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248 Comments on H. R. 4957 -- Proposed S. 1929 "Comprehensive Smoking Prevention Education Act of 1981" Domingo M..Aviado, M. D. President, Atmospheric Health Sciences, Inc. P. 0. Box 307, Short Hills, New Jersey 07078 Adjunct Professor of Pharmacology University of Medicine and Dentistry of New Jersey Consultant and Former Member of the Clean Air Scientific Advisory Committee, Environmental Protection Agency The proposed bill, H.R. 4957, states that "Congress finds that ... smoking is the major cause of chronic obstructive lung diseases such as emphysema" (Section 2 (2)]. The statement paraphrases one sentence in the introduction of the Chapter on non-neoplastic bronchopulmonary diseases of the 1979 Report of the Surgeon General on Smoking and Health, which reads 'cigarette smoking is the most important cause" (1). a careful examination of the chapter raises questions about the validity of that statement because of the complexity of the causation of chronic obstructive lung diseases in general and of pulmonary emphysema in particular. Although there are a multiplicity of suspected pathogenic mechanisms and of etiologic factors, the Surgeon General's Report refers only to those relating to cigarette smoking with an incidental discussion of outdoor pollution, indoor pollution, infections Lung Diseases, March 5, 1982 249 and familial or genetic predisposit. submission intends to discuss investigations and those of others c that smoking is either "the major cz cause" of chronic obstructive lunc reasons are as follows: (a) Animal experiments have pulmonary emphysema from 1 cigarette smoke, although successfully done so for su oxides and other inhalants. (b) Functional and histopath humans show uncertain and in cigarette smoking that do not relationship between ciga chronic obstructive lung dise (c) Epidemiologic stud association of chronic obs several risk factors, such as and indoor pollution, a

Lung Diseases, March 5, 1982 Page 2 t g I n s s e e d a f 1 I s and familial or genetic predisposition. The author of this submission intends to discuss his personal research investigations and those of others questioning the conclusion that smoking is either "the major cause" or "the most important cause" of chronic obstructive lung diseases. Briefly, his reasons are as follows: (a) Animal experiments have failed to reproduce pulmonary emphysema from long-term exposure to cigarette smoke, although this has been successfully done so for sulfur oxides, nitrogen oxides and other inhalants. (b) Functional and histopathological studies in humans show uncertain and inconsistent effects of cigarette smoking that do not support the -causal relationship between cigarette smoking and chronic obstructive lung disease. (c) Epidemiologic studies suggest the association of chronic obstructive disease with several risk factors, such as levels of outdoor and indoor pollution, alcohol consumption,

250 Lung Diseases, March 5, 1982 Page 3 occurrence of previous infections, familial predisposition and genetic susceptibility. A. Exverimental Animal Studies on Pulmonarv Emohvsema. From 1948 to 1977, the author and his colleagues conducted smoking-related research at the University of Pennsylvania School of Medicine where he was a Professor of Pharmacology. The nature of this investigation was guided in part by comments in the 1964 Surgeon General's Report on Smokina and Health which suggested the need for definitive data on the relationship between cigarette smoking and auInb,,:rww ;?.I. ...;J.thcuVtb p.5-ght A° the z.uxhor's publications were mentioned in the 1967, . 1968, 1969 and 1971 Surgeon General's Reports, the coverage was brief and out of co ntext (3-6). Over thirty of his articles on cigarette smoking and over a hundred articles published in the 1970's on related subjects were not mentioned.The government writers cannot be criticized entirely, however, because they have been examining only "Smoking and Health" rather than conducting a global review of all suspected risk factors of chronic obstructive lung diseases. Yet this isolated emphasis on one Y Lung Diseases, March 5, 1982 251 factor has limited the usefulness of scientific documents. a. ExDerimental Pulmonary E 1981 report of the Surgeon Genera no•published studies that acceptably that the development of emphysem. smoking. ... One study in which dog. through chronic tracheotomies re- emphysema [Auerbach, Hammond, Rirr (1967)). The lesions were not con( not been confirmed by others.• The initial series of studie: and his colleagues dealt with the e: cbgs (6-17). These studies failed tcl cigarette smoke caused pulmonary e not surprising that there has been nc study reporting the development of should be noted that the single questioned in the 1981 Surgec h'-ghlighted in earlier Reports (inclu been responsible for the impressio an established cause of pulmonary emp 95-077 0-82--17

I 251 Lung Diseases, March 5, 1982 Page 4 factor has limited the usefulness of Surgeon General Re?crts as scientific documents. a. ExDerimental Pulmonarv Emnhvsema in the Doc. The 1981 report of the Surgeon General (7) states that "there are no•published studies that acceptably show in an animal model that the development of emphysema is induced by cigarette smoking. ... One study in which dogs received smoke directly through chronic tracheotomies reported the development of emphysema (Auerbach, Hammond, Kirman, Garfinkel and Stout (1967)]. The lesions were not conclusive and the results have not been confirmed by others.' The initial series of studies conducted by the author and his colleagues dealt with the effects of cigarette smoke in dogs (8-17). These studies failed to show that inhalation of cigarette smoke caused pulmonary emphysema. It is therefore not surprising that there has been no confirmation of a single study reporting the development of experimental emphysema. It should be noted that the single positive study, although questioned in the 1981 Surgeon General's Report, was highlighted in earlier Reports (including 1979) and may have been responsible for the impression that cigarette smoking is an established cause of pulmonary emphysema. 95-077 0-82--17

Lung Diseases, March 5, 1982 Page 5 b. Exoerimental ?ulmonarv Emai:vsema in the Rat. In 1967, the author and his collaborators developed an experimental model for producing pu lmonary emphysema in rats (18). Unlike other models reported permitted functional measurements in addition histopathologic observations signifying pulmonary emphysema. The exposure of animals to cigarette smoke did not cause pulmonary emphysema (19). Other investigators have also used the same model and have confirmed essentially its acceptability for the study of pulmonary emphysema. c. Exaerimental Pulmonary Emohvsema in the Mouse. In 1974, the author and his collaborators developed a technique for measuring lung function in the mouse that could not be performed previously (20-22). Chronic exposure to cigarette smoke simulating the dosage of smokers did not cause pulmonary changes signifying emphysema. It is a disappointment to the author that the only study comparing high and low nicotine cigarettes on pulmonary function of mice was overlooked in the 1981 Report of the Surgeon General entitled The Changing Cigarette (7). It is possible that the study was ignored .because of the unexpected observations that the lungs seem to adapt to repeated exposure of cigarette smoke. Lung Diseases, March 5, 1982 253 d. ComDarative Studies with ~ rats and mice are useful experimental toxicity of air pollutants. Animals expc products of fuel combustion show imF pathological lesions characteristic of pL bronchitis. The studies are describe Criteria Documents that have " beer Environmental Protection Agency on o2 oxidants (23), nitrogen oxides (24) ar particulates (25). This author questic cigarette smoke "the major use" of pu: primary air pollutants have been shc emphysema in experimental animals, and G cigarette smoking has not. B. Human Studies on Pulmonary : Histopathologic Changes in Cigare• The Chapter on chronic obstructi, 1979. Surgeon General's Report (pages defining the terms chronic bronchitis an( For each definition, there is a structural or pathological alterations si

253 Lung Diseases, March 5, 1982 Page 6 d. Comoarative Studies with Air Pollutants. Dogs, rats and mice are useful experimental models for the study of toxicity of air pollutants. Animals exposed to low levels of products of fuel combustion show impaired lung function and pathological lesions characteristic of pulmonary emphysema and bronchitis. The studies are described in the new series of Criteria Documents that have been prepared by the Environmental Protection Agency on ozone and photochemical oxidants (23), nitrogen oxides (24) and sulfur oxides with particulates (25). This author questions the logic of finding cigarette smoke "the major use" of pulmonary emphysema when primary air pollutants have been shown to cause pulmonary emphysema in experimental animals, and with the same models, cigarette smoking has not. B. Human Studies on Pulmonary Function and Histoaatholoaic Changes in Cigarette Smokers. The Chapter on chronic obstructive lung diseases in the 1979. Surgeon General's Report (pages 6-7 to 6-52) starts by defining the terms chronic bronchitis and pulmonary emphysema. For each definition,• there is a positive statement on structural or pathological alterations such as hypertrophy of

255 mucous secreting apparatus and epithelial metaplasia as well as more classic histopathological evidence of inflammation for bronchitis; and abnormal enlargement of the air spaces distal to the terminal nonrespiratory bronchiole accompanied by destructive changes of the alveolar walls for emphysema. These definitions are completely ignored in the changes and enzymatic contents are regarded as pathological or adverse signs of chronic bronchitis or pulmonary emphysema. The definition of adverse and nonadverse effects has been vigorously debated in recent years by the National Academy of Sciences (26) and the World Health Organization (27, 28). The National Academy of Sciences defines adverse effects as responses that are irreversible; the reversible effects are regarded as adaptation or defense mechanism of the lung in response to the inhalant. The predominant opinion is to establish irreversibility as a prerequisite •to the definition of an adverse effect. In terms of tobacco use, most of the functional effects described in the 1979 Surgeon General's Report are reversible, not adverse in nature, and are indicative of physiological and biochemical adaptation of the, lungs. . - I Lung Diseases, March 5, 1982 a. ResDiratorv svmotoms and chanaes. The section on the natu: obstructive lung disease (pages 6-10 tc qualifying statement that pathologic specific and sensitive parameters r emphysema or chronic bronchitis. It "the relationship of early respiratory development of lung disease is unclear studies demonstrating that individuals w small airways function are at greater r unavailable". Respiratory symptoms and : tests therefore are not necessarily effects or pathological processes. -- That smokers show abnormal lung ": uniformly observed. In addition to a si the Surgeon General's Report, t-here are f during the late 1970's that were not cite b. Clearance Mechanisms. mucociliary transport (page 6-32) i selective citations from the literatu aspects of cigarette smoking, and or, results. Articles that show smoking clearance in humans have been omitted.

255 Lung Diseases, March 5, 1982 Page 8 a. Resoiratorv svira*_o^.s and oulmonarv functional chanaes. The section on the natural history of chronic obstructive lung disease (pages 6-10 to 6-11) ends with the qualifying statement that pathological data are the most specific and sensitive parameters relating to pulmonary emphysema or chronic bronchitis. It is further stated that "the relationship of early respiratory symptoms to subsequent development of lung disease is unclear' and that "longitudinal studies demonstrating that individuals with abnormal tests of small airways function are at greater risk for lung disease are unavailabie'. Respiratory symptoms and small airway functional tests therefore are not necessarily indicators of adverse effects or pathological processes. That smokers show abnormal lung -function-has not been uniformly observed. In addition to a single study mentioned in the Surgeon General's Report, tZiere are five other publications during the late 1970's that were not cited (29-33). b. Clearance Mechanisms. The discussion of mucociliary transport (page 6-32) is another example of selective citations from the literature showing negative aspects of cigarette smoking, and omission of conflicting results. Articles that show smoking accelerates bronchial clearance in humans have been omitted. The studies of Albert q I 0

256 Lung Diseases, March 5, 1982 Page 9 et al on accelerated clearance in donkeys have been cited, but their article on human clearance stimulation in smokers (34) has been omitted, thus giving readers the impression that the phenomenon has only been seen in donkeys. Camner, who pioneered in clearance studies in man and whose technique has been adapted by many clinical pulmonary physiologists, has been overlooked. The basic concept that has evolved from Camner's work is that adrenergic stimulation increases mucociliary transport (35), an effect to be expected from cigarette smoking. Patients with predominant pulmonary emphysema but withcut chronic bronchitis are reported to have no impairment of mucociliary transport (36). Therefore, it is unlikely that smoking, by accelerating airway clearance, would contribute to the paEfiogenesis bf emyphysema. c. Proteolytic lung damace. The hypothesis that cigarette smoke causes a protease-antiprotease imbalance and in turn potentially leads to pulmonary emphysema is based on a group of selected observations. There is no discussion as to why the hypothesis has not been generally accepted. Turino (37), the first researcher to show that proteolytic enzymes_ influence the pulmonary mechanics in vivo, has noted flaws in the hypothesis that emphysema is caused by the imbalance of protease and antiprotease: 257 Lung Diseases, March 5, 1982 "An inconsistency for the prim alteration as a mechanism fo- emphysema has been a failu: alterations in elastin contei human emphysema. Morphologica: have appeared disrupted and c data from human lungs (Johnson Pierce and Eocott 1960; anc with the exception of that of F (1958), have shown no reduc elastin content by gravimetric The above coaiments can be reinforced by of Kuhn et al (38) that hamsters intratracheally and developing emphy elastin content. Even lung fluid smokers and nonsmokers showed no di. enzyme content (38a). C. Ecidemiologic StudiE Increased mortality from pulr chronic bronchitis among smokers cor.

257 Lung Diseases, March 5, 1982 Page 10 "An inconsistency for the primary role of elastin alteration as a mechanism for inducing pulnonary emphysema has been a failure to demonstrate alterations in elastin content or composition in human emphysema. Morphologically, elastin fibers have appeared disrupted and diminished, yet most data from human lungs (Johnson and Andres 1970; Pierce and Hocott 1960; and Pierce et al 1961) with the exception of that of Briscoe and Loring (1958), have shown no reduction of parenchymal elastin content by gravimetric techniques." The above comments can be reinforced by the 1976 observations of Ruhn et al (38) that hamsters treated with elastase intratracheally and developing emphysema also show normal elastin content. Even lung fluid samples collected from smokers and nonsmokers showed no difference in proteolytic enzyme content (38a). C. Epidemiologic Studies. Increased mortality from pulmonary emphysema and/or chronic bronchitis among smokers compared to nonsmokers is

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