male cigarette smokers have a higher death date from coronary artery disease than non-smoking males, but it is not clear that the association has causal significance. 327 REFERENCES 1. Acheson, R. M., Jessop, W. J. E. T b o acco smoking and serum lipids in old men. Brit Med J 2: 1108-1111, 1961. 2. Bargeron, L. M.. Jr., Ehmke, D., Gonlubol, F.: Castellanos, A., Siegal, A., Bing. R. J. Effect of cigarette smoking on coronary blood flow and mpocardial metabo.`ism. Circulation 15 : 251-257, 1957. 3. Blackburn, H., Brozek, J., Taylor, H. L. Common circulatory meas- urements in smokers and nonsmokers. Circulation 22: 1112-1124. 1960. 4. Blackburn. H. W., Brozek, J., Taylor, H. L., Keys, A. Cardiovascular and related `characteristics in habitual smokers and nonsmokers. In: James, G., Rosenthal, T. ed. Tobacco and Health. Springfield. Thomas. 1962. p. 323-351. 5. Blackburn, H., Jr., Orma. E., Hartel, G., Punsar, S. Tobacco smok- ing and blood coagulation: Acute effect on plasma stypven time. Am J Med Sci 238: M-451, 1959. 6. Bronte-Stewart, B. Cigarette smoking and ischaemic heart disease. Brit Med J 1: 379-385, l%l. 7. Brunner, D., Manelis, G. M yocardial infarction among members of communal settlements in Israel. Lancet 2: 1049-1050, 1960. 8. Buechley, R. W., Drake, 1~. M., Breslow, L. Relationship of amount of cigarette smoking to coronary heart disease mortality rates in men. Circulation 18: 1085-1090: 1958. 9. Burn, J. H. Action of nil:otine on the heart. Ann N Y Acad Sci 90: 70-73, l%O. 10. Burn, J. H.. Leach. E. H., Rand, M. J., Thompson, J. W. Peripheral effects of nicotine and acetycholine resembling those of sympathetic stimulation. J Physiol 148: 332-352, 1959. 11. Burn, J. H., Rand. M. J. Action of nicotine on the heart. Brit Med J 1: 137-139, 1958. 12. Cannon, W. B., Gray, H Factors affecting the coagulation time of blood. 11. The hastening or retardin g of coagulation by adrenalin injections. Am J Physiol 34: 232-242, 1914. 13. Cannon. W. B.. Mendenhall. W. L. Factors affecting the coagulation time of blood. III. The hastenin g of coagulation by stimulating the splanchnic nerv-es. Am J Physiol 31: 243-250, 1914. 14. Cannon. W. B.. Mendenhall, W. L. Factors affecting the coagulation time of blood. IV. The hastening of coagulation in pain and rmo- tional excitement. Am J Physiol 34: 251-261, 1914. 15. Cardiovascular diseases mortality. 19541956, 1958-1960. WIlO. Epidemiological Vital Stat Rep 16: 115-205, 1963. 16. Case, R. A. AI. Smoking habits and mortality among workers in ciga- rette factories. Nature (London 1 181 : 84-86, 1958. 17. Comroe. J. H., Jr. The pharmacological actions of nicotine. Ann N Y Acad Sci 90: 48iii, 1960. 18. Damon, A. Constitution and smoking. Science 134: 339-341, 1961. 328 19. Dawber, T. R., Kannel, W. B., Revotskie, N., Stokes, J.. Kagan, A., Gor- don, T. Some factors associated with the development of coronary heart disease. Six years' follow-up experience in the Framingham study. Amer J Public Health 49: 1349-1356, 1959, 20. Dawber, T. R., Moore, F. E., Mann, G. V. II. Coronary heart disease in the Framingham study. Amer J Public Health 47 (Suppl. I : 4-24. April 1957. 21. Doll, R., Hill, A. B. Lung cancer and other causes of death in relation to smoking. A second report on the mortality of British doctors. Brit Med J 2: 1071-1081, 1956. 22. Dorn, H. F. Tobacco consumption and mortality from cancer and other diseases. Public Health Rep 74: 581-593, 1959. 23. Doyle, J. T., Dawher, T. R., Kannel, W. B., Heslin, A. S., Kahn, H. A. Cigarette smoking and coronary heart disease. Combined experience of the Albany and Framingham studies. New Eng J Med 266: 796 801, 1%2. 24. Doyle, J. T., Heslin, A. S., Hilleboe, H. E., Formel, P. F. Early diag- nosis of ischemic heart disease. New Eng J Med 261: 10961101, 1959. 25. Eisen, M. E., Hammond, E. C. The effect of smoking on packed cell volume, red blood cell counts, hemoglobin and platelet counts. Canad Med Ass J 75: 520-523, 1956. 26. English, J. P., Willius, F. A., Berkson, J. Tobacco and coronary disease. JAMA 115: 1327-1329, 1940. 27. Fisher, R. A. Cancer and smoking. Nature (London) 182: 596,1958. 28. Fisher, R. A. Lung cancer and cigarettes? Nature (Londonj 182: 108, 1958. 29. Fontana, V. J. Tobacco hypersensitivity. Ann N Y Acad Sci 90: 138-141, 1960. 30. Forte, I. E., Williams, A. J., Potgieter, L., Schmitthenner, J. E., Hafken- schiel, J. H., Riegel, C. Coronary blood flow and cardiac oxygen metabolism during nicotine-induced increases in left ventricular u-ork. Ann N Y Acad Sci 90: 174-185, 1960. 31. Freund, J., Ward, C. The acute effect of cigarette smoking on the digi- tal circulation in health and disease. Ann N Y Acad Sci 90: 85-101, 1960. 32. Friberg, L., Kaij, L., Dencker, S. J., Jonsson, E. Smoking habits of monozygotic and dizygotic twins. Brit Med J 1: 1090-1092: 1959. 33. Friedmann, M., Rosenman, R. H, Association of specific overt behavior pattern with blood and cardiovascular findings. JAMA 169: 1286 1296, 1959. 34. Friedman, M.. Rosenman, R. H.? Carroll, V. Changes in the serum cholesterol and blood clotting time in men subjected to cyclic varia- tion of occupational stress. Circulation 17: 852-861, 1958. 3.5. Friedman, M., St. George, S., Byers, S. O., Rosenman, R. H. Excretion of catecholamines, li-ketosteroids, 17-hydroxycorticoids and 5-hydroxyindole in men exhibiting a particular behavior pattern (A) associated with high incidence of clinical coronary artery dis- ease. J Clin Invest 39: 758-763, 1960. 32!2 36. Gertler, M. M., Woodbury, M. A., Gottsch, L. G., White, P. D., Rusk, H. A. The candidate for coronary heart disease. Discriminating power of biochemical hereditary and anthropometric measurements. JAMA 170: 149-152, 1959. 37. Haag, H. B., Hanmer, H. R. S mo mg habits and mortality among k' workers in cigarette factories. Industr Med Surg 26: 559-567,1957. 38. Hammond, E. C. The effects of smoking. Sci Amer 207(l) : 3-15. July 1962. 39. Hammond, E. C. Smoking and death rates-a riddle in cause and effect. Amer Sci 46: 331-354, 1958. 40. Hammond. E. C. S mo il in relation to heart disease. k ; g Amer J Public Health 50: 20-26, 1960. 41. Hammond, E. C. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 42. Hammond, E. C., Horn, D. Smoking and death rates-report on forty- four months of follow-up of 187,783 men. I. Total mortality; II. Death rates by cause. JAMA 166: 1159-1172,1294-1308,1958. 43. Harkavy, J. Tobacco allergy in vascular diseases. Rev Allerg 11: 189-212, 1957. 44. Heinzelmann, F. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 45. Hines, E. A. The effects of tobacco on blood pressure and in peripheral vascular diseases. Proc Mayo Clin 35: 337-343, 1960. 46. Jolliffe, N. Fats, cholesterol, and coronary heart disease. A review of recent progress. Circulation 20: 109-127, 1959. 47. Kannel, W. B. Special report to the Surgeon General's Advisory Com- mittee on Smoking and Health. 48. Kaplan, A., Jacques, S.: Gant, M. Effect of long-lasting epinephrine on serum lipid levels. Am J Physiol 191: 8-12, 1957. 49. Karvonen, M., Keys, A., Orma, E., Fidanza, F., Brozek, J. Cigarette smoking, serum-cholesterol, blood-pressure, and body fatness. Ob- servations in Finland. Lancet 1: 492494, 1959. 50. Kershbaum, A., Bellet, S., Dickstein, E. R., Feinberg, L. J. Effect of cigarette smoking and nicotine on serum free fatty acids. Cir Res 9: 631-638, l%l. 51. Kershbaum, A.: Khorsandian, R., Caplan, R. F., Bellet, S., Feinberg. L. J. The role of catecholamines in the free fatty acid response to cigarette smoking. Circulation 28: 52-57, 1963. 52. Keys, A. Diet and epidemiology of coronary heart disease. JAMA 164: 1912-1919, 1957. 53. Kien, G. E., Sherrod. T. R. Action of nicotine and smoking on coro- nary circulation and myocardial oxygen utilization. Ann N Y Acad Sci 90: 161-1'73. 1960. 54. Konttinen, A. Cigarette, smoking and serum lipids in young men. Brit Med J 1: 1115-1117, 1962. 55. Krueger, D. Special report to the Surgeon General's Advisory Com- mittee on Smoking and Health. 56. Larson. P. S. Absorption of nicotine under various conditions of tobacco use. Ann N Y Acad Sci 90: 31-35.1960. 330 57. Larson, P. S., Haag, H. B., Silvette, H. Tobacco: Experimental and clinical studies. Baltimore. Williams and Wilkins Company, 1961. 932 p. 58. Lee, R. E., Schneider, R. F. Hypertension and arteriosclerosis in ex- ecutive and non-executive personnel. JAMA 167: 1447-1450.195s. 59. Lew. E. A. Some implications of mortality statistics relating to coro- nary artery disease. J Ch ronic Dis 6: 192-209, 1957. 60. Lilienfeld. A. M. Emotional and other selected characteristics of ciga- rette smokers and non-smokers as related to epidemiological studies of lung cancer and other disease. J Nat Cancer Inst 22: 259-282. 1959. 61. McKusick. V. A.; Harris. W. S.. Otteson. 0. E., Goodman, R. M.. Shelley. W. M.. Bloodwell, R. D. Buerger's Disease: A distinct clinical and pathological entity. JAMA 181: 5-12, 1962. 62. Miller. D. C.; Stare. F. J., White. P. D., Gordon, J. E. The community problem in coronary heart disease: A challenge for epidemiological research. Amer J Med Sci 232: 329-359, 1956. 63. Miller, D. C., Trulson. M. F.: McCann, M. B., White, P. D., Stare, F. J. Diet, blood 1' `d IPI s and health of Italian men in Boston. Ann Intern Med 49: 1178-1200. 1958. 64. Mills. C. A.. Porter, M. M. Tobacco smoking and automobile driving stress in relation to deaths from cardiac and vascular causes. Amer J Med Sci 234: 35-43, 1957. 65. Morris, J. N. Recent history of coronary disease. Lancet 1: 1-7, 1951. 66. Morris, J. N.. Heady-. J. A., Raffle, P. A. B. Physique of London bus- men. Epidemiology of uniforms. Lancet 2: 569-570, 1956. 67. Morris, J. N., Heady, J. A., Raffle, P. A. B., Roberts, C. G., Park, J. W. Coronary heart-disease and physical activity of work. Lancet 2: 1503-1057, 1111-1120, 1953. 68. Mustard, J. F., Murphy, E. A. Effect of smoking on blood coagulation and platelet survival in man. Brit Med J 1: 846, 1963. 69. Page, I. H., Stare, F. J., Corcoran, A. C., Pollack, H., Wilkinson, C. F. Atherosclerosis and the fat content of the diet. Circulation 16: 163, 1957. 70. Paul, 0. Personal communication to the Surgeon General's Advisory Committee on Smoking and Health. 71. Paul, O.? Lepper, M. H., Phelan, W. H., Dupertius, G. W., MacMillan, A., McKean, H., Heebok, P. A longitudinal study of coronary heart disease. Circulation 28: 20-31, 1963. 72. Pell, S., D'Alonzo, C. A. Myocardial infarction in a one-year in- dustrial study. JAMA 166: 332-337, 1958. 73. Pickering, G. W., Sanderson, P. H. Angina pectoris and tobacco. Clin Sci 5: 275-288, 1945. 74. Regan, T. J., Frank, M. J., McGinty, J. F., Zobl, E., Hellems, H. K., Bing, R. J. Myocardial response to cigarette smoking in normal subjects and patients with coronary disease. Circulation 23 : 365- 369, 1961. 331 Chapter 12 Other Conditions 714-422 O-64-23 Contents RELATIONSHIP OF PEPTIC ULCER TO TOBACCO USE . Conclusion ...................... References ...................... TOBACCO AMBLYOPIA ................. Conclusion ...................... References ...................... SMOKIIXG A!XD CIRRHOSIS OF THE LIVER ...... Conclusion ...................... References ...................... MATERXR;AI, SMOKING AND INFAXT BIRTH WEIGHT . Conclusions .... ................ References ..... ................ SMOKING AWD ACCIDEKTS .............. Conclusion ..... ................ References ..... ................ List of Tables TABLE 1. Summary of methods used in retrospective and cross- bectional studies of peptic ulcer and smoking . . . TABLE 2. Summary of results of retrospective and cross-sectional studies of peptrc ulcer and smoking . . . . . . . TABLE 3. l- have concomitantI>- been introdurrd in the approach to the smokers. and the complex nature of the ht>alinp prn(`- ess, it is difficult to interpret this ohservation. 337 T\HI.K L.-Summary of methods used in retrospeclive and cross-sectional studies of peptic ulcer and smoking Controls Collection of data No. 5(lo I'ntirnts admitted b~twrn l!l13 nlrll l!l26. Only casrs with complctr smoking his- tory sclrctrd. 1. Retrospective review of rcmrds at Peter Bent Brigham Hospital. 2. Ulcer diagnosis probably wll established. `L'ro\$cll, (IX, I!134 .I1 M M&F I- ._ .- 1 .- io 3" .) Not stated 400 275 1. Interviewed by investigator. 2. Ulcer diagnosis confirmed by X-ray and/or surgery. l- Samplr of population in Columbus, Ohio. No details eivrn. Mills, (14) 18.V) Not stated I- Allihonc and Flint, (1) 19.58 l?n~lmd 107 Consecutive admissions to hos- pital of patients with gastric and duodenal hemorrha@z or verforation. 107 Matrhrd hy aw, sex, and time of admission from aeute general surgical cmcrprncy admissions. Patients and rontrols inter- virwcd hy same observer. Patients with non-olwr dis- wscs. Each case nlatched with 2 control patients of same sex. 5-yew agr group. and same type of place of residence. Male patients matchrd by social class. ists were examined and intrr- of all such men on thcsc lists, I- -l. Doll, Jones, and Pywtt 0, It)68 327 Oastric; 338 Duodenal. Ulcer patients in Doll and Hill Lung Cancer Study plus ,additional patients in Central Middlesex IIosvi- tal. , 143 ners' t 84L 1. Same interrieners and ques- tionnaire in ewes and r011tr0ls. 2. ~Jlccr diapnosis probably well established. -. 1,737 men aglxl rxl and over on 11 General Pratt viewed by these practitioners. Hepresents ah (Y% non-response due to death and/or untraced Edwards, McKcown. and Whitfield (ll), 193 Of 14.1 considered to have a peptic ulcer, 53 were con- Ar~ncd by X-ray. TABLE 2.-Summary of results of retrospective and cross-sectional studies of peptic ulcer and smoking Percent Non-smokers Percent Hcary Smokers or hvcragc hmo"nts USEd 1nrcstigator ________ CaSCS Controls -__- -___- Barnett (21 Total Gastric :: Duodenal 20 ; Trowel1 (18) Mills (14) Allihone and Flint (I) Doll et al. (71 3R .54 -1 carrtric Glstric F 5::; 66.8 4. 7 M F 10.6 1. 1 11. 1. 3 1 Duodenal Duodennl M 3. I 5.8 M 10.2 12. 7 F 53.7. 62.0 1 F 1 9 1. 9 Edwards ct al. (11) Perrcnt of Peptic Ulcer hy Smokine Catceory Never smokcd~......--.......-.-~..~...-....--....~~....~... 6.0 Formerly smoked. __ .._.. . . . . ..__......._._..-.......-.... ~.. 6.7 Cigarcttrs: Pipc and cigarettes . ..~. ..~ . . . . .._......._..-_..--...- .._._ 6. 5 TABLE 3.-Expected and observed deaths and mortality ratios for ulcer of stomach and duodenum ++ among current cigarette smokers, from seven prospective studies Investigator Type of Ulrcr Hammond and Horn (13)" . .._..._ ~... Duodenal . . .._. . . . . . Both types ~~..~..-_..~..~ Dorn (S)**.............~......-....-..- Gastric ~~._...-......-._.~ Duodenal _ ~. ._- _ Both types .._ -..~_.. Hammond (lZ)~~~.................-...- Gastric Both typcs.~ .._........_.. Doll and Hill (fi) .._. -_- . . . . . . ..__...... Both types . . .._... . . .~... Dunn et al., Occupational (9)....-.-... Roth types Dunn et al., Legion (lO).~~...- ._..._. ~. Both t)pcs ~.~...~~_.~...~ Best et al. (5) __._._._....._ ..__..__. ~. Iloth types _... ~~._~ _.... Yncludcs ISC numbers 5dn, 541. **The Hammond and IIorn data arc frcnn their original puhlishcd report; the other rcsult~ lisfcrl include more recent data as tahulatrd ior the Conunittcc (SW Ch:qacr 8). 339 Numerous investigators have studied the clinical and physiological effects of snloking on gastric motility and acid secretion in humans with and with- out peptic, ulcer. Great vaiiation of gastric motility and secretion was observed in response to cigarette smoking. Some workers found inhibition of gastric motilit>- (15, 17). Batterman (3 1 showed three types of response in normal subjects and ulcer patients after smoking one cigarette. In one-third no effect was observed. another third complete inhihition of motor activity for a time, and in the rest a period of hypermotility \vas followed by normal or subnormal activity. Smoking appears to produce y;ariable effects also on gastric secretion. In a few studies. gastric secretion increased, while in others no change was obserl-ed or there was depression of secretory activity (4, 15, 16, 17). Ad- ditional studies of the effect of smoking on gastric secretory activity and motility are needed to explain the biological meaning of the statistical asso- ciation between cigarette smoking and peptic ulcer. CONCLUSION Epidemiological studies indicate an association between cigarette smoking and peptic ulcer which is greater for gastric than for duodenal ulcer. REFERENCES 1. Allibone, A.. Flint. F. J. Bronchitis, aspirin, smoking and other factors in the etiology of peptic: ulcer. Lancet 2: 179-82, 1958. 2. Barnett, C. W. Tobacco smoking as a factor in the production of peptic ulcer and gastric neurosis. Boston Med Surg J 197: 457-9. 1927. 3. Batterman. R. C. The gestro-intestinal tract. In: Wynder, E. L. ed. The Biologic Effects of Tobacco. Boston, 1955. Chapter 5, p. 133-S). 4. Batterman. R. C.. Ehrenfeld. I. The influence of smoking upon the managrmcnt of the peptic ulcer l'atient. Gastroenterology 12: 575-85. 19 19. 5. Best. E. W. R.. Josie. G. H.: Walker. C. B. A Canadian study of mor- talit! in relation to smoking habits, a preliminary report. Canad J I'uh Health 52: Y-106: 1961. 0. Ihll. 1-L. llill. A. 1~. Lun g cancer and other causes of death in relation to ~mc~kin~: A r;rcond report on the mortality of British doctors. Rrit \It~l J 2: IOYl-21, 1956. 7. Doll. R.. Jones. F. A.. P!:;ott, F. Effect of smoking on the production and maintenance of gastric, and duodenal ulcers. Lancet 1: 657-62. 1'XX. 8. Darn. 14. F. Tobarco consumption and mortality from cancer and other disrases. Public Health Rep `i-1: 581-93, 1959. 9. Dunn, J. E., Linden, G., Breslow, L. Lung cancer mortality experience of men in certain occupations in California. Amer J Pub Health 50: 1475-87, 1960. 10. Dunn, J. E., Jr., Buell, P., Breslow, L. California State Department of Public Health, Special Report to the Surgeon General's Advisory Committee on Smoking and Health. 11. Edwards, F., McKeown, T., Whitfield, A. G. W. Association between smoking and disease in men over sixty. Lancet 1: 196-200, 1959. 12. Hammond, E. C. Special report to the Surgeon General's advisory Committee on Smoking and Health. 13. 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 JAMA 166: 1294-1308, 1958. 14. Mills, C. A. Tobacco smoking: Some hints of its biologic hazards. Ohio Med J 46: 1165-70, 1950. 15. Packard, R. S. Smoking and the alimentary tract: A review. Gut 1: 171-4, 1960. 16. Schnedorf, J. G., Ivy, A. C. The effect of tobacco smoking on the alimentary tract. JA1lIA 112: 898-903, 1939. IT. Steigmann. F., Dolehide, R. U., Keminski, L. Effects of smoking tobacco on gastric acidity and motility of hospital controls and pa- tients with peptic ulcer. Amer J Gastroent 22: 3991109, 1954. 18. Trowell, 0. A. The relation of tobacco smoking to the incidence of chronic duodenal ulcer. Lancet 1: 80%9. 1934. TOBACCO AMBLYOPIA For more than a century clinicians have attributed certain cases of amblyopia-dimness of vision unexplained by an organic lesion-to the use of tobacco. The distinguishing characteristic of tobacco amblyopia is a specific type of centrocecal scotoma. Since this disease was defined as a distinct clinical entity for the first time in 1930 (4)) the medical literature prior to this date is of relatively little value in the' critical evaluation of the problem (3 ). No epidemiological studies with adequate controls are available to establish for this disease a relative risk among smokers and nonsmokers. Clinical impressions associate tobacco amblyopia with pil)e and cigar smoking and very rarely with cigarette smoking. It has been suggested that this disease, which is now rare in the United States, occurs mainly in individuals with a nutritional deficiency which presumably renders the retina or optic nerve unduly sensitive to tobacco (1,5). Objective attempts at experimentation have been extremely rare and most of the literature is related to uncontrolled clinical impressions ( 2 I. CONCLUSION Tobacco amblyopia had been related to pipe and cigar smoking by clinical impressions. The association has not been substantiated by epidemiological or experimental studies. REFERENCES 1. Heaton, J. M.: McCormick. A. J. A., Freeman, A. G. Tobacco Amblyopia: A clinical manifestation of vitamin B-12 deficiency. Lancet 2: 286- 90, 1958. 2. Potts, A. M. Special report to the Surgeon General's Advisory Commit- tee on Smoking and Health. 3. Schwartz, J. T. Special report to the Surgeon General's Advisory Com- mittee on Smoking and Health. 4. Traquair, H. M. Toxic Amblyopia, including retro-bulbar neuritis. Trans Ophthal Sot U K 50: 351-85, 1930. 5. von Sallmann, L. Special report to the Surgeon General's Advisory Committee on Smoking and Health. SMOKING AND CIRRHOSIS OF THE LIVER Epidemiological studies have noted an association between cigarette smok- ing and mortality from cirrhosis of the liver. The mean mortality ratio for cirrhosis of the liver calculated from all prospective studies was 2.2 (Table 19, Chapter 8). The individual ratios in six of these studies ranged from 1.3 in the Canadian veterans study ( 1) to 4.0 in the California occupational study (3). The earliest prospective study, by Doll and Hill (2) reported no deaths from cirrhosis of the liker among non-smokers. The small amount of information on the biological effects of nicotine and tobacco smoke on the liver of experimental animals is contradictory (5). In several studies (4, 6, 7) it has been reported that heavy smokers also tend to drink alcoholic liquors excessively. It is well established that heav) consumption of alcohol and nutritional deficiencies are associated with in- creased mortality from cirrhosis of the liver. The increased death rate from cirrhosis among smokers may reflect the consumption of alcohol and asso- ciated nutritional deficiencies rather than the effect of cigarette smoking. CONCLUSION Increased mortality of smokers from cirrhosis of the liver has been shown in the prospective studies. The data are not sufficient to support a direct or causal association. 342 REFERENCES 1. Best, E. W. R., Josie, G. H., Walker, C. B. A Canadian study of mortality in relation to smoking habits. a preliminary report. Canad J Pub Health 52: 99-106, 1961. 2. Doll, R., Hill, A. B. Lung cancer and other causes of death in relation to smoking: A second report on the mortality of British doctors. Brit Med J 2: 1071-81, 1956. 3. Dunn, J. E., Linden, G.: Breslow, L. Lung cancer mortality experience of men in certain occupations in California. Amer J Pub Health 50: 1475-87, l%O. 4. Heath, C. W. Differences between smokers and non-smokers. AMh Arch Int Med 101: 377,1958. 5. Larson, P. S., Haag. H. B.. Silvette, H. Tobacco-experimental and clinical studies. A comprehensive account of the \\-orld literature. Balliere, Tindall S Cox. London. 1961. p. 319-321. 6. Matarazzo, J. D.. Saslow, G. Psychological and related charartcristi,cs of smokers and non-smokers. Psycho1 Bull 57: 493, 1960. 7. McArthur, C., Waldron, E., Dickinson, J. The psychology of smoking. J Abnorm Sot Psycho1 56: 267-275, 1958. MATERNAL SMOKING AND INF:lNT BIRTH WEIGHT Five retrospective and two prospective studies have shown an association between maternal smoking during pregnant)- and birth I+.eight of the infant (2, 4, 5, 6, 8, 9, 10). Women smoking during pregnancy have babies of lower birth weight than non-smokers of the same social class. They have also a significantly greater number of premature deliveries (defined as birth weight of 2,500 grams or less) than the non-smoking controls. While several studies reported a slightly c oreater neonatal death rate of the children of smokers 12. 5), others did not demonstrate any significant difference in the fetal and neonatal death rates of the two groups (6, 7). Studies on alterations of placental morphology and function as a response to smoking are insufficient for judgment. The difference in infant weight may be due to vasoconstriction of the placental blood vessels (1) or to toxic substances such as CO in the circulation of the smoker and fetus (3'1. It is not known whether the lower hirth weight of the infants of smokers has any clinical significance. In one of the groups studied ( 5 I there \+as less need for surgical induction of labor among mothers who smoked. CONCLUSIONS 1. Women who smoke cigarettes during pregnancy tend to have babies of lower birth weight. 2. Information is lacking on the mechanism by which this decrease in birth weight is produced. 3. It is not known whether this decrease in birth weight has any influ- ence on the biological fitness of the newborn. 343 REFERENCES 1. Essenherp, J. M., Schwind, J., Patras, A. The effects of nicotine and cigarette smoke on pregnant female albino rats and their offsprings. J Lab Clin Med 25: 708-17, 1940. 2. Frazier, T. M., Davis, G. H., Goldstein, H., Goldberg, I. D. Cigarette smoking and prematurity: a prospective study. Amer J Obstet Gynec 81: 98%96, 1961. 3. Haddon, W. Jr., Nesbitt, R. E. Smoking and pregnancy: carbon mon- oxide in hlood during gestation and at term. Obstet Gynec 18: 262-7, 1961. 4. Herriot, .4., Billewicz, W. F., Hytten, F. E. Cigarette smoking in preg- nanq. Lancet I : 771-3, 1962. 5. Lowe. C. R. Effect of mother's smoking habits on birth weights of their children. Brit Med J 2: 673-6, 1959. 6. O'Lane, J. M. Some fetal effects of maternal cigarette smoking. Obstet Gvnec 22: 181-4, 1963. 7. Save], L. E., Roth, E. Effects of smoking on fetal growth. Obstet Gynec 20: 313-6, 1962. 8. Simpson, W. J. A preliminary report on cigarette smoking and the in- cidence of prematurity. Amer J. Obstet Gyn'ec 73: 808-15. 1957. 9. Villumsen. A. L. Cigarette smoking and low birth weights: A prelimi- nary report. Ugeskr Lang 124: 630-1, 1962. 10. Yerushalmy. J, Statistical considerations and evaluation of epidemio- logical evidence. In: James. George and Rosenthal. Theodore eds. Tobacco and Health. Springfield. Ill. Charles C. Thomas. 1962. p. 208-30. SMOKIYG AND ACCIDENTS Smoking has heen aF.Gociated with a variety of accidents. Among these. fires hale the most obvious and important consequences. In a special stlld\ of home accident fatalities in 1952 through 1953. the Public Health Ser\-ic,e and the Sational Safet! Council reported that 231 I 18c; ) of 1.21-1. deaths from fires 6f known origin were due to cigarettes. cigars or ])ipel; I1 1. The Rletropolitan Life Insuranre Compan!- reported that of 352 deaths in 1956 and 19X anlo p their polir! holder5 from fires and burns with know11 causes in and about the home. ii7 I lC,(; ) were due to smoking 12 1. Of I)h!-sioloFic,al responsr%s rrlated to dri\ inp. snlokin= degrades detectah]!- only thr differralltial hrightne~,s threshold and thi, effect increases \\ith amount of c,tll,kirlg I 1 I. ThcL el)iclemiologic~al data a\ ailaljle on the effect- of srnokillg on traflir ac,r.itlerlts are inconcluiir-e. It has been she\\ n that a level of carhos!-hemogltrl,in of .5 percent- -a le\rl rvhich is not uncon1mon among heat v cigarette smokers i 3. 6) ~~deprca~es visual perception to as great an extent as anosia at KOOO to 10,090 feet altitude (4, 5). 344 CONCLUSION Smoking is associated with accidental deaths from fires in the home. No conclusive information is available on the effects of smoking on traffic accidents. REFERENCES 1. Home Accident Fatalities: 1952-1953. National Office of Vital Statistics,, U.S. Public Health Service, 1956. Mimeographed report. Table 12. 2. How fatal accidents occur in the home. Metrop Life Insur Statist Bull 4Q: 6-8, November-December, 1959. 3. Larson, P. S., Haag, H. B.. Silvette, H. Tobacco: Experimental and Clinical studies. Baltimore, Williams and Wilkins. 1961. Carhoxy- hemoglobin, p. 107-110. 4. McFarland, R. A., Moseley, A. L. Carbon monoxide in trucks and buses and information from other areas of research on carbon monoxide. altitude and cigarette smoking. In : Conference proceedings: Health, medical and drug factors in highway safety. National Academy of Sciences-National Research Council Publication 328, 1954. Sect. 4.17-4.33. 5. McFarland, R. A., Roughton, F. J. W., Halperin, M. H., Niven, J. I. The effects of carbon monoxide and altitude on visual thresholds. J Aviat Med 15: 6, 381-94, 1944. 6. Schrenk, H. H. Results of laboratory tests. Determination of concen- tration of carbon monoxide in blood. Pub Health Hull 278: 36-49, 1942. 345 Chapter 13 Characterization of the Tobacco Habit and Beneficial Effects of Tobacco Contents CHARACTERIZATION OF THE TOBACCO HABIT . . . . Nicotine . . . . . . . . . . . . . . . . . . . . . . . Distinction Between Drug Addiction and Drug Habituation . Tobacco Habit Characterized as Habituation . . . . . . . Relationship of Smoking to Use of Addicting Drugs . . . . Measures for Cure of Tobacco Habit . . . . . . . . . . . Summary. . . . . . . . . . . . . . . . . . . . . . . BENEFICIAL EFFECTS 01' TOBACCO . . . . . . . . . Summary. . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . Page 349 349 350 351 352 354 354 355 356 356 348 Chapter 13 CHARACTERIZATION OF THE TOBACCO HABIT NICOTINE Of the known chemical substances present in tobacco and tobacco smoke. only nicotine has been given serious pharmacological consideration in rela- tionship to the tobacco habit. Lewin (17) stated. "The decisive factor in the effects of tobacco, desired or undesired, is nicotine . . . and it matters little whether it passes directly into the organism or is smoked." Support for this statement is based mostly on rationalizations from smoking behavior. analoPT to other habits involving pharmacological agents and. to a much lesser extent, on established scientific fact. The latter may be summarized brielly as follows: 1. Only plants with active pharmacological principles have been employed habitually by large populations over long periods; e.g., tobacco (nicotine) ; coffee, tea, and cocoa (caffeine) ; betel nut morsel (arecoline) ; marihuana (cannibinols) ; khat (pseudoephedrine) ; opium ( morphine) ; coca leaves (cocaine) ; and others (see Lewin, 17). 2. Denicotinized tobacco has not found general public acceptance as a substitute (16, pp. 531-532). 3. Chewing tobacco and using snuff, although providing oral gratification, also furnish nicotine for absorption to produce systemic effects (34). 4. Many but not all smokers can detect a reduction in nicotine content of cigarettes (9) . 5. The administration of nicotine mimics the subjective effects of smoking (13). In uncontrolled experiments Johnston administered nicotine hypodermically, intravenously, or orally to smokers and non-smokers. Non- smokers found the effects "queer," whereas many smokers, including John- ston himself, claimed the subjective effects to be identical to those obtained by inhaling cigarette smoke and found that the urge to smoke was greatly reduced during nicotine administration. In spite of the anecdotal nature of most of this information, the facts are that nicotine is present in tobacco in significant amounts, is absorbed readily from all routes of administration, and exerts detectable pharmacological effects on many organs and structures including the nervous system. The classical pharmacological characterization of nicotine-cellular stimulation followed by depression which is noted in isolated tissue and organ systems- has been invoked to explain the widely differing subjective responses of smokers, many of whom describe the effects as stimulating ("smoking relieves the depression of the spirits"), while others obtain a soothing and tranquiliz- ing effect (16, p. 533). Wilder (33) summarized the literature by noting ". . . observations that cigarette smoking obviously serves a dual purpose: it will mostly pick US UP 349 when we are tired or depressed and will relax and sedate us when we are tense and excited." In order to ascribe such biphasic effects solely to the direct action of nicotine it would be necessary to discount psychological re- sponses and alterations in mood from all other types of stimuli associated with smoking or the use of tobacco, an obvious impossibility. Although Knapp and Domino (15) have shown nicotine in small amounts to exert potent arousal effects in the electroencephalogram in animals, this evidence is difficult to interpret as it relates to smoking in man. A consensus among modern authors (27) appears to be that smoking, and presumably nicotine, exert a predominantly tranquilizing and relaxing effect. The act of smoking is of such complexity that the difficulties associated with objective analysis of whether smoking induces pleasure by creating euphoria or by relieving dysphoria renders objective analysis virtually impossible. The anecdotal literature suggests that sedation plays a more important subjective role in pipe and cigar smoking than with cigarette smoking. Since most pipe and cigar smokers do not inhale, this suggests that bronchial and pulmonary irritation from cigarette smoke after inhaling may contribute an important sensory input to the central nervous system which could modify the sedative effects of nicotine. so that some individuals would describe the experience as stimulating rather than sedative. Heavy cigarette smokers who inhale often describe the act as a pleasant sensory experience which constitutes for them one of the prime drives to continue to smoke. Freedman (10) used the term "pulmonary erotism." Mulhall ( 19 ) and Robicsek i 22) have commented on this concept. An interesting psychoanalytical approach by Jonas (14)) which postulates central nervous system counterirritation to constant pul- monary irritation from smoking, is based upon this concept. If pulmonary irritation is a pleasure factor it probably is not related to nicotine alone but to other irritants in smoke and could represent a non-specific increase in afferent sensory discharge from the whole respiratory tract. A gap in knowl- edge exists in this area. F ur th ermore, until carefully controlled experiments with nicotine are conducted in man, the literature will be burdened further with anecdote and hypothesis rather than fact. DISTINCTION BETWEEN DRUG ADDICTION AND DRUG HABITUATION Smokers and users of tobacco in other forms usually develop some degree of dependence upon the practice. some to the point where significant emo- tional disturbances occur if they are deprived of its use. The evidence indi- cates this dependence to be psychogenic in origin. In medical and scientific terminology the practice should be labeled habituation to distinguish it clearly from addichm, since the biological effects of tobacco, like coffee and other caffeine-containing beverages: betel morsel chewing and the like, are not comparable to those produced by morphine, alcohol, barbiturates, and many other potent addicting drugs. In fact. to make this distinction, the World Health Organization Expert Committee on Drugs Liable to Produce Addiction (35) created the following definitions which are accepted throughout the wcrld as the basis for control of potentially dangerous drugs. 350