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Activitas Nervosa Superior (Praha) 8(l) : 6&67, 1966. 85 CHAPTER 2 Smoking and Chronic Bronchopulmonary Diseases (Non-neoplastic) CONTENTS Introduction _____ - ____ ---_-- ____________ --- _____ - _______ Chronic Bronchopulmonary Disease Mortality-------------- Chronic Bronchopulmonary Disease Morbidity- _ _ _ _ _ _ _ _ _ _ _ _ Studies Relating Smoking to Respiratory Symptoms- -- _ _ Studies Relating Smoking to Pulmonary Function- - _ _ - - - _ Relation of Smoking to Heredity or to Constitutional Factors-- Pat,hologyStudies----- ____ - ___________ ---- ____ -_--__---_ AnimalExperiments ____ --_-- __________ ----- _____ - _______ CiliatoxicEffectsofCigaretteSmoke ____ ----- _____ --___--_ Other Factors Associated with Chronic Bronchitis or Em- physemaorBoth_------..-- __________ -----___-_-___---_ Additional Considerations Regarding Smoking and Em- physema---_____--__----------------------------- CYted References--- __________ --__--_- ___________________ Sqplemental References------------------ _______ - _____ -_ PW 89 90 96 96 99 101 104 106 107 108 110 111 117 2-U-384 O-W-7 87 INTRODUCTION PURWSE OF THIS RE~RT This report reviews additional pertinent data relative to smoking and chronic bronchopulmonary diseases-specifically chronic bron- &tis and pulmonary emphysema. The reader is referred to the Surgeon General's 1964 Report (68) and recent textbooks for background information on the chemistry of tobacco smoke, the metabolism and toxicity of specific components of tobacco smoke, the physics of its retention in the air passages and the lungs, and the mechanics of pulmonary function. DBFINITIONS The scope of this chapter will be limited to emphysema and chronic bronchitis and it may be useful to present definitions of both terms. There have been many definitions of chronic bronchitis and emphy- sema. Those used in *he Surgeon General's 1964 Report had been pro- posed by the American Thoracic Society in 1962 (37). With the in- creasing public health interest in chronic bronchopulmonary disease, attempts have been made to develop precise definitions to ca.tegorize these diseases and to isolate them satisfactorily from other pulmonary conditions. ,4 task force sponsored by the Chronic Respiratory Dis- eases Control Program of the Public Health `Service and the National Tuberculosis Association deliberated this together with related prob- lems for a week in October 1966. They adopted the following definitions (71) : "Chronic bronchitis is a clinical disorder characterized by excessive mucous secretion in the bronchial tree. It is manifested by chronic or recurrent productive cough. The diagnosis of chronic bronchitis can be made only if other bronchopulmonary or cardiac disorders are ex- cluded a~ the cause for t.hese symptoms. The predominant pathologic cllange is hypertrophy and hyperplasia of the mucous secreting glands in the trachea and bronchi. Pulmonary emphysema is an anatomic alteration of the lung characterized by destruction of alveolar walls a;ccompanied by abnor- mal enlargement of the air spaces distal to t.he terminal, nonrespira- tory bronchiole." These definitions will be used to describe chronic bronchitis and emphysema as understood in the present report. They are being used 89 to emphasize the lack of progress in defining the two conditions for purposes of differentiating them from other diseases of the lung. I&,& erence may be made to the Surgeon General's 1964 Report where near- ly identical definitions will be found. SInability to distinguish between chronic bronchitis and emphym has hampered medical research and exchange of information. The P.H.S.-N.T.A. task force report states further : "Although patients having only chronic bronchitis tend to have more cqugh and sputum than do those having only pulmonary emphy- sema, the array of symptoms, physical findings, and pulmonary physiologic abnormalities are similar in ,both diseases. "Chronic bronchitis and emphysema coexist in many patients * * $9' This statement may help to explain some of the di&ulties encoun- tered by research workers in studying these diseases and why the re- searchers are limited to describing symptoms and signs observed in &e populations under investigation. It may also explain why it is di.& cult to distinguish these conditions in the present report which seeks to record the research findings related to smoking and chronic respira- tory disease published since the Surgeon General's 1964 Report. Re- search findings on both diseases are not considered separately in this report but are grouped in population studies, pathology studies, and animal experiments. Additional considerations pertinent to pul- monary emphysema nre then provided. CHRONIC BRONCHOPULMONARY DISEASE MORTALITY l Mortality from chronic bronchopulmonary diseases has continued the upward trend well established at the time of publication of the conclusions cited in the Surgeon General's 1964 Report. Deaths in the United St,ates from emphysema or chronic bronchitis or both have risen steadily from about 3,000 in 1950 to more than 20,000 in 1964, as can be seen in table 1. TABLE l.-Mort&ty from emphysema ad/or chronic bronchitis (IN2 Year Number of deaths -- -- 1964 _________ 20,208 1963 --------- 19,443 1962--------- 15,915 1961_________ 13,302 1960 _________ 12,426 - YW NUmbI of deaths Year Number of desths .- 1959 ---__ -___ 10,433 1954- - - - - - - - - 4,877 1958- _ _ _ _ _ _ _ _ 9,328 1953- - - - - - - - - 4,657 1957-- -- ___ __ 8, 136 1952 --------_ 3,846 1956- - - - - - _ - _ 6,535 1951- _ - -- - --- 3,660 1955--------- 5,616 1950- - - - - - - - _ 3,157 SOWCB: Vltaf Statfstl*l of the Unftad States. 1esCrli (70). ' AlI death rates throughout this chapter are per 100,000 population, unless otherwise indicated. 90 The increase and aging of the population during the same period does not account for this rise. Age-adjusted mortality rates for emphy- sema without mention of chronic bronchitis increased about ten times for men, from 1.3 per 100,000 in $950 to 12.6 in 1964. A similar, al- though perhaps somewhat less drama.tic, increase occurred among 1vomen, from 0.2 per 100,000 in 1950 to 1.6 in 1964. Death rates from chronic bronchitis rose less precipitously, doubling during the same period (69,70). How much of this increase is the result of improved diagnosis of these diseases and how much the result of a true change in mortality patterns cannot be determined at the present time. Asso- ciations have been demonstrated between these conditions and smoking. POPULAlTON 6TDolES Included in this broad category are investigations that collected information from ma group or groups of persons either by a series of questions, by some form of physical examination, or by a review of recorded data such as hospital records and death certificates. PRosPzcTrvz STuDIzs In the Surgeon General's 1964 Report, Endings from seven prospec- tive studies were presented. Additional data have .been reported from four of these investigations in the past 3 years. Information relevant to smoking and chronic respiratory disease will be summarized here. The study of mortality among policyholders of U.S. Government Life Insurance policies available to persons who served in the Armed Forces between 1917 and 1940 was initiated in 1952. Almost all the 293,658 policyholders were white males. Recently Kahn (&) pub- lished a report that included all deaths from July 1954 through De- cember 1962, a period of S+$ years. The relation of cigarette smoking to death from bronchitis and emphysema is presented by mortality ratios in table 2 and by specific risk of mortality in table 2A. Given the definitions previously cited, t.hese tables also illustrate the difficulties in separating these diseases. The first row of table 2 gives combined mortality ratios and the next two rows give the same data in an attempt to delineate the specific dis- eases. Mortality ratios are given by the number of cigarettes smoked per day at the time the men were enrolled in the study. Mortality from these diseases is much higher among cigarette smokers than among those who never smoked and rises with the number of ciga- rettes smoked daily. The ratios are much higher for emphysema alone than for chronic bronchitis with or without mention of emphysema. A similar study of veterans was begun in Canada in 1955. Answered questionnaires were returned by nearly 78,000 men whose subsequent mortality for a period of 6 years was recently analyzed by Best and 91 his associates (I$). Deaths from chronic bronchitis and emphysema have been summarized in table 3 which gives mortality ratios by the number of cigarettes smoked each day. Here, again, the mortality is much higher among smokers .and is directly related to the number of cigarettes smoked. The mortality ratios reported for both diseases combined are similar to those reported for the U.S. Veterans study. TABLE 2.-Age-adjuhd mortulity ratios for current smokers of &ret& only, by number of c@aret&s smoked o?u$y Bronchitis or emphysema or both (500-502, 527.1)-----------------------_--_-____ Bronchitis with or without emphysema (500-502) _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ Emphysema (527.1) ________ -__- _________ I 1.0 1.0 3.6 4.5 1.0 5.3 14.0 4.6 10.0 SOUXCE: U.S. Vetemu study (4). 11.8 18.2 4.6 8.3 17.0 25.3 TABLE 2A.-Age-specijic a7112ual probabilities of death per lOO,ooO 1 person-years, for current smokers of cigarettes only Chronic bronchitis and/or emphysema: Age 55 to 64- _ _ _____ ___ __ Age 65 to74------------- Chronic bronchitis: Age 55 to 64 ___________ -_ Age 65 to 74- _ __ ___ __ ___ _ Emphysema without bronchitis: Age55to64 _____________ Age65to74 ____ -__-___-_ - I cigarettea smoked per day at entrance to study h8_lomI ormwr smoked 2 10 1 5 1 5 l-g 12 32 30 39 29 66 100 141 322 113 5 15 5 22 27 78 5 5 4 30 46 23 ? 52 26 34 25 111 276 90 le20 21-29 &lla%&d 1 Annual probabilititv of death at each single year of age were comb&d into IO-year age gxunp8 by m weights proportional to the distribution of the U.S. male population in 1080. Not shown if less thm 50 person-years of observation at any single year of age in the l&year interval. SOUBCE: U.S. Veterans study (44). When ,the two diseases are separated, the ratios for emphysema in the Canadian study are similar to those for chronic bronchitis in the U.S. study, and the ratios for chronic bronchitis are similar to those attributed to emphysema in the United States. This illustrates the 92 problems of definition and one of the difhculties of direct comparison between studies, especially dPhen different countries are involved. TABLE &-Age-adjusted mOd4dity ratios for 8?nokers of cigarettes only by number of cigarettes smoked daily c8aSe Of death Non- 1-Q lo-20 21+ smokers ---- Bronchitis or emphysema or both _______ - ______ 1.0 6.11 10.0' 10.4' Bronchitis with or without emphysema (500-502)- 1.0 7.0 13.7 14.6 Emphysema (527.1)--- __ _ __ _ __ ___ ___ __ _ __ _ __ _ 1.0 4.8 6.1 6.9 1 Calculated from (id). SOURCE: Canedi81l &IlSiOnerS study (fa). A study among British physicians, the first of the large prospective studies, was started in 1951 with the sending of a short questionnaire to the 59,600 registered physicians then resident in the United King- dom. Usable replies were received from 34,455 men and 6,192 women. Ten years of observation of mortality in relation to smoking was recently reported for this population by Doll and Hill (99,30). Their findings on mortality from chronic bronchitis as related to smoking included emphysema and are given in table 4. Only the standardized death rates were presented in the report but the mortality ratios have been calcul.ated from them to offer an easier comparison with the other two studies. Again, it is clear that mortality from these combined diseases (no attempt was made to differentiate them in the published report) is strongly and directly related to the amount of cigarette smoking. TABLE 4.-Standardized deuth rates, per 100,000 population, for bronchi& and emphysema for male smokers of cigarettes only, by number of cigarettes smoked daily CaIlS8 of death Cig8lBttes SIIl0ke.d per day 8t k?IltTanCe ta study Nier 1 I-14 1 15-24 1 25-k smoked Bronchitis (including emphysema-502, 527.1)-------_--____________________ 5 Mortality ratios ____ __________ - ________ 1.0 SOWCB: Study of British Physiclam (2#, 20). 34 64 106 6.8 12.8 21.2 93 The fourth of the prosp&ive studies is the largest. More i&r 1 million men and women living in 25 States were enrolled in t& investigation in late 1959 and early 1960. A report of the fist 4 yam of observation was published recently by Hammond (36) and mar- tahty from emphysema and chronic bronchitis as related to smoking is given in table 5. A slight departure from the usual assignment of cause of death should be mentioned. When the cause of d&h was listed as chronic bronchitis with emphysema, it was oombined with emphy. sema alone. For this reason, the cause of death in table 5 is not quite the same as any of the causes listed in the other tables. Again, it is clear that mortality from these entities is related to smoking for both men and women. This was the only one of the four studies with enough women enrolled to provide meanlingful data. TABLE &-Mortality ratios for deaths due to emphysema and bronchi uiul emphysema for cigarette makers--men and women in 2 we iP'UP8 t Cause of death Emphysema and bronchitis with emphy- sema (502, 527.1) ______ - _____ - _______ 6.5 11. 4 4.9 7.5 ' t Mortality ratios of nonsmoker In the above categories 8re 1.00 by definition. ' CaiCtllated ifom (ss). SOUBCE: Hammond. E. C. (ss). Before summarizing the data presented from these four investiga- tions, two further points should be made. Excessive mortality was largely confmed to cigarette smokers. The mortality ratio for chronic bronchitis and emphysema, for pipe and cigar smokers combined, in the U.S. veterans study, was only 0.99; in the Canadian study it was about 1.6 (based on only nine deaths) ; in the study of men from 25 States it was 1.37; and among British doctors the standardized d&h rate was 15 (compared with five among nonsmokers). Whatever may be the relationship of p!ipe and cigar smoking to chronic bronchitis and emphysema, it is clear that it is substantially less important than the relationship of cigarette smoking. In two of these studies, stopping cigarette smoking is seen to have an effect on subsequent mortafity from chronic bronchitis and emphy- sema. In the course of the followup of the British physicians (39, 30) it was possible to estimate the number of years a man con- tinued smoking after he had answered the initial questionnaire. For chronic bronchitis the mortaltty rates at first increased after cessation of smoking and later fell well below the rate for men who contirmed to smoke. The death rate from chronic bronchitis, per 100,~ 04 ex-smokers of 5 years or more was 37 compared with a rate of 59 for sll other smokers. Similarly, in the study of U.S. veterans, the mor- tality ratio for chronic bronchitis and emphysema was 10.1 for all male current digarette smokers but only 7.6 for men who had stopped smoking for reasons other than "Doctor's orders." Wicken (76) made a study of lung cancer and bronchitis mortality in Northern Ireland. During the 3 years, 1960-62, a total of 1,262 men and 630 women, aged 35 years or more, were certified as having died of bronchitis. For each of tihese persons a control was selected-the uest person in the Register of the same sex and &year age group who last resided in the same area and who died of a nonrespiratory ilhmas. Personal interviews with relatives of the decedents were carried out for about 94 percent of the subjects and controls to determine the decedents' smoking habits. In addition, a random sample of about 1,500 households in Northern Ireland was selected and one member of each household was interviewed to obtain detiils of the age, sex, smok- ing habits, and other information on all adult members. This informa- tion on all adult members was used to define the adult pop&&ion of Northern Ireland in order to calculate death rates. Bronchitis mortality for both men and women was associated with smoking and directly related to the number of cigarettes smoked daily, as seen in table 6. TABLE 6.-Age-ddardized d&h rates per 100,000 popdatiun front bronchitis for adults &5 years okI and over aa dated to smoking habits Number of cigarettes smoked daily Smoker of- Nonsmoker l-10 II-22 23s. Cl ettes, Pi&F p:glY -- Men- _ __ (124)' 64 (245) 189 (300) 220 (168) 284 (62) 99 (289) 118 Women-- (490) 58 (57) 77 (20) 118 (15) 201 __________ (2) 165 ' Figuraa in pmnthma show the number of deaths upon which the rates 818 based. SOURCE: Wick'en study (75). Using these data, Wicken applied the bronchitis death rates observed among male non-smokers to all the male population of Northern Ire- land and estimated that had these rates prevailed, only 45 percent of the male deaths from bronchitis would have occurred. Recent data from the four prospective studies and the one retrospec- tive study all reveal, for men, an association between cigarette smok- 95 ing and mortality from bronchitis and emphysema. All report an increasing gradient of mortality with an increasing amount smoked. This was also true among women although only one prospective study and the retrospective study included enough women to permit calcula- tion of death rates. Mortality was consistently higher among cigarette smokers than among men who smoked pipes or cigars. These are consistent associations that might be expected if there were a causal relation between cigarette smoking and these diseases. In addition, if such a relationship exists, cessation of smoking should be followed by a reduction in mortality. This did occur in the two studies that in- cluded information on changes in smoking habits. These data, then, strongly support the conclusion that cigarette smoking is at least one of the causes of chronic bronchitis and emphysema. CHRONIC BRONCHOPlJLlMONARY DISEASE MORBIDITY STUDIES RELATING SIEOIUNQ TO RESPIRATORY ~+ZMPTOM:~ Most surveys of chronic respiratory disease are confined to the fre- quency of signs or symptoms of disease. The National Center for Health Statistics, however, in interviews from July 1964 to June 1965, asked about certain chronic conditions including chronic bronchitis and emphysema (76). This was asked in a national sample of 42,966 households containing about 134,060 persons. After answering ques- tions about health for himself and other members of the household, the respondent was asked questions about their smoking habits. A strong relationship was found between smoking habits and the presence of chronic bronchitis or emphysema or both. This is presented in table 7. TABLE `I.-Ageadjwted prevaknce rates of chronic bronchitis and/or tmphystma per 100 persons 17 years and over, by sex, and mokbg status-numbe-r of &are&~ per day (heaviest amount) Preaelltsmokeln l-10 11-m a+ Men ________ -_- ____ - _________ 1.0 1.1 2.3 3.3 Women ____________ - _________ 1.6 4.0 6.5 loumx: National Center for Hedth 8tatMlca (7#, Ffg. EL 96 In another study of the epidemiology of persistent cough, Wynder (80) and his associates evaluated the smoking habits, occupation, and residence (urban or rural) in a male population comprised of 315 hospital patients in New York, and 315 in California, and of 239 Seventh-Day Adventists living in California who were not hospital patients. Persistent cough was reported from 23 percent of the Ad- l*entists (who do not smoke), 45 percent of the New York patients, and 53 percent of the California patients. Coughing was more fre- quently reported by cigarette smokers than by those who smoked pipes or cigars, as shown in table 8. Inhalers also had a higher rate of persistent cough and the rate of cough increased with smoking in each age group. Wynder found no correlation between urban or rural resi- dence and persistent cough. Analysis of the California group showed a higher rata of persistent cough that was independent of the number of cigarettes smoked. TABLE 8.--Percent of men with persistent cough as related to smoking ?mbii% Non- smoker Tgt' cigarettea only Mixed smoker l-10 11-m zo+ -- ---- New York patients- _ _ - _ _ _ __ ___ _-- 14 33 -IT 45 46 67 51 California patients ________________ 22 30 45 74 74 66 Seventh-Day Adventists- _ _- _ __ -__ _ 23 ________________________ ______ SOURCE: Wynder, E. L. et al. (so). Deane and her associates (28) studied symptoms in relation to smok- ing in a group of about 500 outside telephone workers over age 40 working in the San Francisco and Los Angeles areas. Symptoms were reported on a modified version of the British Medical Research Council questionnaire. Regardless of the definition of the respiratory symp- tom-persistent cough and phlegm, persistent cough, phlegm, and shortness of breath-it was consistently experienced by a greater pro- portion of those who currently smoked cigarettes than those who did not. Co&es and his coworkers (@) also found among 1,584 postal work- ers aged 40 or more (all employees of the Detroit Main Post Office), that for every symptom-cough and phlegm, chronic phlegm alone, wheezing, shortness of breath-the prevalence was two to three times greater among moderate (15-24 cigarettes per day) and heavy (25 or more) smokers t.han among those who did not smoke. These differences in symptom prevalence were observed for both men and women but "chronic bronchitis" was reported more often by men, which Coates ascribes to their being heavier smokers. The prevalence of chronic cough and phlegm among ex-smokers was no greater than in nonsmokers. Very few studies have been carried out to estimate the association of morbidity and smoking in young people. Peters and Ferris (60) retro. spectively tallied the number of visits to the clinic at the University of Health Services for 1,623 Harvard students and 404 Radcliffe stu- dents. Smoking information had been gathered on these students in their freshman and senior years. Smokers made significantly more visits to the clinic in total and for respiratory diseases in particular. There was a positive correlation between years smoked and the num- ber of respiratory disease visits. 111 contrast to most studies which select population groups, H&i (&?) studied virtually the entire population, age 40-64, in a immune in western Finland. Although it was a mostly rural population, some industrial workers were included. More than 95 percent of the men and women invited responded to the survey. Questionnaires (based on that of the British Medical Research Council) and medical examina- tions were completed for 730 men and 890 women. Only 18.7 percent of the men were nonsmokers and 21.6 percent ex-smokers, compared with 86.1 percent nonsmokers and 3.6 percent es-smokers among women. Prevalence of both cough and phlegm production was signif% cantly higher among smokers than nonsmokers as seen in tible 9. TABLE O.-Percent of men and women with cough (3 months in the year) and with phlegm (3 months in the year), related to smoking h&de Cough: Men__------------------. Women--- ______ - _______ _ Phlegm: Men-__--_____--_-------~ Women---------- ________ cigfmttes smoked pa day l-14 31.5 10.4 38.0 10.4 15-24 25-b -- 40.8 42.4 (3 of 7 women smoking 15+ cigarettes/day) 42.9 I 42.4 (4 of 7 women smoking 15 + cigarettes/day) Non- smokml 4. 1 4.5 10.7 5.9 EI- smoti 8.5 13.3 17.7 13.3 8OUBCE: Fhhti, E. (4.3). In all the prevalence studies that have been identified and reviewed, significantly more cigarette smokers consistently reported having symptoms related to chronic respiratory disease. This was true for cough, production of phlegm, wheezing, and shortness of breath. It 98 was also true when the respondents were asked not about symptoms hut about disease, that is, chronic bronchitis and emphysema, and in one instance was reflected in the number of clinic visits for respiratory diseases. Prevalence of these symptoms increased with the amount of (*igarettes smoked. It was less among pipe and cigar smokers, and ex- cigarette smokers among whom the prevalence, in some reports, ap- proached that of nonsmokers. STDDIES RELATING SMOKING TO PULMONARY FUNCXION Many of the surveys outlined in the previous section on respiratory symptoms also included lung function tests as part of the examination, Huhti (43)) for example, in his Finnish study took chest X-rays and collected information on vital capacity, l-second forced expiratory volume ( FEV,.o) and peak expiratory flow (PEF) as shown in table 10. TABLE 10' .-Mean mlues of lung junctiom tests among men and women by smoking h&its Cigarettes smoked per day - I I-14 -- FEVI .O (liters) : Men_-----_-___-_---_---- 3.17 Women _____________ - ____ 2. 74 FVC (liters) : Men------------- ___-___ 4.40 Women _____________ _-___ Z53 PEF (c.c./sec.) : Men_--__---___-___-___-_ 518 Women- _ _ ____ ____ _______ 431 IS-24 25+ -- 4.51 4.26 (`1 (3 537 517 (9 (`1 Non- ES- SlIlOkf?l3 ElUOkerS --- 3. 46 3. 39 2. 42 2. 32 4.40 4.51 3. 18 3. 19 569 551 410 403 1 Although this table presents data for all ages combined, the same dilferences were apparent in each byear age grouping. 2 Only 7 women smoked 15 or more cigarettes per day. SOURCE: Huhti, E. (@). Among men the FEV,, value was lower for smokers than nonsmok- ers. The PEF value was slightly lower, but the vital capacity was un- related to smoking. In this study none of the values seemed to be clear- ly related to the number of cigarettes smoked. *4mong the relatively small number of female smokers in this study, most of whom smoked between one and 14 cigarettes per day, almost all the lung function values were better than in the female nonsmokers. Female smokers were slightly taller in height and slightly lighter in weight than fe- male nonsmokers, which may account for this finding. However, fe- male ex-smokers had slightly reduced FEVl.o and PEF when compared 99 with female nonsmokers, similar to the relationship noted between male ex-smokers and male nonsmokers. Coates (90) observed no relation between smoking habits and vital capacity or FEV1., He did find, however, that the ratio of FEV& VC was significantly lower among heavy smokers (25 or more ciga- rettes per day) than nonsmokers. This was found for all but the old- est group of workers, but here the number of subjects was small. Peters and Ferris (69) asked 133 Harvard College seniors to com- plete a questionnaire on respiratory symptoms and to perform some sample tests of pulmonary functions. Of these, 124 responded. Wha classified by smoking history, the smokers were found to record more frequent cough, phlegm production, breathlessness, and wheezing with or apart from colds. There was no difference in vital capacity be- tween smokers and nonsmokers. Although the forced expiratory vol- ume in 1 second (FEV1.o) was less for heavy smokers than nonsmok- ers, this was not significant by itself. As a ratio of vital capacity this did show a significant decrease. The air flow rate using the Wright peak-flow meter and other flow rates determined from tracings of the Stead-Wells spirometer' (FRla%, FR,%, FRZa%, FRlo%) did show statistically significant reductions in heavy smokers as compared to nonsmokers. These data show that relatively young cigarette smokers have some impairments of ventilatory function, in turn suggesting the possibility of a rather immediate effect of cigarette smoking on respiratory symptoms and ventilatory ,function. A series of experiments has been done by Krumholz and his asso- ciates (49, 50, 61) to evaluate cardiopulmonary function in young apparently healthy persons. The first experiment (~$9) involved 18 house staff physicians ranging in age from 24 to 37 years. Nine had smoked at least one pack of cigarettes a day for the preceding 5 years and nine had not smoked for at least the same time period. Extensive pulmonary function studies were done at rest and after exercise. The smokers were found to have a greater oxygen debt after exercise, de- creased diffusing capacity at rest and with exercise, and decreased total lung capacity and vital capacity. In the second Krumholz experiment (50) 10 young staff physicians, all of whom had smoked at least one pack a day for 5 years, were given pulmonary function tests immediately after and again 3 weeks after abstinence from smoking. Six physicians refrained from smoking for G weeks and were tested again. After 6 weeks of no smoking, expira- tory peak flow and pulmonary diffusing capacity were significantly increased. Heart rate and oxygen debt after exercise were decreased. After 6 weeks functional residual capacity was decreased and inspira- tory reserve volume and maximal voluntary ventilation were increased. 100