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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