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259 suggested by seven prospective studies summarized in the 1979 Report (page 6-10). However, these studies are far from being consistent and tend to suggest that many risk factors including cigarette smoking need to be considered in studying the etiology of chronic obstructive lung disease. a. Air Pollution. The role of air pollution as a risk factor in chronic obstructive lung disease has been the subject of several publications not cited in the 1979 Report. Studies in Tucson, Arizona (39) and in Busselton, Australia (40) showed that an urban environment may contribute to thp normal increase in closing volume with age and to the incidence England than in the United States has been cited as a cause of the lower ventilatory functional measurements among British males (41). b. Socioeconomic Status. The presented in the 1979 Report (page 6-39) by Higgins of residents of Tecumseh, Michigan. prevalence of chronic bronchitis for various groups ranged from 12.3 for professionals and managers to 30.0 for laborers. An uncited 1977 survey by Lebowitz (42) is more accurate because the diagnosis of emphysema and chronic bronchitis was confirmed by medical examination. His most t: Lung Diseases, March 5, 1982 important conclusion is that smoke: incidence of chronic obstructive 1; or exsmokers when the adults were grc and educational backgrounds. E inversely related to prevalence of even after controlling for sex, age a C. A1Dhalantitryosin def statement in the 1979 Report tha deficiency have the onset of symptc lung disease probably •abbreviated selected citations. Two publications accurately quoted. Chan-Yueng et only examine subjects with mild defic with severe antitrypsin deficiency with smoking. 1Cidokoro et al (43) co: subjects with severe deficiency tha- and cigarette smoking, influence the : d. Other genetic and familic discussion in the .1979 Report increasing evidence of familial obstructive lung disease. The stuc of lung disease conducted by Cohen et there is a familial factor unrelate

259 Lung Diseases, March 5, 1982 Page '_2 important conclusion is that smokers do not have~ a higher incidence of chronic obstructive lung diseases than nonsmokers or exsmokers when the adults were grouped according to income and educational backgrounds. Education and income were inversely related to prevalence of obstructive lung diseases even after controlling for sex, age and smoking. c. Alohalantitrynsirr deficiency. The summary L 2 1 t 0 c t statement in the 1979 Report that individuals with severe deficiency have the onset of symptomatic chronic obstructive lung disease probably "abbreviated by smoking" was based on selected citations. Two publications in Chapter 6 were not accurately quoted. Chan-Yueng et al and Morse et al did not only examine subjects with mild deficiency but also individuals with severe antitrypsin deficiency which did not deteriorate with smoking. Kidokoro et al (43) concluded in their study of subjects with severe deficiency that "variables other than age and cigarette smoking, influence the severity of emphysema." d. Other aenetic and familial factors. The limited discussion in the .1979 Report needs expansion due to increasing evidence of familial aggregation of chronic obstructive lung disease. The studies of familial orevalence of lung disease conducted by Cohen et al clearly indicate that there is a familial factor unrelated to cigarette smoking and

260 Lung Diseases, March 5, 1982 Page 13 antitrypsin deficiency that is involved in chronic obstructive pulmonary disease (44). Familial aggregation of chronic bronchitis independent of cigarette smoking, sex, respiratory illness history, residence in common household, geographical distribution and antitrypsin variants has also been reported by Tager et al (45) in 1978. There has also been revived interest in the concept of a congenital or developmental etiology of pulmonary emphysema (46). 'Additional research directed at the basic cause of emphysema may lead to the identification of additional genetic factors that result in developmental abnormalities leading to adult pulmonary emphysema. e. Infections. A recent report on the Tecumseh study reveals that acute infection may play an independent role in the pathogenesis of chronic respiratory disease (47). For serologic infection rates for three viruses and M. Dneumoniae in males, the incidence of bronchitis is higher for nonsmokers (23%) than in smokers (8.8%). Lebowitz and Burrows (48) arrived at a similar conclusion, i.e. acute respiratory illness is a major risk factor in the etiology of chronic obstructive •lung disease. f. Alcohol consumption. Since 1977, there have been:~'s:• -several reports that consumption of alcohol is associated with ° 263 Lung Diseases, March 5, 1982 higher incidence of chronic bronc.`. study, Lebowitz (52) has cor.cl independent risk factor for chroni There are also earlier observa rats causes pulmonary cellula immunologic reaction, and increasE (53-55). D. CONCLQDING It is the opinion of the au cigarette smoking is not "th obstructive lung diseases, such as opinion is based on the author's interpretation of literature on.the additional research is needed different risk factors for chronic important in a causal sense. ~ ~.J . ~ ~ ~ ~ ~ .

261 Lung Diseases, March 5, 1982 ?age 1.4 higher incidence of chronic bronc=itis (49-51). _*n the Tucsor. ttudy, Lebowitz (52) has concluded that alcoholism is an independent risk factor for chronic obstructive luns disease. There are also earlier observations that alcohol feeding in rats causes pulmonary cellular changes, depression of iamunologic reaction, and increased susceptibility to infection (53-55 ). : . D. CONCLUDING REMARKS It is the opinion of the author of this submission that cigarette smoking is not "the major cause" of chronic obstructive lung diseases, such as pulmonary emphysema. This opinion is based on the author's own research studies and his interpretation of literature on the subject. It is clear that additional research is needed to determine which of the different risk factors for chronic obstructive lung disease are important in a causal sense. _ .

262 Lung Diseases, March 5, 1982 Page 15 E. BI3LIOGRaPH° 3. Report of the Surgeon General: The Health Consequences of Smoking, 1967, 117. 4. Report of the Surgeon General: The Health Consecuences of Smoking 1968 Suoolement, 76. 5. Report of the Surgeon General: The Health Consecuences " of Smoking, 1969 Supplement, 50. 6. Report of the Surgeon General: The Health Consecuences of Smoking, 1971, 135-230. 7. Report of the Surgeon General: The Health Consequences of Smoking The Chancinc Cigarette, 1981, 142. 8. Aviado DM, Samanek M: Bronchopulmonary effects of tobacco and related substances. I. Bronchoconstrictor and bronchodilation: influence of lung denervation. Arch Environ Health , 1965, 11, 141-151. 9. Samanek M, Aviado DM: Bronchopulmonary effects of tobacco and related substances. II. Bronchial arterial injections of nicotine and histamine. Arch Environ Health, 1965, 11, 152-159. 10. Samanek M, Aviado DM, Peskin GW: Bronchopulmonary effects of tobacco and related substances. III. Axon reflexes elicited from the visceral pleura. Arch Environ Health, 1965, 11, 160-166.. 11. Samanek M, Aviado DM: Bronchopulmonary effects of tobacco ~ and related substances. IV. Bronchial vascular and ~ bronchomotor responses; their suggested defense . function. Arch ' Environ Health, 1965, 11, 167-176. 263 Lung Diseases, March 5, 1982 histamine during inhalation anoxemia in the heart-lung Arch Environ Health, 1966, 12, 13. Folle LE, Samanek M, Aviado D. of tobacco and related substa. effects of cigarette smoke a: Health, 1966, 12, 712-716. 14. Samanek M, Aviado DM: Cardiooi and related substances. III. of cigarette smoke and nicoti 1966, 12, 717-724. :5. Aviado DM, Palacek F: Pulmona related substances. I. resistance in the anestheti Health, 1967, 15, 187-193. 16. Palacek F, Aviado DM: Pulmonar 17. 18. 19. 20. related substances. II. Comp smoke, nicotine and histamine Arch Environ Health, 1967, 15, Palacek F, Oskoui M, Aviado tobacco and related substan: synthesis of histamine in vario: Health, 1967, 15, 204-213. Palacek F, Palecekova M, Ac immature rats: condition constriction and papain. Arch F 332-342. Ito H, Aviado DM: Pulmonarv smoke: experimental inductior. in rats. Arch Environ Health, 1 Aviado DM, Watanabe T: Function on the lung following inhala constituents. I. High- and 1 mice. Toxicol Appl Pharmacol, 1 21. Watanabe T, Aviado DM: Function. 12. Aviado DM, Samanek M, Folle LE: Cardiopulmonary effects on the lung following inhala of tobacco and related substances. I. The release of constituents. II. Skatole, Ac_

263 Lung Diseases, March 5, 1982 Page 16 histamine during inhalation of cigarette smoke and anoxemia in the heart-lung and intact dog preparation. Arch Environ Health, 1966, 12, 605-711. 13. Folle LE, Samanek M, Aviado DM: Cardiopulmonary effects of tobacco and related substances. II. Coronary vascular effects of cigarette smoke and nicotine. Arch Environ Health, 1966, 12, 712-716. 14. Samanek M, Aviado DM: Cardioou Lmonary effects of tobacco and related substances. III. Pulmonary vascular effects of cigarette smoke and nicotine. Arch Environ Health, 1966, 12, 717-724. 15. Aviado OM, Palacek F: Pulmonary effect of tobacco and related substances. I. Pulmonary compliance and resistance in the anesthetized dog. Arch Environ Health, 1967, 15, 187-193. 16. Palacek F, Aviado DM: Pulmonary effects of tobacco and related substances. II. Comparative effects of cigarette smoke, nicotine and histamine on the anesthetized cat. Arch Environ Health, 1967, 15, 194-203. 17. Palacek F, Oskoui M, Aviado DM: Pulmonary effects of tobacco and related substances. III. Inhibition of synthesis of histamine in various species. Arch Environ Health, 1967, 15, 204-213. 18. Palacek F, Palecekova M, Aviado DM: Emphysema in immature rats: condition produced by tracheal constriction and papain. Arch Environ Health, 1967, 15, 332-342. 19. Ito H, Aviado DM: Pulmonary emphysema and cigarette 20. smoke: experimental induction and use of bronchodilators in rats. Arch Environ Health, 1968, 16, 865-869. Aviado DM, Watanabe T: Functional and biochemical effects on the lung following inhalation of cigarette smoke and constituents. I. High- and low-nicotine cigarettes in mice. Toxicol Apol Pharmacol, 1974, 30, 185-200. u• Watanabe T, Aviado DM: Functional and biochemical effects on the lung following inhalation of cigarette smoke and constituents. II. Skatole, Acrolein, and Acetaldehyde. I

264 Lung Diseases, March 5, 1982 Page 17 Toxicol Anol Pharmacol, 1974, 30, 201-209. 22. Ito H, Watanabe T, Shore SR, Aviado DM: Functional and biochemical effects on the lung following inhalation of cigarette smoke and its constituents. III. Serum antitrypsin and bronchomotor responses in rats. Toxicol 23. 24. 25. IV, Health Effects. 1980. Anol Pharmacol, 1975, 35, 403-411. II. S. Environmental Protection Agency: Air Quality Criteria for ozone and other ohotochemical oxidants. Vol. I and II, 1978, EPA-600/8-78-004. U. S. Environmental Protection Agency: Air oualitv criteria for oxides of nitroaer.. Vol I to IV. 1978. U. S. Environmental Protection Agency: Air cualitv criteria for oarticulate matter and sulfur oxides. Vol. 26. National Academy of Sciences: PrinciDles for evaluatinc chemicals in the environment. Washington, 1975, 124-126. 27. World Health Organization: Princioles and methods for evaluatina the toxicitv of chemicals. Part I. Environmental Health Criteria 6. Geneva, 1978, 31-33. 28. World Health Organization: Methods used in establishinc oermissible levels in occuoational exDosure to harmful agents. Technical Report Series 601, Geneva, 1977, 33-36. 29. Robinson M, Lonsdale D, Macrae K, Guz A: The flow/volume curve breathing air or helium-oxygen: an analysis of bias, dispersion, and correlation in 10 indices and a comparison of non-smokers with asymptomatic smokers. Bull Eur Physiooathol Reso, 1977, 13, 96P-97P. 30. Chinn DJ, Lee - WR: Within- and between- subject variability of indices from the closing volume and flow volume traces. Bull Eur Phvsiooath ResD, 1977, 13, 789-802. 31. Williams DE, Miller DE, Taylor WE: Pulmonary function studies in healthy Pakistani adults. Thorax, 1978, 33, 243-249. 265 Lung Diseases, March 5, 1982 32. Senpanen A: Comparison of diffe evaluation of lung function nonsmokers. Ann Clin Res, 1977, 33. 34. 35.. Wicht CL, De Kock MA, Van Wvk Kc PG, Vad De Wal BW, Ver epidemiological study of the dif syndrome. S Afr Med J Suool, 19 Albert RE, Peterson HT Jr. Short-term , effects of cigare clearance i n humans. Arch En 361-367. Camner P, Strandberg K, mucociliary transport by adr Environ Health, 1976, 3, 79-82. 36. Mossberg B, Philipson R,".Cam clearance in patients with alphal-antitrypsin deficiency. 59, 1-7. 37. 3a. 38a. 39. 40. Chrzanowski PJ, Turino GM: concepts and questions. Bull 13, 471-477. Kuhn C, Yu SY, Chraplyvy M, Linc induction of emphysema with connective tissue. Lab Invest, : Harris JO, Olsen GN, Castle JR, t proteolytic enzyme activity macrophages and blood leukc nonsmokers. Am Rev Reso Dis, 19" Lebowitz MD, Burrows B: Tucsor obstructive lung disease. II. factors on the prevalence of c Am J Enidmiol, 1975 „ 102, 153-1E Woolcock AJ, Leeder SR, Armstronc Cullen KJ: The single breath : urban smokers and non-smokers. R-eso, 1978, 14, 127-135.

265 Lung Diseases, March 5, 1982 Page 18 m 32. Seppanen A: Comparison of different kinds of tests in tc:e evaluation of lung function among healthy smokers and nonsmokers. Ann C1in Res, 1977, 9, 275-280. 33. Wicht CL, De Kock MA, Van Wyk Kotze TJ, Pienaar GJ, Stevn PG, Vad De Wal B'ri, Vermaak JC, Weich EirH: An epidemiological study of the diffuse obstructive pulmonary syndrome. S Afr Med J SuDC1, 1977, 1-15. 34. Albert RE, Peterson HT Jr., Bohing DE, Lipomann ML: Short-term effects of cigarette smoking on bronchial clearance in humans. Arch Environ Health, 1975, 30, 361-367. 35.. Camner P, Strandberg F, Philipson K: increased mucociliary transport by adrenergic stimulation Arch Environ Health, 1976, 3, 79-82. 36. Mossberg B, Philipson K, Camner P: Tracheobronchial clearance in patients with emphysema associated with alphal-antitrypsin deficiency. Scand J Res Dis, 1978, 59, 1-7. 37. Chrzanowski PJ, Turino GM: Experimental emphysema concepts and questions. Bull Eur Phvsiooath Reso, 1977, 13, 471-477. 38. Kuhn C, Yu SY, Chraplyvy M, Linder HE, Senior RM: The induction of emphysema with elastase. II. Changes in connective tissue. Lab Invest, 1976, 34, 372-380. 38a. Harris JO, Olsen GN, Castle JR, Maloney AS: Comparison of proteolytic enzyme activity in pulmonary alveolar macrophages and blood leukocytes in smokers and nonsmokers. Am Rev Resn Dis, 1975, 111, 579-586. 39. Lebowitz MD, Burrows B: Tucsorr epidemiologic study of obstructive lung disease. II. Effects of in-migration factors on the prevalence of obstructive lung disease. 40. urban smokers and non-smokers. Bull Eur Phvsionath Resp, 1978, 14, 127-135. Am J Epidmiol, 1975 „ 102, 153-163. Woolcock AJ, Leeder SR, Armstrong JG, Peat JK, Coman M, Cullen KJ: The single breath nitrogen tests in rural and 0 n

266 Lung Diseases, March 5, 1982 Page 19 41. Holland WW, Gilerdale S: The epidemioiogy of chronic bronchitis. Commun Health, 1975, 6, 2737-2778. '42. Lebowitz MD: The relationship of socio-environmental factors to the prevalence of obstructive lung diseases and other chronic conditions. J Chron Dis, 1977, 30, 599-611. 43. Ridokoro Y, Kravis TC, Moser KM, Taylor JC, Crawford IP: Relationship of leukocyte elastase concentration to: severity of emphysema in homozygous alpha -antitrypsin-deficient persons. Am Rev Reso Dis, 1977, 115, 793-803. 44. Cohen BE, Chase GA: Familial aggregation of chronic, obstructive pulmonary disease. Epidemiologic and genetic approaches. Lung Biol Health Dis. 1978, 11 „ 201-255. 45. Tager I, Tishler PV, Rosner B, Speizer FR, Litt M::. Studies of the familial aggregation of chronic bronchitis and obstructive airways disease. int J EDidemiol, 1978, 7, 55-62. 46. Rilburn RH: New clues for the emphysemas. Editorial. Am J Med, 1975, 58, 591-600. 47. Monto AS, Ross HW: The Tecumseh study of respiratory illness. X. Relation of acute infections to smoking, lung function and chronic symptoms. Am J£Didemiol, 1978, 107, 57-64. 48. Lebowitz MD,- Burrow B: The relationship of acute respiratory illness history to the prevalence and incidence of obstructive lung disorders. Am J Epidemiol, 1977, 105, 544-554. 49. Saric M, Lucic-Palaic S, Horton RJM: Chronic non-specific lung disease and alcohol consumption. Environ Res, 1977, 14, 14-21. 50. Heinemann 30: Alcohol and the lung. A brief review. J Med , 1977, 63, 81-85. 51. Emirgil C, Sobol BJ: Pulmonary function in former alcoholics. Chest, 19977, 72, 45-51. 267 Lung Diseases, March 5, 1982 52. Lebowitz MD: Respiratory sy:apt alcohol consumption and smok 106, 248. 53. Rossi MA: Alcohol-induced F Exoerientia, 1975, 31, 573-575. 54. Palmer DL: Alcohol cc immunocompetence. Laryngoscor 13-17. 55. Hurley DL: Infectious comF • Postgrad Med, 1977, 6, 160-162. 95-077 0-82-18

267 Lung Diseases, March 5, 1982 Page 20 52. Lebowitz MD: Respiratory synptoms, and disease related to alcohol consumption and ssoking. Am J Boidemiol, 1977, 106, 248. 53. Rossi MA: Alcohol-induced pulmonary changes in rats. ExDerientia, 1975, 31, 573-575. 54. Palmer DL: Alcohol consumption and cellular immunocompetence. Larynaoscofle Supol, 1978, 88 Part 2, 13-17. 55. Hurley DL: Infectious complications of alcoholism. ' Postgrad Med, 1977, 6, 160-162. 95--077 0-82-18