The final study (51) ag ain used 20 young medical persons divided alnong 10 smokers and 10 nonsmokers. The mean pulmonary com- pliance was significantly greater for the nonsmokers than for the smokers. Since cigarette smokers have a chronically elevated carboxy- hemoglobin level, usually greater than 2 percent and occasionally exceeding 10 percent, a study (19) was performed ha.ving nonsmokers inhale enough carbon monoxide to raise their carboxyhemoglobin levels to the range seen in a control group of cigarette smokers. This lnaneuver caused the development, in the study group of nonsmokers, of an increased oxygen debt with exercise and a reduced pulmonary diffusing capacity at rest. These changes after carbon monoxide in- halat.ion were similar to those found without carbon monoxide in- halst,ion when comparing cigarette smokers to nonsmokers. (Further data concerning smoking and carbon monoxide is presented and dis- cussed in the chapter on cardiovascular diseases in this report.) Findings from various studies relating smoking to pulmonary func- tion are less consistent for certain criteria of measurement than from t,hose relating smoking to respiratory symptoms. They are, however, consistent in that they all report some form of diminished pulmonary function among cigarette smokers, even when relatively young smokers were studied. This is true of the studies outlined here as well as others that have not been included (18, @, 56,58,81). The usual measure- ment found to be lower among smokers is the l-second forced expira- tory volume (FEV l.O) either alone or as a ratio of the vital capacity (FEVJVC). Vital capacity alone was generally not found to be associated with smoking but diminished flow rates, such as FR,a, FRso and the peak expiratory flow (PEF), were often observed. In these studies, distinct quantitative ,relationships were not observed between impairment of pulmonary function and the number of cigarettes smoked daily. RELATION OF SMOKING TO HEREDITY OR TO CON- STITUTIONAL FACTORS Although various surveys and studies consistently show an associa- tion between smoking and respiratory symptoms and mortality from respiratory disease, there have been objections to interpreting this relation as causal. Arguments have been made that smokers and non- smokers may differ in some respects, perhaps biological, that are relevant to the occurrence of disease. Others have suggested that pre- 101 dispositions to smoking and respiratory disease may have a common genetic basis. One method of trying to estimate the importance of heredity and constitutional factors is to study the effect of tobacco smoking among pairs of twins, particularly identical (monozygotic) twins. If, when one twin in each pair of monozygotic and dizygotic twins is a smoker and the other is not, an excess morbidity does not appear among the smoking twins, it would seem that the exposure to tobacco smoke was insufficient to result in greater morbidity. Cederlof and his associates (26, 17) in Sweden studied smoking in relation to morbidity from various causes among 12,889 pairs of twins. Replies to a mailed ques- tionnaire dealing with smoking habits and residential ,history were received from 10,947 pairs (85 percent). Replies to a second question- naire with medical questions were received from both members of 9,319 pairs-another response of about 85 percent. A subject, who answered "Yes" to the question, "DO you redarly have a cough?" was *regarded as having "cough." If, when asked, "For how many consecutive months a year do you have a cough?," the subject checked more than 3 months, he ww regarded as having "bronchitis." If the group comprising only one of each twin pair (the fi? twin on the twin registry) is considered as a random population, the as- sociation observed between smoking and respiratory symptoms is given in table 11. TABLE 11 .-Prevdeme of "cough" and "bronchitie" among smokers and no-nemokere by eex and age Sex and birth year Men: 1886-95---_-__---_--_---. 1896-1905---------------. 1906-15----- __-- -- ------_ 1916-25- - - - - - - - - - -- -- - -- - Women: 17.7 15.5 15.0 13.8 1888-95___-__-____--_---- 25.0 1896-1905- ___- ___________ 18.0 1906-15------ _---_------_ 14.2 1916-25 ___________ - __-- -. 11.1 i - smoke2 Nonsmoker 17.8 6.6 5.5 3.5 8.7 7.0 5.5 3.8 7.4 6.7 6.3 4.9 8.3 8.0 4.8 2.9 -- 5.5 2.5 1.6 1.2 2.7 2.4 1.4 .6 SOUECE: Cedwlof# R., et d. (II). These findings are similar to those previously reported for various populations. These respiratory symptoms were then analyzed among twin pairs with discordant smoking habits, that is, one twin of the 102 pair never smoked and t.he other either had smoked or still smoked at the time of the survey. The findings are presented in table 12. TABLE 12.-Preualence of "cough" and "bronchit~" among smokers and nonsmokers in smoking-discordant twin pairs Cough BKOllChltis Twin8 Smoker Nonsmoker Smoker Nonmuoker Nsof Monozygotic: Men----------------- Women-- ___ _____ -___ Dizygotic: 14.6 7.7 6.6 1.1 274 13.6 7.6 3.0 2.3 264 Men----------------- 12.3 5.5 4.5 1.8 733 Women- _ _ _ _ _ _ _ _ _ _ _ _ _ 14.5 5.7 5.5 1.8 653 SCUECE: CeddOf, R., et 81. (17). This table shows that the prevalence of respiratory symptoms was much higher among the smokers in twin pairs than the nonsmokers. The authors concluded that this hypermorbidity "speaks in favor of a causal interpretation." In a further analysis of the data from monozygotic twin pairs with discordant smoking habits, Cederlof and his coworkers (15) divided the series into a "low risk group" in which the nonsmoking twin did not have "cough," and a "high risk group" in which .the non- smoking twin had "cough." The two groups of smoking co-twins corresponding to the two nonsmoking risk groups had higher than ex- pected prevalence rates. The observed value for smokers in the low risk group, however, was only half that expected for nonsmokers in the high risk group. This suggests that for some i7w%~~~& the genetic influence may be more important than smoking in the devel- opment of cough. But, because any high risk group is only a small part of the population, the total genetic effect will be much smaller than the effect of tobacco. Lundman (53) made a detailed study of twin pairs in Sweden. Of 247 twin pairs asked to participate, 196 pairs were examined (80 percent), of which 92 were monozygotic and 104 dizygotic. All par- ticipants were interviewed and examined without knowledge of their smoking habits. All twin pairs were concordant with respect to urban/ rural residence and discordant in smoking habits. After estimation of lifetime exposure to smoking, 30 pairs were considered concordant, thus limiting analysis to 77 monozygotic and 89 dizygotic pairs. The smokers in both groups of twins had significantly higher frequencies of some respiratory symptoms, such as persistent cough and morning phlegm, but not of other symptoms such as dyspnea, "day cough", and "day phlegm". Smokers also had "an increase in the unevenness of 211-394 o-07---8 103 ventilation measured by nitrogen washout, and an increase in aim-my resistance as measured by dynamic spirometry." Two recent studies (17,58) of populations of identical and fraternal twins show that for some individuals in the populations studied a genetic element appears to be of some importance for the development of cough. However, the effect of smoking was clearly shown to be much more important for most ofthe individuals in the total popula- tions studied. One study (53) also clearly showed that smoking twins more often had reduced ventilatory function tests as compared to their respective nonsmoking twins. These data provide strong confirmatory evidence that cigarette smoking can cause chronic bronchitis; however, no inferences with respect to pulmonary emphysema can be based on these data. Studies such as these, when specifically designed to provide additional in- formation about pulmonary function, may be helpful in evaluating the relationship between cigarette smoking and pulmonary emphysema. PATHOLOGY STUDIES Very few papers relating. the gross and microscopic appearance of the trachea, bronchi, and lung parenchyma to tobacco smoking have appeared in the last 3 years. Auerbach and his coworkers have con- tinued their analysis of bronchial tissues taken f&m 758 subjects (7) and lung parenchymal tissue taken from 1,340 men (8). They pub- lished a report (9) correlating findings in the bronchial ltree with findings in the lung parenchyma of 267 men who were included in both previous studies. They reported a high correlation between fibrosis in the lung parenchyma and different abnormalities of the bronchial epithelium, such as hyperactive glands, increased number of cell rows in the ciliated epithelium, and increased frequency of cells with atypical nuclei. As reported previously by and summarized in the Surgeon General's 1964 Report, more frequent and more severe ab- normalities were observed among cigarette smokers. Sections of the bronchial tree among ex-smokers were more like those of nonsmokers while fibrotic changes in the lung parenchyma were more like those observed among smokers. Changes in the bronchial tree similar to those described by Auer- bath and his coworkers were reported in a series of 100 random adult autopsies by Hernandez and Anderson and their associates (38). They reported a higher frequency of abnormal epithelial hyperplasia, goblet cell hyperplasia, round cell infiltration, congestion, and edema in 104 bronchi from smokers than nonsmokers. There was, however, no evi- dence of more bronchial gland hyperplasia. These same workers also studied macroscopic sections of single lungs from 211 routine autopsies on adults (I, 8). Analysis was limited to 165 of these cases on whom smoking histories were obtained, usually from relatives. Without knowing the identity of the subject or his smoking history, each lung section was classified on a sca.le from 0 to 6 by severity of emphysematous changes. The type of emphysema was also described as panlobular (changes throughout the secondary pul- monary lobules), centrilobular (changes located around the centers of the secondary lobules), or mixed. The severity of emphysematous changes was about the same for men and women, but for each sex, changes were more severe among smokers than nonsmokers, as seen in t.able 13. TABLE 13.~Mean severity of emphysema clastS$ed by mamosedions by sex and smoking history Mean de Numbfu %Z- -- Men: Women : Smokers _______ _ 96 2. 3 Smokers-- ______ 18 2.1 Nonsmokers- _ _ - 11 1. 1 Nonsmokers---- 40 .3 SOUSCE: Andemm, A. E.. Jr., et al. (8. Perhaps more important was the observat.ion that the type of pa- thology seemed strongly related to smoking (9). Of 48 subjects whose lung macrosections were classified as having mainly centrilobular emphysema, 45 persons had been smokers. Ih contrast, the 62 subjects judged to have panlobular emphysema were divided in t.he expected proportions, 33 smokers and 24 nonsmokers. Petty and his associates (61) also studied postmortem Endings in the lungs of a series of 253 men over age 40, unselected for smoking, who died in two Denver hospitals during a 6-year period from 1959 to 1965. The presence and severity of emphysema was estimated and graded in four categories, from 0 to 3 + . During the last 3 years of t.he study bronchi of 179 men were examined for mucous gland hyper- plasia. Independent of the morphological studies, smoking histories were obtained for each person, apparently `by questioning relatives, although this is not clearly stated. Men were grouped according to the amount of cigarettes smoked during their lifet.imes by calculating pack-years of smoking. (One pack-year is the number of cigarettes smoked if a person smoked one pack per day for a year. A pack-year could also mean smoking two packs a day for 6 months, one-half pack a day for 2 years, or any equivalent amount.) 105 Of the group of 179 individuals, 54 had mucous gland hyperplasia. Of the 54 persons involved, 51 had smoked more than 20 pack-years, and the remaining three were essentially nonsmokers. In contrast, approximately one-third of the 125 men in whom mucous gland hyper- plasia was not found were essentially nonsmokers. When the total group of 253 men was studied for evidence of pulmonary emphysema, 114 were found to have moderate or severe pulmonary emphysema. Of the 114, 98 had smoked more than 20 pack-years. The other six, who essentially were nonsmokers, had either asthma, previous tuberculosis, deep-seated lung infections or other demonstrable relationships with previous pulmonary disease. In contrast, approximately one-third of the remaining 139 men, who had either very mild or no emphysema, were essentially nonsmokers. Only one study has been found in which the frequency of abnormal bronchial epithelial cells in living persons is compared with smoking history. Robbins (63) studied a group of 103 college students between the ages of 17 and 24. Of the 45 who had never smoked, atypical epithelial cells were found in six (13 percent). This compares to 26 (45 percent) of the 58 students who had been smoking 10 or more cigarettes daily for 1 to 8 years. Cytological examination was done without knowledge of whether the specimen came from a smoker or nonsmoker. ANIMAL EXPERIMENTS Results of two experimental studies relating smoke inhalation to lung parenchymal changes in dogs have been published in the last 3 years. Hernandez and his coworkers (39) used 23 healthy greyhounds retired from racing. Eight served as controls and 15 were exposed to high concentrations of cigarette smoke ,for 30-45 minutes twice daily in wooden inhalation chambers. Seven animals were exposed for ap- proximately 5 months and the remaining eight were sacrificed after almost 15 months of smoke inhalation. Disruption of the lung paren- chyma was assessed macroscopically by comparison with preselected standards graded in severity from 0 to 3. Assessment was made without knowledge of the source of the lung specimen. Lung damage among dogs that were exposed longer showed significantly greater disruption of the lung parenchyma. Auerbach and his associates (6,8) tracheostomized 10 adult .beagles and, in an attempt to approximate human smoking more closely, exposed them to cigarette smoke through the tracheostomy tube. Five dogs died during this experiment and the remaining five were sacrificed after approximately 14 months of exposure. Other beagles 106 mere kept as controls; two had tracheostomy openings. These control do@ were sacrificed at the time the last five smoking dogs were sacri- ficed. Lungs of the dogs exposed to cigarette smoke showed microscop- ic&y the presence of dilated air spaces, especially beneath the pleural surface. Here the alveolar septa showed a fibrous thickening of the \valls with areas of rupture and dilated air sacs. Padlike attachments to alveolar septa were found. These zones of connective tissue sur- rounding dilated air sacs were also visible macroscopically as white areas on the lung surface. There was no t.hickening of the walls of small arteries and arterioles within the lung. The lungs of the control dogs were normal in appearance with none of these changes. These :tbnormalities approximate `but are not fully concordant with some of the typical pathological tidings in human emphysema. This ex- periment does indicate that inhaled cigarette smoke apparently can damage the pulmonary parenchyma of dogs. Other findings (6) as yet unpublished, indicate t.hat abnormalities of the bronchial epi- thebum resulted that approximate many of lthe histopathologic flnd- ings of human chronic bronchitis. Rockey et al. (64) have noted that cigarette smoke produces bron- chial and parenchymal changes in dogs that approximate some of the histopathologic findings found in human smokers who have chronic bronchitis and/or pulmonary emphysema. Mouzakis (57) has noted similar changes in rabbits, and in dogs exposed to cigarette smoke through tracheostomies. Researchers carrying out pathological studies have consistently re- ported epithelial hyperplasia of the bronchial tree associated with smoking. They have also reported that fibrosis and emphysematous changes in the lung parenchyma, although observed among non- smokers, occur much more frequently among men and women who have histories of smoking. Changes in the lung parenchyma, approximating some of the changes noted in human emphysema, have also been pro duced experimentally in dogs by exposure to cigarette smoke. CILIATOXIC EFFECTS OF CIGARETTE SMOKE The toxic effect of tobacco smoke on the ciliary defense mechanism of the respiratory system has ,been confirmed by additional experi- mental studies (9, 10, 13, 93, 24, $36, $7, 46, 47, 77, 78) which seek to determine more exactly the mode of action of the ciliatoxic agents contained in tobacco smoke. As yet, hydrogen cyanide and acrolein appear to have the greateet ciliatoxic effects of the agents that have been identified in the gaseous phase of tobacco smoke, although for- 107 maldehyde, crotonaldehyde, formic acid, acetic acid, proprionic acid, and some phenols are also ciliatoxic (25, & 48, 73, 77, 79). Further information may be obtained from a special symposium on ciliary activity held in 1965 (48). A recent study ($22) suggests that oxidative enzymes such as adenoeine triphosphatase, apparently important to ciliary activity, may be adversely affected by cigarette smoke. Addi- tional research is necessary before precise conclusions can be stated concerning which, if any, of the identified ciliatoxic agents contained in tobacco smoke are most damaging to the human respiratory system. OTHER FACTORS ASSOCIATED WITH CHRONIC BRON- CHITIS OR EMPHYSEMA OR BOTH It is not the purpose of this report to discuss all the factors that may play a role in the development of chronic bronchitis and em- physema. It is important, however, to recognize that these condi- tions do exist among people who do not smoke and that many smokers apparently escape all signs of aflliction. It is also important to recog- nize that other factors have been associated with the development of chronic respiratory disease, or chronic bronchitis and emphysema, as we have defined chronic respiratory disease. We must be concerned with the multiple etiology of .biological processes. One factor already cited is the role of hereditary or constitutional factors in the develop- ment of respiratory symptoms, either operating alone or in conjunc- tion with other factors such as smoking. Aside from the personal pulmonary pollution inherent in smok- ing, occupational exposures (a wider form of pollution) and exposure to various pollutants in the atmosphere have both been shown Ito influ- ence the prevalence of respiratory signs and symptoms. Studies made in some specific industries-for example, pulp mill workers in New England (S$?), coal miners in West Virginia (31), and gold miners in South Africa (66, 67)-ha ve shown an increased frequency of respiratory symptoms or of diminished pulmonary function among men exposed ito certain dusts and fumes. These studies indicate that cigarette smoking is generally more important than the occupational exposures in producing respiratory disease in the workers. These studies also suggest that cigarette smok- ing may interact with some occupational exposures to produce even greater deleterious effects. Cigarette smokers outnumber by far the workers subjected to unusual environmental exposures. Also, there has been a general improvement in many occupational environments, in the continuing effort to remove or reduce the exposure to specific indus- t,rial air pollutants. 108 Climatic and meteorologic variations involved with differences in quantity and quality of specific air pollutants make investigations of atmospheric pollution very complex. There have been many studies, however, attempting to examine the association of air pollution with chronic respiratory disease. Often comparisons of mortality and mor- bidity are made between urban and rural areas, assuming a difference in air pollution but not measuring it directly. Wicken (75) in his retrospective study of mortality from chronic bronchitis in Northern Ireland found higher mortality rates with greater degrees of urbaniza- tion. Air pollution was suggested as a factor. Holland and Reid (43) compared the prevalence of respiratory symptoms, sputum production, and lung fun&ion in London and in three county towns. The London men had more and severer symptoms, produced more sputum and had poorer lung function test results. Smoking habits were shown to be closely related to respiratory dii- turbance but urban-rural differences in these habits could not explain the greater frequency of respiratory symptoms in London. A Canadian study reported by Bates et al. (11) indicates that among four cities studied, the city with the lowest amount of industrial dust- fall and sulfur dioxide levels had the study group wit.h the lowest prevalence of chronic bronchitis. Preliminary results also indicate that this group had the lowest decline of pulmonary function. The groups of males in each city were approximately concordant for other factors, including the influence of cigarette smoking. Ferris and associates (3, 4, 33) studied air pollution and its effect on respiratory symptoms and functions in two separate towns-chilli- wack, British Columbia, and Berlin, N.H. After standardizing the data for age and cigarette smoking, they observed a correlation be- tween symptoms of chronic bronchitis and the level of air pollution as measured by the mean sulfation rate. They also found pulmonary function tests to be better in Chilliwack when controlled for smoking habits and age. This may be .associated with the lower level of air pol- lution in Chilliwack. Studies of populations of twins are especially valuable in assessing the influences of constitutional factors and environmental considera- tions, such as cigarette smoking and air pollution. Cederlof (14)) using interview techniques on a large population of twins in Sweden, found that compared with smoking, air pollution was of secondary im- portance in causing respiratory symptoms indicative of chronic bron- chitis and/or emphysema. In both the monozygotic and dixygotic twins, again using the co-twin control method, individual variations suggested that the propensity to develop cough from smoking also may well be pertinent with regard to air pollution but that, when considering the total population, individual variations appear to be of minor influence (15). 109 Other studies (55,76) have suggested a relation between air pollu- tion and symptoms or mortality from chronic respiratory disease, although they were not controlled for differences in cigarette smoking. The contributions of air pollution, industrial pollution, and personal pollution have been summarized recently by Higgins (~$0). He con- cluded, as we must from the available evidence, that all "* * * three types of pollution are associated with increased amounts of respiratory disease and respiratory disability. " All the recent evidence, however, does not alter the conclusion in the Surgeon General's 1964 Report that "the dominant association in the United States is between cigarette smoking and chronic respiratory disease." ADDITIONAL CONSIDERATIONS REGARDING SMOKING AND EBXPEYSEMA This crucial question must be answered affirmatively before an infer- ence can be made that smoking directly causes pulmonary emphysema : Does inhaled tobacco smoke have a direct toxic effect on the alveolar tissue in the lung parenchyma which is important in the pathogenesis of pulmonary emphysema? At present, it cannot Abe answered. If future evidence supports such a finding of a direct toxic effect, we will have the missing link to the present chain of evidence showing a strong association between cigarette smoking and many cases of pulmonary emphysema and an inference of oausation may validly be made. The available evidence that follows has only indirect pertinence to the question. The experiments of the Auerbach, Hernandez, and Rockey groups support the thesis that there is a direct toxic effect of cigarette smoke on the pulmonary tissue. Possibly this direct toxic effect, if proven to exist, contributes to the rupture and fibrosis of the alveolar tissue. However, in these animal studies there were also some differences from the typical anatomic findings of human pulmonary emphysema. Surfactant, a fluid substance lining the alveolar cell walls, appar- ently is important for maintaining tissue surface tension and thus the spatial configuration of the alveolar walls (65). Zn vitro abnormalities have been noted in surfactant as a result of cigarette smoke (B, 74). Alveolar macrophages (specialized cells that incorporate and remove foreign material from the affected lung area) are reportedly damaged in vitro by cigarette smoke (35). Abnormalities of the alveolar macro- phages and lipophages with inhalation of cigarette smoke are also reported (54) in cytological studies of human bronchial washings, apparently reflecting damage in viva. Studies (@,50,51,63) of the pulmonary function of relatively young smokersand nonsmokers also indicate that abnormalities of pulmonary diffusion noted in cigarette smokers, may, in part, be related to a direct toxic effect of cigarette smoke. However, some of these abnormal- ities are related to the unevenness of pulmonary ventilation associated 110 with airway abnormalities. Damage to the pulmonary arterial capil- laries has frequently been noted on autopsy examination of smokers. This damage may be a direct effect'of smoke inhalation and, function- ally, may impair the vascular perfusion of the alveolar tissue, thus leading to further deficiencies in alveolar tissue function. The possibility must also be considered that the accelerated in vitro thromhus formation (discussed in the cardiovascular chapter of this report), associated with cigarette smoking, may be the basis for mul- tiple small thromboses in the pulmonary arterial capillaries. Additional research is also needed to answer questions concerning other factors that may account for the apparent increased suscepti- bility of some individuals to cigarette smoke, such that they have a marked excess mortality from this disease. Genetic and constitutional factors may be important to some individuals' development of pulmo- JJaq emphysema, just as these factors appear to be important in the development of cough in smokers, as reported by Cederlof and his associates (1.4, 15,16, 17). An increased susceptibility of some indi- viduals to the emphysema associated with cigarette smoking has been suggested, but not proved, by the occasional reports of "familial" emphysema (42, 529. Other probable causes of pulmonary emphysema, such as allergic or infectious disease processes, alsoshould be investigated for interactions with and without smoking. Other apparent causes of pulmonary emphysema, such as possibly atmospheric air pollution, may be inter- `acting with cigarette smoking to produce effects even more deleterious to human health. The observation that other probable causes of pulmonary emphy- sema may exist should not detract from the strong relationship that has been shown to exist between cigarette smoking and pulmonary emphysema. Further investigations of the mechanisms of injury to the cellular and subcellular structures of the lung tissue are recommended (34). 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CHAPTER 3 Smoking and Cancer CONTENTS General Chemical and Experimental Data on Carcinogenesis and Tobacco Smoke ________-_ - __________ - ____ -- _______ In Vi.t~o Cellular Changes by Tobacco Smoke ______ _ _ __ _ In V&o Tumor Formation by Tobacco Smoke- _ _ _ _ _ - _ _ - Tumor-Promoting Agents in Tobacco Products---------- LungCancer_------------------------------------------ MortalityData_------------------------------------ Histopathology of Lung Tumors--- _ _ _ _ _ _ ____ ______ ___ Experimental Pulmonary Carcinogenesis- - _ _ _ _ _ _ _ _ _ _ _ _ _ Additional Evidence Concerning Experimental Carcino- genesis-__---------------------------------------- Cancer of the Buccal Cavity and Pharynx (Lip, Mouth, Throat) _____________ - ______ - _________________________ CanceroftheLarynx__-_-------------------------------- Cancer of theEsophagus ____ ---_-__-_-_--___-__- _______ -_ Cancer of the Urinary Bladder------ _____________ -- _______ CanceroftheStomach____-_----------------------------- Cancer of the Pancreas _________ - ____ -_-__- ____ --___- ____ Cited References ________________ -_- ____ -- _____________ -- Supplemental References------------------- ____ -- ______ -_ 127 129 129 130 131 131 140 144 144 145 148 149 153 157 158 161 167 125