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in 1943, were impressed not only with the clinical observations of a high proportion of tobacco smokers among lung cancer patients but also with the rise in the percentage of lung cancers in autopsy series in Cologne and Jena. Among the early observations in the United States were those of Ochsner and DeBakey (258) who were impressed by the probable relationship be- tween cigarette smoking, and luna cancer. The initial observations prior to Muller's work were not, however, corroborated by surveys including controls without lung cancer. As early as 1928, Lombard and Doering (221) in a studyof'~ cancer patients' habits in Massachusetts, wrote that "any study of the habits of individuals with cancer is of little value without a similar study of individ- uals without cancer." Their analysis of 217 cases of cancer and 217 controls identified, among other things, an association between heavy smok- ing (all types combined ) and cancer in~ general, and between pipe smoking, and oral cancer in~ particular. The pipe smokers then~ constituted the bulk (73.1 percent)i of the heavy smokers. This is of historical interest in rela- tion to the present-day percentage of heavy cigarette smokers. Further- more, since there were but five lung cancers in Lombard°s test group in an era before much of the rise in hing cancer incidence had occurred, the data were not adequate to demonstrate an, association between lung cancer and cigarette smoking. Probably the first study designed to explore this association system- aticallk- was by Miiller in 1939 (250) who had noted the increase in~ per- centage of primary carcinomas of the lung, being diagnosed at autopsy be- tween the years 1918 and 1937 in Cologne, an~ increase almost entirely in males. Although consid'ering other variables as possibly, related to the rise in lung, cancer mortality, such as increases in street dusts, automobilee exhaust! gases, war gas exposure in World War I, increased use of X-rays, influenza, trauma, tubercul'bsis, and industrial growth (air pollution?), he took special cognizance of the preponderant increase: of~ lung, cancer among, males and the parallel rise in tobacco consumption f'rom~ shortly before and since World War I and selec.tedl this variable for study. In what appears to be a caref'ully conducted inquiry of smoking habits in a series of 86 lung cancer patients and 86 apparently~~ healthy controls; matched by age,, a significant excess of heavy smokers was observed among the lung cancer patients. In the next ten years, three more case-control studies or comparisons withh cancers of other sites reached the literature (280, 309, 363) and from 1950 to the present time 25 additional retrospective (38, 82, 138, 147, 150, 152, 192, 199, 207, 211, 222, 236, 238, 277, 283, 301, 311, 314, 316, 335, 337, 365, 375, 379, 381) and 7 prospective studies (25, 83i 84, 87, 88; 96, 97, 157, 162, 163) were undertaken. Retrospective Studies The 29 retrospective studies of the association between~ tobacco smoking and lung cancer are sumarized in Tables 2 and 3. As these tables suggest, the studies varied considerablly in design and method. Methodologic varia- tions have occurred in the omission, inclusion, or;treatment of the f'ollowing: 150

METHODOLOGIC VARIABLES Subject SelectionL 1. Males and/or females. 2. Occupational groups 3. Hospitalized cases 4. Autopsy series 5. Total lung cancer deaths in an area 6. Samplings of nationwide lung cancer deaths Control Selection- 1. Age matching vs. age groups 2. Healthy individhals 3. Patients hospitalized for other cancers 4. Patients hospitalized! for causes other than cancer S. Deaths fromicancers of other sites 6. Deaths fromiother causes than cancer 7. Samplings of the general population Method' of Interviewing- 1. Mailed questionnaires 2. Personall interviewing of subjects (or relatives) and controls a): By professional personnel b) By non-professional personnel Tobacco-use Histories- 1. By type of smoking (separately and combined ). 2. By amount and type 3. By amount, type, and duration 4. By inhalation~ practices Other Variables Concurrently Studied- 1. Geographic distribution a) Regional bY Urban-rural 2. Occupation 3. Marital status 4. Coffee and alcohol consumption 5 Other nutritional factors 6. Parity 7. War gas exposures 8. Other pathologic conditions 9. Hereditary factors 10. Air pollution 11. Previous respiratory conditions This listing of methodologic variations is by no means complete, nor does it imply that't'he individual retrospective studies should be criticized for their choice of study methods and factors for observation. The individual points of criticism have usually applied to one or two studies but not t'oall. It is indeed striking that every one of the retrospective studies ofl male lung cancer cases showed an association betweem smoking and lung, cancer. All1 have shown that proportionately more heavy smokers, are found among the lung cancer patients than in the control populations and proportionately fewer non-smokers among the cases than among the con- trols. Furthermore, the disparities in proportions of heavy smokers between "test" groups and controls are statistically significant in all the studies. The differences in proportions of non•smokers among the two groups are also~statisticallly significant in all studies but one (236)I; in the latter study, although there were fewer non-smokers among lung cancer patients, the difference was very small. In the studies which dealt wi'th female cases of lung cancer~, similar find- ings are noted in all of them with one exception (238). In this latter study, although significantly more heavy smokers were found among, the lung cancer cases than among the controls, the proportion of non-smokers among the cases was distinctly higher than among the controls. This is the only inconsistent finding among, all the retrospective studies. Its meaning is not clear but the aut'hors have indicated that non-response among their female cases was 50 percent. The weight to be attached to the consistency of the findings in the retro- spective studies is enhanced when one considers that these studies exhibit considerable diversity in method'olbgic approach. 151

N ;.r:rAfia'Ls's TABLE 2.-Outline of methods used in retrospective studies of smoking in relation to lung cancer Number of persons and method of selection Investigator year and Country Sex of Collection of data , , reference cases Cases - - Controls MUller 1930 (250) Germany M 86 Lung cancer decedents, BOrger 86 Healthy men of the sanre age Cases: Questionnaire sent to relatives of Ilospital, Cologne. deceased. Controls: Not stated. Sehaircr and Schoenfger Germany M 93 Cancer decede.nts autopsied at Jena --- 270 Men of the, city of Jena aged 53 and Cases: Questionnaire sent to next of kin 1943 (309). Pathological Institute, 1930-1941: - 54(average age of lung cancer victuns= (195 for hmg canrer). Controls: Ques- - a3.9). - tionnaire sent to 700. Potter and'fully 1945 (280) U.S.A. M 43 Male patients aged over 40 in Mas- 1,847 Patients of same group with - Cases and controls interviewed in clinlc9 ---- - sachusetts cancer clinics with cancer diagnoses he rt ha n ncer. o t cx - ---- of respiratory tract. _ _ _ _ _ _ _ _ - - -- Wessink 1948 (363) Netherlands M 134 Male clinic patients with lung can- 100 Normal men of same age groups as Cases: Interviewed In cllnic. Controls: cer. cases. Not stated. Schrek et al., 19,50 (311) U.B.A. M 82 Male lung cancer niLses among 5,003 - 522 Miscellaneous tumors other than Smoking habits recorded during routine - -- - -- -- - - - - patients recorded, 1941-4!}. - Iung, larynx and pliarynz. - hospital interview. - . Mills and I'orter 1950 (237) U.$.A. M 444 Respiratory cancer decedents in 4;30 Samplo of residents matched by age Ca.ses: Relatives queried by mail ques- - in Detroit, Cincinnati, 1940-45 and in Cobunbus, Ohio, from census tracts tionnaire or personalvisit. Controls: _ 1942--16. " stratificd by degrec of air pollution. House-to-house interviews. Levin et al., 19.50 (207) U.8.A. M 236 Cancer hospital patients diagnosed 481 Patients in same hospital with non- Cases and controls: Routine clinical lung caneer. cancer diagnoses, history taken before diagnosis. " VJ der & Graham 1950 U.S.A. M-F 605 Hospital and private lung cancer --- 780 Patients of several hospitals with Nearly all data by personal interview; a - 381). patients in many cities. diagnoses other than lung cancer. few cases by questionnaire; a fow from intimate acquaintane,es. Some Inter- views with knowledge or presumption -- of diagnosis, some with none. - McConnellet a1.,1952 (236) England M-F 100 Lung cancer patients, unselected, 200 Inpatients of same hospitals, Personal interviews by the authors of - in 3 hospitals in Liverpool area, matcheil by age and sei, without c[m• both cases and controls, with few ex- 1940-19. - --- ---- cer, 1944-50. ceptions:__ Doll and Hill 1952 (82) Great M-F ,465 Patients with lung cancer in hos- 1 1,465 Patients in same hospitals, Personal interviews of cases and controls Britain. _ _ pitals of several cities. matched by sex and age group; some by almoners. with cancer of other sites, sofne with- out cancer. Sadowsky et al., 1953 (301) U.B.A. M 477 Patients with lung cancer I_n_ hos- 615 Patients in same hospitals with il1- Personal questioning by trained intsr- pitals in 4 states. nesses other than cancer. viewers. ~ 6z~`.4S94f:0 ,, _

wynuer and Cornneld U.d.A. M 63 Physicians reported in A.M.A. 133 Physicians of same group dying of Mailquestionnairetoestatesofdeoedonts 1953 (379). Journal as dying of cancer of t3ie cancer of certain other sites. lung Koulumies 1953 (192) Finland M-F 812 Lung cancer patients diagnosed at 300 Outpatients of same hospital aged Cases and controls questioned about one hospital in 16 years. over 40, living in similar circum- - smoking ha bits -wh en- taking case stances, and without cancer, February _ _ _ histories. and March-1952: Lick_in_ t_ 1953 (211) Germany M-F 246 Lung cancer patients in a number 2.002 Sample of persons without cancer Personal interviews by staff members of of hospitals and clinics. living in the same area and of same sex cooperating hospitals and clinics, and age range as cases. . . corresponding in time to Interviews of . . . . ... ..... . ... . . ea5es. Breslow et al., 1954 (38) U.S.A. __- M-F - 818 Lung cancer patients in il Califor- 518 Patients admitted to same hospitals Cases and controls questioned by trained n_ ia hospitals, ospitals, 1949-52 about the same time, for conditions interviewers, each matched pair by the other than cancer or chest disease, same person. matched for race, sex, and age group. Watson and Conte 1954 U.S.A. M-F 301 All patients of Thoracic Clinic at 468 All patients of same clinic during The 769 consecutive patients of case and (365). Memorial Hospital who were diag- same period with diagnoses other than control Qroupswere questioned by the nosed lung cancer, 1950-52. lung cancer, same trained interviewer. Osell 19.M (138) -- - -- Switzerland -- M 135 Men with diagnosis of bronchial 135 Similar hospital patients with diag- Personal interviews, all by the same carcimmma. noses other than lung cancer, and of person. - the same age. Randig 1954 (283) Germany M-F 448 Lung cancer patients in a number 512 Patients with other diagnoses, Controls were interviewed at about the of West Berlin hospitals, 1952-.1951. - matched for a¢e: same time as the cases, each case- pair by the same physician. 8tocks and Campbell 1955 - (Preliminary; see 19.57 report below.) - (337). Wynder et al., 1959 (375) U.S.A. F 105 Patients with lunq cancer in sev- 1,304 Patients at Memorial Center with Cases: Personal Interview or question- eral New York City hospitals, 1953- tumors of sites other than respiratory nairemailedtocloserelatlves or friends - 5. or upper alimentary, 1953-1955. Controls: Personal lutervlew. Segi et al., 1957 (316) Japan M-F 207 Patients with lung cancer in 33 5,636 Patients free of cancer In 420 local Cases and controls by personal interview hospitals in all parts of the country, health centers, selected to approxi- using long questionnaire on occupa- 1053-55. mate the sex and age distributions of tional and medical history and living cas~s. habits. Mills and Porter 1957 (238) U.S. A. M-F 578 Residents of defined areas dying of 3,310 Population sample approximately Cases: From death certiflcates, hospital respiratory cancer; I947-55. proportional to oases as regards areas records, and close relatives or friends. of residence, and 10 years or more in Controls: Personal home visits or tele- the area. phone calls, usually interviewing housewife: -- Stocks 1957 (335) England M-F - 2,356 Patients suffering from or dying - 9,362 Unselected patients of the same Cases: Histories taken at the hospital or with lung cancer within certain area admitted for conditions other from relativesby health visitors. areas. than cancer. Controls: Personai lnterview in hospital.

TABLE 2.-Outline of methods used in retrospective stu dies o f smoking in relation to lung cancer-Continued Number of persons and method of selection Investigator, year, and Country Sex of Collection of data reference cws_e_s_ Cases Controls Schwartz and Denoix 1957 France M 602 Patients with bronchopulmonary 1,204; 3 groups: patients ]n same hospi- Personal interviews in the hospital; cases (313). cancer in hospitals in Paris and a tals with -other cancer, with non- and controls at about the same time by few other cities. cancer illness, and accident cases, the same interviewer. matched by age group. - - ------ Haenszel et al., 1958 (150) U.S.A. F 158 Lung cancer patients available for 339 Patients in same hospital a nd service Personal interviews by resident, medical interview in 29 hospitals, 1955-57. _ at same time, next older and next social worker, or clinic secretary. younger than-each-case.--- Lombard and Snegireff U.S.A. M 500 Men dying or lung cancer, micro- 4,238 Controls in 7 groups including Personal interviews by trained workers. _ 1959 (222). scopically confirmed, 1952-5.9. volunteers, hospital and clinic pa- tients, random population sample, and house-to-house survey samples. Pernu 1960 (277) Finland M-F 1,606 Respiratory cancer patients in 4 1,773 Cancer-free persons recruited by Cases: From ease histories or mailed hospitals and from cancer registry Parish Sisters of 2 institutes in all questionnaires. between 1944 and 1958. parts of the country. Controls: Questionnaires distributed by Parish Sisters. - Haenszel et al., 1962 (147) U.S.A. M 2,19( Sample of 10 percent of white 31,516 Random sample from Current Cases: By mail from certifying physi- male lung cancer deaths in the U.S. Population Survey used to estimato cians and family informants. in 1959. population base. - Populatlon: Personal interview by Census enumerators. Lancaster 1962 (199) Australia M 238 Hospital patients with lung cancer 476 Twogr oups, one with other cancer, Personal interviews of both cases and one with some other disease, matched - eontrois in hospitals. by sex and age. Haenszel and Taeuber U.S.A. F 749 Sample of 10 percent of white 34,339 Random sample from Current Cases: By mail from certifying physi- 1963 1 (152). female lung cancer deaths in the Population Survey used to estimate cians and family informants. U.S. in 1858and 1959. - population base. Population: Personal interview by Census enumerators. I To be published. I-4 S911f;0 -a.

Germane to this concordance is a recent study (386) of Seventh Day Adventists, a religious group in which smoking, and alcohol consumption are uncommon. On the basis of expectancy ofi male lung, cancer incidence derived from the control population~ only 101percent of the cases expected were actually found among Seventh Day Adventists. FORM OF TOBACCO USE In considering the details of the individual retrospective studies listed in Tables 2 and 3, 13' of'~ the studies, combining, all forms of tobacco consump- tion, found a significant association between smoking of any type and lung cancer (138, 1199, 211, 250, 277, 280, 283, 309, 316, 363, 365, 379, 381) ; 16 studies yielded an even stronger association with cigarettes albne as com- pared! to pipe and/or cigar smoking (38, 82, 147, 192, 207, 222, 236;, 237, 238, 277, 283, 301, 311, 314, 335, 379) when these forms -)f smoking were considered separately and in combinations for males. The females, in the studies investigating the relationship of smoking and lung cancer among them, were almost invariably cigarette smokers so that comparisons with other forms of tobacco use were not indicated. AMOUNT SMOKED Twenty-six of the studies quantitated the amount of smoking, per day either by combining weights of tobacco consumed in any form, or, more often, by quantities of the specific forms of tobacco. In each of the studies investigating male lung cancer, the degree of association increased as the amount of smoking, increased (38, 82, 138, 147, 150, 192, 199, 211, 222, 236, 250, 277, 280, 283, 301, 309, 311, 314, 316, 335, 363, 365, 379, 381). One retrospective study (82) by Doll and Hill found a sharper difference in amount smoked between cases and controls among recent smokers (10 years preceding onset of the disease) than in a: comparison of the maximum amount ever smoked. The authors cautione& against accepting this finding as being against their hypothesis of a gradient of risk (which would more properly be tested by the whole life history of! "exposure to risk") by citing the inaccuracies resulting from "requiring the patient to remember habits of many years past." Of the 11 retrospective studies with data on females and tobacco use by amount smoked daily, six (211, 236, 277, 283, 365, 381) showed trends of increasing, association with amount smoked daily, but had too few cases for reliability of the trend. However, five studies (82, 150, 152, 335, 375) did have large numbers of female lung cancer cases for analysis by smoking class; three of these (150; 152, 375) were directed towards female cases only. In each of these latter five studies, the degree of association increased with the amount of cigarettes smoked daily. Four of the retrospective studies dealt~ with ex-srnokers as well (147, 152, 211, 314)~; in one of these (31i4.), where relative risks were derived indirectly by the Cornfield method (61), and in another by conventional use of' stand- ardized mortality ratios (147), male ex-smokers showed a lower risk than 155 -A

TABLE 3.--Croup characteristics in retrospective studies on lung cancer and tobacco use Authors $efer-. enCe Year MOller _____ (250) 1939 Schairer & Schoeniger=== (309) 1943 Potter &'Fully -_ _ (280) 1945 Wassink____ ____ (363) 1918 Schrek et al_____________ '311) 1950 Mills & Porter__________ (237) 1950 Levin et al______________ (207) 1950 Wynder & Flraham_____ (381) 1950 McConnell et al_-.______ (236) 1952 Doll & II111_____________ (82) 1952 Sadowsky et al.._____-__. (301) 1953 Wynder & CornOeld___. (379) 1953 #oulumles__________ ____ _ (192) 1953 Lickint_________________ (211) 1953 Breslow et al____________ (38) 1954 Watson & Conte________ (365) 1954 Osell-------------------- (138) 1954 RandlB--------------•--- (283) 1954 Stocks & Campbell__.__ (337) 1955 Wynder et al_=_____-____ (375) 1956 Segtet al________________ (316) 1957 Mills & Porter__________ (238) 1957 Stocks------------------ (335) 1957 Schwartz & DenolY._ (313) 1957 Haenszelet al_:______(150) 1958 Males Females Cases Controls Cases Controls Remarks Num- Percent Percent Num- Percent Percent Num- Percent Percent Num- Percent Percent ber non- heavy ber non- heavy her non- heavy her non= heavy smokers smokers ~ smokers smokers I smokers smokers r smokers smokers I 88 3.5 85.1 80 18.3 36.0 93 3.2 31.2 270 15.9 9.3 (•) (•) 181emale cases not 43 7. 0 30.2 1,847 26.0 23 0 ? S ( (q 134 4.8 54.8 100 19.2 19.2 (') extlm Percentages chart. 82 14.6 18.3 522 23.9 9.2 (t) 444 7.2 S •? 430 30.5 (•') (•) 236 15.3 (") 481 21.7 (") (') Quantity smoked sldered . 605 1.3 51.2 780 14.8 19.1 40 57.5 25. 0 552 79.6 1.2 93 5.4 38.5 186 6.5 23.2 7 67.1 (") 14 78.6 (") 1.357 0.5 25.1 1.357 4.5 13.4 108 37.0 11.1 108 54.6 0.9 Percentage "heavy understated. 477 3.8 (") 615 13.2 ('•) (') (7redient with smoked. 63 4.1 87.8 133 20.8 29.3 f') (') (') ( ) (~) (') 812 0.8 58.9 300 18:0 25:0 f••) (•') ('•) (•) (') (') 224 1: 8 35.8 1.000 16. 0 4.8 22 64.0 4.5 1, 002 90.4 0. 1 b18 3.7 74.1 518 10.8 42.7 (•') O (•') (") (") ('•) Data include 493 females. 265 1.9 71.7 287 9.7 51.8 36 58.3 2.8 181 82.0 1.1 135 0.7 68.1 135 16.0 14.0 (•) (') (') (•) (*) (') 415 1.2 34.2 381 5.4 17:9 33 51.5 3.0 131 70.3 0 (See reference ( 335) helow ) ('3 (') (') 105 56.2 16.2 1,304 66.0 3. 4 166 (••) (•') 2,124 (") Quantities smoked averages only. D are statistically s 484 8.4 26.0 1,588 27.6 5.3 94 83.0 4.3 1,722 73.3 0.8 Percent "heasy" understated. O survey respons female cases. 2,101 1.0 28. 2 5,960 8.7 22.3 255 67.6 17.2 3,402 88_ 8 10.7 602 1 58. 2 1,204 9.6 36.2 (') (') (') (') (') (') (*) (0) (') (') (•) (') 158 51. 9 14.6 A.~9 6n 6 A 2 analyzed. ated from not oon- " smokers amount males, 25 stated as iffereneee ignificant. smokers nly 50% e among C`'LS94f:U

} ombard & L Snegirott____ (222) 1959 500 1.6 ('•) 4,238 11.0 (••) Authors' calculations fo heavy smoking o based lifetime number of pack of cigarettes. emu___________________ (277) 1960 1,477 6.6 34.5 713 37.2 20.8 129 85.3 26.4 1,060 91.6 0.7 Quantitl es given only I Haenazel et al___________ (147) 1962 2.191 3.4 41.9 f') 16.2 12.0 - grams per day. Population sample of 31,61 used as base. Not a case controi study. . ancaster--------------- (199) 1962 238 2.5 86.1 476 20.1 71.2 Haenszel & Taeuber_••_ (152) r19fi3 (•) (•) 749 60.9 11.5 (1) 67.3 2.5 Population sample of 34,33 used as base. Not a cese control study. I For this table heavy smokers are deflned as those smoking 20 or more cigarettes per day. I To be published. - •Does not apply. '•Data not given. r n a n 6 = 9 •

current smokers but greater than non-smokers. In a third study (152) of lung cancer in women, the ex-smoker risk was lower than the current-smoker risk but approximately equal to that for the non-smoker. i 0 DURATION OF SMOKING Duration of smoking was considered im 12 of the retrospective studies (82, 150, 207; 222, 236, 283, 301, 311, 316, 335, 375, 381). In only six of them, however, were : the data treated im such a way as to permit evaltiation of the relationship between duratiom of smoking and lung cancer-two studies in males (207,, 301) ; two in males and! females (82, 236)~; and two in females only (150, 375). Among the studies of male lung cancer, Levin (207), correcting his data for age, found a relationship between the number of years of cigarette smoking and lung cancer. McConnell (236) found a significant difference in duration of smoking, between cases and controls, but was reluctant to draw any definite conclusions. On the other hand, Dolli and Hill (82), in their age: and sex-matched study, showed a distinct and statistically significant association between the duration of smoking among males. In a well-conceived analytic study, Sadowsky et al. (301), recognizing that' duration of smoking is a function of age„ controlled the age variable, and found an increasing prevalence rate of lung cancer with an increase in duration of smoking among all age groups (age at diagnosis). Among the studies including data on female lung cancer, McConnell had too few female cases to resolve the question ofl dbration of smoking (236) and Doll and Hill, though finding differences between cases and controls, could not establish statisticall significance (82). In the two investigations in which only female lung cancer cases were studied (150, 375), neither showed an independent association between, duration of smoking and lung cancer. Haenszel states, however, that "among women, the association of' starting age and duration of tobacco use with current rate is so strong that it may be unrealistic to expect' to find a separate duration effect in retro- spective studies of limited size" (150). AGE STARTED SMOKING Closely related' to duration of smoking, and thus pertinent to the length of time that subjects have been, exposed to tobacco smoke is the variable of age when smoking was startedl Relatively few of the retrospective studies have dealt with this variable. Koulumies (192) found that males with lung, cancer had started smoking significantly earlier in life. In fact, 143 of his 845 cases or 17 percent began to smoke below 10 years of age as compared to 6.5 percent among his matched controls. The study of male cases and controls by Breslow et al. (38) found a definite trend in the same direction. Pernu (277) found a statistically significant difference in age at start of smoking, with a higher proportion of the male lung cancer group starting at under 15 years of age. Lancaster (199) indicated that the male lung cancer patients began to smoke at a significantly younger age. One other study (283) showed no difference. Of the three investigations of female lung cancer which explored this variable, there were too few smokers in one study for a test of significance (277), and in the remaining two (150, 283), no differences were found. 158

INHALATION If the association between smoking, particularly cigarette smoking, and lung cancer is a causal' relationship, then inhalation, should provide more exposure than non-inhalation and should thus contribute significantly to the lung cancer loadl Four retrospective investigations were addressed to this question. In the earlier Doll and Hill study (82), no difference in the proportioni of smokers inhaling was found among male and female cases and controls. However, four subsequent studies of men (38, 211, 222, 313')) found' inhalation of cigarettes significantly associated with lung cancer. Although in Breslow's study (38) of age-, sex- and race-matched case and control patients, the variable ` quantity-smoked" was not held' constant in the comparison when type of smoking though not quantity was controlled, an association was found! between inhalation and lung cancer. In the studyy by Schwartz and Denoix ('3'13) who held constant both type of smoking and' amount of cigarettes smoked, the relationship of inhalation was significant for those smoking cigarettes alone but not for the smokers of both cigarettes and pipes. Furthermore, although inhalers among lung cancer patients averaged a significantly higher number of cigarettes per day than dld the controls, the relative risk differences between inhalers and non-inhalers, calculated' by the Cornfield method (61), become smaller and almost equal each other at the highest cigarette consumption levels. Lombard and Snegireff (222) demonstrated similar relative risk ratios. HISTOLOGIC TYPE The earliest retrospective study which considered histologic type of lung cancer was by Wynder and Graham (381) in 1950: These authors presented data on smoking habits of male and female adenocarcinomatous patients and for female patients with epidermoid cancers which were but 25 in number. With this partial analysis only a hint of' a higher proportion of smokers among female epidermoid cases could be derived. Of the 1,465 lung cancers in the Dolll and Hiill retrospective study(;82) , 995 werehistologically, con- firmed (916 males and 79 females). Of the confirmed cases, 85 percent of thee males and 71 percent of the females were of the epidermoid or anaplastic types. Although no statistically significant difference in smoking habits was elicited for the several types, a relatively higher proportion of non-smokers and light smokers were found among patients of both sexes wit'h ad'enocarcinoma. Following the presentation by Kreyberg, of a Typing Classification of the epid'ermoid and oat cell or anaplastic types as Group I and the adenocar- cinoma and bronchiolar or alveolar cell types as Group II', and the suggestion of' a relationship between Group I and smoking (196), several ensuing retrospective studies dealt with this question. Breslow's study revealed a higher percentage of non-smokers among the patients with: adenocarcinoma than among those with epidermoid types (38). In rapid succession six additional retrospective studies analyzed the rela- tionship between histologic type of lung cancer and smoking. The 1956 study of female lung cancers by Wynder et al. (375) indicated that adeno- carcinomata apparently had little or no relationship to smoking but that a relationship did exist between smoking and the epidermoid and anaplastic: types. Schwartz et al. (313), similarly, in 1957, found a highly significant 714-422 0-64-12 159

association between, smoking of cigarettes, amount of smoking as well as inhaling, and the epidermoid and anaplastic types of tumors. No such association with "type cylindrique" was noted. In that same year Doll and' Hill furnished Kreyberg with lung cancer slides from 933 British patients. Kreyberg, without knowledge of the patients' smoking history or clinical data, separated these into two groups. A strong correlation was found between smoking history and histologic type; smoking and amount were highly associated with~ the epidermoid and anaplastic types, and non-smokers were predominantly among the adenocarcinomatous types (86). In this study of lung cancer in women, Haenszel, et al. (150) found statis- tically significant relative risk gradients for amount of cigarette smoking among Group I cancer patients. No increased risk was established for Group II cancers: In his later study of a current mortality sample of white males for 11958, Haenszel found relative risk gradients f'or the several smok- ing classes for both adenocarcinomas and epid'ermoid' cancers (147). A parallell study of white females for the current mortality sample of 1958 and 1959 showed essentially the same findings, except possibly for a lower effect on adenocarcinomas among smokers of less than one pack daily (152). Haenszel points out that: in both these studies a "true differential in risks" for the two histologic types could well have been dilYrted seriously by report- ing and classification errors whi& were definitely known to exist from re- inquiry of a sub-sample of deaths (152)1. (iFor current evaluation, see section on Typing of Lung Tumors. ) RELATIVE RISK RATIOS FROM, RETROSPECTIVE STUDIES Retrospective studies are usually designed to establish the probability of association of an attribute A with disease X; or, given disease X, what is the probability that A will be found in association (P [AJX] )~? Pro- cedurally, one compares a supposedly representative group of patients with disease X, witL another group as controls, in regard' to the percentages of individuals with and without the attribute A. This procedure may reveal significant differences leading to judgments of association but it does not yield' an estimate of the magnitude of the relative risk of disease X among those with attribute A and those without. A method which estimates this relative risk, developed by Cornfield (61):, has been referred to several times earlier and can be applied to data derived from retrospective studies if two assumptions, inherent in the first procedure of judging the association, are made: (a) that patients with disease X interviewed or otherwise studied are a representative sample of all cases with disease X, and (b) that thee controls without disease X or who have escaped disease X are a representativee sample of all persons without disease X. An estimate of the prevalence of disease X in the population is a requisite. Such an approach was utilized by a number of investigators in retro- spective studies on lung cancer. Dolll and' Hill (82) made similar calcula- tions and found a linear gradient of deaths f'rom~ lung cancer for men~ and women increasing with amount of tobacco smoked daily. Sadowsky et al. (301) found similar increases in risk for amount smoked' daily in virtually all but the oldest age groups and calculated an age-standardized risk ratio of 4.6:1 for all smokers compared to non-smokers. These authors also 160 I

utilized the data of Wynder and Graham (381) an& Doll and Hill (82) for calculating similar risk ratios, deriving ratios of 13.6:1 and 13.8:1, respec- tively. Their calculations of estimated prevalences by quantity smoked daily for age groupings similar to their own also showed linear increases of risk. Breslow et al. (38) treated their retrospective data similarly and developed relative risk ratios of 7.7:1 for males aged 50-59 years and 4.6:1 for those aged 60-69. In considering heavy smokers (40 or more cigarettes per day), they showed relative risk ratios of 17:1 and 25.5:1, respectively. Randig (283)' also demonstrated a linear progression of risk with increasing amounts of daily tobacco consumption and an over-all ratio of 5.1:1 for all smokers to non-smokers among males and 2.2:1 for females. Schwartz and Denoix (313)' reported' similar findings in amount smoked daily and a risk ratio of smokers to non.smokers of approximately 8:1. Lombard and Snegireff (222) approached their data in a different way, utilizing,"life- time number of packs of cigarettes consumed" as a measure of exposure. Their estimated' prevalence rates also increase linearly' with amount smoked. The risk ratio which can be calculated from their tabulated data ranges from 2.4:1 for light smokers to 34,1:1 for heaviest smokers. Haenszel, in his two studies on male and female lung cancer mortalitv as related to residence and smoking histories, calculated relative risk ratios of 4.1:1 for one pack or less daily and 16.6:11 for more than one pack a day among males (147), and 2.5:1 and 10.8:1, respectively, among females (152). Table 4 summarizes the relative risk findings of the nine studies. TABLE 4'.-Rel'ative risks of lung cancer for smokers from retrospective studies Author and~ Reference Year Sex Relative risk-Smokes:': non-smokers Sadowsky et~ al. (301) 1953 M 4.6 Doll and Hill (82) 1952 M 113.8 K'qnder and Graham (381) 1950 1 M i 13:~ Rreslow et al. (38) 1954 M 7.7 aee 50-59 4.6 " 60--fi9: ' 17.0 " 50-59 ' „ }veryheavysmokers ~.5 ~9 Randig. (283) 1954 M-F 5. 1 M. 2.2 F Schwartz and Denoix (313) 1957 M 8.0 Lombard and Snegireff (222). 1959 M 2.4 ]ight'smokers 34.1 heavy smokers Haensul (147). 1962 M 4.1<1~pack/day. 16.6>i pack/day. Haenszel (152)' Unpnblishedl F 2.5<1 pack/day 10.H>1 pack/day 1 Calculated by Sadowsky et a11 (301)' from other autliors' data. Prospective Studies It lias been pointed' out that in retrospective studies the usual approach is to determine the frequency of an attribute among cases and controls. This measure does not provide estimates of the risks of developing, the disease 161

i J, a among individuals with and without the attribute unless one makes assump• tions referred to above. The validity of such assumptions may at times be suspect, for the: cases may not be representative of the total population with the disease nor the controls representative of the population without the disease. Thus, some retrospective studfes may not truly assess the existent risks with reasonable accuracy. However, when all the cases of a disease in an~ area and a representative sample of the population without the disease are included in a study, the estimates of risk bear high validity. Despite the criticisms leveled at the retrospective method in~ general and its obvious defects as practiced by some investigators, a number of the retro- spective studies on lung, cancer have indeed overcome most of the criticisms of major import leveled at the method'. These criticisms and their implica- tions will be treated specifically below in the section om an Evaluation of the Association Between Smoking and Lung Cancer. Suffice it to say at this point that certain shortcomings of the retrospective survey approach, some real and some exaggerated, led severall courageous investigators to under- take the necessarily protracted, expensive, and difficult prospective approach. The first prospective study encompassing total and cause-specific mortality in a: human population was initiated in October 1951 among British physi- cians by Doll and Hill (83, 84)'. There then followed im rather rapid suc- cession, five additional independent studies in the United States and Canada (25, 87, 88, 96, 97; 157,,162, 163), all' but one of which continue to be active. The earlier study, by Hammon& and Horn, among,187;783 white males aged 50-69 years, initiated between January and May 1952, was terminated after 44 months of'~ follow-up (162, 163). This has been succeeded by the current Hammond study which broadened its age-base ('35-89 years) and contains 1.085,000 persons (in25 states)' of whom 447,831 are males (157). These studies have been described in detail, analyzed, and'. evaluated in Chapter 8 of this Report where a discussion of differences in total mortality between smokers and non-smokers has been presented, and are summarized in Table 1 of that chapter. All the prospective studies thus far have shown a remarkable consistency in the significantly elevated mortality ratios of smokers particularly among the "cigarettes only" smoking class. Of special interest is the fact that in a number of the studies the magnitude of the as- sociatiom between cigarette smoking and total death rates has increased as the studies have progressed. This has particularly beem true for lung can- cer. The presently calculated total mortality ratios have been presented im Table 2 of Chapter 8 of this Report. With reference to the smoking and lung cancer relationship, each of the seven prospective studies has thus far revealed am impressively high lung, cancer mortality ratio for smokers to non-smokers. Examination of Table 5, which presents in summary form the lung cancer mortality ratios for the seven studies by smoking type and amount, derived both from the published reports of these studies and current information from the investigators wherever available, reveals a range of ratios from 6.0 to 25.2 with a median value of 10.7 for all smokers irrespective of type or amount. For smokers currently using cigarettes only at the time of enrollment't in the studies, the ratios range from 4.9 to 20.2 with a mean value of 10.4 as derived from a summation of observe& and expecte& values of most recent' data. 162

Several of the studies have fortunately provided data for a measure of the "dose of exposure" relationship (84, 88, 96, 157, 163). It can readily he seen from Table 5 that the mortality ratios increase progressively with amount of smoking. The pivot level appears to be 20 cigarettes per day. Cigar and/or pipe smokers (to the exclusion of cigarettes) manifest ratioss lower than any of the cigarette smoking classes, including combinations of cigarettes with pipes and%or cigars (25, 84, 88, 157,,163 ). One study pro- vided data on occasional smokers (163). These have a ratio very close to: that of non-smokers. Ex-smokers of cigarettes (83, 88, 163) fall into levels of risk ratios below those for current smokers of cigarettes depending upom the length of the interval since smoking was stopped. In the Doll and Hill study (83), the ex-smoker ratio was less than the current smoker ratio even when cessation, had' occurred less than 10 years before entry into the study. This, however, was not true for the first Hammond and H'orn study (163). In this latter study, if smoking had ceased more than 10 years before entry, the lung cancer mortality ratios were lower than for current smokers at the corresponding daily consumption levels, but if cessation of smoking had occurred less than 10 years before entry, the ratios were virtually identical to those for current cigarette smokers at the corresponding daily consumption levels. The Dorn material (87, 88), currently brought up,t'o date (89')~, provides a measure of relative risk by amounts of smoking prior to st'opping. The ratios thus elicited are again below those for cur- rent cigarette smokers of corresponding, daily amounts. At this time it is difficult to assess the effect of other variables such as duration of smoking and starting age on lung cancer mortality since cross- classification by these variables, and amount' smoked as well, leads to cells with small numbers of deaths. Most prospective studies have thus far con- fined themselves to analyzing the effect of these additional variables on deaths from all causes, or in one case (157) from cardiovascular diseases. The current Hammond study is concerned with inhalation practices, but here also the total number of lung cancer deaths analyzed to date does not permit extensive classification by age, type of smoking, amount smoked daily, present smoking, status, and age when smoking was begun. In the studies of total mortality ratios, duration of smoking, obviously immediately dependent upon the age of the individual, was in turn dependent upon age when~ smoking (cigarettes) was begun. Age when smoking began was also a determinant, not only of the number of cigarettes smokedl daily, but of thee degree of inhalation, with smokers starting at earlier ages very distinctly tending to smoke more and inhale more deeply than those starting,to smokee at older ages (157). According to Hammond, men who smoke more per day also tended to inhale more deeply thani those who smoke fewer ciga- rettes per day. When inhalation and quantity smoked were held constant, the total mortality ratios also increased as age at start of smoking decreased. The stability of the lung cancer mortality ratios referred to in Table 5 is to a great extent dependent upon the number of observed lung cancer deaths among non•smokers from which the expected values for the several smoker clhsses are calculated! Referring again to Table 5, in at least two of the studies (83, 96), caleulationi of the expected deaths among smoker classes had to be based on extremely small numbers of non-smokers. However, 163

i ~14,ss44Co ,~--,.--,--- TABLE 5.-Mortality ratios f or lung cancer by smoking status, type o f smoking, and amount smoked, f rom seven prospective studies Dunn, Dunn, Best, Study Doll and Hammond Dorn Linden and Buell and Josie and Hammond H111 and Elotn Breslow- Breslow- Walker Occupational Legion - Lung cancer deathsin Study--------------------------------------------- 129 -- 448 536 - 139 98 221 --- - 414 Lung cancer deaths Non-smokers---------------------------------------- 13 t25 }68 }3 f12 18 t18 - - (Reference number) (83) -- (163) (88) ---- (96) (97) (25) - (1b7) MORTALITY RATIOS: - All Smokers---------------------------------------------------.----- 12.8 - 10.7 6.0 - -. '2b.2 t8.1 1-14 gm. tobacco-------------------------------------------------- 8.7 - =- - - - - 15-24 gm:tobacco------------------------------------------------- 12.3 - - - - - - -- 25 gm:tobacco---------------------------------------------------- 23.7 - - - - - - - • Current: " Cigarettes only--------------------------------------------------- t2d• 2 }10.0 t12.0 }15.9 t4.9 }11. 7 t9.8 <10---------------------------------------------------------- ------ - - 4.4 t5. 8 r5. 2 5)- 8.3 }8: 4 10-20 . ... 10:8 }7.3 Y9. 4 ~10)- 9.0 - ... Y13:5 - 21-39 __ __---- --- ___ ---- -- `-~ -------------------------------------------- ----- - -- --------- -------------- - 1 y 43.7 / f15.9 121.7 t18:1 t23:3 (20)-19.4 (30)-25.1 - 1 . . f t16.1 _ (40) 28. 7 ;5 1 pack ?------------------------------------------------------------ 8.1 8.9 8.1 13.6 4.2 11.8 >1 pack t------------------------------------------------------------- 43.8 16.9 18.0 24.1 7.4 I5:1 Pipes only- , b. 4l 2 8 1. 3j _ --- Cigars only ------------ - } } t4. 8 1.0~ }1. 3 1. 5 } L1. 8 - };1.1 } 11. b Pipes and clgars-------------------------- f JJJ _ - - I - - JJJ 111 Cigarettes, pipes and clgars------------------------- _ _______________ 9.7 10.7 8.2 - - t24.4 - Occasional------------------------------------------------------------ - 1.3 - - - - - Ex-Smokers: - >10 yrs0 since stopped-------------------------------------------- 5.0 - - - - - - <20 cigarettes------------------------------------------------ - 2.4 - >20 cigarettes-------------------- ---------------------------- - 17.8 - - - <10 yrs. sincestopped-------------------------------------------- 8.4 _ - - - - <20 cigarettes--------------------------------- --------------- - 10.4 - - - - - >2D clgarettes---------------------------°------------------- - 22.8 - - - - - <20 cigarettes (lrrespective of when stopped)______________ ______ - - t1.3 - - - - >20 cigarettes (irrespective of when stopped)_______________ - - t1.8 - - - - 'Current and ex-smokers combined. tMost recent information. -Data not avallable ar not available for designated clasaes. ••Two California studies and current Hammond study include all cigarette smokers (cigarettes and other and current and ez-cigarette smokers). ,

the other studies have now yielde& significantly greater numbers of non- smoker lung cancer deaths and in at least three of them (88, 157, 163) these are now appreciable. Experimental Pulmonary Carcinogenesis ATTEMPTS TO INDUCE LUNG CANCER WITH TOBACCO AND TOBACCO SMOKE Few attempts have been made to produce bronchogenic carcinoma in experimental animals with tobacco extracts, smoke, or smoke condensates. With one possible exception (289), none has been successful (331). Mice rarely develop spontaneous bronchogenic, oral, esophageal. gastric, prostatic, lhryngeal, or vesical carcinomas, but cerrt'ain~ inbred strains have a high incidence of spontaneous pulmonary adenomas (6). The adminis- tration, by any route, of carcinogenic polycyclic hydrocarbons, including some found in tobacco tar, increases the incidence and decreases the time of occurrence of pulmonary adenomas. These tumors are usually regarde& as beni¢n,,and probably arise from the alveolar epithelium (4, 5, 6, 13!1i, 330) rather than the bronchial walll They have no resemblance to most humani bronchogenic carcinomas. Essenberg (106) and Miihlbock (248)' exposed mice to cigarette smoke, but their reported results are equivocalL Lorenz et al. (224), and Leuchten- berger et' al. (206)' did not observe an increase in pulmonary adenomas in, mice that inhaled cigarette smoke. Leuchtenberger et alL (205a.): described a sequence ofi microscopic changes in htngs of mice exposed to cigarette smoke resembling somewhat those found by Auerbach et al. in the lungs of human smokers. No dose-response effect was reported. The morphologic findings consisted of bronchitis with proliferationi of the epithelium. Some areas of hyperplasia showed atypicall changes. However, the changes were reversible when exposure to smoke was stopped. The production of' bronchogenic carcinomas has not been reported by any investigator exposing experimental animals to tobacco smoke. Most experiments in which tobacco tars were brought into direct contact with the lung and tracheobronchial tree of experimental animals have yielded negative results (1273, 274, 275). Blacklock (29): found one car- cinoma when tar from cigarette filters was placed in olive oil together with killed tuberele bacilli and injected into the hilum of a small number of rats. Rockey et al. (289) painted tobacco tar three to five times each week on the trachea of dogs with a tracheocutaneous fistula. Hyperplastic changes with squamous metaplasia of the bronchial epithelium were seen in seven dogs that survived~ 178 to 320 days. Carcinoma-in-situ was reported to occur in three,, and invasive carcinoma in one out of 137 dogs, but this work has not yet been confirmed: SoM MA.xY.-Bronchogenic carcinoma has not been produced by the application of tobacco extracts, smoke, or condensates to the lung or the tr~acheobronehial tree of experimental animals witL the possible exception of dogs. 165

i' SUSCEPTIBILITY OF LUNG OF LABORATORY ANIMALS TO CARCINOGENS POLYCYCLIC AROMATIC HYDROCARBONS.-Epidermoid carcinoma has been induced in mice by Andervont by the transfixion of the lungs or bronchi with a thread'coated~with a carcinogen (5) and by Kotin and Wiseley (191) by treatment with an, aerosol of ozonized gasoline plus mouse-adapted influenza viruses. Kuschner et al. (197, 197a) induce& epiderrnoid carcinomas in the lungs of rats by the local application of polycyclic aromatic hydrocarbons, either by thread transfixation or pellet implantatiom Distant metastases occurred from some of! the carcinomas. The changesin the bronchial tree at different times prior to the appearance of cancer included hyperplasia, metaplasia and anaplasia of the surface epithelium as well as of the subjacent glands. These changes resembled those described by Auerbach in the tracheo- bronchial tree of human smokers (9). Stanton and Blackwell (324) induced epidermoid carcinoma inAhe lungs of rats that had received 3-methylcholanthrene intravenously. The car- cinogen was deposited'in areas of pulmonary infarction. Saffiotti et al: (302) produced squamous cell bronchogenic carcinomas in hamsters by weekly intubation and insufflation of benzo(a)pyrene (4 per- cent) ground with iron oxide (96 percent) resulting in a dust with particles smaller than 1.0 micron. A proliferative response followed by metaplasia pre- ceded the appearance of the carcinomas, but was not an invariable antecedent. VIRidsEs.-Bronchogenie carcinoma has been induced in animals inocu- lated with polyoma virus by Rabson et al. (282). Carcinogens enhance the effect of viruses known to cause cancer in animals (99)' and localize the neoplastic lesions at the site of inoculation of the virus (98). However, no evidence has been forthcoming to date implicating a virus in the etiology of cancer in man. PosSIBLE INDUSTRIAL CARCINOGENS.-Vorwald reported that exposure of rats to beryllium sulfate aerosol resulted in carcinomas of the lung; 12 per- cent were epidermoid but most were adenocarcinomas. The tumors usually arose from the alveolar or bronchiolar epithelium. He also produced broncho- genic carcinomas in two out of ten rhesus monkeys injected: with beryllium oxide and in three out of ten exposed to beryllium oxide by inhalation (357). Lisco and Finkel in 1949 (217) reported the production of epidermoid cancer of the lung in rats with radioactive cerium. Subsequently many other investigators have succeeded in producing carcinomas of the lung, predominantly of the epidermoid type, in a high percentage of rats and mice with other radioactive substances. The various modes of exposure incllided inhalation, intratracheal injection, or insufflation and implantation of wire or cylinder. These experiments were reviewed by Gates and Warren in 1961 (125). Hueper exposed rats and gpinea pigs to nickel dust and found metaplastic and anaplastic changes in the bronchi (180). Following up earlier work in which squamous metaplasia of the bronchial epithelium was found in rats exposed to nickel carbonyl (341), Sunderrnan and Sunderman (342) in- duced bronchogenic carcinoma in rats by exposure to this compound. This 166

i group also found 1.59 to 3.07 µg, of nickel per cigarette in the ash and in the smoke in several, different brands. About three-fourths was contained in the ash. Although Hueper and Payne (182,,183) and Payne (270) have demonstrated that pure chromiumi compounds will produce both sarcomas and carcinomas in, several tissues in rats and mice, bronchogenic carcinomas have not been produced by inhalation, of chromium compounds in experi- mental animals. Experiments designed to test the carcinogenicity of', ar- senical compounds have been either negative or inconclusive. Asbestosis cani be produced without difficulty in experimental animals by inhalation of asbestos fibers (359)', but efforts to produce bronchogenicc carcinoma have been unsuccessful (129, 181, 227, 358)'. SLJ:KMAxY: The lungs of, mice, rats, hamsters, and primates have been found to be susceptible to the inductyoni of bronchogenic carcinoma by thee administration of polycyclic aromatic hydrocarbons; certain metals, radio- active substances, and oncogenic: viruses. The histopathologic characteristics of the tumors produced are similar to those observed in man and: are fre- quently of the squamous variety. ROLE OF GENETIC FACTORS IN PULMONARY ADENOMAS IN MICE Genetic factors exert a determining influence on the spontaneous develop- ment and induction of lung tumors in mice. Early studies of Murphy and Sturm (251) and of Lynch (225, 226) demonstrated the development of pulmonary tumors in mice after the skin was painted with coal tar, and Lynch (225) indicated the existence of genetic factors in the development of these tumors. Later investigations of Heston (169, 170) on the effect of intravenous injection~of dibenzanthracene.and the studies of several other investigators (3, 4, 27, 47, 320)' utilizing different techniques gave addi- tional evidence of the operation of genetic factors in indwcedl tumors. Link- age betweeni multiplL genes for susceptibility to spontaneous and induced tumors in, mice and specific chromosomes has also been established (47, 168) an& transplantation experiments (171, 173) indicate that the genetic susceptibility resides within the pulmonary parenchyma. A number of in- vestigators (136, 47, 124, 131): demonstrated conclusively that these tumors usually arise distal to the bronchus and are probably alveogenic. Metastases rarely occur. The relative importance of genes for susceptibility to these tumors of the lung is indicated by an incidence ranging from a few tumors to over 90 percent, depending on the inbred strain~ examined. Spontaneous tumors of the lungs are rare in species of laboratory animals other than mice, and the genetics of these neoplasms in other species has been investigated only superficially. SuMm[ARY.-Genetic susceptibility plays a significant role in the develop• ment of pulmonary adenomas in mice. Pathology-Morphology RELATIONSHIP OF SMOKING TO HISTOPATHOLOGICAL CHANGES INI THE' TRACHEOBRONCHIAL TREE In~ an extensive and controlled blind study of the tracheobronchial tree of 402 male patients, Auerbach et al. (11, 13, 15)' observed that several 167 ~A

kinds of changes' of the epithelium were much more common in the trachea and bronchi of cigarette smokers and subjects with lung cancer than of non-smokers and of patients without lung, cancer (Table 6). The epithelial changes observed were (a) loss of cilia, (b) basal cell hyperplasia (more than two layers of basal cells), and (c) presence of atypical' cells. The atypical cells had hyperchromatic nuclei which varied in size and shape. The arrangement of such cells was frequently disorderly (see illustrations below). Hyperplastic changes were also seen in the bronchialiglands. TABLE 6.-Percent of slides with selected lesions,' by smoking status and presence of lung cancer Group Percent of slides with cilia absent and averaging 4 or more cell rows in depth Number cases , Number , slides No :cells atypical sOme oells latypical All I cells atypical 3 Total Cases without lung cancer Never smoked regular]y-------------- 65 3,324 110 0.03 - 1. 1 Es-cigarette smokers-_--------------- 72 3,436 3.5 0. 4 Q 2 4.1 Cigarettes-S~ pk. a day-------------- 36 1,824 0.2 4. 2 0.3 4.7 Cigarettes-Sti-1 pk. a day------------ 59 3,016 h--------- 7:1i 0.8 7. 9 Cigarettes-1~2 pks: a day----__----- 14.3 7,062 12: 6 4.3 16. 9 Cigarettes-2+ pks: a day_----------- 36' 1,787 26.2 11.4 37:5 Lung,cancer cases °---------------- ------- 63 2, 784 12.5 14.3 28.8 I ]n some sections, two or more lesions were found. In such instances, all of the lesions were counted and are inc]uded in both individual columns and in the total colhnin of the table. Lesions found at the edge of an ulcer were excluded. r These lesions may he called careinoma-in-situ. J Orthe 63 who died of lung cancer, 55 regularlysmoked'cigarettes up to thee time of diagnosis, 5 regularly smokedicigarettes but stopped before diagnosis, i smoked cigars„1 smoked pipe and'eigars; 1 was an occa- sionalicigar smoker. Each of the three kinds of epithelial changes was found to increase with the number of cigarettes smoked (Table 6). In smokers who had no cancers, frequency and intensity of these changes correlated with the number of EXAMPLES OF NORMAL AND ABNORMAL BRONCHIAL EPITHELIUM 1. Normal 168

2. Basal=cell hyperplasia-replacement of ciliary epithelium with a thick layer of cells resembling stratified squamous epithelium. 3. Extensive basal-cell hyperplasia with numerous atypical cells. Source: Auerbach, Oscar. Special communicationi to the Surgeon General's Advisory Committee on Smoking and Health. cigarettes smoked. Among non-smokers, lesions composed entirely of atypi- cal cells with loss of cilia were uniformly absent, although a few could be seen with more than two rows of basal cells containing some atypicali cells. In contrast, atypical cells were found in all lesions seen in the tracheobron- chial tree of patients who smoked two or more packs of cigarettes a day, irrespective of the presence of hyperplasia and/or cilia loss or whether the patients died of lung cancer. The most severe lesion, aside from invasive carcinoma, consisted of! loss of cilia,, and hyperplasia up to five or more cell rows composed entirely of atypical cells. This lesion, was never found among, men who did not smoke regularly and was found only rarely among light, smokers. However, it was found in 4.3 percent of sections from men 169

who smoked one to two packs a day, in 11.4 percent of sections from those who smoked two or more packs a day, and in 14.3 percent of sections from smokers who died of lung cancer (15). . While epithelial changes were found in all portions of the tracheobronchial tree, quantitative differences were found between the changes in the trachea and those in the bronchi; hyperplastic lesions consisting entirely of atypical cells without cilia were found in all regions of the bronchial mucosa but only rarely in the trachea. It is notable that cancer rarely occurs in the trachea. In 35 children less than 15 years of'age, Auerbach et al. (16) found the same percent of epithelial changes in the tracheobronchial tree as in the same number of adults who had never smoked regularly (16.6 percent of children and 16.8 percent of adults). Nb hyperplasia with atypical cells was seen in any section. Later, Auerbach et al. (15a.) studied the morphology of the tracheobron- chial tree from 302 women and'456 meniwith respect to additional variables~- sex, age, pneumonia, and amount smoked. One or more epithelial lesions were found ini 68.2 percent of sections from men smokers and 68.6 percent from womeni smokers when matched groups were examined. However, on further study, hyperplastic lesions composed entireHy of atypical cells were found in 6.9 percent of the sections from the male group and in 2.5 percent of those from females. Matched groups of male cigarette smokers of two age groups (averages of 37 and 67 years) were compared. Many more lesions, characterized by a large number of cells with~ atypical nuclei, were observed in the older than in the younger group. In a parallel study of women who did not smoke (average ages of 46 and' 7fi years), no difference in the number or type of lesions was noted. Few changes in the bronchial epithelium were found in sections from 27 women non-smokers over 85 years of age. Occasional atypicaL changes were found in women non-smokers (a) who died of pneumonia, (b) who died of various other causes but had pneumonia at the time of death, and (c) who died with no evidence of pneumonia. However, basal'cell hyperplasia, loss of cilia, and ulceration were found moree frequently in sections from women who died with pneumonia than from women who had no evidence of pneumonia. These observations are in agreement with those of other investigators who found metaplasia of the bronchial epithelium to be more frequent in patients with various non- neoplastic pulmonary diseases than in~ controls without such disease (256,, 305,,352, 366):. Far fewer epithelialilesions were found in non-smokers than in pipe, cigar,, or cigarette smokers (15a.), the difference being particularly evident in the occurrence of atypical cells. However, sections from pipe and cigar smokers showed fewer epithelial lesions than did sections from cigarette smokers. Cells with atypical nuclei were found far more frequently in cigarette smokers than in cigar or pipe smokers (Table 7). In 72 male ex-cigarette smokers who had smoked for at least ten years and had not': smoked for at least five years prior to the time of death, there were less hyperplasia, less loss of' cilia, and fewer atypical cells than in~ sections from current cigarette smokers (14). An interesting by-product of this stud'y was the finding of "cells with disintegrating nuclei"' in~ the 170

TABLE 7.-Changes in bronchial epithelium in matched triads o f male non-smokers and smokers o f di ff erent types o f tobacco." Group Number of sub- jects Total sections with epi- thelium Sections with 1 or more epithelial lesions 3+cell rows with cilia present Cilia absent Atypical cells present Atypical cells present with cilia absent Entirely atypical cells with cilia absent + Number Percent Number Percent Number Percent Number Percent Number Percent Number Percent 7th set (none vs, pipe vs. cigarette)a - - - - - - Non-smokers ----------------------- 20 985 214 21.7 110 11.2 101 10.3 26 2.6 3 0.3 0 __-___-__ Plpe sinokerv__===___:_____::::_::__= 20 924 605 65.5 352 38.1 117 12.7 342 37.0 29 3.1 0 _________ Ciearette smoker__s------------------ 20 914 885 96.8 810 88:6 116 12:7 870 95:2 111 12.1 35 ------3:8 8th set (none vs. pipe vs. cigarette) Non-smokers------------------------ 25 1,246 285 22.9 167 13.4 132 10.6 9 0.7 1 0.1 0 _________ Pipe smokers________________________ 25 1,164 800 68.7 451 38.7 172 14.8 445 38.2 38 3.3 0 _--_----- Cigarettesmokers-------------------- 25 1,126 1,084 96.3 999 88.7 238 21.1 1,008 89.5 205 18.2 70 6. 2 9th set (none vs. cigar vs. cigarette) Non-smokers ________:_____:_______ 35 1,706 467 27.4 216 12.7 281 16.5 14 0.8 3 0.2 0 ______.-- Pipe smokers------------------------ 35 1,733 1,573 90.8 694 40.0 247 14.3 1,275 73.6 173 10.0 5 0.3 Cigarette smokers____________________ 35 1,526 1,511 99.0 1.414 92.7 428 28.0 1,493 97:8 417 27:3 196 12:8 ~ Modified table from Auerbach et a]. (15a). a Carcinoma In situ. a'f`riads were matched for age, occupation, residency and (for smokers) by amount of tobacco used. g}7t.4ss4eo

bronchial epithelium of 43 out of 72 ex-smokers. These cells were not found in the bronchial epithelium of current cigarette smokers or non- smokers. They'were considered by Auerbach et al. to be pathognomonic of the ex-smoker. Many of the histopathologic findings observed by Auerbach et al. in the bronchial' epithelium of smokers have been confirmed by other investigators (64, 155, 189, 304). The significance of the hyperplastic changes in the bronchial epithelium for the pathogenesis of lung,cancer in, smokers is not fully understood. The establishment of a link between the hyperplastic changes and the subsequent development of lung cancer would relate smoking causally to lung cancer. However, the non-specificity of! hyperplasia of the bronchial epithelium is universally recognized. Furthermore, similar changes are known to be reversible. On the other hand; evidence from both human and experimental observa- tions points strongly to the conclusion that some hyperplastic changes of' the bronchial epithelium, especially those with many atypical alterations, are probably premalignant. It is well documented that the bronchial trees of patients with lung cancer have areas, sometimes very widespread, of epithelial hyperplasia containing many atypical and' bizarre cells: This was reported by Lindberg in 1935 (216) and by many other investigators (10, 12, 28, 52, 134, 265, 285, 349, 370). Black and Ackerman (28) have carried out an extensive study of the relationship between metaplasia and anaplasia and lung cancer in human lungs and' have presented strong circumstantial evidence for the opin- ion that the basal: cell hyperplasia with advance& atypical changes and loss of! cilia (the so-calle& carcinoma: in-situ) represent a stage in the devel- opment of lung cancer. They also emphasized, as has Auerbach et al. (12), the frequent occurrence of atypical' basal cell hyperplasia at multiple sites in the bronchial tree considerably removed from the site of the lung cancer. They have pointed out the similarities between the atypical hyperplasias in the traeheobronchial' tree and carcinoma in-situ in other sites, such as the cervix, skin, and larynx. Lung cancer was induced in animals by radioactive substances (1198,,217), chemical carcinogens (198, 340), andl air pollutants plus influenza virus (191). These studies have demonstrated the occurrence of extensive atyp- ical hyperplastic changes in the bronchial epithelium of experimental animals preceding the appearance of lung cancer. The changes described are, on the whole, similar to;those seen by Auerbach et al. in the bronchial epithelium of heavy cigarette smokers and by others in, patients with lung cancer. The hyperplastic lesions in animals do not invariably develop into cancer. This appears to be the case also in man (14). In view of these observations, it seems probable that some of the lesions f'ound in the tracheobronchial tree in cigarette smokers are capable of de- veloping intb lung cancer. Thus, these: lesions may be a link in the patho- genesis of lung cancer in smokers. SuNtmnRY: Several types of epithelial changes are much more common in the trachea and bronchi of cigarette smokers, with or without lung cancer, than of non-smokers and of patients without lung cancer. These epithelial 172

changes are (a) loss of cilia, (b) basal cell hyperplasia, and (c) appearance of atypical cells with irregular hyperchromatic nuclei, The degree of each (if the epithelial changes in general increases with the number of cigarettes ,moked: Extensive atypical changes have been seen most frequently in men who smoked two or more packs of cigarettes a day. Hyperplasia without ahypical changes was seen in the bronchial tree of children under 15 years of age and in women~ non-smokers at all ages who died with pneumonia. Women cigarette smokers, in general, have the same epithelial changes as ,Io menismofcers. However, at given levels of cigarette use, women appear !') show fewer atypical cells than do men. Older men smokers have many nu>re atypical cells thani do younger men smokers. Men who smoke pipes 'Ir cigars have more epitheliall changes than do non-smokers, but, have fewer , 6ungestihan d'o cigarette smokers consuming approximately the same amount -i' tobacco. Male ex-cigarette smokers have less hyperplasia and fewer 3tyIpical!cells than d'o current cigarette smokers. CoNcLUS[oN:-It may be concluded on the basis of human and experimental idence that some of the advanced epithelial hyperplastic lesions with many.it\"pical cells, seen in the bronchi of some cigarette smokers, are probably I, remalignantim fl'PI\'G OF LUNG TUMORS Historical aspects of the typing of lung tumors in relation to possible otiological agents are reviewed in the section on Retrospective Studies, His- t-dogic Types, Krevberg 1196, 196) noted that the increase of lung cancer in recent dec- lirs seemed to occur for only certain types of lung cancers (his Group I), ~rrl that other typesdid not increase (his Group II)~. Kreyberg''sclassifica- ~:l)n is compared with~ the World Health Organization classification in TAIile 8. His Group I includes epidermoid carcinomas and! small-cell' ana- i lhstic carcinomas. His Group II includes adenocarcinomas and a few rare tvpes. He postulated that a determination of the ratio between Groups I nd II is a good index of the occurrence and magnitude of an increase im lung cancer in a: given locality and his epidcmiologic studies linked the increase almost entirely to the use of cigarettes. His thesis has been aa cepted by many whilc disputed by others. The results of the study of lung cancer at! Los Angeles County General Hospital' (LACGH) by Herman and Crittenden (167) did not confirm Krey- berg's conclusions. These investigators, analyzing the autopsy data on lung cancer from 1927 to 1957 at LACGH's observed a marked increase im the number ofl lung cancer cases as had been noted by many other investigators. However, the ratio of Kreyberg's Group I to Group II had not changed per- ceptibly over this period and was notably lower than in~ other series studied. The Committee on Smoking and Health sponsored a workshop in which~ slides from coded cases of lung cancer from four different institutions in~ three areas ofl the United States were typed "blind" by Dr. Kreyberg an& pathoingist's from the cooperat'ing institutions.' There was good agreement a; to: typing. The low ratio of Group I to Group II cancers at'. LACGH was confirmed. When typing of the reviewed cases was compared witL smoking ' Workshop on typing of lung tumors held in Washington, D.C., April 11, 1963. 173

TABLE 8.-Relation between WHO and Kreyberg classi fccations of lung tumors WHO classiBCation I A. F,piUhetial Tumors 1. Epidermoid carcinomas---------------------------------------------------------- a. highly differentiated b. moderately differentiated c. slightly differentiated 2, Smallaeell anaplastic carcinomas------------------------------------- ------------ a. with ovalcell structure ("oat:cel]" carcinoma) 8. Adenocarcinomas ---------------------------------------------------------------- a. acinar (with or without formation of mucus), b. papillary (with or without.formation ofimucus) e. tumors with a predominance of "large cells"'some of which show forma- tion ofiglands andJor productioniof mucus. 4. Large-.rll undifferentiated carcinomas_-----_----------------------------------- 5. Combined eqidermoid and adenocarcinomas-_----_------------___--___---_ Fi. Bronchiolo-alteolar cell carcinomss.--------_----------------------------------- 7. Carcinoid tumors (solidi trabecular, alveolar)-----------------_---_---______ 8. 'Pumors of mucous ghlnds-------------------------------------------------------- a. cylindroma b. mucor,pidermoid tumors ~ 9. Papillomas of the surface epittielium__--------_-------------------_------_-- a. epidermoid b. epidermoid with goblet cells. P..,Sarcomas- ---------------------------------------------- ------------------------------ C., Combined Tumors of EpitheliaLand Mesenchymal Qella------------------ _.------------- D: hfesotheliomas ofthe Pleura------------------------------------------------------------- li Localized 2. Diffuse E., Tumors L'nclassifted~ ffreyberg classiflea- tion r Group I Group I Group II Other i' Othcr Group II Group II Group SI Other Other Other Other I Committee on Cancer of the Lung, World Health Organization. i'Kreyherg, L. Histological Lung Cancer Types. A Morphological and Biological Correlation. Nor- wegian Universities Press, 1862,, 3 Types marked "other" are not includediin either of Kreyberg groups. histories, moreover, it became evident that both Group I an& Group II were increased' among heavy smokers. Several factors were recognized' to influence Group I/Group II ratios: (a)' source of material (for example, significant differences in the ratio were found between autopsy and surgical materials, an& between surgical materials obtained by biopsy and by resection during operation for lung cancer)~; (b) failure to autopsy certain cases which were judged to be inoperable (the patient being sent home as incurable); (c) the fact that Group I (squamous and oval-cell) carcinomas are more likely to be among the operable cases and among those accessible to bronchoscopy, and (d)) variations in selection of patients in different institutions. An independent review of the histopathology of 1,146 lung cancer cases from the U.S. veterans study (policyholders) by Dorn, Herrold and Haens- zel (Table 9) (89) showed high mortality ratios for both Group I and Group II cancers in current heavy smokers (~over 20! cigarettes/day), al- though Group I had a higher mortality ratio (31.2) than Group' 11 (7.2). Another study of! Haenszel on white females (152), as well as studies of female patients at Massachusetts General Hospital (54!), Roswell. Park Memorial Institute (133), Presbyterian~ Hospital (323), and Washington University (260), indicated that adenocarcinoma is also contributing to the increment of lung cancer in women. CoNCLUSIONS-(a) The histologicall typing of lung, cancer is reliable. However, the use of the ratio of Group I and~ Group lI is an index to the mag- nitude of increase in lung cancer is of limited value. 174

TABLE 9.-Mortality ratios for cancer of the lung by smoking class and by type o f' tumor, U.S. veterans study All Deaths (]roup I Group II Nonsmokers I ------------------------------------------------------- 1.01 1.0 I 1.01 Pipe and7or ciear smokers _ ______________________ ______________ 1.5~ 2,2 0.61 CiRarette smokers, totai =_ _______________ --------------------------- 8.2 15.4 5.1 Current Total ------------------------------------------------------- 10. 0 18.9 5.A, <= 2t)'CiearettPSlda}"__________________________________________ 7.1 12.9 5.1 >20~ciearettes/day------------------------------------------ 1&01 31.2 7.2 Discontinued (By Maximum Amt. Ever Smoked) Total_ ---------------------------------------------------- 4.7 8.4 3.7 <= 20 ~ciearettes!day------------------------------------------ 3.5 6.6 27 >21)'Clgarettesiaay_°____ -------------------------- 7.4 12,1 5.6 Includes occasional Ismokers. ~ Includes men who werevsing pipe and/or cigars in addition to cigarettes: Source: Dorn, H. F., Haenszel, W. and Herrold, K. (89) (see Chapter 8 also): (b) Squamous and oval-cell carcinomas (Group I) comprise the pre- dominant types. associated with the increase.of lung, cancer in both males andi females. In several studies, adenocarcinomas(Group II) have also increased in both sexes although to a lesser degree. Evaluation of the flssociation between' Smoking, and Lung Cancer It is not practical to attempt an experiment ini man to test whether a causal relationship exists betweeni smoking of tobacco and lung cancer. Such an experiment would imply the random selection of very young subjects living under environmental conditions as' nearly identical as possible, and rand'om selection of those who were to be smokers and those who were to be the non-smoker controls. Their smoking, and other habits would need to be held constant f'or many years. Because of the relatiively low incidence of lung cancer in the human population, both~ the test and the control groupss would have to be very large. As such an experiment in man is not feasible, the judgment of' causality must be made on other grounds. The epidemiologic method, when, coupled with cltinieal' or laboratory observations, can provide the basis from which j udgments of causality may be derived. INDIRECT' MEASURE' OF THE ASSOCIATION The crudest indieators of an association between lung cancer andl smoking are. cert'ain, indirect measures: (a) a correlative increase in lung cancer mortality rates and in per capita tobacco consumption in a number of countries, (76, 138; 211, 239, 255), and (b) disparities between male and female lung cancer mortality' rates correlated with corresponding differences in smoking habits of men and women, both by' amounts smoked and duration of smoking (65, 151, 344). Figure 9 shows a correlation of crude male death rates from lung, cancer in 11 countries in~ 1950'with the per capita consumption of cigarettes in these countries in 1930, as presented by Dolt (76). Assuming a 20-year induction period for the appearance of lung,cancer, Doll found a significant correlation (0.73+0.30) between the death rates. and cigarette consumption. Since virtually all the tobacco consumption in 1930 was among men in the countries 7 14-422 0-64-13 175

CRUDE MALE DEATH RATE FOR LUNG CANCER IN 1950 AND PER CAPITA CONSUMPTION OF CIGARETTES IN 1930 IN VARIOUS COUNTRIES. i GREAT BRITAIN ~ RINLAND ~ SWITZERLAND r _ 0•73'*- 030 HOLLAND ~ U.S.A. DENMA'RK~ ~ AUSTRALIA ~ CANADA *SWEDEN ~NORWAY' ~ ICELAND 25 0 5 00 7 50 10 00 12 50 150 CIGARETTE CONSUMPTION FicuxE 9: Source: Do11~ R (76) represented (Great Britain, Finland„Switzerland,,Holland, the United States, Australia, Denmark, Canada, Sweden, Norway, and Iceland)',, it seemed reasonable to compare the annual per capita consumption of each country with the crude, male lung cancer death rates. It will be noted in Figure 9 that the data from the United States show a relatively low death rate in relation to cigarette consumption. Doll sug- gested two explanations: the influence of a higher proportion of young 176 0

people in the U.S. population and the method of smoking, with the U.S. smokers consuming less of each cigarette than, the British smokers. Since Doll's explanations of the discrepancy, additionall information has become available. Studies on length of cigarette butts discarded have shown Amer- ican discards to be significantly longer than British discards; 30.9 mm (156) and 18.7 mm (85) respectively. Also, there is a significantly greater percentage of smokers in Great Britain than in the United States in the agee groups in which lung cancer occurs at high rates (52.6 percent in 60+ year age group and 29.2 percent in 65 + year age group respectively ). Strictly comparable data do not exist on inhalation~ practices for the two countries. Such information would aid in explaining this discrepancy ass well as a similar disparity between~ Holland and Great Britain. In Holland (156) the length of the cigarette butts was almost the same as in~ Great! Britain (1I9.7mm), but the crude male lung cancer death rate in Hollan& was significantly lower than in Great Britain. This correlates well, as shown in Figure 9, with the annual per capita consumption of cigarettes in Holland which has been much lower than in Great Britain. It should be mentioned that differences in intensity of air pollution and industrial exposures in these countries have not been taken into accountL However, for reasons given below, these latter factors do not account for the magnitude of the difference in incidence of lung cancer nearly as well as the amount of each cigarette smoked and the degree of inhalation. Finally, the varying composition of the tobacco in the several countries was not considered in these studies. An elaboration of the disparities between male and female lung cancer mortality rates and their correlation with differences in smoking patterns is also in order, for the sex disparity has also been posed! as contradictory to the smoking-lung cancer hypothesis. Although the opponents of the hypothesis, pointing to the sex disparity (116, 229), have minimized the differences in smoking habits, the fact remains that the magnitudes of the differences are quite large. In a representative cross-sectional survey of smoking habits coupled with the Current Population Survey of the Bureau of the Census in~ 1955, Haenszel, et al. (151) found the following disparities between male and female smoking, patterns: 1. Whereas only 22.9 percent of males had never smoked, 67.5 percent of females had not. 2. Males showed relatively little variation among the component age groups in~ percentage not smoking, whereas females after age 25-34 showed a consistently increasing percentage of non-smokers in successively higher age groups (Figure 10). 3. Sixty-five percent of males smoked cigarettes as compared with 32 percent of females. 4. Cohort analyses revealed the adoption of cigarette smoking late in life for both males and females among, cohorts born before 1890; but male cohorts born after 1900 successively began to smoke earlier in life. Large-scale adoption of cigarette smoking by women did not occur until the decades of the 1920's and 1930's: 177

PERCENTAGE OF PERSONS WHO HAVE NEVER SMOKED, BY SEX AND AGE, UNITED STATES, 1955 Age (in years) 18 and under 18-24 25-34 35-44 45-54 55-64 65 and over ~"r,.. . .?1.:.. . . r rr ~" j t Y, ~~S ~~J23 Lf \L P s j ` I ~'~ t~~`JS + ! ~ 1 ~ N y ir Ts~ ~~»~.1 PERCEN'rNEVER',SMOKED _ MALES M FEMALES FICURE 10: Source: I$aenszel„ W'. M. et; all (151) 5. The median age at which males started smoking has remained fairly stable for the several age cohorts: from 19.3 years for ages 65 and over to 17.9 years for age 25-34;, the median age that females started smoking has dropped diramatically from 39.9 years for the age group 65 and over to 20.0 years for age 25-34. 6. Males in alli age groups smoked considerably more cigarettes per day than did'femalas. In ages 55 and over, 6.9 percent of the 178 20 40 60 80 1oa

males smoked more than a pack a day,, compared with only 0.6 percent of the females. Although urban-rural and' geographic re- gional differences were noted, significant disparities between male and female smoking were maintained' throughout. Thus it can readily be deduced that these findings are consistent not only with the sex disparity in lung cancer mortality but also with the slower but nevertheless continuing rise im female lung cancer mortality. British: studies (344) also: revealed that females, especially before World War II, consumed much~ less tobacco than did males. A correction for the marked disparity im smoking habits of males and females reduced the ob- sem~ed 5-fold excess of male lung cancer deaths to: a 1.4•fold excess as of 1953 (149). Supporting, this finding are the data f'rom two retrospective studies (147, 152 ): in which the age-adjusted'lung cancer death rates ini 1958- 59 among male and female non-smokers were 12.5 and 9.4 respectively for a ratio of 1.33 (145). This residual ratio, implies that there may be other factors operating to produce a: portioni of the sex differential in mortality. DIRECT MEASURE OF THE ASSOCIATION For a direct measure of the association between, lung cancer and smoking it is, of course, essential that', both variables or attributes be measured in the same populations: The 29 retrospective studies, described earlier, consider smoking (usually kind, amount, and duration) andinon-smoking among cases of lung cancer and individuals without lung cancer. The seven prospective studies consider the occurrence or lack of occurrence of' lung, cancer among smokers and non-smokers. ESTABLISHMENT OF AssOCIATION.-A number of investigators, though ac- cepting the existence of an association, have questioned its signipicance: im terms of a causal hypothesis (58, 102, 114, 115, 116, 117, 141, 178, 218, 219, 287, 288, 298, 299). Some of these doubts have been on #hee basis of a possible genetic underlay which might determine bot'h, smoking and lung cancer (114, 115, 116, 117). Some have followed contradictory obser- vations in the dissenter's own work (58, 102, 141), incorrectly assessed evi- dence of lung cancer mortality trends, or the belief that the causal hypothesis requires cigarette smoking to be the sole cause of lung cancer(178, 287, 288). Others believe that the lung cancer rise is spurious and can be at- tributed either to improvements in diagnosis and reporting_ (218, 219, 287, 288, 298, 299) or to the aging of the populatiom In the latter explhnation they ignore the fact that aging of the population does not affect age-specific mortality rates which, f'or lung cancer, are also rising, with the passage of time. Still others express doubt on, the basis of the lack of a concomitant rise in cancers of the oral cavity (178, 298) or of the skini of the fingers (178). Finally, some doubts have been based on supposed incongruencies between the cigarette-smoking,hypothesis and urban-rural as well as sex dif- ferences in lung cancer mortality (116, 178, 229);. There are a few investi- gators who maintain that the association may he spurious or that it has not been proved (22, 23, 24, 228, 229, 230). A number of these objections have been assessed in earlier discussions in this sectfion;, others willl be evaluated below. These latter criticisms have revolved about defects inherent in the retrospective or the prospective 179 . . . , . _, _ ,. , • -,. . .

methods of approach, biases of selection in either method, biases of non- response, the validity of the results in the early phases of a prospective study, and the misclassification of both variables: smoking habits and lung, cancer. spective and prospective studies, diagnostic accuracy was not a critical factor im the establishment of an association between smoking and lung cancer. The qpestion of selection bias is,, of course, a more complicated problem. Several criticisms have been leveled at both the retrospective and prospective method's: Although in retrospective studies the selection of a control group may pose a more serious problem, even the selection of the case material may interject difficulties. It has been claimed by Berkson (24) that the selection of hospitalized cases may lead to bias if smokers with lung cancer in the general population. It would thus appear that in the data from retro- studies yield' relative risks of lung cancer by various smoking categories whi& approximate those found in the Doll and Hill: study (83)) where, obviously, diagnostic evidence would be more readily available than for those with less well-established diagnoses. Most of the prospective underestimated has been presented by Hammond and Horn~ (162, 163), who f'ound higher relative risk ratios among smokers for confirmed cases than smoking demonstrated' in all of the studies. Evidence that the specific estimates of'~ risk f'or lung cancer among smokers actually might have been rates higher than those for non-smokers and with a gradient by amount of from any cause were involved in the calculations, with the cigarette smoker In retrospective studies the investigator can confine himself to cases with accurate diagnoses. In the prospective approach, accuracy of diagnosis may not always be attainable, but all cases must be included. In assessing the results of the prospective studies it must be kept in mind that all deaths spective studies, this factor is less of a problem. history would thus appear to be markedly above the critical level for the firm establishment of an association by the retrospective method. In pro- carcinoma (86, 150;,163, 3113, 375). The reliability of response to smoking Finally,, this bias cannot have influenced the findings of several: studies in which a significantly greater proportion of cigarette smokers and heavy cigarette smokers were associated with epidermoid cancers than with adeno r after interview, were found not to have the disease, reported smoking, his- tories similar to the controll groups and not the lung cancer groups (84). patient and interviewer were unaware of the diagnosis of lung cancer, the smoking histories having been obtained before the diagnosis was made (207). Furthermore, patients initially believed to have lung, cancer who, of smoking habits (158, 229). In at least one retrospective study, both tively minor in a reliability study by Finkner (113) ; and that, in at least three prospective studies, in which subjects were requestioned on smoking habits at intervals of at least two years, the replies were closely reproducible (87, 88, 157, 159, 162, 163), particularly if no illness had intervened (159). With regard to the retrospective studies, it has also been suggeste& that knowledge of the illiiess might' have introduced bias in relation to histories results highly consistent with data on tobacco production and taxation (151) ; that classification errors in terms of amount of smoking were rela- It should be noted that the Current Population Survey of 1955 yielded 180

t i were more often hospitalized than~ non-smokers with the disease. However, nearly all lung, cancer cases are hospitalizeds a point which; he concedes, would thus minimize this bias. Furthermore, several retrospective studies have surveyed all the cases in the area regardless: of hospitalization (238, 335), or all deaths regardless of cause or hospitalization (379). Another criticism of patient selection in retrospective studies deals with the danger that, in studies highly cross-sectional in time, if smokers live longer than non-smokers, there would obviously be more smokers in the disease group, and thus a spurious association of disease with smoking would result 1254)'. There is no evidence for this basic assumption. Furthermore, it is inapplicable because almost all the retrospective studies were actually based on newly diagnosed cases collected serially over an interval of time long enough to remove this bias. Control groups pose a problem in retrospective studies. In 27 of the 29' retrospective studies (exceptions are references 147 and 152)~ the controls were subjects without lung cancer, such as patients with other cancers, with diseases other than cancer, or so-called normals selected from the population. Analysis of the prospective studies proved that the biases interjected by the selection of sick controls in the retrospective studies actually operated' to produce an underestimation of the association, for it has been shown~ that a number of other diseases are also associated with smoking. Furthermore, several studies have, in addition to controls with other diseases, selected a second set of random controls from the general population (82, 150; 222)', only to find that the association utilizing sick controls, significant though it, proved to be,,was intermediate to the association utilizing random~population controls. The problem of selection bias in prospective studies is much more subtle, since there may be self-selection, on the basis of illness existing, at the time the study begins. This is essentially a problemi of non-response which has been handled in detail in Chapter 8! The character of this non-response presents at least two nuances: a combination of self-selection and operat'or selection, as in the volunteer studies of Hammond and Horn (162) and Ham- mond (157) and the response to questionnaires in a total population study such~ as Dorn's (88)!. Suffice it to say at this point that, regardless of whether there is over- representation of sick smokers or well non-smokers or both in a prospective study, with the passage of time more deaths of sick persons would occur (without regard' to the independent variable of smoking). Thus the death rates of! smokers would tend to approach the death rate of non-smokers, removing the original selection bias and providing greater confidence in the residuali association of the death rate with smoking if it persisted. In two of the studies (157, 162, 163) exclusion of ill persons on entry did take place. Further, in the studies that provide this comparison, the high lung cancer mortality ratio of cigarette smokers was maintained with the passage of time. In the Dorn study the mortality ratio was 9:9 after three years experience and 12.0 after six years experience; the Hammond study gave 9.0 after 10.5 months (157) and 9.6 after 22 months, while Doll and Hill (84) showed that the gradient of increase in lung cancer death rate with increasing amount smoked appeared consistently in each of the first four years of their studiy. 1 181

This also weakens the criticism by Mainland and Herrera (230) of the use of non-professional volunteer workers for subject selection. Thus it would appear that an association between cigarette smoking and lung cancer does indeed exist. CAUSAL SIGNIFICANCE OF THE ASSOCIATION'.-AS already stated, statistical methods cannot establish proof of a causal relationship in an association. The causal significance of an association is a matter ofjudgment which goes beyond any statement of statistieal' probability: To judge or evaluate the causal significance of the association between cigarette smoking and htng cancer a: number of criteria must be utilized, no one of which by itself is pathognomonic or a sine qua non for judgment. These criteria include: (a) The consistencyy of the association (b) The strength of the association (c) The specificity of the association (d) The temporal relationship of' the association (e) The coherence of the association. THE CONSISTENCY OF THE ASSOCIATION.-This cIiterioni implies that di- verse methods of approach in the stud'y of an association will provide similar conclusions. It~ is noteworthyy that all 29 retrospective studies found' an asso- ciation between cigarette smoking, and lung cancer. The very nature of the criticisms leveled against these retrospective studies indicates a diver- sity of characteristics of approach and, for that matter, marked differencess in shortcomings which have been discussed in~ detail above. It is indeed remarkable that no reasonably we111 designed restrospective study has found results to the contrary. Seven prospective studies have also revealed highly significant associations. Where relative risks could be calculated on the basis of some reasonable assumptions in some of the retrospective studies, a consistency not only among them (38, 82, 147,,152, 222, 283, 301, 313, 381) but also with the prospective studies could! be demonstrated. Such a situation would prevail if the association were either causal, or spurious on the basis of an unknown source of bias. It is difficult to conceive of a universally acting bias in all the diverse approaches unless it' be a consti• tutional genetic characteristic or one acquired early' in life, which will be discussed later in the section, Constitutional Hypothesis. Two studies of tobacco workers (58, 1411) have been cited as inconsistent with the 29 retrospective and particularly the 7' prospective studies cited in detail in the early portions of this section. Both these studies can be dis- missed because of major defects in methodology and concept. The heavier smoking among the tobacco workers in, these studies was considered'y but no comparison of observed-to-expected rates was made om the basis of smoking ' classes within this population. Furthermore their conclusions are based on expectancies in the general population without regard to the fact that persons with acute, chronic, or disabling illness are initially excluded from employ- ment and that those developing permanent illness are lost to employee rolls. THE STRENGTH OF THE ASSOCIATIO:V.-The most direct measure of the strength of the association between smoking and lung cancer is the ratio of lung cancer rates for smokers to the rates for non-smokers, provided these two rates have been adjusted for the age characteristics of each group. An- other way of expressing this is the ratio of the number of observed' cases 182

in the smoker group to the expected number calculated by apply ing the non-smoker rate to: the population of smokers. This provides us with a measure ofl relative risk which camyield a judgment on the size of the e fject of a factor on a disease and which, even in the presence of another~ agent without causal effect, but correlated with the causal agent'6 will not be obscured by the presence of the non-causal agent. Cornfield! et al. (62) have not only provided us with a detailed analysis of the applications of both absolute and relative measures of risk, but have also: demonstrated the useful• ness of the relative risk measure in judging causal and non-causal effects with mathematical proof of their statements. An absolute measure of difference in prevalence of a disease between populations with~ or without the agent (e.g., cigarette smoke), where the agent may be causal in its effect on several diseases, can provide us with the means of appraising, the public health significance of the disease, i.e. the size of the problem, in relation to other diseases. It is less effective for appraising the non~causal nature of agents having apparent effects, the importance of one agent with respect to ot}ier agents, or the effect's of' refine- ment of disease classification. This, Cornfield and his co-authors (62) have demonstrated. In essence, then, a relative risk ratio measuring the strength of ani asso- ciation provides for an evaluation of whether this factor is important in, the production of a disease. In the data of! the nine retrospective studies for which relative risks of lung cancer among smokers and non-smokers were calculated, the ratios were not only high in all of the studies but showed a remarkable similaritv in magnitude. More importanty in the seven pros- pective studies which inherently can~ reveal direct estimates of risks among smokers and non-smokers, the relative risk ratios for lung cancer were uni- formly high and, again, remarkably close in magnitude. Furthermore, the retrospective an& prospective studies yielded quite similar ratios. Important to the strength as well as to the coherence of the association is the dose-effect phenomenon. In every prospective study that provided this information, the dose-effect was apparent, with the relative risk ratio increas- ing as the amount of tobacco (84)i or of. cigarettes (25, 88, 96, 97, 163)) smoked per day increased (Table 5). Even the retrospective studies for which relative risks were calculated by amount smoked' (38, 147, 152, 222) showed similar increases ini risks with amount smoked (Table 4). It may be estimated from the data in! the prospective studies that, in com- parison withi non-smokers, average smokers of' cigarettes have a 9- to 10-fold risk of developing lung cancer, and heavy smokers, at least a 20-fold risk. Thus it would appear that the: strengihi of the association between cigarette: smoking and lhng cancer must be judged to be high. THE SPECIFICITY oF' THE ASSOCLATION.-This concept cannot be: entirely dissociated fromithe con,cept inherent inithe strength of the association. It implies the precision with which one component of an associated pair can be utilized to predict the occurrence of the other, i.e., how frequent!ly the presence of one variable (e.g., lung, cancer) will predict,, ini the same indi- vidual„the presence:of another (e:g., cigarette smoking). In a discussion of the specificity of the relationship between any factor possibDy causall in character and a disease it may produce, it must be rec-

l ognized that rarely, if ever, in our biologic universe, does the presence of an agent invariably predict the occurrence of a disease. Second, but not less important, is our growing, recognition that a given disease may have multiple causes. The ideal state in which smoking or smoking of cigarettes and every case of lung cancer was correlated one-to-one would pose much less difl'iculty in a judgment of causality, but the existence of lung cancer in non-smokers does indeed complicate matters somewhat. It is evident that the greater the number of causali agents producing a given disease the less strong and the less specific will be the association between any one of them and the total load of the disease. But this could not be posed as a contra- diction to a causal hypothesis for any one of them even thoughithe predictive value of any one of themi might be small. For example, the pathologist who examines a lung at autopsy and finds tubercle formation and' caseation necrosis would almost invariably be able to predict the coexistence of tu- bercle bacilli. Experience has shown that the lesions are highly specific for Mycobacterium tuberculosis. On the other hand,, a clinician may encounter a combination of signs and symptoms including stiff neck, stiff back, fever, nausea, vomiting, and! lymphocytes in the spinal fluid. Experience has re- vealed that any one of a number of organisms may be associated with this syndrome: polio virus, ECHO viruses, Coxsackie viruses and Leptospirae, to name but a few. The predictability of the coexistence of polio virus per se is rather low. In other words, the syndrome as noted is not very specific for polio virus. This may well be the condition which prevails in coronary heart disease where the mortality ratio is between 1.6 and 1.8 or a 60 to 80 percent excess among smokers of cigarettes. If this ratio is appli- cable to the entire population from which the sample data are derived, another way of expressing,this relationship is that, of the total load of coronary heart disease mortality among males only 61 to 64 percent is associated with ciga- rette smoking, The large residuall among non-cigarette smokers implies either other causes in addition to smoking, or, as a somewhat greater possi- bility, factors actually causally related to coronary heart disease and fre- quently, but not invariably, associated with smoking. However, in lung cancer, we are dealing with relative risk ratios averaging 9.0 to 10.0 for cigarette smokers compared to non-smokers. This is an excess of 900 to 1,000 percent among smokers of cigarettes. Similarly, this means that of the total load of lung cancer in~ males about 90 percent is associated with cigarette smoking. In order to account for risk ratios of this magnitude as due to an association of smoking history with still another causative factor X (hormonal, constitutional, or other), a necessary con- dition would be that factor X be present at least nine times more frequently among smokers than non-smokers. No such factors with such high relative prevalence among smokers have yet been demonstrated. Another aspect of specificity requires some insight. Several critics of the causal hypothesis haved questioned the significance of the association on the grounds that the existence of an association witL such a wide varietyy of diseases, as elicited in the prospective studies, detracts from specificity for any one of them (22, 7). In a sense, this viewpoint is an exaggeration, for not all the specific disease mortality ratios in excess of 1.0 are large 184

enough to warrant secure judgments of the strength of the association and of causal significance. A detailed discussion of this latter point has been presented' in Chapter 8. The number of diseases in which the ratios remain significantly high~ after consideration of the non-response bias, is not so great as to cast serious doubt on~ the causal! hypothesis. Even if! we were: dealing with a single pure substance in the environment, the production of a number of disease entities does not contradict the hypothesis. It is well known that a single substance may have several modes of action on the several organ systems and that neither inhalation nor ingestion implies actioni restricted' to the respiratory or digestive tracts, respectively. In tobacco we encounter a complex of substances whose additive and synergistic characteristics before and after combustion remain inadequately explbred. It would not be surprising to find that the diverse substances in tobacco smoke could produce more than a single disease. Actually, the finding that an excess risk for smokers does na occur for every one of the causes of death reinforces the specificity of the excess risk for those causes where the excess is significant. Thus, it is reasonable to conclude that the association between cigarette smoking and lung cancer has a high degree of specificity. TEMPORAL RELATIONSHIP OF'ASSOCIATED VARIABLES.-In chronic diseases, insidious onset and ignorance of precise induction periods automatically present' problems on which came first-the suspected agent or the disease. In any evaluation of the significance of an association, exposure to an agent presumed to be causal must precede, temporally, the onset of a: dls- ease which it is purported to prodtrce. The early exposure to tobacco smoke and late manifestation of lung cancer among smokers, seem, at least superficially, to fulfill this condition. This does not, however, preclude the possibility that such patients who, many years after the initiation of smoking are diagnosed as having lung cancer, may have had the primitive cellular changes or anlage (as postulated by Cohnheim) before the advent of their smoking. However, no evidence has thus farr been, brought forth to indicate that the initiation of the carcinomatous process in a smoker who developed lung cancer antedated the onset of smoking. COHERENCE OF THE ASSOCIATION.-A final criterion for the appraisal of causal significance of an association is its coherence with known facts in the natural history and biology of the disease. In the lung cancer-cigarette smoking relationship the following should be noted: (1. ) Rise in Lung Cancer Mortality: The increases in per capita consump- tion of cigarettes (76, 138, 211, 239, 255) and the age-cohort patterns of smoking among males and females (151i) are highly compatible with a real increase in lung cancer mortality. (12.) Sex Differential in Mortality.-The current sex differences in tobacco use (151, 160), the pronuonced differences in age-cohort patterns between males and females, particularly in the older age groups-over 55 (151) and over 50 (160)-and the more recent adoption of cigarette smoking by women (151, 344)~ are all compatible with the high male-to-female ratio of lung, cancer mortality and also with the lower ratios of 30 years ago (130). Haenzel and Shimkin (149) developed a statistical model for determining whether the results of the retrospective and prospective studies 185

"were compatible with the information on distribution of'~ lung cancer and thus valid for generalization to larger' populations." Applying their model of scheduled relative risks to data on cigarette consumption~ by age and sex derived from~ the Current Population Survey of 1955, their predicted male/ female ratio came quite close to the observed ratio in the general population. (3J' Urban-Rural Differences in Lung Cancer Mortality.-A number of sources in this country (90, 136, 1A$; 1I75„238, 252) and overseas (82, 199, 335) have firmly established the existence of an urban excess in lung cancer mortality. Because of the possible implication of an air pollution effect, this urbanilung cancer mortality excess has been cited as either being incom• patible with the smoking,lung, cancer hypothesis (1784 229)i or minimizing its significanee (69, 70, 71„ 101, 190). The data of the studies of a number of authors have clearly shown, however, that although adjustment: for smoking history does not equalize the urban-rural lung cancer mortality ratio (149), control on the urban-rural residence factor nevertheless leaves a large mortality risk difference between smokers and non-smokers. Haenszel has demonstrated this fact in his two population sample: studies on males and' females ('147, 152). Mills and Porter (238) demonstrated a much greater effect of smoking, on lung, cancer mortality thani the urban-rural factor. Stocks (335) also demonstrated that though smoking is not the sole factor, as manifested by a rural~ urban~ gradient among non-smokers, it represented~ a much more preponderant~ factor in accounting for the lung cancer mortality than did presumed air pollution or at least urbanization. He noted that his regression lines on amount smoked were parallel for the different' areas in England and North~ Wales and that the urban-rural mor- tality ratios declined from 2.3 among non-smokers and 2.5 among light cigarette smokers to unity among heavy smokers. The first prospective study of Hammond and Horn (162) also showed higher lung cancer mor- tality rates irrespective of residence. In Dean's second study in South Africa (70), in which he corrected the critical defect in his first study of not studying the smoking habits of the test populations, he continued to emphasize urbanization or air pollution as the major factor in lung, cancen A perusal of his data; however, shows that by controlling on smoking, the lung cancer mortality rates are doubled by the factor of country of ori- gin; whereas, with country of origin controlled„the lung cancer risk increases from 3 to 20 times as the amount of cigarette smoking increases. After smoking, patterns are controlled, the residuals in the urban over rural excess imply other factors, although~the smoking factor preponderates in the urban- rural differences in lung, cancer mortality in all of these studies. Thus the urban excess of lung cancer mortality is not incompatible with the smoking- lung cancer hypothesis. (4.) Socio-Econornic Differentials in Lung Cancer Mortality.-Distinct socio-economic differentials have been demonstrated' convincingly in the epidemiology of lung cancer. Cohart (57) found a 40-percent excess of lung cancer incidence among the lowest economic class (both sexes) in the New Haven population, and the morbidity survey by Dorn and Cutler (90) demonstrated a distinct gradient by income class among white males, with the highest rates among the lowest income groups: In Denmark, Clemmesen and Nielsen,, utilizing, data derived from the Danish Cancer Registry, also 186

i i i s found a much higher incidence of lung cancer among males in the lower rental groups (55). In relation to the contribution which smoking makes to this differential, there is evidence that cigarette smoking mayy be inversely related to socio-economic status. The components of socio-economic status are, at best, difficult to define, compartmentalize, and measure. Direct inquiries of family income are rare and, when made, are subject to con- siderable error. Studies based on rental values, as in the Danish studies, express more adequately socio-economic status. Another high correlate of income is educational achievement, which has been considered by Hammond in his current prospective study (161) in relation to smoking, habits. Among males, the highest proportion of ciga- rette smokers (past or present) and the:highest proportion of those smoking 20 or more cigarettes per day (past or present) were found in the group classifiedl as "some high school education (but not high school graduates)," whereas the lowest': proportion was found'among college graduates. The highest proportion of ex-cigarette smokers (as of' 1i961-62) was among college graduates. Although the relation of smoking and educational level in women is more complicated, the group which had been to college also had the highest proportion, of ex-smokers. Finally, college graduates had the next to the lowest proportion of heavy cigarette smokers. None of the female gradients was a sharp as those for the men. Occupation has also been utilized as a measure of socio-economic status, but this measure obviously has severe limitations. 1`o definitive study has been reported in which lung cancer has been correlated with occupation and smoking class; thecurrent! Hammond (157) and Dorn ('88)~ prospec- tive studies may ultimately yield definitive findings in this regard. However, some indirect evidence of a partial correlation between the observed higher lung cancer death rates in lower socio-economic groups may be found in Table 26 of the Survey of Tobacco Smoking Patterns in the United States. (151). Keeping in mind that type of occupation is not a critical index of income, it will nevertheless be noted that the professional an& farmer an& farm manager groups had higher proportions of non•smokers among them than did the laborers and' craftsmen. This finding is in the proper direc- tion for compatibility with the socio-economic differential inilung cancer mor- tality but the disparity does not appear to be sufficient to provide a satisfying correction: In fact, in this U.S: study, analyses by amount of cigarettes smoked tended to obscure the ordering by social class. In Great Britain, however, the inverse relationship of socio-economic class to heavy cigarette smoking remained apparent (174)'. In the U.S: study, classification by industry showed the highest proportions of non-smokers to he in the pro- fessional and agricultural groups and the lowest among industries. Thus, though the measures are admittedly crude, they are compatible with the socio-economic differential in lung cancer mortality. (5.) The Dose-Response Relationship.-If cigarette smoking is an~ im- portant factor in lung cancer, then the risk should be related to the amount smoked, amount inhaled, duration of smoking, age when started smoking,, discontinuance of smoking, time since discontinuance, and amount smoked prior to discontinuance. Herein lies the-greatest coherence with the: known facts of the disease. In almost every study for which data were adequate 187 4W ~ ~ i C!t ~ A .4L

an& which was directed to amount~ of' smoking, duration of smoking, and age when smoking was begun, the associations or calculated~ relative risks (direa or indirect) revealed gradients im the direction of supporting a true dose effect. Where discontinuance, time since discontinuance, and amount smoked prior to discontinuance were considered in either retrospective studies or, with more detail, in prospective studies, these all showed lower risks for ex-smokers, still lower risks as the length of time since discon- tinuance increased, and' lower risks among ex-smokers if they had been light smokers. These findings have been described in detail in the section on Retrospective Studies. Some contradictory information has been presented in regard to inhalation of tobacco smoke. This is tlhe lack of association between inhalation and lung cancer as noted by Doll and Hill (82) alluded to earlier. These authors have begun ~ collecting data (in their prospective study) on inhalation for the mortality experience since 1958. These data are not presently available (80). However, until the current ongoing prospective studies will have yielded in- formation on this point in regard to lung cancer, four retrospective studies provide information on inhalation contrary to the Doll and Hill early nega- tive findings (38;,211, 222, 313). In two of these (222, 313) inhalation and amount of smoking were considere& and led to the provocative finding that'~ with increase in daily amounts of cigarettes smoked the differences in risks between inhalers and noninhalers diminished. There is no immediate ex- planation for this apparent discrepancy. Hammond has studied the smoking habits of the men and women in his current prospective study quite intensively (160). He has observed that the majority of! men (92.9 percent), who smoke cigarettes inhale, and of these the majority inhale "moderately" to "deeply." Pipe or cigar smokers inhale rarely. Combination smokers (i.e., cigarettes in combination wit.h pipes and/ or cigars)' inhale in proportions intermediate totliese. These findings become compatible with the hypothesis that' the degree of inhalation accounts f'or a gradient of lung cancer risks, high to low, f'or smokers of cigarettes only, combination smokers, and pipe or cigar smokers (Table 5)i. Am explana- tion of the diminishing differences in risks between "inhalers" and "non- inhalers" with increase in amount smoked might be obtained if a more obj ective measure of inhalation were available. (b.) Localization of Cancer in Relation to Type of Smoking.-Although historically a relationship between cancer and smoking was suspected by Holland (176)' and Soemmerring (322), with reference to the lbwer lip, it was not until the systematic, controlled study of lung, lip, pharynx, esophagus, colon and rectum cancers in relation to types of smoking by Levin in 1950 that significantly distinctive associations between localization of the cancer and type of smoking were elicited (1207). Levin noted that statistical sig- nificance was achieved for cigarette smoking and' lung cancer and for pipe smoking and lip cancer and stated'y "It is somewhat surprising that type of smoking is the associated factor, rather than the actual use of tobacco." Since then other studies have pointed up the relationship between type of smoking and localization of cancer. Sadowsky (301) in relative risk estima- tions of types of smoking and cancer site, also noted the highest significant values for cigarettes with lung, larynx and esophagus; for pipes with lip, 188

tongue and oral cavity; and for cigars with tongue and oral cavity. The complexities involved in a rational explanation for these phenomena: are legion, especially since critics of the smoking-lung cancer hypothesis would I J , point to no phenomenal rise of laryngeal cancer (only a slight rise for whites between 1930 and 1955) in the face of increased cigarette consumption. Although among cigarette smokers, the relative risk of mortality from lung cancer is presently greater than the relative risk for laryngeal cancer, the reverse seems to be true among cigar andl pipe smokers (Chapter 8, Tables 19 and 24)~. Furthermore, the per capita rise in cigarette consumption has been accompanied by a concomitant' decline in consumption of pipe and eigar tobacco, the smoke of which was not deeply inhaled. It is thus con- !1&' ceivable that the increase in cigarette consumption (and decline in cigar and pipe smoking)' couldl affect an increase in lung cancer more significantly than in lar n eal c er y g anc . ~~ f t Finally, there is no reason to assume that the susceptibility of the larynx to cancer equals that of the bronchus. Thus, a: reasonable explanation for I ~~ i the difference in localization and relative risk is apparent, especially when it'. is known that in certain industrial exposures in which the irritant is in, haled and lung cancer is associate& with such inhalation (;chromates), laryngeal and tracheal cancer is rare. It is, on the other hand, easier to visualize a mode ofi action for pipe and cigar tobacco in production of lip and tongue and other oral cavity cancers. Thus, none of these considerations de- tract~ from~ the coherence of' the association between, cigarette smoking and lung cancer. HISTOPATHOLOGIC EVIDENCE In earlier sections of this Chapter it has been noted that the application of tobacco extracts, smoke or condensates to the lung, or tracheobronehiall tree of experimental animals has failed to produce bronchogenic carcinoma, except possibly in dogs (289). In addition, no animal experiments have thus far been devised to duplicate precisely the act of smoking as it is practiced by man. However, that the lungs of experimental animals are susceptible to ear- cinogens, particularly polycyclic aromatic hydrocarbons isolated from to- A A' bacco~ smoke, has been demonstrated by a number of workers (5,,197; 302):. Of immediate import to, the smoking-lung cancer relationship is the observa- tion that the histopathologic characteristics off the cancers thus produced are similar to those observed in man and: are predominantly squamous in type. Furthermore, certain bronchial epithelial changes, sequentially observed prior to the malignant changes in animals exposed to these carcinogens are similar to those in the bronchial epithelium~ of human~ smokers (9). In this latter extensive and well~controlled! study, these changes were rarely seen among, non-smokers, but increased im frequency and intensity with thee number of cigarettes smoked daily by individuals without lung cancer and were most frequent and intense in patients dying of lung cancer (Table 6 of this Chapt'er). Ex-cigarette smokers and pipe an& cigar smokers yielded a higher frequency of such cellular changes than non-smokers but less than did current cigarette smokers. Thus, the histopathologic evidence derived from laboratory and clinical material support the cigarette smoking-lung cancer hypothesis. 189

CONSTITUTIONAL HYPOTHESIS GENETIC CONSIDERATIONS.-Thus far in the evaluation, the Committee has considered whether the available data; are consistent with the hypothesis that smoking causes cancer of the lung. The analysis must consider with equal attention the alternative hypothesis that both the smoking, of cigarettes and cancer of the lung have a common cause which determines both that an individual shall become a smoker and also that he shall be predisposed to lung cancer. This has often beenicalledithe constitutional hypothesis. How- ever, one should distinguish between the morphologic and physiologic char- acteristics of any individual, due to a given environment and those character- istics (phenotype) that are due to an interaction of hereditary susceptibility and! the environment. The characteristics of individuals studied'i in relation to smoking,have been numerous and varied. Some of them have been physical attributes such as physique or somatotype, height an& weight and their ratios, masculinity, anthropometric variables,, physiologic variables (heart rate, pu1Ge pressure, blood pressure, cholesterol levels), and physical activity; others have been psychosocial ( ineluding, personality) in character (Chapter 14). Cigarette smokers have been described as consuming more alcohol, drinking more black coffee, being, more neurotic, engaging, more often in~ athletics, and as being more likely to have at least one parent with hypertension or coronary disease (115U, 214, 235). Many studies have been poorly designed and controlled, others have yielded contradictory findings, and still others, by admission of their authors, have includ'ed characteristics that could either have been acquired or have been produced by smoking. None of these constitutional attributes have been included im a prospective stud'y of mor- tality from lung cancer fulfilling satisfactory epidemiological criteria; except for a breakdowni by longevity of parents and grandparents in one study (159)~. The genetics of the characteristics themselves has not been deter- mined, and adequate analysis of common genetic determinants in relation to the habit of smoking has not been attempted. No environmental deter- minants that would universally induce smoking and also produce the char- acteristics are evident (62) or have been proposed. Fisher (118) has been foremost in calling attention to the possibility that cancer of the lung and the habit of smoking may be due to a common geno- type. Selection of smokers then would automatically provide a population in which pulmonary cancer would appear on the basis of genetic suscepti- bilitv. Studies on the concordance of smoking,in twins (122, 127„281, 356) were used to support the hypothesis, since more monozygotic pairs have similar smoking habits than~ do dizygotic pairs. Although the d'ata on the smoking habit's of identical and fraternal twins raised apart are compatible with this hypothesis, the history of cancer in twins whose smoking,habits are known has never been documented sufficiently to be useful in helping to resolve the question of whether the concept of the constitutional hypothesis is valid. Also information about the habits and medicall history of other siblings, offspring, and parents is singularly scanty, and efforts to: separate genetic factors from influences of the environment ini such studies have been only rudimentary. 190 . .,..._ . _. 9:k~;i:+e.c..:..w_....:

s Although single genes may be involved in a few exceptional neoplastic and preneoplastic states such as retinoblastoma! and precancerous colonic poly- posis, genes for susceptibility to human cancer are usually multiple (48). Whether multiple genes for susceptibility may also be operating in the instance of cancer of the lung has not been established. The linkage (in a genetic sense) between multiple genes related to a habit (smoking)~ and a disease (lung cancer) in an heterogeneous population would require numer- ous coincidences with small probabilities. Also, in order to adhere to a con- sistent argument in explaining,the reduced incidence of cancer of the lung,in this group, it would be necessary Yo postulate another common genotype for those who smoke and subsequently terminate the habit. The argument becomes even more laboredl when multiple examples of identical genotypes for susceptibility t'o~ smoking and respective specific types of cancer are re- quired by the hypothesis to explain the multiple types of cancer associated with smoking, Since cancer of the lung occurs in both men and women who do not smoke, susceptibility genes acting alone or in combination witll~ extrinsicc or additional intrinsic factors can be effective without exposure to tobacco ,smoke. The occurrence of the disease, therefore, is not invariably linked to hypothetieall genes responsible for the habit of smoking. Since susceptibility to cancer may be due to multiple genes with variable penetrance, and sincee the expression of these genes may change wiYhi environmental conditions, a minor portion of the cases of pulmonary cancer cani be explained as the expression of genetic susceptibility in an environment exeluding, the habit of smoking. Smoking, then may add an, extrinsic determinant which can increase the incidence of cancer of the lung beyond that which would otherwise prevail in the same population. It should be emphasized' that comparisons of lung cancer mortality in smokers, non-smokers and ex-smokers have been made on different popula- tions. Thus, in considering the fact that the incidence of lung cancer appears to decrease when smoking is discontinued, it must be remembered that the population which can stop or does stop smoking may differ from that which continues. It is possible that the ability to terminate the habit may also be determined' genetically. In assessing the importance of a: possible genetic influence in the etiology of lung cancer, it should be recalled that the great rise in lung cancer inci- d'ence in both men and women~ has occurred in recent decades. This points either to a: change in the genic pool, or to the introduction of an agent into the environment, or a quantitative increase of an agent or agents capable of inducing this type of'~ cancer. The genetic factors in man were evidently, not'~ strong enough to cause the development of many cases of lung cancer under environmental conditions which existed half a century ago. In~ terms of what is known about rates, pressures, and equilibria: of human mutations thee assumption that the genome of man could have changed gradually, simul- taneously and identically in many countries during this century is almost inconceivable. 714-422 0-64-14 191

Smoking may be placed more properly in the role of an environmental determinant than as part of the phenotype of the pluripotential gene or genes, interacting with the environment~ and resulting in cancer of the lung. Current evidence is compatible with the opinion~ that genetic factors play a minor role compared to the contribution of the smoking habit in the etiology of lung cancer today. EPIDEMIOLOGICAL CONSIDERATIONs.-Although evidences for the consti- tutional hypothesis are, at present, either tenuous or actually lacking, the basic philosophical and logical prerequisites'for this hypothesis are contra- ` dicted by a number of well-established observations (62) : (L) Lung Cancer Mortality.-Lung cancer mortality has been increasing in the last' 50 years and much more in males than females. This in- crease could be due to either an environmental change or a mutation. Since an unchanging constitutional makeup cannot of itself explain the in- crease, we must postulate either that there are genetic differences which make some individuals sensitive to a new environmental factor (not tobacco),, or that differences in constitutional makeup 'are not genetic but the result of differential exposure to some new factor that predisposes to lhng cancer and creates the desire to smoke, or that the mutation has produced an increased susceptibility and a desire to smoke• For the first two postulates a new en- vironmental factor, other than tobacco, is required. Such a factor, it must, be remembered, must be correlated with lung, cancer as highly as are ciga- rettes and also highly correlated with cigarette consumption. None has yet been found. In order to account for the magnitude of the lung cancer mortality increase, the third' postulate would require a mutation rate which f ar exceeds any observed. (2.) Tobacco Tars.-Tobacco tars have been found to be carcinogenic for experimental animals. Although carcinogenicity of tobacco tars has not been demonstrated in man, the constitutional hypothesis would require that they are not, and' that the association with lung cancer in~ man~ of substances found to be carcinogenic for experimental animals is a coincidence. (3.), Pipe and Cigar Smoking.-Pipe and cigar smoking appears to have a higher correlation withl laryngeal and oral cancer than with lung cancer. The constitutional hypothesis would require that there shall be two consti- tutionall makeups, one predisposing to cigarette smoking but not to pipe and cigar smoking andi also to cancer of the lung; the other predisposing to to- bacco consumption in any form and to cancer of the larynx and oral cavity but' not to cancer of the lung, The alternative within this hypothesis would require that the speciaU constitutional makeup predisposes to cigarette smok- ing and lung cancer, but that tobacco smoke, whether from cigarettes, cigars or pipes, is carcinogenic for the larynx and oral cavity but not for the lung. These requirements are unrealistic. (4.) Ex-cigarette Smokers-Ex~cigarette smokers have a lower lung-can- cer mortality and a gradient is noted'by length of'time smoking has been dis- continued and' by the amount previously smoked. This would require complicated genetic interrelationships if the constitutional hypothesis were to be satisfied. A simpler hypothesis, which involves a causal relationship be- 192

I tween~ smoking and lung cancer, but recognizes differences,, define& or ill defined, between smokers and non-smokers may be stated as follows: There are factors in the individual acquired early (ior genetic) which predispose to cigarette smoking, and cigarette smoking by direct action of smoke on the bronchial epithelium is a major factor in producing lung,cancer in susceptible individuals. A detailed discussion of the significances of the data on, psycho-social, constitutional; and physical characteristics of smokers and' non-smokers is presented later in this report (Chapters 14 and 15). The role of the genetic factor in carcinogenesis has been discussed earlier in this Chapter. OTHER ETIOLOGIC FACTORS AND CONFOUNDING VARIABLES Throughout this evaluation, it has been recoguized that a causal hypothesis for the cigarette smoking-lung cancer relationship dbes not exclude other factors. This is attested to by the fact that a small but not insignificant percentage of cases of lung cancer does occur among non-smokers. Some estimates in retrospective studies and most of the prospective studies indi- cate that approximately 10 percent of the lung cancer cases are in non- smokers. Doll (78'), has provided a higher estimate of! 20 percent. Further- more,, the inability to account for the higher lung-cancer incidence in the lower economic classes entirely by disparities in smoking habits, which do exist, does imply other causali factors. Several other possible etiologic factors which have been explored merit discussion. These include occupational hazards, urbanization or industrial- ization and air pollution, and previous illness. (1.) Occupationat Hazards.-In an extensive review of the literature on lung cancer in chromium and nickel workers and in uranium miners, Seltser (318) found the evidence for an,excess off lung cancer mortality among chro- mate workers highly consistent. However, because of the smallness of the numbers involved, caution must be exercised in any calculation of the magni- tude of the risk. Furthermore no evidence has been~ presented either for or against an excess risk of lung cancer among workers exposed to other chromium products or chromium mining. The evidence for an excess risk among nickel processing workers in refineries was even more consistent than for chromate workers. The lung, cancer risk was five times greater among nickel processing workers than in other occupational groups in the same area (the risk for nasal cancer was 150 times higher).. Among, urani= miners an excess risk is apparent ('360), and is greater than~ in~ certain other miners of similar ores without the high radioactivity component (361). Although the induction of'lung cancer by radio nuclides is probable ini man, the evi, dence is not as firm as in animals. In addition, Doll has found a significant excess of lung cancer deaths among coal gas workers (81)~ and asbestos workers (77). In another revieww article, Doll (79) has added arsenic and hematite as suspects to the list , with isopropyl oil, beryllium, copper, and printing ink as possible risks. The evidence for the possible role of arsenic as a factor in the etiology of lung cancer has been summarized by Hueper (178)', and Buechley ('45)! has 193

recently suggested that it~ merits epidemiological investigation. The chief points of evidence cited include 1) the universality of arsenic in many ores and in the atmospheres in and near smelters; 2) the widespread use of arsenic as an insecticide and the consequent exposure of workers in insecti- cide manufacture, agricultural workers, and those handling or consuming crops with arsenic residues; and 3) reports of a: relatively high incidence of lung cancers in people living around smelters processing arsenic-containing ores, and also in vineyard workers exposed to large amounts of arsenical pesticides and consuming large amounts of arsenic:cont'aminated beverages: It is noteworthy that for the nickel and chromate material the lung cancer niortality is referrable to a high exposure period in the respective industries, a situation which probably does not prevail today. Of greater importance is the regrettable fact that in none of these occupational hazardl studies were smoking histories obtained. Thus the contribution which smoking, as a contributory or etiologic factor, may have made to the lung cancer picture in these risk situations is unknown. However, the series of cases in non- smoking chromate workers is large enough to exclude the possibility that cancers of' the lung in chromate workers develop only in those who smoke cigarettes. Nevertheless, it must be emphasized quite strongly that the popu- lation exposed to industrial carcinogens is relatively smalli and that these agents cannot account for the increasing lung cancer risk in the general population. (2.) Urbanization, Industrialization, and Air Pollution.-The urban.rural differences im lung cancer mortality risk, though small and accounted for in part by differences in smoking habits (see section entitled! Coherence of Association), nevertheless may have a residual which implies other etiolbgic factors in an urbam environment. This has been the explanation offered in the studies by Stocks and Campbell (337) and' Stocks (335) who noted a gradient among non-smokers, light'cigarette smokers and pipe smokers by density of population but who found no gradient among heavy smokers. Less direct evidence was derived by Eastcott (101) and Dean (69, 71) who found higher lung cancer rates among migrants from Great Britain to New Zealand, South Africa and Australia,, respectively. Their inferences were that these immigrants had had significant exposure to air pollution in Eng- land prior to coming to the Commonwealth countries. Unfortunately, these interpretations were untenable for there was no individual case-control in- formatiom on tobacco consumption. A correction of method by Dean in a later study (70) did elicit smoking histories and revealed a marked influence of cigarette smoking but a significant though lesser factor of urbanization. Doll's study of non-smoking lung cancer cases (78) reveale& no differences in risk among,men and women and in residents of areas of different popula- tioni density. His findings cannot be considered to be conclusive of a nega- tive result, for density of population need not necessarily be highly correlated with pollution. In a: more recent', as yet unpublished, paper by Stocks` a •Stocks, P.: A Study of~ Tobacco Smoking, Air Pollution, Residential and Occupa- tional Hi'stories and Mortality from Cancer of the Lung, in Two Cities:, Inter-regional. Symposium on Criteria for Air Quality and Methods of Measurement, W.H.O.,, Geneva, Switzerland, August 6-12, 1963. 194

mathematical model embodying amount of smoking, age, air pollution~ measurements by specific carcinogenic constituents, proportion of life spent in country and town, and lung cancer mortality was applied to the data de- rived from Belfast and Dublin. The lung cancer death rates were found! to be compatible with an1ypothesis that in Belfast about two-thirds of the deaths of men resulted from cigarette smoking and one-third from air pollution by smoke and, in Dublin; 75 percent from cigarette smoking and 25 percent from air pollution. These data are not offered as proof but represent the ap- proaches necessary for future research in the area of proportional contribu- tions to lung cancer mortality. Such applications may be useful inAetermin- ing the role of air pollution in~ such disparate lung cancer mortality rates between, for example, the United States and Great Britain when adjustments in smoking habits still do not eliminate the difference completely. Two studies (147, 152) have also indicated that migration of rural people into urban areas subjects them to lung cancer risks greater than for life- time urban residents. This effect is noted among non-smokers as well. The least that can be said is that the intensity of urbanization or indilstrializa- tion~ may have a residual influence on lung cancer mortality. (3.) Previous Respiratory Infections.-Relatively few soundly designed studies have tested the effect of prior respiratory disease, particularly infec- tions, on the development of lung cancer. Winternitz (371) called attention in 11920 to proliferative changes in cases of post-infliienzal pneumonia similar to those seen in invasive,, malignant neoplasms of the lung but this report stimulated relatively few epidemiologic observations. In the retrospective study of the smoking-lung cancer rela- tionship by Doll and Hill (82) inquiry into a history of previous respiratory infections led to finding, a significant excess of antecedent chronic bronchitiss and pneumonia among lung, cancer patients even when smoking class was controlled. However, because a collaterall comparison with another controll group of patients, for whom a lUng cancer diagnosis was subsequently found to be in error, failed to reveal a difference, Doll and Hill concluded that either "chronic bronchitis and pneumonia predispose to a whole group of respiratory disorders . . . or that patients with respiratory disorders recall previous chronic bronchitis and pneumonia more readily than~ do patients with diseases with other symptoms." However, almost simultaneously Beebe (20) investigated the relationship between mustard gas exposure,, chronic bronchitis, pneumonia and' influenza and lung cancer, and Case and Lea (53) between mustard! gas exposure and/or chronic bronchitis and lung, cancer. Smoking histories were controlled in these studies. Beebe found no evidence of an increased lung cancer risk with an antecedent history of influenzall pneumonia and primary pneumonia but there did appear a highly suggestive association between mustard gas exposure and lung cancer. Nb relationship between chronic bronchitis and lung, cancer was noted. Case and Lea, however, interpreted their findings to mean a sequential relation- • ship between mustard gas exposure, chronic bronchitis, and lung cancer. The lung cancer risk was doubled by pre-existing chronic bronchitis. Doll, 195

in a later review (76), however, indicated that since the smoking•lung cancer 9- to 10-fold'risk in average cigarette smokers and the 20+ fold risk in~heavy smokers. sociatPd with lung, cancer via the smoking component)' as compared to the does more than double the risk (and' sometimes these are noted to be as- aleohol consumption, nutritional status, and beer drinking,,have been studied and some associations with lung cancer have been found, but' none of them (4.) Other Factors.-Numerous other factors, such as coffee drinking, to lung cancer. The war gas component was strong enough to double the risk of lung,cancer even~with control on smoking,class. Thus, the observations on previous respiratory illness are too few in number to place any degree of assurance on a relationship, but the studies by Case and Lea and by Denoix et al. remain interesting. found a history of exposure to war gas and chronic bronchitis to predispose strongly associated with lung cancer than smoking of cigarettes, they et al. (72) studied 1160 characteristics. Among other factors, much less In an epidemiologic approach to other factors in lung cancer risks, Denoix chronic bronchitis is not a necessary intermediate pathogenetic process. The failure of the Beebe study to affirm the Case and Lea findings in regard to chronic bronchitis may lie in the problem of differences in British and American diagnoses of chronic: bronchitis. relationship is stronger than the chronic bronchitis-lung cancer relationship, Conclusions and the number of cigarettes smoke& per day, and is diminished by dis- continuing smoking. 3. The risk of developing cancer of the lung for the combined group of pipe smokers, cigar smokers, and pipe and cigar smokers is greater than in non-smokers, but much less than for cigarette smokers. The data are in- sufficient to warrant a conclusion ~ for each group individually. 1. Cigarette smoking is causalliy related to lung, cancer in men; the mag- nitude of the effect of cigarette smoking far outweighs all other factors. The data for women, though less extensive, point in the same direction. 2. The risk of developing lung cancer increases with duration~ of smoking ORAL CANCER Epidemiological Evidence been recorded. The investigators noted the proportions of users of' the same observation. In the present era, additional clinical observations have of the lip among users of tobacco. In 1795, Soemmering, (322) made the The suspicion of an association between use of tobacco and orall cancer dates back to the early 18th Century when Holland (176)i first noted cancer 196

various forms of tobacco among, the various cases of oral cancer and found clues to a relationship. These observations lacked controls. Notable among, these reports are the review by Haase (142) emphasizing, location of the cancer of the lip and mouth according to where the pipe was held'; the analysis by Ahlbom (1) by specific type of tobacco use in relation to site; and the work of Potter an& Tully (280) which indicated an increase in risk of oral cancer with increase in smoking. From the first two studies mentioned (li, 142),, it is immediately apparent that any reasonably meaningful'1 study of the relationship between tobacco and oral cancer must take into account not only the specific sites (lip, cheek, gingiva, tongue, oropharynx, etc.)! but, also the precise form of tobacco use (pipes, cigars, cigarettes, chewing tobacco, snuff, etc. ) . Of additional interest is the specialized use of tobacco as a component, of betel nut quids in certain areas of the world; several observations suggest an association with oral cancer (66, 67, 269, 319). In contrast, observations of populations using betel nut quids without tobacco (104, 234, 367) in certain other areas of the world show no association of betel nut witL oral cavity cancer. More formalized case-control or retrospective studies varying in spe- cific approach, in~ suitability of controls and in~ sample size have appeared between 1920 and the present (26, 41, 103, 202, 207, 221, 237, 245, 272, 301, 306, 314, 326, 355, 369, 385, 387, 388, 398). These studies are described in Table 10 which includes general smoking data, for the most part, on com• binations of; specific sites of oral cancer. A number of these investigations either did' not separate the several sites of the oral cavity because of the small number of cases for each site or, upon separation into such sites, found the smokin~,classes too numerous for testing of significance (26„221, 237, 388). Since associations with form of tobacco use varied according to smoking classes and, wherever possible, to specific sites (Table 10A), in this sum- mary table, a statistically significant positive association is designated by a plus sign, whereas the lack of such an association is d'esignate& by a minus sigm A plus-minus sign indicates that there was some evidence of an asso- ciation which was not, however, statistically significant. It wilt immediately be noted that in 10 of 17' studies all oral sites were combined in an attempt to elicit an association with~ forms of tobacco-use (26,, 202, 221, 237, 245, 272, 306, 314, 3264 , 388). Although, eight of these showed positive association, they were so scattered among the several forms of tobacco use that little can be derived from them. Furthermore, distinctly specific site associations may be masked by such combinations. In examin- ing the data for specific site localizations and forms of tobacco use, several associations become clarified. It would appear that pipe smoking is associated with lip cancer in all six studies in which this site and form of tobacco use was analyzed (41, 103, 207, 301, 378, 385 ) . In one additional study (237)' an, association with pipe and cigars com- 197

TABLE 10.-Outline of retrospective studies of tobacco use and cancer of the oral cavity Cases Controls Investigator and year Ref- Country Sex Collection of data erence - Number Method of selection Number Method of selection Broders 1920 (41) U.S.A. M 526 Series ot clinic patients with epi- 500 Series of clinic patients without Apparently by Inter-vlew in the F 71 thelioma of the lip. epithelioma of the lip. clinic. 80.5% tobacco users 78.6% tolfacco users 75.1% smokers 75.2% sinokcrs 0.9% cigarettes 44.4% ciRarEttes 24.0% chew -- 13.4% chew 59.0% pipes 28.fi% pipes 38.5% cigars 44.0% cigars Lombard and Doer- - (221) U.S.A. M-F 217 Clinic patients with cancer of 217 Clinic patients without cancer, Personalintervlewbyinvestlgators ing 1928. various sites. Site breakdown matahed by sex and age. Smok- in clinics. and smoking data not clear. inR_ data not clear. Bigelow and (26) U.S.A. M-F (") Clinic and hospital patients, a p- (7) Paticnts without cancer, In com- Personal interview in hospitals and Lombard, 1933. parently several hundred. parable numbers. -" clinics. - 14 a`J~-non-users 26.5% non-users 36.4% excessive users (Table 111). 24.0°, excessive users (Table 111). Ebenius 1943 (103) Sweden M 439 Clinic patients with cancer of the Not defined. F 33 lip. -- 68.7% tobacco users, M - 79.7% tobacco users, M I-to 2%' tobacco users, F 57.6% tobacco user4, F (all pipes) 22.9% liipes, M 61•8%pi[fes. M 47.4% chew or use snuff, M fi0.7,%,q chew ar use snuff, M 32.5~o cigars and cigarettes,-M 12.9% cigars and cigarettes, M - - ----- Levin et al. 1950 (207) U.S.A. M 143 Cancer institute patients with 51 Cancer institute patients with Routine cllnic interview. cancer of the lip. - non-cancerdiseasesofs_amesite• - 84.5% smokers - 74A%srnokers - 45.3% cigarettes 43.0% cigarettes 48.1% pipes .. .. 30.7% pipes 26:5% cigars 34.9% cigars Mills and Porter 195_0 (297 ) U.S.A. M 124 24 1)eaths from cancer oi oral cavity 183 Sample of populatlon of Colum- From next of kin of deceased by iu Cincinnati and Detroit,1941t- bus, Ohio, and in same proportion mail questionnaire or by personal 46 and 1942-46, Pespectively. of color, sex, and age as in cases. interview. Controls by house- 35.5`7 ciprettes only 54.8% pipes, cigacs. or combina- 32.4%cigarett€s only 29.7% pipes, eigars, or combina- to-house interview. tions. tions. - 549`.,~;9LE0

C ~ ~ Moore et al. 1953 (245) U.S.A. M 112 rarlencs over 50 yrs. old since 1951 38 Patients of same age groups with Personal interview of controls; for with cancer of oral cavity, benign oral Iesions or benign cases, nextof-kin were visited or 58.0% chew surgical conditionS- contacted by letter. 42:01,1,, pil5es 31.6% chew - -- - - 38.4% cigars and cigarettes 47.4% pipes 52.6% cigars and cigarettes Sadowsky et al., 1953 (301) U.S.A. M 1,136 liospital patients with oral and 615 Patients with illness other than By trained lay Interviewers. pharynqeal cancer, 1938_43. cancer. - . 42.3% cigarettes only 53.3% cigarettes only 4.0% cigars only 3.4°a-cigars only 17.8% IirEies anly 7.0% pipes only 28.2% mixed 23.1% mixed Sanghvi et al., 1955 (306) India M 657 Ilospital patients with cancer of M 288 Hospital patients with diseases Personal history interview in hos- F 81 orsl cavity and pharynx. F 112 other than cancer. pital. 38.8°o srnoke and chew, M; 3.7% F -- 24.0% smoke and chew, M; 0% F 46.7% smoke only; M; 6.2%F 50.0% smoke only, M; 6.3% F- 11:7io chew only, M; 64.2% F 8.7%-chew on1y,M; 23.2%-F 2.7% neither, M; 25.9% F 17.3% neither, M; 70.5% F (Smoking is of bidis among both cases and controls.) Ledermann 1955 (202) France M 240 Patients with cancer of oral cavity 62 Patients with cancer of skin, bone, 4, pharynx. muscle. 4.601, non-smokers 17.2% non-smokers 23.4%>20 cigarettes per day 18.6%>20 cigarettes per day Wynder et al., 1957 (378) U.S.A. M 543 Patients with cancer of oral cavity M 207 Patients with cancer of other sites Personal interviews in hospital or F 116 F 232 iiiid benign diseuses. clinic. 3% non-users, M; 47% F 10% non-users, M; 70% F 20%ciFars; M--- -- 13% cigars, M 11% pipes, M 6% pipes, M 8% mixed, M 8% mixed, M 17% chew, M 8% chew, M 57% cigarettes, M; 53% F 63% cigarettes, M; 30% F 29%>35 cigarettes per day, M 17;%0>35 ciga[ettes per day, M 34%>16 cigarettes per day, F 11 %>16 cigarettes per day, F Wilkins and Vogler (369) - U.S.A. M 37 Clinic and hospital patients with None. Clinic and hospital histories. 1957. F 44 cancer of gingiva. 32% chew or chew and smoke, M 20% smokers, M 52% use snutT, F 9%srnokers,. F. Schwartz et al. (314) Franee M 332 lIospital patients with cancer of 608 Hospital patients with non-cancer Questioned about the same time oral cavity and pharynx. illness and accident cases, by the same interviewer. matched by age. 16.4% non-smokers 23.4So non-smokers 62.7% cigarettes only 5821Se cigarettes only 3.3% pipes only - 3.0% pi/Ses oiily

IS r 9 LL44S944E0 TABLE 10.-Outtifie of retrospective studies o f tobacco use and cancer of the oral cavity-Continued Cases Controls Investigator and year Ref- Country Sex -- Collection of data erence Number Method of selection Number Method of selection Wynder at al. 1957 - (388) -- Cuba M 178 - Hospital clinic patients with M 220 - Patients In same clinics with Personal questioning in clinic, all F 34 eancer of oral cavity and F 214 non-malignant conditions, by2intervlewers. pharynx. - - matched by sex and age. - 4% non-smokers, M; 24% F 16% non=smokers, M; 66% F 45% cigarettes predom., M; 62% F 45% cigarettes predom., M; 27% F 33 a cigars predom., M; 12% F 22% cigars predom., M; 6% F Wynder et al. 1957 (385) Sweden M 115 Hospital patients with cancer of M 115 Patients in seme hospital with Personal interview in hospital; and F 140 oral cavity and pharynx. F 156 cancer of sites other than oral, medical histories. -- pharynx iarynx, lung, esopha- gus and irreast. - --- 36.5%a cigarettes, M 36~-cigarettes, M 13:0%a cigars, M 9% cigars, M 12.2% pipes, M 16% pipes, M 15.7% mixed, M 13% mixed, M Peacock et al. 1960 (272) U.B.A. M 25 IIospital patients with oral cancer M 74 Patlents in same hospital without Personal interviews. F 20 F 72 oral cancer and 117 male and 100 female randomly selected outpatients. - - 55.6%a chewed or used snuff over 32.6% of first group, 20 years. 43.3% of second group chewed or - used snuff over 20 years. 8taszewski 1960 (327) Poland M 383 Male patients with oral cancer 912 Male patients with other cancer Personal lnterviews. and non-cancerous conditions. -- 5.7% non-smokers 17.3% non-smokers 72.8% "heavy" smoking index ----- - 49.0% "heavy^ smoking index 72.3% cigarettes-only 60.5% cigarettes only - 12.8% pipes and/or cigars 11.1% pipes arrd/or cigars - Vogler et al. 1962 - (355) U.S.A. M - 188 - Clinic patients with cancer of lip - - M 521 -- Patients of same clinic with other - Personal intervlews in clinic. - - - - F 92 and oral cavity. --- F 1,064 cancer or-non-malignant condi- - - -- - tions. 32.9% chewers, M y 6.1% snuff dippers, F y 22.9% excessive chewers, M 5_6 % tobacco users, M + F 72:0% snuff dippers, F 41.3% excessive snufi dippers, F 90% tobacco users, M + F- r Estimate of prevalence o use. 2 Due to varying tabular treatment of the data, the percentages of tobaoeo users are not all based on the same numbers of caees. - - 1 ~If:'9:Ci

V. P 1 I 94CaS944E0 TABLE 10A. Summary o f results o retrospective studies o f smoking by type and oral cancer of detailed sites ; Investigator and reference Cigarettes Pipes Cigars Chewing Miscellaneous Broders(41)--------------- - (Lip)----------------------- (Lip) - ---------------------- - -- (Llp)----------------------- (Lip)+• - Lombard and Doering ---------------------- (Oral)+ (221).- - Bigelow and Lombard (26) - - _____________ ___ -- _- .- ------------------------------ -... - ------------------------ (Allformscombined-oral){- Ebenlus(103) -------------- (Lip).. r-------------------- - Llp)+ ------------ --- - (Lip)-- Levin et al. (207)-------- - (Lip) -------------- (Lip)-I . ....... . (Lip)f Mills and Porter (237) ---- (Oial)t--------------------- -------- --------- ------- -------------------- ----- ----------------------- (Plpesand cigarscombined- Moore et al. (245)---------- (Lip, mouth)- 2 ------------ (Lip, mouth)-____---------- -_-__ _ ------------'-- -- --- (Lip, mouth)-F---------- ocal)+ . (Snu(i-lip, mouth)+. Sadowsky et al. (301)------ (Lip, tongue, other oral, (Lip, tongue, other oral)+___ . (Tongue, other oral)+. pharynx)-. Sanghvi et al. (300)-------- (Oropharynx){-3 ------------ ------------------------------ ------------------------------ (Oral){----------------- (If smoke and chew-base 01 Ledermann (202)----- ------ (Oral) }. tongue, hyp_op_harynz){. WyYideketal.(378)-------- fM,-fF(Floorofmouth)-- (Esshsiteexcepttongue)-},__ (Eachsite)+------------ ---- (Oingiva,iip)t. Schwartze6al.(314)------- (Pharynx)+I --------------- (Oral)-. Wynder et al. (388)-------- M-, F+ (Oral and phar- (Lip)+---------------------- M+, F+ (oral and phar_ Wynder et al. (385) -------- . ynx). (P,harynx)+, (Other - -- yn=) gingiva, phar - -------------------------- (Pipes, and cigars com- sites)- ynx)i-. .. - . bined-tongue)+. Peacock et al. (272) -------- ------- ------ --- ---- ------ ------- - -- ---------- _ (Oral)+ --------------- ° . (6nuft-oral)+.3 Staszewski (328)----------- (Lip, oral cavity)+--------- ------------------------------ - - ---------- ----------- --- - ---------- ------- (Pipes and cigats combined- Vogler et al. (355) ---------- ----- -- ---------------- lip, oral cavity)t. (All forms combined)+, I F+ (snuff-lip and buccal cavity In both cases). '+=8igniflcant association. -=Assoeiation absent or not significant. f=.Association of doubtful significance. 2 Cigarettes and cigars. I Bidis. 4 Includes cigarettes and other. 5 Only in individuals of low economic statua and over 60 years old.

bined~ was noted. Among four studies of lip cancer the chewing, of tobacco and/or snuff was found to be associated in two of them (41, 245 ) ~. There is some indication of an association of! tongue cancer with cigar smoking in three studies (301, 378, 385) and in one oflthese (385) with pipe and cigar smoking combine& In two studies an association of gingival cancer with cigar smoking was demonstrated (378, 385) ; in one of thesee (378)~ an association also noted with pipe smoking, and a suggestion of an association with chewing of tobacco. Pharyngeal cancer was considered as a separate site in~ four studies (301, 306, 3784 385). An associationi with cigarette smoking was noted! in two out of three (306, 385)i; with cigars in two (378, 385)~; and with pipe in one (378). Among the better studies in which the sample sizes were large and con- trols adequate, one deserves special mention (301). In this investigation by Sadowsky and others, it was possible to establish gradients for lip cancer by number of' pipefuls smoked a: day, for tongue cancer by amount of to- bacco in pipes and's cigars combined, and for other oral cavity cancers by number of pipefuls. Nb gradient by amount smoked~ was noted for cigarettes. The seven prospective studies have yielded 152 cases of oral cavity cancer associated with cigarette smoking; with ani adjusted expectancy of 37.0 cases giving a: weighted mean mortality ratio of 4.1. This is the third highest mor- tality ratio of cigarette smokers to non-smokers among the several specific types of cancer deaths and the fourth highest, among all causes of' death as- sociated with cigarette smoking. The mortality ratios ranged from 1.0 in the Dunn, Linden, Breslow occupational study (96), in which only seven cases have thus far been observed; to 9.2 in the current Hammond study (157). (See Table 1 of this chapter.). For cigar and pipe smokers,, oral cancer has the highest mortality ratio, 3.3, of all causes of death, exceeding cancer of the esophagus, larynx and lung. Recently calculated data from six of the prospective studies (excluding, the current Hammond' study) show a slight gradient in the mean~ mortality, ratios for cigarette smokers of more than, a: pack a day as compared to smok- ers of one pack or less. Estimates of gradients by amount, of smoking of pipes and/or cigars, by durationiof smoking and'bydiscontinuanee are notlyet available, because of the relatively, smaller number of deaths from oral cancer. Inasmuch as the incidence of female oral cancer is markedly lower than in males, data on these variables for the female, to be derived from the cur- rent Hammond study, will reqµire an inordinately prolonged observation period. Carcinogenesis Cigarette smoke and' cigarette smoke condensates have failed to produce cancer when applied to the oral cavity of mice (75, 177, 240) and rabbits (312) or to the palate of'~ hamsters (194, 303). Exposure of the hamster cheek pouch to cigarette tar, snuff, or tobacco also failed to induce cancer 202

(95, 194, 243, 24A., 245, 24.6, 271, 272, 303, 303a). Leukoplakia was re• ported to have been induce&by the injection of tobacco smoke condensates into the gingiva of rabbits (296)!. The oral mucosa appears to: be resistant in general to cancer induction even when highly active carcinogens such as benzo (a) pyrene (95, 194, 209, 243, 244, 245, 246, 271!, 272, 296, 303) are applied. Mechanical factors, such as secretion of saliva, interfere with the retention of carcinogenic agents. Saliva may also play a chemical role in modifying the action of'~ carcinogenicc agents on the tissues of the oral cavity and the pharynx. The only positive results with carcinogens have been obtaine&with benzo(a)pyrene; 20-methyl- cholanthrene, and 9,10-dimethyl-1,2-benzanthracene applied to the cheek pouch of the: hamster (244, 303, 343). The cheek pouch, however, lacks salivary glands, and its structure and function differ from those of the oral mucosa. Pathology There is a strong clinical impression linking the occurrence of leukoplakia of'the mouth with the use of tobacco in its various forms (201). However, in almost all the studies, the diagnosis of leukoplakia was made without his- topathologic examination. It is difficult to distinguish clinically between hyperplasia of the surface epithelium with keratinization (termed pachyderma oralis) and "true" leukoplakia, which resembles microscopically senile kera- tosis, a preneoplastic lesion of~ the skin, showing atypical changes and mitotic figures, in addition to hyperplasia. In a study of the tissue changes in the palate of women in a part of India where the burning end of a cigar is held inside the mouth, Reddy and Rao (284) found ulceration, increased pigmentation of the epithelium of the palate and leukoplakia. Many of these women develop cancer at the same site. The carcinomas found are epidermoid and are frequently surrounded by an area of leukoplakia which sometimes shows changes characteristic of carcinoma-in-situ. Leukoplakia is a common finding,in patients with multiple oral'carcinomas, the majority of whom use tobacco (241). A histopathologicc study of lesions in the oral mucosa in betel nut-tobacco chewers in Malaya showed frequent epithelial hyperplasia with atypical changes and papilloma formation (233). These lesions were considered to be frequent sites for thee subsequent development of cancer. An association between~ leukoplakia an& oral cancer has been noted by other investigators in studies on individuals with, the habit of: dipping snuff (179, 200). Although these results do not warrant any conelusion~ by themselves, they are consistent with the suggestion that oral cancer is frequently pre- ceded by characteristic premalignant changes and that these have a relation- ship~to the use of tobacco. Evaluation Because of the diversity of sites involved in the category oral cancer and the need to delineate forms of tobacco use in each of them, the number of retrospective studies is inadequate to furnish sufficient material for a 203

j udgment of consistency of the association except for cancer of the lip and pipe smoking. Inasmuch as only one retrospective study (301)' had large enough numbers of cases to derive the relative risks for specific site associations, reliance for strength of the association must' be placed on the prospective studies. Since, in turn, the numbers of deaths from cancer of these sites so far have been small, only a combination of such sites could be analyzed for relative risk determinations. Five of the seven studies show reasonably high rela- tive risk ratios for cigarette smokers and for cigar and pipe smokers. Specificity of the association cannot be said to be as high as that noted for lung cancer. The prospective studies provide no information~ as to specific localizations within the oral cavity. Sadowsky et al. (301) showed an association of pipe smoking with cancer of' the lip and of pipe and cigar smoking,with cancer of the tongue. Data are presently inadequate for a reliable assessment of the coherence of the association. However, it should be noted that the prospective studies provide a definite suggestion that a gradient of risk by amount smoked does exist for oral cancer and that in one large retrospective study (301)~ prevalence rates for every specific age group of smokers was consistently in excess over non.smokers. It has been noted that during the past 30 years cancer of the oral cavity and pharynx has declined, primarily because of a decrease in lip cancer among males (130). Cancer of the lip has never been an important localiza- tion~ for females and the rates in females have remained fairly constant. In males pipe smoking has decreased markedly in the United States during the past 30 years, so that the decline in lip cancer among males is not neces- sarily incompatible with a strong association between cancer of the lip and pipe smoking. Furthermore, other probable factors in the production of oral cavitycaneer such as mouth1ygiene, nutrition, and particularly alcohol consumption have not remained stable. In two studies (314, 378) alcohol consumption is clearly also associated with oral cancer and in one (378) evidence is presented for independent operation of this factor. The problem of heat from burning tobacco has not been investigated, as far as could be determined. It is of interest that cancer of the palate has been associated with smoking of cigars with the lighted end in~ the mouth (186) . The heat factor should be kept in mind with respect to the excess of lip cancers among,the cigar an& pipe smokers. Although cancer of the oral cavity has not been produced experimentally by the exposure of animals to tobacco smoke, it has occurred following repeated applications of benzo(a)pyrene and other hydrocarbons to the cheek pouch of the hamster. The relationship of leukoplakia to tobacco use has been described earlier. Conclusions 1. The causali relationship of the smoking, of pipes to the development of cancer of the lip appears to be established. I 204 O W ~ ~ C!t ~ ~ N

2. Although there are suggestions of relationships between cancer of other specific sites of the oral cavity and the several forms of tobacco use, their causal, implications cannot at presenf be stated.- LARYNGEAL CANCER Epidemiologic Evidence RETROSPECTIVE STUDIES. The possible association between tobacco smoking and laryngeal cancer received some attention in studies as early as 1937 (1, 185). Ahlbom noted a marked association between cigar and cigarette smoking and cancers of the pharynx, larynx and esophagus, but because of the small sample size, the three sites as defined were grouped together (1)~. The Kennaways calculated standardized' mortality ratios for various occupational groups (against thee age-specific mortality rates for the general population of England and Wales for 1921-32) and found barmen, cellarmen, and tobacconists to have sig- nificantly higher ratios (185). This latter study was repeated in 1947 and again the tobacconists and their assistants were noted to have an excess mor- tality for cancer of the larynx (184). It is difficult to attach~ much impor- tance to these studies though they contain clues which should be investigated. The earliest controlled study, retrospective in approach, was that of Schrek and'co-workers (311) ~ in 1950: Their very carefully analyzed data showed an association between smoking an& cancer of' the larynx but the evidence is not firm, for the association was found in only one out of four age groups, perhaps because of the small number of cases in the study sample. There then followed nine additional retrospective studies, two more im the United' States (301, 376) and one each in Czechoslovakia (353),, Germany (30), France (314), Sweden (385), Cuba (388), India (100), and Polan& (327) (Table 11)1. These were stimulated in part by the retrospective studies of lung cancer and the general prospective studies: Most of the studies (30, 100, 301, 311, 314, 327, 376, 385, 388) show a stronger association between cigarette smoking and laryngeal cancer than for other forms of tobacco use but one of the studies shows a borderline relation- ship witL cigar smoking (385). Wynder et al. (376) also distinguished be- tween intrinsic and extrinsic primary laryngeal cancers. It is of further interest that an excess risk of laryngeal cancer among cigar and pipe smokers in this study could be attributed to the extrinsic laryngeal cancer group. One study disclosed a relationship between laryngeal cancer and the combined smoking of cigarettes, pipes and cigars, as well as with cigarette smoking alone (301). In another (376) there is an impression that cigar and pipe smoking is more closely associated with cancers of the larynx than with cancer of the lung. A gradient of risk with amount smoked was demon- strated in two~studies (301, 376) and suggested in four others (30;,311, 314, 327). In the study by Sadowsky et al., this gradient was noted not only for cigarette smokers but for pipe smokers and combination smokers as well. 205

9 TABI,E 11.-Outline of retrospective studies of tobacco use and cancer of the larynx Ret- Qases Controls Investigator and year er- Country Sex Collection of data ence Num- Method of selection Num- Method of selection tier ber Schrek et al. 1950 (311) U.S.A. M 73 Referrals from V.A. hospitals in 522 From same set of referrals, patients Random sample of 50o3admissions; "entire midwest" to V.A. Can- withtumorsotherthanlip,lung, questionnaires from Hines re- cer Center, Hines, Illinois, dur- larynx-pharynx. ferrals for 1942-44; records In- ing 1942-44: patientswith larynx- cluded smoking history. harynx turnors clinically or Eistologically diagnoseli. 13.7% non-smokers 23.9% non-smokers 79.5% cigarettes 59.2% cigarettes ' 3.7% cigars 10.0% cigars 6.8% pipe.s 11.5% pipes Valko 1952 (353) Czecho- M-_ F 226 Clinic patients with cancer of the 108 Clinic patients of same age group Medical history and questionnaire slovakia. iarynx. with other diagnoses: in clinic. 83.2% cigarettes 4.4% cigars 10.6% pipes - 7.5% non-smokers 22.2% non-smokers Sadowsky et al. (1953) (301) U.S.A. M -- 273 - Admissions to hospitals In N.Y.C. 615 - From same set of adrtlissions: Sample of 2605 out of 2847 lnter- Missouri; New Orleans, Chica- patients with illnesses -other views (including smoking his- go: patients with diagnosed than cancer, tory) by trained lay interviewers. laryngeal tumors, 1938-1943. - -- -- ---- - 4.0% non-smokers 13.2% non-smokers 60.1% cigarettes only 63.3% cigarettes only 2.2% cigars only 3.4% cigars only ' 4.8% pipe only 7.0% pipe only 28.9%soine combination 23.1%sonie combination Bl9mlein 1955 (30) Germany M 241 - Clinic patients with cancer of the 200 Paticnts with no laryngeal disease. Personal history taken in cllnia. larynx. 0.8% non-smokers 18.0% non-smokers 79.3% heavy smokers 4.3% heavy smokers 95.0%,; inhalers - - 17.0% inhalers Wynder et al. 1956 (376) U.B.A. M 209 Inpatients Memorial Cancer Re- 209 Patients with other than epider- Trained lay Interviewers. search Center during 1952 to mold cancer, individually 1954, with benign or malignant matched eontrols in same insti- epidermoid tumors of larynx. tutions.- 0.b% non-smokers - 10.5% non-smokers 86.0% cigarettes 73.7% cigarettes 7.5% cigars 10.1% cigars 5.0% pipes 3.8% piix' 1.0% 0igarslpipes 1.9% aigarsipipes E8GS9C.E0

India M 132 Laryngeal cancer patients at Tata 132 Controls Individually matched as Interviews for smoking and medi- MemorialIlospital, 1952-1954. - for U.S.A. data above. eal histories. 13.6% non-smokers 30.3% non-smokers - - - 78.8% bldis 62.1% bidis 5.3% clgarettes 4.5% cigarettes 1.5% hookah 0.8% hookah 0.8% chilum 2.3% chilurn Schwartz et al. 1957. - (314) France M - 121 -- Patients hospitalized from 1954 242 - ---- Same time and sources; patients - - - Cases and controls indfvidually throuFh 1956 with laryngeal can- hospitalized for non-cancerous matched within institutions; cer, in Paris and other large conditions s or trauma. each member of a set questioned cities. by the same trained lay inter- 96°5 smokers 84% smokers viewer. 58% in halers 47% inhalers 44% roll their own cigarettes 31% roll their own cigarettes Wynder et al. 1957--_- (385) Sweden M-F__ 63 - -- Patients at Radiumhemmet with 271 -- - - --- -- - - - Patients from same source and - - By trained lay Interviewers in squamous-cell cancer of larynz, tirne, with cancer other than hospital. from 1952 through 1955. squamous-cell of larynx. - - Males: - Males: 5% non-smokers 24% non-smokers 47% cigarettes 36% cigarettes 17% cigars - 9% cigars 15% liipes 16% pipes 17% maxed 18%nifxed Wynder et al. 1958. (388) Cuba M 142 Clinic patients In Havana during M 220 Same source and time; apparently Interview of patients in clinic. F 32 1956, 57, with histologically di- F 214 patients with cancers other than agnosed epidermoid cancer of larynx, lung, or oral cavity, larynz:- - - -- - matched for age. - - 1%a non-smokers, M; 13% F 16%non-smokers; M; 66% F 62% cigarettes, M; 72% F 45% cigarettes, ad ; 27% F 20%cigars,M;6%aF 22% cigars,M;6%F 1%pipes, M - - l%pipes, M . - 16% mixed, M; 9% F 16% mixed, M; 0% F Dutta-Choudhurl et - (100) India - M-F ~ 582 - - ----- Patients in Calcutta cancer hos- - 288 _ _ Not speci0ed. _------ Tobacco histories obtained during 81.1959. - - pital during 195o-54, with laryn- -- - 1951-54, apparentlybyinterv9ewy geal tumor diagnosed and con- firMed by biopsy or smear. 14.1% non-users 41.7% non-users 77.8% cigarettes or bidi 52.1 % cigarettes or bidl 3.1%chew. 3.8% chew 5.0% both 2.4% both

TABLE 11.--Outli.rce o f retrospective studies o f tobacco use and cancer o f the larynx-Continued Ref- Cases Controls Inveetigator and year er- Country Sex - Collection of data ence Num- Method of selection Num- Method of selection ber ber Bteacewskl 1960. (327) Poland M 207 Patients admitted to chronic dis- M 912 Patients admitted during 1957 & Author interviewed patients aua F 13 ease hospital during 1957 & F 1813 1958 to chronic disease center pected of lung cancer [or smoking 1958 with histologically con- for cancerous and non-cancerous history and background. firmed squamous-cell carcinoma conditions presumably not re- of the larynx, lated to tobacco consumption. 0.5% non-smokers 17.3% non-amokers 87.9% cigarottes only 60.5% cigarettes only 1.9% pipes and/or cigars 11.1% pipes and/or cigars 88.4%° heavy smokers" 49.0%"heavy smokers" 98.1% inhalers 08.8% inhalers 30.8% smoke, F 8.4% smoke; F

A combination group of lung and laryngeal cancer cases was also included' by Wynder et al. (376) and relative risks for lung cancer as well as laryngeali cancer among the several smoking, categories were calculated. It is of inter- est that the risks attending the several categories of amounts of' cigarettes smoked were similar for both lung and laryngeal cancer, but the risk of laryngeal cancer among cigar and pipe smokers was 2.5 times that for lung cancer. Four of the retrospective studies concerned themselves with inhalation practices and a significant association between inhalation of cigarette smoke and laryngeal cancer was noted in three of them (30, 314,, 327)- The fourth study by Wynder et al. (376) found an association with inhalation among light cigarette smokers and among, pipe and cigar smokers. For botL whites and non-whites the male-to-female age-adjusted sex ratios in laryngeal cancer are higher than for any other site common to both sexes (130). Despite the fact that the female case materiaU is exceedingly sparse, at least two studies concerned themselves with laryngeal cancer in the female (377, 388). The material in one study was adequate to establish an associa- tion with cigarette smoking (388) whereas in the other only a suggestion~ was elicited in view of the paucity of the material (377). Wynder and co-workers (387) in their study of Seventh Day Adventists noted that cancer of the larynx was an extremely uncommon reason for ad- mission to a hospital and that this type of cancer was very infrequent among all cancer admissions. Smoking and drinking, among adherents of this religious sect are uncommon. PROSPECTIVE STUDIES In the seven prospective studies previously described, laryngeal cancer has in each one of them been observed among smokers in frequencies in excess of the expected. Although in four of these studies (25, 84, 96, 97) the number of observed cases is so smalli as to weaken the stability of any calcu- lable ratios, in the three maj or studies, the number of observed' cases among, cigarette smokers is reasonably large and yields ratios of 3.7 [current Ham- mond study (157) ], 5.8 [Dorn (88) ], and 13.1 [Hammond and Horn (163) ]. A summation of all seven studies yields a mean~ mortality ratio of 5.4 (Table 1) for cigarette smokers. For five studies in which laryngeal cancer cases were associated with cigar and pipe smoking, the mean mor- tality ratio was 2.8. However,, this was calculated from only nine casess observed and 3.2 expected (Table 24,,Chapter 8)i. None of the studies currently in progress has yielded a sufficient number of cases of laryngeal! cancer to permit analysis of smoking class categoriess by inhalation practices, duration of smoking, and age started smoking. However, the recently calculated material from six prospective studies (Table 23, Chapter 8)' shows a gradient of risk ratios from 5.3 for smokers of one pack or less of cigarettes per day to 7.5 for smokers of more than a pack per day. Because of the relatively low yield of cancers of this site, the current prospective studies, (25, 84, 88, 96, 97, 157) will' have to continue for a considerable length of time to provide answers to the other components of the problem. 209

Carcinogenesis So far as known, no attempts to induce carcinoma of the larynx by to- bacco smoke or smoke condensates have been reported. Pathology For information about histological changes in the larynx of smokers, see Chapter 1'0, Non-Neoplastic Respiratory Diseases. Evaluation of the Evidence The 10 retrospective studies have a high d'eg,ree of consistency despite the weakness of the control selections in one or two of them. A sufficient number of these studies have an adequate sample size for categorization of type of smoking and t'hese all show consistency in designating cigarette smoking as the significant' associative class. The fact that each of the prospective studies yielde& an excess of cases among cigarette smokers over the number expected from the incidence among non-smokers adds to the level of consistency noted. The calculations for cigarette smoking alone,, as well as for the combination of cigarettes, pipes, and cigars, were almost identical to those in the prospective studies. The relative strength of the association as measured by the specific mor- tality ratio ('as an average of combined experiences) is admittedly not as high as that noted for lung, cancer, but two of the three major prospective studies with adequate case loads indicate that the real value of the relative risk may approach that for lung cancer. As has been discussed! in the sec- tion on lung cancer, the implication of a lower relative risk is that other factors of etiologic significance may be independently associated with the disease. That this may be true for laryngeal cancer, as it seems to he for oral cancer, is reasonable because alcohol consumptions though frequently associated with heavy smoking, appears to be associated with laryngeal cancer independently from smoking (376, 377). As with, lung cancer a dose-effect of smoking, is also demonstrable. Thee majority of the retrospective studies have shown a greater association with heavy smoking and in two of them gradients with increasing amounts of tobacco consumed have been elicited. The prospective studies (Chapter 8, Table 21) also suggest a gradient although the numbers of deaths are small. Inhalation, a crude indicator of exposure, has also been noted as being asssoci- ated with laryngeal cancer in each of the studies in which such analyses were attempted. The parallelism with lung, cancer, though not as complete be- cause of a smaller amount of material,,is remarkable. In an assessment of the coherence of the association between smoking and laryngeal cancer with the facts of the natural history and biology of the disease an approach similar to that utilized in the lung, cancer analysis can be helpful. I TIME TRENDS Although~ laryngeal cancer mortaliUy has increased somewhat over the past three decades, the increase has been much less than that for lung cancer 210

mortality. In this regard it has also been mentione& that in at least one d'e- tailed study (376) the laryngeal cancer risk for cigarette smokers, irrespective of amount smoked, seems to be equal to that, for pipe and cigar smokers (as a combined group). Furthermore, while the per capita consumption of cigarettes has risen, the consumption of pipe and cigar tobacco has declined. In addition, there is no evidence or reason to assume that the susceptibility of the larynx for cancer is equal to that of! the bronchus. Finally, evidence has also been presented (stemming from the implications of lower mortality ratios of smokers to non-smokers), that other factors may play a significant role in the productioni of laryngeal cancer, such! as alcohol and inadequate nutrition (1376). Thus a diminution of' such other factors in time could well have counterbalanced, in great part, a rise which could have attended increased cigarette consumption. Tobacco: chewing has also declined to such a; great extent ini this country that adequate case materiall among chewers is not available for analysis. However, evidence derived f'rom, studies amona betel nut chewers in India indicates that even among smokers of cigarettes, cigars, pipes or bidis * the addition of tobacco to the material chewed is associated with an even greater risk of laryngeal cancer (100, 376). The evidence from the retro- spective andl prospective st'udies is compatible with the small rise in laryngeal cancer incidence observed! SEX DIFFERENTIAL IN MORTALITY As has been noted in the discussion of lung cancer, the much later advent of cigarette smoking, among females would be compatible with their lower laryngeal cancer mortality rates. Furthermore, the negligible degree of pipe and cigar smoking and tobacco chewing among females would not! only be compatible with a significantly lower risk of cancer of the larynx among them today as compared to males (WM: WF'= 1!0.8) but also with a lower sex ratio 30 years ago (WM: WF=6.3) (130). Assuming a reasonable induction period, the mortality rates W years ago could have been a reflec- tion of the much lbwer consumption of tobacco even among males between 1900-1910 (239). One cannot overlook the role of alcohol consumption in, this differential. The greater alcohol consumption among males and a strong association be- lween laryngeal cancer and alcohol consumption (376, 377) must be con- sidered as contributing to the excess ratio of male to female laryngeai cancer mortality. The role of inherent sex differences (e.g., hormonal, laryngeal anatomy)' as determinants in the difference in mortality related to smoking cannot be fully evaluated from the limited information available. LOCALIZATION OF LESIONS'. Two studies have dealt analytzcally with laryngeal cancer from the stand- point of specific locallzation, i.e., extrinsic vs. intrinsic laryngeal cancer (327, 376). (Most laryngeal cancers designated as extrinsic arise in the larynx proper; about 30 percent designated as extrinsic: arise in adjacent *Bidi (variant~ of biri)-a locally made cigarette of~ tobacco flakes rolled in the dried leaf of a varietyof bauhinia (306). 211

structures such as the epiglottis, its valleculae and on the arytenoid folds.). In only one of these studies (376) were the data analyzed in sufficient detail to permit tentative interpretatiom It should first be noted' that intrinsic laryngeal cancer was more often~ associated with cigarette smoking, whereas a higher percentage of pipe and/or cigar smokers was found among extrinsic than among intrinsic cancers. Secondly, in both the United States and the Indian data referred to by Wynder, chewing of tobacco seems to be associated with a higher risk for the extrinsic type, implying that tobacco juice makes contact readily with such extrinsic structures as the epiglottis ('37:6 percent of the extrinsic cancers were in this location). Finally, males predominate in intrinsic cancers of the larynx, whereas the ratio for extrinsic cancers, though lower, still shows an excess for the male. Thus far, the tobacco smoking and chewing, patterns of males vs. females are compatible with the: data on localization differences between the sexes. Extrinsic laryngeal cancer is relatively more common among rural than urban females. This evidence was presented by Wynder as indicating that some other factor whi& does not influence intrinsic lesions is operating. From some sugges- tive data he proposed dietary deficiency as a plausible explanation and cited the Swedish experience (385)~ as indicating the possibility of an iron-vitamin B complex deficiency. This remains to be adequately tested. In any event, the male excess of cigarette smoking and the inhalation factor are compatible with the male preponderance of the intrinsic type of laryngeal cancer. Pipe and' cigar smoking is also not devoid of some uncon- scious inhaling, at least to the level of the larynx. Furthermore, the more common findings of pipe and cigar smoking among cases of extrinsic laryngeal cancer are compatible with exposure to tobacco juice from this form of smoking. And, finalHy„ the obvious exposure to such juice from tobacco chewing, is compatible with the preponderance of extrinsic typess among such users of tobacco. is a significant factor in the causation of laryngeal cancer in the male. Evaluation of the evidence leads to the judgment that cigarette smoking, Conclusion. ESOPHAGEAL CANCER were collected in the period 1938-43. These investigators found associa- patients with cancers of the pharynx, larynx, and esophagus and found an excess frequency of cigarette and cigar smokers among the combined group. The first controlled retrospective study directed specifically to the esopha- gus was by Sadowsky et al. (301) published in 1953, the data for which of the two variables as early as in 1937. Ahlbom (1) studied a group of tween~ smoking and esophageal cancer led to more or less controlled studies As with cancers of other sites, clinical impressions of an association be- Epidemiologic Evidence RETRQSPECTIVE STUDIES 212

tions with cigarette and with cigar smoking but only the cigarette smoking relationship was noted to be statistically significant. Since then there have been six other retrospective studies (306, 315, 325, 329;, 374, 385) (Tables 12 and 13). It should be noted, however, that one of these (329')~ is an autopsy series with no reliable data on smoking his- tories. Among, the five remaining studies with better data collection meth- ods, significantly excess frequencies of tobacco smoking among esophageal cancer cases were noted in two (315, 325) excess frequencies of cigarette smoking were noted in two others (374, 385) but in only one of these (374!) was the excess statistically significant. Cigar smoking and pipe smoking were implicated separately in these same two studies but again the excesses for each were statistically significant in only one study (374). In this latter study a significant association with tobacco chewing was also found. A por- tion~ of this same study was devoted to analyses of data collected in India. The Indian data should not be given the same weight as the others, since only 10 percent of the male cases and 4 percent of the female cases were histologically confirmed. It is of interest, however, that an association be- tween tobacco smoking and esophageal cancer was observed. The rerraining study in this group is that of Sanghvi et al. (306) who found no significant associations with tobacco chewing alone and with cig- arette and bidi smoking alone, but found a significant association for thee combination of smoking, and tobacco chewing. Several of the studies were concerned with the amounts of tobacco smoked. The Swedish study by Wynder and co-workers (385)' which had demon- strated excess frequencies of cigarette and cigar smokers among the esopha- geal cancer cases not to be statistically significantS showed a significant excess of amount of tobacco smoked among the cancer cases. A later study ,by Wynder and Bross (374)~ found significant excesses of heavy smokers among both male and female esophageal cancer cases. Staszewski (325) found a highly significant excess of heavy smokers among the cases in his Polish study. Schwartz and his co-workers (315) in the most extensive study of all, found significantly more smokers among cases than among controls. However, the difference in daily amount of cigarettes smoked was not significant. A refinement of the data in two studies (301, 374) by classes of number of cigarettes smoked daily showed a gradiea of'~ increasing risks for esophageal cancer in both. Inhalation practices were explored in two of the retrospective studies (315, 325). In neither of them was a significant difference found in percentage of inhalers between cases and controls. Relative risk ratios were calculated from the data available in each of the retrospective studies (Table 13). The relative risks for all smokers in these studies ranged from 2.1 to 4.0 for American males and 2.0 to 4.1 for Ameri- can females. Data were available for calculation of relative risks with regard to heavy smoking in only two~ of the studies (325, 374). The Polish data revealed a: relative risk ratio of 16:1 for heavy smokers as compared with: non-smokers, whereas the latest Wynder study revealed ratios paradoxically lower for heavy smokers than for the category "all smokers."' In view of previous studies which had revealed an association between esophageal cancer and alcohol consumption, Wynder and Bross (374) tested 213

TASL>; 12.-Summary of methods used in retrospective studies ol tobacco use and cancer of th.e esophagus - C ases I Con trols Investigator year and , , reference Country Sex N - ' - Collection of data tiem Method of selection be~ Method of selection Badowskyeta1.1953 (301) U.S.A. M 104 White patients admitted during 615 White patients with illnesses other (1) Obtained by 4 especially trained 193t}-43 to selected hospitals in than cancer admitted to same lay lnterviewers. N.Y. City Missouri, New Or-_ < group of hospitals during same i d (2) 242 records out of a total of 2,847 te d d b f in o l l leans, and ( hicago. o . per c mp exc u ecause o e or e questionable smoking histories. Sangbvl et al. 1955 (306) India M - 73 Consecutive clinic admissions to (1) 288 - --- - - -- Consecutive clinic admissions of - - By means of 'detailed qucstlonary'. Tata Memorial Hospital, Bom- patients withouEcancer No-other detafls given. bay. (2) 107 Coasecutive admissions of patients with cancers other than intraoral or esophagus. Steiner 1956 (329) U.S.A. M+ 116 Consecutive cases studied at aa- 464 Autopsy eases comprising: Not clear how smoking histories were F topsy in University of Chicago - 116stomach cancer obtalned-from hospital records, Dept. of Pathology during 1901- 1161ung cancer - probably, which indicates they 1954. 116 malignant lymphatic dis. may be inadequate. 116 cases without any malignant neoplasm. Matched by age, sex, race and year of autopsy. Wynder et al. 1957 (3&5) Sweden M 39 Patients admitted to Badlumhem- 115 Patients admitted to same hospital met, Stockholm during 1952-1955. with cancer of skin, and bead and - ncc.k region other than squamous cell cancer, leukemia, colon, other sites. No matching. Staszewskl 1960 (326, 327) Poland M 24 Patlents admitted to Oncolog ical 912 Other patients sent to Institute with No details given on method of data _ _ Institute during 1957-59. syinptoms probably not etiologi- collection. No age adjustment or cally connected either with smok- matching. Average age of cancer Ing or with diseases of esophagus, patients=60.5 an l-of control_s=53: stomach or duodenum. Schwartz et al. 1961 (315) France M 362 Admissions to hospitals in Paris and 362 Ilealthy indlviduals admitted to Interviewed by team of spcclal inter- a few large provincial cities since same hospital because of work or viewers who interviewed the 1954. trafllc-acciilents-matched by 5 largest proportion possible of al: yr.~igegrbup and time oCadmis- cancer - patients. Cases and slon. matched coYitrols-Intervlewed by - same person. t64S9GE0

Wynder and Bross, 1961 U.S.A. M 150 Cancer patients seen in Memnrial 150 Patients seen In same hospitals dnr- Data collected by trained inter- (374). Hospital, N.Y.C. and Kings- iug same time period with other viewers. bridge and Brooklyn VA Ilospi- tumors. fit%-malil;nanG tumors; tals during i950-69 (8fi% white). 36%-lienign conditions. Matched hy age with cancer patients F 37 Same hospitals and same time period 37 Same as with regard to male con- as male patients (86% whit2+)e trols. 43% had malignant and 37% t enign tumors. Wynder and Bross 1961 India M 67 Admitted to Tata Memorial Hospi- 134 Patients with other forms of cancer (1) Interviewed by one person. (374). F 27 tal, Bombay. except for oral cavity and lungs; a.c (2) 10% of male cancer cases histolog- well as various benign diseases. ically confirmed and 4%bf female cancer cases. ~61•S9c,Fb

TABLE 13.---Summary of results of retrospective studies of tobacco use and cancer of the esophagus Percent non-smokers Percent heavy smokers Percent Inhalers among Relative risk: ratio to smokers - - non-smokers - Investigator, year, and reference - - Cases Controls Cases Controls Cases Controls All smokers Heavy smoker9 - 8adowcky et al. 1953 (301) ---------------------------------- 3.8---------- 13.2--------- -- - ------------- -°--------°• - -------------- - ------------° 4.0 ---------°--- - 8angvhtet al. 1955 (308)------------------------------------- 6.5 ----•---•- 17.3--------- Average num ber of bidis - -------------- -------------- 3.6 - -------------- emoked _ -------- 15.3 14.1 Wynderet al. 1957 (385): M----------------------------------------------------- 13----------- 24----------- --'-'--------- -- •----------- -------------- -------------- 2.1 ----------•-•_ --- r--------°---°---------°-------^---------°------- atioat 65----- about 92-^-- -------- ^------------ -------------- -------------- - - -----^°°- 2.0 -- - -°°--°----- - -- Btasrewski1@6(1(328,327)---------------------------'------ 0------------ -- 18----------- 95.8 59 87.5 80 -- -------------- 16 8chwartL et a1.1981 (315)-------------------- ---------------- 3------------ 1Z----------- Total am ountsm oked 39 38 - 6.6 -------------- daily (cigarettes) 16.8 16.0 Wynder and Bross 1981 (374): (1) Am erican males----------------------------------- 5------------ 15----------- 48 33 -------------- ---------- ---- 3.4 1.8 (2) American feitialee------'--------------------------- 41----------- 78-°------° 27 16 ---.-.. . -------------- -------------- -4:1 ' (3) Indian maies--------------------------------------- - 13----------- 28 ---------- -------------- -- ° --- ---------- ------•'------ 2.6 -----°------- (4) Indian femules------------------ ----------------- 78 --'------- 94 -----•--'-- ------------ - ------ ---'- - ---'---------- - -------------- 4-b -----------'-- C6Z.S9G£0

this independent variable. Since a relationship between alcohol consumption and tobacco use is known to exist, these investigators analyzed the relation- ship between tobacco consumption and'esophageal cancer after adjusting for alcohol intake. Of extreme interest is their observation that in the absence of~ alcohol consumption~ there was no association with tobacco consumption, but in~ the presence of alcohol consumption~ an increasing relative risk with increasing number of cigarettes smoke& was apparent. In the presence of alcohol consumption, a high association between esophageal cancer and cigar and pipe smoking was also noted. PROSPECTIVE' STUDIES. In the seven prospective studies (Table 1 of this Chapter) some deathss from esophageal cancer have been accumulated to date. The mortality ratios range from 0:7 in the California; Occupational study to 6.6 in the Dorn study. Combining, the observed deaths from this cause for all seven studies yields a total mortality ratio of 3.4. The stability of the ratios for three of the studies (84, 96;, 97) is of low order, for they are based on only 7, 4 and 9 cases respectively. The mean mortality ratio for cancer of the esophagus in cigar and pipe smokers is 3.2, second only to that for cancer of the oral cavity, 3.4 (Table 24, Chapter 8)'. This ratio is based on 33 cases of esoph- ageal cancer in cigar and pipe smokers in five studies. Recently calculated data from six prospective studies (Table 23, Chapter 8) ~ reveal a gradient of risk ratios f'rom, 3.0 for smokers of one pack or less of cigarettes per day to 4.9 for smokers of more than~ a pack per day. It is obvious that witLso few cases to date, further cross-classification by duration of smoking, inhalation practices, and discontinued smoking is not feasible ati the present time. Cdreinogenesis So far as known, no attempts to induce carcinoma of the esophagus by tobacco smoke or smoke condensates have been, reported. A further note, indicative of needed research, is in order. In the recent Wynder and Bross study (374) these authors report that injection of ethyl alcohol' into or painting of ethyl alcohol on the skin of mice promotes the carcinogenic activity of cigarette smoke condensate when applied to the skim No data are presented in evidence. Evaluation o f Evidence Five of the seven retrospective and six of the seven prospectYve studies show sigpificant associations between esophageal cancer and tobacco con- sumption. One prospective study showed a mortality ratio less than unity (96) but this is base& on only four observed cases among smokers. Al- though two of the seven retrospective studies investigating esophageal cancer did not find the smoker-excess among cases statistically significant, all showed such excesses. Furthermore, it is noteworthy that despite the variations in the quality of the control groups the calculated relative risks in~ the retro- spective studies fall within the same range of mortality ratios as in thee prospective studies. This level of consistency is not to be ignored although few of the studies revealed increasing gradients of risk with amount smoked.

I H'ere, only two studies (301, 374) and possibly a~ third retrospective study (i385) show such a gradient. Whether this subclass inconsistency is due to inadequacy of data because of small sample size cannot be determined at the present time. The prospective studies have, however„revealedi sueh a gradient for amount of cigarette smoking, when the data of six studies were combined. Although not as marked a: gradient as in the lung cancer group, the increase in risk for esophageal cancer among smokers of more than a pack a day is greater than for laryngeal and oral cancer. Inhalhtion data: are extremely sparse but in the two studies in which the data were analyzed (315, 325), no correlation could be found. This is com- patible with an hypothesisthat postulates an action on esophageal mucosa by swallowing of tobacco condensates or tars. Evidence for this is lacking; but the associations between esophageal cancer and several'forrns of tobacco use„ viz., cigarette, cigar and pipe smoking and tobacco chewing, would support such an hypothesis. It is also supported by the fact that the mortalfity ratio for cigar and pipe smokers, though based on a relatively small number of cases, is approximately equal to the ratio for cigarette smokers (3.3 vs. :?•.0) . Mortality from esophageal cancer in the United States has shown a: tend, ency to rise slightly among whites in the last! 30 years; non-whites show a greater rise, but this is usually attributed to improvement and increased availability of diagnostic facilities. The smallness of the rise d'oes not negate the significance of an association with tobacco:use, some forms of which have been concurrently rising. This has been discussed earlier but it should be emphasi7ed that declines im other environment'al factors may counterbalance the otherwise rising influence of the variable under study. Since neither prospective nor retrospective studies were executed in the decades of 1910- 1930, conjectures om such an hypothesis are speculative. Inasmuch as the interaction between alcohol and tobacco use is documented in only one study, it would at the present! time be unwise to attempt any more detailed evaluation of the relationship of tobacco use to trends in the incidence and mortality of esophageal cancer. Suffice it to say that, if the component of tobacco use involves the swallowing of t'obaeco: juice, then the time trends im types of tobacco use over the past 50 years are relevant and not incompatible with the hypothesis. Conclusion. The evidence on the tobacco-esophageal cancer relationship supports the beliefi that an association exists. However, the data are not adequate to decide whether the relationship is causal. URINARY BLADDER CANCER Epidemiologic Evidence RETROSPECTIVE STUDIES The experimental work of Holsti and Ermala (177) in 1955 prompted the first retrospective study of the relationship between smoking, of tobacco 218

and cancer of the urinary bladder. After the lips and~ oral mucosa of albino mice of al "mixed known strain" were painted with tobacco tar daily for fivee months, 10 percent of the animals developed malignant papillary carcinomas of the urinary bladder. No carcinomatous change was observed in the oral cavity. The report of this work led Lilienfeld (2i5) to undertake a study of bladder cancer cases admitted! between 1945 and 1955 at Roswell Park Memorial Institute. Before being seen by clinicians for diagnosis, all patients at this institution are interviewed regarding smoking histories. Lil- ienfeld found a significant association between cigarette smoking and urinary bladder cancer among males but'~ not among females. This stud~~, though carefullyy controlled, was done before much knowledge of'cigarette smoking, relationships to other diseases had accumulated and before the results of the earliest prospective study had revealed' a relationship of smok- ing to urinary bladder cancer. Thus, information on amount smokeds age: at onset of! smoking, duration of smoking, and inhalation was either not collected or not analyzed. Only three additional retrospective studfies (220, 315, 389) have appeared since Lilienfeld's publication in 1956. The methodology and results of these studies are presented in Tables 14 and 15. All of these investigators found a significant association between cigarette smoking andi urinary bladder cancer in males. Three of these studies (215. 220, 389)' concerned themselves with the study of female cases as well. Two! of them foun& no relationship between smoking and' urinary bladder cancer in females, but one study (389) found the relationship to bee signific.ant.Three of the studies examined otherr forms of smoking. Schwartz et al. (315)~, in France where cigar smoking is negligible, separated pipe smokers and mixed smokers from; cigarette smokers and found only a suggestion of an association with pipe smoking, but the number of cases in this cate- gory were too few for meaningful inferences. Lockwood (2201 found sig- nificant associations between both pipe and cigar smoking and urinaryy bladder cancer in the male. Wynder and co-workers (389'): found no excess frequencies of pipe-only and cigar-only smokers among the urinary bladder cases. Here, too, the number of such smokers was even smaller than in the Danish study by Lockwood. Only two studies (220, 389) are concerned with amount o f smoking. In each, a significant excess, of heavyy smokers was noted among male patients with urinary bladder cancer. In the Danish study,, female cases and con- trols had equal proportions of heavy smokers but Wynder found only a suggestion of an excess of heavy smokers among the cases (Table 15). Inhalation was examined in two studies, the French and the Danish (220, 315)'. Schwartz et al. (315) found a profound! effect of inhalation on~ the associratiom between~ smoking and urinary bladder cancer. When compari- sons between cases and controls were made in each of the classes of amount smoked, the bladder cancer cases showe& a greater frequency of inhalers in each class. When inhalation was controlled, the eff'ect ofl amount of cigarette smoking disappeared. Thus the implication is clear that! the essen- tial relationship is between inhalation of either cigarette or pipe smoke with urinary bladder cancer. Lockwood (220)1 found statistically signifi- 219. ~,_.~. ..~.......... . ...--.... . .., - . .-., w?4...~.i'sFv::.x.+.1~...-.iM~.'.~urr+

M "Z,s9c,eo TABLE 14.--Sruwnary of methods used in retrospective studies of smoking and cancer of the bladder- _ Cases Controls Investigator year and - , , relerenoe Country 8ez - -- -- Collection of data Num- Method of selection Number Method of selection ber Lilienteld et al., 1958 U.B.A. M 321 AdmLssions to Roswell Park 337 Notiisease patients. Interview of patients by groups of (215). - -- ---- - -- - Memoriul Institute.--1945-55 over 287 Prostate cancer. interviewers-at time of Ist vislt to 45 yrs: oi age: Institute beTore seen and diagnosed by hy i ians: ^ F - 116 Same as males 109 Benign bladder conditions. p s c 317 No-disease patients. 763 Breast cancer - Schwartz et al., 1961 France - M - 214 -- - Admissions to hospitals in Paris and 214 IIeEilthy individuals admitted to Interviewed by team of specialized (315): a few large provincial citles since same hospital because of work or interviewers who intervfewed the 1954. --- traffic accident-matefied by 5 yr: largest-proportlonpossibie-of all age group, & admitted during cancer patients admitted to these same time to same hospital as hospitals. Cases and matched cases. controls Interviewed by same person. Lockwood 1961 (220). Denmark - M - 282 All bladder tumors reported to 292 - ----- --- - -- - A. From election rolls matched with - - -- - Cases-59 cases Interviewed by F 87 -Danish- Caneer Register during 87 cases according to ser, age, marital Clemrtiesen and 310 by Lockwood 1942-1958 and living at time of i C i t ie h d status; occupation and residence. Election Itoil Controls-2 inter- view Cl mm d b d 367 b erv w agen an open n n Fredericksburg. B. Another control group obtained e y y e esenim Lockwood. from sample of Danish Morbidity Survey (1952-53 & 54) compared 'with respect to smoking histories. Wynder 1963 (389). U.S.A. First Phaae M 200 Admission to several hospitals in 200 Admission to same hospitals (ex- Trained tntervlewers. N.Y.C. during January, 1957- cluded cancer of respiratory sys- (To be published). F 50 December, 1960. 50 tern, upper alimentary, tract, myocardlalinfarction). Matched by sex and age. Second Phase - M 100 Admission to same hospital during 100 Same as above. F 20 1961. 20 t

TABLE 15.-Summary of results of retrospective studies of smoking (irrespective of type) and cancer of the bladder Percent non-smokers Percent heavy smokers Percent inhalers among Relative risk: ratio to smokers non-smokers Investigator, year, and reference Sex Cases Controls Cases Controls Cases Controls All smokers Heavy smokers Lillenfeid at al., 1958 (215)----------------------- --- jM lF 15 87 29 83 -------------- ------- -------------- - -------------- -------------- --- - - 2-3 I:4 -------------- -------------- -- Sehwartz,1961 (315)----------------------•---------- - M 11 20 - -------------- - -------------- - 54 - 37 - - 2.0 --- -------------- - Lockwood 1961 (220) - M ~ 9 17 30 15 -- 33 9 2.1 2.4 , -------------------------------- F 58 88 4 4 '------------- -_____-------- 1.5 1.0 Cancer Caves------------------------------•----- f M -lF 11 59 -------------- -------------- -------------- -------------- . -°-----°-'-- -------------- ~ 14 -------------- -------------- -------------- ... -------------- ----.--------- -------------- PaPilloma Cases--------------------- ------- {M 8 5 -------------- -- ---- ------ - ----------- -------°--- ------------ -- - 31 14 ------- ------ -------"--'-- -------------- ------------- -------------- '-------- Wynder et a1.,1983 (389) (Phase A and B combined) _ . . .. _ . .... - ~M F 7 61 ls SB 47 8 23 0 ___ --- ----•----- ------------- -------------- 2.9 3.9 3,0 --------- ss4s94co

cant relationships with inhalation also buty unf'ortunately; he did not attempt cross-classification of inhalation with amount and type of tobacco smoked. Schwartz analyzed this even though his numbers were smaller and his sample more heterogenous in tobacco1abits thanLockwood's: Only one study analyzed data on age at onset o f smoking. Lockwood (220) found that his patients began smoking larger amounts of tobacco at an earlier age thani did his controls. Other variables were examined in three studies, not only as a check on possible biases and inHuence of confounding variables on the association /'220, 315) but also as a means of eliciting other environmental factors (389). In the latter study by Wynd'er, which included analysis of occupation, an excess of leather workers andi shoe repairers was noted among the urin- ary bladder cancer cases although their numbers were small. It is possible that exposure to aniline dyes also occurred~ Relative risk ratios were calculated from the data; contained in the origi- nal!papers, and are presented in Table 15 and 15A. For male smokers these ratios varied from 2.0 to 2:9. In one study of males (220) heavy smoking tended to increase the risk slightly (2.1 to 2.4). The female ratios were near unityy except for the finding of 3.9 from Wynder's data. Relative risk ratios for male cigarette smokers only ranged from 2.0 to 3.3. TABLE 1St1.-Summary of results of retrospectiv.e studies of cigarette smokingg and cancer of the bladder in males Rercrnt Cigarette Smokers Relative Risk: . lnvestieat'or, and ClassifiraUionof Cigarette Smoking Ratio of Ci¢a- rettc Smokers Cases Controls to Non-9mokerr [biliarnfCld (cigarette R'other). (2t5)1056 61 44. 2,0 Schµ-art'z(cigarettconly)~(31.5)1!tfi1 g3 70 2.1 Lockwood (,Ciqarette, is main inode oismoking) (Q2(1)' 1961 30 15 2.4 ltynder(ciearette Gother)(3R9)1963 85 63 3,3 PROSPECTIVE STUDIES Six of the seven prospective studies. showed bladder cancer mortality ratios ranging from 1.7 in the current study by Best, et al., in Canada (25)) to 6.0 in the Calif'ornia occupational study of Dunn et all (96). The only disparate finding is in the Doll and Hill study (84) where, oni the basis of 12 bladder cancer deaths among the physicians of the. study, the mortality ratio is 0:9(Table1)1. Two studies (96, 97) show relatively few deaths from urinary bladder cancer to date. If these studies are tentatively omitted and the:remaining four studies ('25; 88; 157i, 163) with significantly larger numbers of deaths are scrutinized, the range of the mortality ratios is narrow: 1.7 to 2.2. The mean mortality ratio for all seven prospective studies is 1.9: For smokers of cigars, and pipes the mean mortality ratio is 0.9 (Table 22, Chapter 8) . Further information on sub-classes of tobacco use, e.g., inhalation practices, age at onset of smoking, and duration of smoking are 222 . r :-, - a-w-~~ :

not presently available. Some information on a gradient' for amount of cigarette smoking was obtained from previously published data of Dorn 188) ; the mortality ratios by quantity of cigarettes were as follows: less than 10 cigarettes, 1.0; 10 to 20, 1.8;, more than 20, 2.75. In the original Hammondl and Horn study (163), a gradient with number of cigarettes smoked was perceptible for all cancers of the genito-urinary tract! (less than 10 cigarettes, 2'.0; 10-20, 2.0; more than 20, 3.1). Data for cancer of the bladder per se were not then available. In, the Dorn study, even at the 1959 mark in its progress, a distinct, gradient was noted. These data have recently been augmented by caleulations of up-to-date data from six of the prospective studies. These reveal a; distinct gradient by amount of cigarettes smoked daily. The mean mortality ratio for urinary bladder cancer among male smokers of one pack or less per day is 1.4, whereas thee iatio for smokers of more than a pack is 3'.1 (Chapter 8, Table 23)i. Carcinogenesis. In a studly whose original' aim was to determine the effect of tobacco tars on the tissues of the oral cavity in mice, Holsti and Ermala (1177) observed papillary carcinomas of the urinary bladder in 15 percent of the animals that survived, representing,10 percent of the 60 originally treated. The lesions were histologically classifie& as carcinomas, though no metastases were ob- servedl Benign papillomatoses were observed in 87.5 percent of the ani- mals. In a similar study, DiPaolo and 11Toore (7,5) observed only slight hyperplasia of the mucosa„ but in one mouse anaplhstic sarcoma of the uri, nary bladder was encountered. The significance of these experiments as well as earlier ones reported by Ro$'o (295) is obscure. Evaluation of the Evidence Relatively few retrospective studies of the smoking-urinary bladder cancer relationship have been undertaken. The four existing studies showed a consistency in association between cigarette smoking and cancer of the uri- narybladder ini males. Two investigators who studied the dose-ef]ect found a correlation of increasing risk with amount smoked. Those examining the practice of! inhalation of smoke have found an, even greater association and; although but one study dealt with age at onset of! smoking, this showed that patients with bladder cancer started heavy smoking at an earlier age than the.controls. The relative risks calculated from data available in the retrospective studies are of an almost similar order of magnitude not only among themselves but in comparison,to the mortality ratios derived from the larger of the prospec- tive studies. Two of three retrospective studies show, no association with other forms of smoking and' this is consistent with the findings of a bladder cancer mortality ratio of somewhat less than unity among cigar and' pipe smokers as elieited4rom the prospective studies. Because of this consistency in the male studies, only a brief discussion~ of the elements of observer-bias, misclassification, non-response bias, and other possible causes of error, willi be necessary. Suffice it to say, that in the 714-422 0-64-16 223 ~.

Lilienfeld study, aff interviewing for smoking history was done on all admis- sions for any complaint prior to diagnosis: In the Schwartz study, matched healthy controls were utilized; comparisons were made for area of residence, famil;v status, and! occupation; and these variables were tested for relation- ship to smoking and inhalation histories: Such relationships, when found, were slight and not to the degree of association of smoking to urinary bladder cancer. Information on histological confirmation of all cases of this study by Schwartz was lacking. Since the bladder cancer cases in this study had originally served as controls in a lung cancer study, some of the observer-bias arising from knowledge of the distinction between cases and controls was probably neutralized. Furthermore, the results of the early phase of the study were consistent with the findings in the entire study reporte& om later. The Lockwood study, executed to elicit environmental factors which might be operating to explain an increase in Copenhagen in incidence of bladder tumors both benign and malignant, included all bladder tumors, 24 percent of which were malignant. Since differences of opinion with respect to cri- teria of malignancy in these tumors exists, it' is possible that this type of tumor was similar to those diagnosed as cancers in other countries. Never- theless, Lockwood's group did analyze the material' separately and found the smoking, relationship to both benigni and, malignant tumors to be essen- tially the same. These authors also utilized al second control group derived from the Danish Morbidity Survey. Their study controli group and the probability sample from the survey were similar with respect to amount of smoking~ Both cases and controls were similar with respect to alcohol con- sumption, marit'alistatus, housing, history of pyelitis and cystitis, sulfonamide consumptioni and other variables. The Wynder study (389) involved controls matched by age and sex and liospital of adrnission. Variables of'comparison included race, marital status, religion, place oflbirth, dietary habits, education, residence, alcohotconsump- tion„ weight, orall hv.giene, blood' group, circumcision status, occupation, and genito-urinary diseases. Cases and controls were similar for all variables except for occupat'ion, and genito•urinary diseases. The excess of leather workers and shoe repairers among the blad'der cancer cases has been noted above. The bladder cancer cases also had a higher freq;uency of'~ bladder stones or cystitis. These conditions may have etiologic implications. Several conflicting findings do exist, however, in relation to the association between smoking and urinary bladder cancer. The first is the finding by Wynder of a highly significant association between smoking and bladder can- cer in females. This latter association is weakened, however, by the equivo- cal finding of only a slight excess of heavy smokers among the cases. A second inconsistent' finding is am association with cigar smoking, as reported for males by Lockwood. Inhalation was tested by him~ but it' is not clear whether the cigar smokers inhaled in sufficient amount and depth to charac- terize them as being different from cigar smokers in the United States. Fi- naldy, the urinary bladder cancer mortality ratio~ im the Doll and Hill pros- pective study is approximately unity, a finding inconsistent with the other six prospective studies. In addition to the finding of an association with smoking in female casesin a single study (389)~ is the fact that no associatiom exists for women in two other retrospective studies: If cigarette smoking is ac- 224

tually associated with male bladder cancer, should not an association be found in the female„as with lung, larynx, oral, and possibly esophageallcancer?' The clues to the solution of this dilemma may be first, that inhalation seems to be the more important factor in the relationship between smoking and bladder cancer, and'secondly„that other etiologic factors may have a"swamp- ing" effect in the female to counteract her lower frequency of inhaling. Evidence for support of this hypothesis is lacking at present. If correct. then the Wynder finding requires explanation, which may be looke& for in the disparities in smoking habits between cases and controls. The strength and specificity of the association are obviously of low order because the mean mortality ratio is 1.9. This also implies that factors other than smoking may be associated etiologically wit6 urinary bladder cancer. Little can be saidi regarding the coherence of the association beyond thee scanty data on d'ose-effect. Furthermore, adequate information is lacking for ani intelligent discussion oflf the sex differential, which is the lowest for any of the cancer sites for which an association, direct or indirect„with smok- ing has hitherto been suspected. An urban-rural differential is virtuallw non-existent in urinary bladder cancer. Since there: seem to be differences in patterns of smoking between rural and urban groups, additional factors must be sought to account for the lack of such a differential in the disease. The experimental work of Holsti and Ermala (177) has been described earlier. This is a solitary finding requiring repetition with the same strain of mice. DiPaolb and Moore utilizing different methods of preparation of the tobacco tar and different strains of mice obtained essentially negative results (75). Further retrospective studies of female cases, studies with large enough numbers of male cases to provide for further cross-classification by amount and duration of smoking and inhalation~ practices, and the ultimately forth- coming results on female subjects in the current Hammond prospective study will be necessary to provide more nearly adequate data: in urinary bladder cancer. ConclusionAvailable data; suggest an associatSon: between cigarette smoking and uri- narybladd'er cancer in the male but are not sudicient'tosupport a: judgment on the causal significance of this association. STOMACH CANCER Epidemiologic Evidence. RETROSPECTIVE STUDIES Very little interest in~ the relationship between smoking and gastric cancer seems to exist since only four (94, 193, 315, 325)' retrospective studies havee appeared in the literature since 19=16. The method'ology and findings of these studies have been summarized in Tables 16 and 17. Of the four studfies, two (94, 315) failed to find any association between smoking and' gastric 225

TABLE 16.-Summary of methods used in retrospective studies of smoking and cancer of the stomach r E08S9GE0 Cases Controls Investigator, year, and Country Sex - Collection of data reference - - - - No. Method of selection No. Method of selection -- Dunham & Brunschwig - U.S.A. - M&F 40 - - Not clear. Patients in Dept. of 40 - Not clear. Patients without gastric - - Not specified 1946 (94). Surgery, Univ. of Chicago. tumor. Kraus et al., 1957 (193). U.S.A. M 66 Admissions to Roswell Park Me- 677 Patients admitted to Roswcll Park Questioned by trained interviewers "-- - - -- modal Inst., 11/48-9/5 1, --- 25-74 during same time period in follow- - - --- _ years of age. -- Ing 4 diagnostic groups: - (1) Digestive cancer other than esophagus or stomach. - (2) Canccr-.other than diges- tive-respiratory, urinary, skin, hemat. (3) Non-tumor diag. of digestive system other than esophagus or storriach. (4) Non-tumor diag. other than --d i ge s t i v e-re s p i r a t or y; --u r i n s r y, skin, hemat. Each control Rroup matched to cancer group by age and popula- tion sizebf place of residence. Staszewski 1960 (327). Poland M 136 Patients admitted to Oncological 912 See'}`ABLE 11 See TABLE 11. Two-thirds of can- Institute during 1957-59. cer of stomach diagnoses were hi s- _ tologically contirmed. Schwartz et al., 1961 (315). France M 263 See TABLE 11 263 Patients hospitalized from 1954-1956 See TABLE II - -- - - ----- -- -- with gastric cancer in Paris and other large cities.

77 TABLE 17.-Summary of results of retrospective studies of smoking and cancer of the stomach Percent non-smokers Percent heavy smokers Percent inhalers among Relative risk: ratio to - - --- - -- - - -- - - smokers non-smokers reference and year Investigator , , Cases Controls Cases Controls Cases Controls A1l8mokers Heavy Smokers Dunham and Brunschwig 1948 (94) ------------------------ 47.5 47.5 -------------- -------- ------ - ------------ ---------------- ----- 0 -- ---- - Kraus et al. 1957 (193)-------------------------------------- ------ 19.2 - 24.2 - -- ----- - ---------------- .3 -1.3 - - ------------- --- ---- _ - 6taszewsk11980 (325) --------------------------------------- - 12.5 -- 18 - - 88.2 -- 80 - 1.5 ----- 2 1 - -- Schwartz et al. 1961 (315)----------------------------------- ------- -- 16 17 - Total cigarettes smoked -- 37 - - - 34 1.0 ---__-------- daily - 14.6 I 15.3 VOgS9L.E0

cancer. The other two studies, to date, suggested an association but these were not statistically significant (193, 325). Two of the studies did not approach the smoking variable specifically but as part of attempts to examine directed to the role of smoking (315, 325)~. The relative risks as calculated are not significantly different from unity. severall possible etiological factors (94, 193) ; the other two were specifically cancer mortality ratio~~ of'~ 1~~J (Table 29J, Chapter 8)~. For cigar and pipe smokers the combined studies provide a mean gastric smoked. In neither of these is any gradient apparent. or mortality ratios for the severall cigarette smoking classes by amount Two of the earlier reports (84, 88)' provi,de information on mortality rates ratio is not statistically significant (p=0.12) (163). and Horn study (163) (Table 1 of this chapter),. The Hammond and Horn Dunn, Linden, Breslow occupational' study (96) to 2.3' in the Hammond described earlier. The individual studies, however, with fairly adequate numbers for stability, show a range of mortality ratios from 0:8 in the calculated to be 1.4. This is obviously lower than for any of, the sites cancer. The mean gastric cancer mort'ality ratio for the seven studies is Hammond and Horn study) have yielded a total of 413 deaths from gastric The seven prospective studies brought up-to-date (except for the original PROSPECTIVE STUDIES condensates have not been successful (294). Attempts at production of cancer of the stomach with tobacco tars or into the glandular stomach wall between the serosa and mucosa (332, 333). rats by the intramural injection of carcinogenic hydrocarbons (17, 19, 187, 339) or by inserting a silk thread impregnated with 2-methylcholanthrene Adenocarcinoma has been produced in the glandular stomach of mice and oral administration~ of carcinogens (249). Rats also develop squamous cell tumors in the forestomach after prolonge& injecting 20-methylcholanthrene intramurally. Lorenz (333) produced the same type of' cancer in the forestomach by incidence of such cancers in~ mice varies with the strain used. Stewart and covered with squamous epithelium extending down from the esophagus. The 59; 276, 364). It should be noted that the forestomach of mice and rats is 19, 59, 113a, 223, 276, 308, 334, 364, 368) including benzo(a)pyrene (19, by the oral administration of various polycyclic aromatic hydrocarbons (8, Cdreir?ogenesis Squamous cell carcinoma has been produced in the forestomach of mice the fore- or glandular stomach. None of the retrospective studies shows an association between gastric cancer and smoking, Nor do the prospective studies yield gastric cancer mortality ratios significantly higher than the total mice with benzo(',a)pyrene and'dibenz (a,h) anthracene ihjected directly into Squamous and adeno-carcinomas have been produced experimentally in Eual'uation, o fthe Evidence 228

mortality ratio, In fact, the mean gastric cancer mortality ratio for ciga- rette smokers is below the mean total mortality ratio, and for cigar and pipe smokers it is approximately the same. Even a gradient by amount smoked is lacking in~ at least two of~ the prospective studies. Conclusion. No relationship has been established between tobacco use and stomach~ cancer. SUMMARIES AND CONCLUSIONS Cancer deaths per year increased seven-fold (,in the United States death registration area: of 1900) between 1900 and 1960-from 10,000 in 1900 to 80;000' in 1960. Less than half of this increase was due to aging and growth of the population. A large part of the increase was due to lung cancer. LUNG CANCER' While part of the rising trend for llmg cancer is attributable tb improve- ments in diagnosis, the continuing experience of the State registers and the autopsy series of large general hospitals leave little doubt! that a true increase in the lung cancer deatL rate has taken place. About 5,700 women and 33,200 men died of lung cancer in the United States in 1961; as recent'lyas 1955, the corresponding totals were 4,100'women and 22;700 men. This extraordinary rise has not been, recorded for cancer of any other site. When any separate cohort (a group of persons born during,the same ten- year period) is scrutinized over successive decades, its lung cancer mortality rates vary directly with theaecency of the birt6 of the group: the more recent the eohort, the higher the risk of lung cancer throughout life. Within; each cohorts lung cancer mortality apparently increases unabated to the end of the life span. The pattern~ would sug~esG that the mortality differences may be due to differences in exposure to one or more factors or to a progressive change in population composition among the several cohorts. A considerable amount of experimental work in many species of animals has demonstrated that certain polycyclic aromatic hydrocarbons identified in~ cigarette smoke can produce cancer. Other substances in tobacco and smoke, though not carcinogenic: tliemselves, promote cancer production or lower the threshold to a known carcinogen. The amount of known carcinogens in cigarette smoke appears to be too small to account for their carcinogenic activity. There is abundant evidence, however, that cancer of the skin can be in- d'uced in man by industrial, exposure to soots, coal tar, pitch and mineral oils; all of these contain various polycyclic aromatic hydrocarbons known to be carcinogenic in many species of animals. Some: of these compounds are also present, in tobacco smoke. Although it is noted that the few attempts to produce bronchogenic carcinoma directly with tobacco extracts, smoke, or 229

condensates applie& to ~ the lung or the tracheobronchial tree of experimental animals have not been successful, the administration of polycyclic aromaticc hydrocarbons, certain metals, radioactive substances, and certain viruses have 1 of the association between tobacco smoking and lung, cancer (summarized in Tables 2 and 3 of Chapter 9), varied considerably ini design and method. Despite these variations, every one of the retrospective studies showed an association between smoking and lung cancer. All showed that proportion- ately more heavy smokers are found among the lhng cancer patients than in the control populations and proportionately fewer non-smokers among, the cases than among the controls. The differences are statistically significant in all the studies. Thirteen of 7 prospective studies (described in Chapter 8). The 29 retrospective studiess with~ lung cancer and appropriate "controls" without lung cancer and from cancer comes primarily from 29 retrospective studies of groups of' personss to fix a safe dose of chemical carcinogens for men. The systematic evidence for the association between smoking and lung Neither the available epidemiologicall nor the experimental deta is adequate aromatic hydrocarbons that produce cancer in~ experimental animals. man are susceptible to the carcinogenic action of some of the same polycyclic been shown to produce such~ cancers. The characteristics of the tumors pro- duced are similar to: those observed in man. Since the response of most human tissues to carcinogenic substances is qualitatively similar to that observed in experimental animals, it is highly probable that the tissues of the studies, combining all forms of tobacco consumption, found a significant association between smoking of any type and lung cancer; 16 studies yielded an even stronger association with cigarettes alone. The degree of association between smoking, and lung cancer increased as the amounts of smoking, in- creased. Ex-smokers generally showed a lower risk than current smokers but greater thani non-smokers. Relatively few of the retrospective studies have dealt with "age started smoking," but alli except one of these studies found that; male lung cancer patients began tol smoke at a significantly younger age than the controls. Except at the highest cigarette consumption levels, the relationship: of inhalation to lung cancer was significant for those smoking cigarettes alone. Several investigators have utilized mathematical techniques to calculate,, fromi retrospective studies, the relative risks of lung cancer f'or smokers as compared with non-smokers. All of the 9 studies in which relative risk ratios were derived showed' a significantly greater risk among smokers, ranging from as low as 2,d-to-1! for light smokers to as much as 34.1-to-1 for heavy smokers, with most of the ratios betweeni these two extremes. All seveni of the prospective studies show a remarkable consistency in the higher mortality of smokers, particularly from lung cancer. Of' special interest is that the size of the association between cigarette smoking and! totall lung cancer death rates has increased with the ongoing progress of the studies. Depending oni the kind of population studied'y the relative risks of lung cancer for current cigarette smokers in America comparedl with, non-smokers range from 4.9'in one study to 15.9 in another. A study among British doctors showed a ratio of 20.2. For the studies as a whole; cigarette smokers have a risk of developing lung cancer 10.8 times greater than non- 230

smokers. The mortality ratios increase progressively with amount of smok- ing; the pivot levell appears t'o be 20 cigarettes a day. For those who smoke pipes andl/or cigars (to the exclusion of ciaarettes ), the lung cancer ratioss are lower than for any of the cigarette smoking classes includinr, combina- tions of cigarettes with pine and /or ciaars. In extensive and controlled blind studies of the tracheobronchial tree of 402 male patients, it' was observed that several kinds of changes of the epithelium were much more common in the trachea and bronchi of cigarette smokers and subjects with lung cancer than in nonrsmokers and patients without lungcancer. 'liheepithelia] changes observed are (1) loss of ciliated cells, (2) basallcell hyperplasia (more than two layers of basal cells), an& (31 presence of atypicali cells. Each of the three kinds of epitheliall changes was found to increase with the number of cigarettes smoked. Extensive atypical changes were seen most frequently in men who smoked two or more Uackss of cigarettes a day. Men who smoke pipes or cigarettes have more epithelia] changes than non-smokers but have fewer changes than cigarette smokers consuming approximately the same amount of tobacco. It may be concluded, on the basis of human and experimenCall evidence; that some of! the advanced epithelial lesions with many atypical! cells, as seen in the bronchi of cigarette smokers, are probably pre-malignant. Other pathologic studies show that squamous and oval~cell carcinomas are the predominant types associated withi the increase of lung cancer in the male population, and that a significant relationship exists between smok- ing and the epidermoid and anaplastic types. In several studies, adenocar- cinomas have also shown a definite increase, although to a lesser extent. Various studies have suggested that adenocarcinomas have little or less relationship to smoking. In general, the association between smoking and lung cancer may be measured by certain crrud'e indirect indicators as well as by the direct measures (retrospective and prospective studiesldescribed earlier. Indirect measures include: a parallel increase in lung, cancer mortality rates and in per capita consumption of tobacco; disparities between male and female lung cancer rates andi the corresponding differences bet'ween smoking habits of men and women by amounts smoked' and duration of smoking. The retrospective and prospective studies directly measure the occurrence and relationship of smoking and lung cancer in the same kinds ofl population. Careful analysis of these studies demonstrates that neitherdiarnostSc errorsnor classification errors in terms of amount smoked are of! sufficient size to invalidate the results. Possible bias due to selection of subjects is diminished by the fact that in the continuing studies, lung cancer death rate differentials increase with the passage of'~ time. Thus, it would appear that an association between cigarette smoking and ltrng cancer does indeed exist. No single criterion is sufficient to evaluate the causal significance of'~ this association; but a number of different kinds of criteria, considered together, provid'e an adequate test: the association is consistent; no prospective: study and no reasonably designed retrospective study has found results to the con- trary. In the nine retrospective studies, f'or which relative risks for smokers and non-smokers were calculated, and in the seven prospective studies, the relative risk ratios for lung cancer were uniformly high and remarkably 231

close in magnitude, attesting to the strength of the association. Moreover a dose-effect phenomenon is apparent in that the relative risk ratio increases with the amount of tobacco consumed or of cigarettes smoked. From the prospective studies, it is estimated that in comparison witL non-smokers, average smokers of cigarettes have approximately a 9- to 10-fold! risk of developing lung cancer and heavy smokers aEleast a 20:fold risk. An important criterion~ for the appraisal' of causal significance of an as- sociation is its coherence with known~ facts of the natural history and biology of the disease. Careful examination of the natural history of smoking and of lung cancer shows the relationship to be coherent in every aspect that could be investigate& The probability that genetic inflhences might under- lie both the tendency toward lung, cancer and the tend'eney to smoke weree also examined. The great rise in lung cancer recorded in man, that has occurred in recent decades, points to the introduction of new determinants without which genetic influences would! have had little or no potency. The genetic factors in man were evidently not strong enough to cause the develop- ment of lung cancer in large numbers of people under environmental' condi- tions that existed! half a century ago: The assumption that the genetic constitution of man could have changed gradually, simultaneously, an& identically in many countries during this century is most unlikely. More- over, the risk of developing lung cancer diminishes when smoking is dis- continued; although the genetic constitution must be assumed to have remained the same. It has been reeognized that a: causal' relationship between cigarette smok- ing and lhng cancer does not exclude other factors. Approximately 10 percent of lung cancer cases occur among non-smokers. The available evi- dence on occupational hazards, urbanization or industrialization and air pollution, and previous illness was considered for possible etiologic factors. A significant excess of lung cancer deaths was found among workers in certain industzies-notably chromate, nickel processing, coal gas, and as- bestos-but the population exposed to industrial carcinogens is relatively small; these agents cannot account for the increasing lung cancer risk in the general population. The urban-rural diff'erences in lung cancer mortality risk, though small and accounted for in part by differences in smoking habits,, imply that intensity of urbanizationi or industrialization and' air pollution may have a residual influence on lung cancer mortality. Observations on, previous respiratory illness are too few in number to place any degree of assurance on relat'ionship with lung cancer. Conclusions 1. Cigarette smoking is causally related to lung cancer in men; the magni- tude of the effect of cigarette smoking far outweighs all other factors. The data for women, though less extensive, point in the same direction. 2. The risk of developing lung cancer increases with duration of smoking and the number of cigarettes smoked per day, and is diminished by dis- continuing smoking. 232 . ... . ..,. ..~........... ... ,....-. _.x,;..:.~+a,. ...r,. :-.'.is- .~~+r•

3. The risk of developing cancer of'~ the lung for the combined group: of pipe smokers; cigar smokers, and pipe and cigar smokers is greater than in non-smokers, but much less than for cigarette smokers. The data are insufficient to warranY a conclusion for each group individually.. ORAL CANCER The suspicion of an association between use of tobacco and oral cancer dates back to the early 18th century when cancer of the lip was first noted among users of tobacco. In modern times, 20! retrospective studies have shown a significant association of oral cancer with smoking or chewing of tobacco or use of snuff. Associations between oral cancer and smoking of cigarettes, cigars, and pipes were noted in nearly all of these studies, but in many, of them pipes and cigars seemed to exert a stronger influence. Im a study in which the sample size was large and controls adequate, it was possible to establish gradients for lip cancer by number of pipefuls smoked a day, for tongue cancer by amount of tobacco in pipes and cigars, and~ orall cancers by number of pipefuls. No gradientiby amount smoked was noted for cigarettes. The seven prospective studies show that cigarette smokers have propor- tionately 4.1 times as much mortality from, oral cancer as non-smokers. This is the third highest mortality ratio of cigarette smokers to non-smokers among the several specific types of cancer deaths and the fourth highest among all causes of death associated with cigarette smoking, For cigar and pipe smok- ers comparedl with non.smokers, oral cancer has the highest mortality ratio4 3.3, of all causes of death, exceeding cancer of the esophagus, larynx, and lung... Cancer of the orali cavity has not been, produced experimentallyy by the ex- posure of anin-ials to tobacco smoke or to carcinogenic aromatic polycyclic hydrocarbons except in the special case of benQo(a) pyrene and other hydFo- carbons oni the cheek pouch ofi the hamster. Leukoplakia was reported too have been inducedl by the injection of tobacco smoke condensates into the gingi'va! of rabbits. A strong, clinical impression links the occurrence of leukoplakia of the mouth with the use of tobacco in its various forms. Conclzcsions 1. The causall relation of'~ the smoking of pipes to the development of can- cer of the lip appears to be established. 2. Although there are suggestions of relationships between cancer of other specific sites of the oral' cavity and the several forms of tobacco use, their causal implications cannot' at present be stated. LARYNX Retrospective studies with adequate sample size all designate cigarette smoking as the most significant class associated with cancer of the larynx. 233 I

In each ofl the seven prospective studies, laryngeal cancer has been observed among smokers in frequencies inexcess of the expected. A summation yields a mean mortality ratio of' 5.3 for cigarette smokers. Recently calculated material from six prospective studies shows a gradient of risk ratios from 5.3 for smokers of' one pack or less of cigarettes per day to 7.5 for smokers of more than a pack per day. Laryngeal cancer cases were also associated with cigar and pipe smoking, but the number of cases is not yet large enough for judgment.. The relative strength of the association, as measured by the specific mor- tality ratio (as an average of combined experiences), is not as high~ as that noted for lung cancer, but two of the three major studies with adequate case load'sindicate that the reall value of the relative risk may approach that for lung cancer. As with lung cancer, a dose-effect of smoking is also demon- strable. The majority of the retrospective studies have shown a greater association with heavy smoking, So far as known, no attempts to induce carcinoma of the larynx by tobacco smoke or smoke condensates have beenn reported. Conclusion Evaluation of the evidence leads to the j udgment that cigarette smoking is a significant factor in~ the causation of laryngeal cancer in the male. ESOPHAG'US Both, the retrospective and prospective studies show an association~ between esophageal cancer and tobacco consumption. In the seven prospective studies, smokers have died of esophageal cancer 3-4 times as frequently ass non-smokers; the mortality ratio for pipe and cigar smokers (compared too non-smokers) is 3.2, second only to that for oral cancer. Recent data from six of the prospective studies show a gradient of risk ratios from 3.0 for smokers of one pack or less of! cigarettes per dayto, 4.9 for smokers of more than a pack per day. So far as known, no attempts to induce carcinoma of the esophagus by tobacco smoke or smoke condensates have been reported. Conclusion. The evidence on the tobacco-esophageal cancer relationship supports thee belief that an association exists. However, the data are not adequate to decide whether the relationship is causal. URINARY BLADDER In 1955, when~ the lips and oral mucosa of mice were painted with tobacco tars for five months, 10 percent of the animal5 developed carcinoma of the urinary bladder. This experimental work led to four retrospective studies, all of whi& found a significant association between cigarette smoking and 234 t.

urinary bladder cancer in males. Two of the studies also fbun& significant associations with pipe or cigarette smoking. Compared with non-smokers, the relative risk of smokers developing cancer of the urinary bladder varied from 2.0:to 2.9. The mean mortality ratio-cigaretrte smokers to non-smokers-for alll seven prospective studies is 1.9. Among smokers of one pack or less per day the mortality from urinary, bladder cancer is 1.4 times that of non-smokers; for smokers of more than a daily pack, it is 3,1. Conclusion Available data suggest an associatiom between cigarette smoking andl urinary bladder cancer in the male but are not sufficient to support! judgment on the causal significance of this association. STOMACH None of the retrospective studies shows an association between gastric cancer and smoking. The prospective studies show that cigarette smokers die of gastric cancer 1.4 times more ofteni than; non-smokers, buU this is below the total mortality ratio. No gradient of risk by amount smoked is apparent. Attempts to produce cancer of the stomach in experimental animals with tobacco tars have not been successful. Conclusion No relationship has been established between tobacco use and st'omach cancer. REFERENCES 1. Ahlbom, H. E. Pradisponierende Faktoren Fiir Plattenepithelkar- zinom in Mund; Hals und Speiserohre. Eine Statistische Unter- suchung am Material des Radiumhemmets, Stockholm. Acta Radiol 18: 163-85, 1937. 2. Alexander, P., Horning, E. S. Observations on the Oppenheimer method! of inducing tumours by subcutaneous implantation of plastic films., In Ciba Found'ation Symposium on Carcinogenesis. J & A Churchill, Ltd., Londony 1959. p. 12-25. 3. Andervont, H. B. Further studies on the suseeptibilfit'y of hybrid mice to induced and spontaneous tumors. J Nat Cancer Inst 1: 135-45, 1940. 4. Andervont, H. B. Pul'monary tumors in~ mice. VIII. The induction of pulmonary tumors in mice of strains D, M, C57 brown and C5 7 black by 1,2,5,6-dihenzanthracene. Pub Health Rep 54: 152-1-9; 1939. 235

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Non-Neoplastic Respiratory Diseases, Particularly Chronic Bronchitis and Pulmonary Emphysema I

Contents Page ALTERATIONS IN THE RESPIRATORY TRACT AND IN PULMONARY PAREN!CHYMA INDUCED BY TOBACCO SMOKE . . . . . . . . . . . . . . . . . . . . . . . . 263 Characteristics of the Exposure . . . . . . . . . . . . . 263 Composition of Tobacco Smoke . . . . . . . . . . . . 263 Regional Deposition or Retention of Tobacco Smoke ... 263 Mouth Retention of Tobacco Smoke . . . . . . . . . 264 Retention of Particles by the Trachea, Bronchiy and Pulmonary Tissue . . . . . . . . . . . . . . . . 264 Retention of Gases by the Trachea, Bronchi, and Pul- monary Parenchyma . . . . . . . . . . . . . . . 265 Metabolism and Toxicity of Specific Components in Tobacco Smoke . . . . . . . . . . . . . . . . . . 265 Clearance of Smoke Deposits . . . . . . . . . . . . . 267 Effects of' Tobacco Smoke on Defense Mechanisms of the Respiratory System . . . . . . . . . . . . . . . . . 267 Pulmonary IIygiene and Ciliary Activity .... ... 267 Mucus Secretion . . . . . . . . . . . . . . . . . 268 Alveolar Lining . . . . . . . . . . . . . . . . . . 269 Phagocytosis . . . . . . . . . . . . . . . . . . . 269 Other Mechanisms . . . . . . . . . . . . . . . . . 270 Histopathologic Alterations . . . . . . . . . . . . . . . 270 RELATION OF' SMOKING TO DISEASES OF THE RESPI- RATORY SYSTEM . . . . . . . . . . . . . . . . . . . Effects of Smoking on the Nose, Mouth, and Throat .... Smoking and Asthma . . . . . . . . . . . . . . . . . Relation of Smoking and Infectious Diseases .... ... Chronic Bronchopulmonary Diseases . . . . . . . . . . . Chronic Bronchitis and Emphysema . . . . . . . . . . Definitions . . . . . . . . . . . . . . . . . . . . Diagnosis . . . . . . . . . . . . . . . . . . . . . Relationship Between Chronic Bronchitis and Em- phy sema . . . . . . . . . . . . . . . . . . . . 260 275 275 275 276 277 278 278 278 279 I

RELATION OF SMOKING TO DISEASES OF TIIE RES- PIRATORY SYSTEM-Continued Chronic Bronchopulmonary Diseases-Continued Evidence Relating Smoking to Chronic Bronchitis and E'mphysema. . . . . . . . . . . . . . . . . . . Epidemiological Evidence . . . . . . . . . . . . . Prevalence Studies . . . . . . . . . . . . . . . ('1.) Smoking and Respiratory Symptoms . . . . (a.)' Chronic Cough . . . . . . . . . . . (b.) Sputum . . . . . . . . . . . . (c.) Cough and Sputum . . . . . . . . . (d.) Breathlessness. . . . . . . . . . . . (e.) Smoking, an& Chest Illness. . . . . . . (f.) ~ Combinations of Symptoms . . . . . . (g.) RelationsliipBet'ween Symptoms or Signs and Amount Smoked . . . . . (h.) Relationship Between Symptoms and~ Signs and Method of Smoking, . . . ('i,) Ventilatory Function. . . . . . . . . Prospective Studies . . . . . . . . . . . . . . Clinical Evidence . . . . . . . . . . . . . . . Relationship of Smoking, Environmental Factors, and Chronic Respiratorv Disease . . . . . . . . . . . . Atmospheric Pollution . . . . . . Basis for Interrelationship and Relative it'Iagnitude of Exposure . . . . . . . . . . . . . . . . (1.) Experimental Evidence . . . . . . . . . (2.) Relative Magnitude of the Exposure ... E pidemiologicall Evidence . . . . . . . . . . . . Occupational Factors . . . . . . . . .. . . . . . . SUMMARY . . . . . . . . . . . . . . . . . . . . . . . CONCLUSIOI S'. . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . Page 280 280 280 280 280 283 283 286 287 288 289 289 289 293 294 295 295 295 295 296 297 298 300 302 302 Figure FIGURE 1.-Black pigment and emphysema in lungs of 83' patients . . . . . . . . . . . . . . . . . . . 273 List of Tables, TABLE' I.-Summary of reports on the prevalence of cough in relation to smoking . . . . . . . . . .. 281 TABLE 2.-Summary of reports on the prevalence of sputum in relation to smoking . . . . . . . . . . . . . 283 TABLE 3.-Summary of reports on the prevalence of cough and sputum in relation to smoking . . . . . . . . 284' TABLE 4.-Summary of reports on the prevalence of breathless- ness, in relation to smoking . . . . . . . . . 285 TABLE S.-Summary of reports on history of chest illness in the past three years in relation to smoking ..... 28? TABLE 6.-Summaryof'reports on the prevalence of combinations of certain symptoms in relation to smok.ing . . . . 288 261 l

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I I Chapter 10 This chapter presents the evidence on smoking in relation to the develop- ment and progression of the non-neoplastic respiratory diseases. The chfonic bronchopulmonary diseases pose a healtLproblem~of substantial and steadily growing importance. Bronchiths and emphysema, in particular, severely disable large numbers of men of' working age, and have a considerable effect upon mortality as a direct or contributory cause of death. Because ofl the importance of these diseases to public health, they receive the most~ attention in this chapter, in accord with the fundamentall purpose of! the Committee's Report. The design of this chapter is to consider first the experimental and patho- logical data, then the clinical and epidemiological data: ALTERATIONS IN THE' RESPIRATORY TRACT AND IN PULMONARY PARENCHYMA INDUCED BY TOBACCO SMOKE CHARACTERISTICS OF THE EYPOSURE' Composition of Tobacco Smoke Although the material under this subtitle is dealt with in greater detail in Chapter 6, Chemical' and Physical Characteristics of Tobacco and To- bacco~Smoke, it is considere&here because particle size and other properties of tobacco smoke constituents are of prime importance in the relation be- tween smoking and respiratory diseases. Tobacco smoke is a heterogeneous mixture of a large number of com+ pounds with gaseous and particulate phases. As it enters the mouth, ciga- rette smoke is an extremely concentrated aerosol with several hundred million to several hundred billion liquid particles in each cubic centimeter (107, 116, 1'22). Measurements of the median particle size range from about 0.5 to 1.5 microns; the majority of the measurements have a median closer to 03 microns (2). Some of the majpr classes of compounds which con- stitute the: particulate phase of cigarette smoke and notation of their tbxic action~on the lung, (2) are presented in Table 1 of Chapter 6: Nine of the gases present in cigarette smoke are considered irritant to the lting (2)1; Table 2 in Chapter 6 lfists some of the known constituents of the gas phase. Regional Deposition or Retention, of Tobacco Smoke Little is known about the exact composition, of cigarette smoke in the respiratory tract after it leaves the mouth. Inhalation of cigarette smoke und'oubtedly exposes the airways and pulmonary parenchyma to smoke with 263

substantialNy different characteristics from the smoke that first enters the mouth. Insufficient direct evidence is available to characterize this exposure, and existing, information is derived largely from substances with analogous physicaliand chemical features. The retention or deposition of smoke constituents in the several regions of the respiratory system varies because many factors alter the characteristicss of the smoke and' probably result in losses as the constituents are drawn deeper into the respiratory system. Included among such factors are the amount' and composition of the constituents immediately after burning the tobacco, themethod'of smoking, the depth of inhalation„and the temperature and! humidity of inhaled smoke. The physical laws which govern deposition of particles and absorption of gases an& the anatomic structure ultimately determine the pattern ofl regional retention (2). When cigarette smoke is inhaled, total retention of particles in the mouth, respiratory tract, and pulmonary parenchyma is about 80-90 percent', even when the smoke is held in~ the lung for a relatively short period, two-to.five seconds. When delfiberratelyy held for periods as long as 30 seconds, retention of particles is almost complete (135). MOUTH RETENTION OF TOBACCO SMOKE Removal of tobacco smoke constituents while in4he mouth has been studied incompletely. When cigarette smoke is drawn into the mouth and promptly expelled without inhalation, the analyzed weight or fluorescence of the re- tained tars ranges from 33 percent to fifi percent (18, 71, 135). Experiments utilizing, amod'el of the mouth and airways, but~ without the deeper portions of the lung,, have demonstrated! differential regional deposition of certain tar distillation, fractions. A cigarette tar fraction distilling, at less than~ 120°' C. was deposited in concentrations three times greater in the simulated bronchi than in the mouth; a high~boiling fraction, however, was deposited equally in~tihe mouth and bronchi (57). The available information suggests that removal of smoke constituents in t'he mouth~ may be an important defense mechanism that prevents delivery of certain noxious agents to the tracheobronchial tree and lungparenchyma, but such information is not sufficient to determine which substance may be removed while tobacco smoke components are in the mouth. RETENTION OF PARTICLES BY THE' TRACHEA, BRONCHI, AND PULMONARY TISSUE Most information pertaining to retention of smoke constituents by the tracheobronchial tree: and'pultnonary tissue is based on knowledge of physical factors which determine retention of inhaled aerosol particles and on analo- gies drawn from physiologic studies of aerosol retention in man. In gen- eral, the particles of greater size and density are less able to traverse the twist'ing course of the airways and tend to be removed high in the tracheo- bronchial tree. Smaller particles penetrate more deeply into the lung and are deposited: through~ gravitational settling, or inertiall impingement, except for very fine particles which diffuse onto the surfaee. The size of virtually all t'he individuali particles in inhaled smoke is probably less than two microns. Data from al number of laboratories indi- 264 O W ~ ~ Ctt 1 W CD

cate that particles smaller than two microns are deposited in the lower respiratory tract' during normal breathing under rest conditions. Deep: breathing shifts deposition of larger particles into the lower respiratory tract also (2, 83). The lowest proportiom of deposition occurs f'or particless between 0.25-0.50 microns. Diffusion increases for particles belbw 0.25 microns, and extremely fine particles, approaching, molecular size, diffusee so rapidly that many probablyy remain om the upper bronchial tree. The importance of such minute particles in tobacco smoke, even if present initially, probably is not great since they act as nuclei for vapor condensa- tion and would' be expected to grow rapidly (2, 3). Data on sites of intra- pultnonary deposition derived from phy.siological' studies indicate that even for particles smaller t'han two microns, only about five percent are deposited along the bronchiali tree. Radioactive tracers in smoke have been used'' to study site deposition in animals. Deposition in a diffuse pattern was obtained in dogs inhaling smoke from cigarettes impregnated with K 42, Na 24, an& As 76 (192). A similar experiment using I 131 as the tracer demonstrated substantial bronchial deposition but the physical state of the tracer, whether vapor or particulate, remains uncertain (191). In rabbits, cigarettes impregnated with As 76 produced deposition on the larynx, carina, and major bronchi~ but this deposition contributed only a small fraction of the total activity retained by the smaller bronchi, bronchioles, and pulmonary tissue (100)~. From indirect data, therefore, it is most probable that the vast majority of cigarette smoke particles penetrate deeply into the respiratory tract andl are deposited on the surface of the terminal bronchioles, respiratory bronchioles, and pulmonary parenchyma: RETENTION OF GASES BY THE TRACHEA, BRONCHI, AND PULMO- NARY PAREITCHY1bIA Insufficient data are available on the intrapulmonary fate of gases of cigarette smoke to warrant detailledl consideration at~ present. Thorough re- vieww of the available information andithe known physical characteristics of gas absorption suggest that the speed and depth of inhalation may affect both the amount andi site of gas retention; moreover, while the distribution pattern may be diffuse, it seems possible, although not yet demonstrated, that a substantial portion of inhale& tobacco gas and vapor will deposit along the upper bronchial tree (2). In view of the ability of certain of these gases to interfere with normal function of' the cleansing mechanisms of the respiratory system (e.g.,, ciliary motility), such deposition could be of significance in production or augmentation of diseases of the bronchi. ll'letabolismandToxicityofSpecific Components in Tobacco Smoke Little is known about the metabolismi of mostcompounds in tobacco smoke. The f'ragmentarydata have been thoroughly reviewed (2). Hydrogen cyanide is present in cigarette smoke in concentrations that would be fatal for mani were it not for a number of factors which accrue too prevent such a lethal consequence of smoking (2, 60). Among these factors are dilution of the small smoke volume, discontinuous exposure, rapid de- 265

toxification, and absence of cumulative effect. The cyanide ion is capable of stbpping cellular respiration abruptly through inactivation of cytochrome oxid'ase. In sublethal exposures, the cyanide ion is gradually released from its combinationi with the ferric ion of cytochrome oxidase, converted to thiocyanate ion (SCN), and! excreted in the urine. Thiocyanate blood levels ini smokers are three times higher than in non-smokers and differences in relative urinary excretion are even more pronounced (46;, 127)i. It seems quite likely, therefore;, that cyanide derived from cigarette smoke is metabo- lized rapidly in the body, and! harmful effects have not been detected. The principali oxides of nitrogen, nitric oxide and nitrogen dioxide, are present ini cigarette smoke in tot'al concentrations varying from 145 to 665 ppm (123). Oxides of nitrogen are partially absorbed in the mouth; absorp- tion after inhalation, however, is almost complete(23, 811). Nitric oxide: one principal oxide of nitrogen in cigarette smoke, is mainly ani asphyxiant and! is only about one-fifth astbxic as nitrogen dioxide. There is no d'ocu- mented instance of human poisoning due to nitric oxide. Nitrogen dioxide, however,, is a primary lung, irritant, presumably as a result of its hydration into nitrous and nitric acids which are subsequently converted to nitrites. Exposure to, relatively high, coneentrations of nitro- gen dioxide produces injury sufficient in the human lung to result in pul- monary edema (187). Obliterating fibrosis ofl the bronchioles has also been observed ini man folloccing, moderately high exposures (126). In physiologic studies, changes which resemble those of pulmonary obstructive disease have beeni observed in men who are occupationally exposed to high concentrations of nitrogen oxides (I19'). Experimental studies indicate that nitrogen dioxide is capable also ofl producing pulmonary damage (24;, 74, 76). A severe, but reversible, inflammatory reaction in the respiratory bronchioles of rats, rabbits and guinea pigs occurs after a single ri+-o-hour exposure to 80-1100; ppm. of nitrogen dioxide. Five daily exposures at 15-25 ppmL for two-hour periods produce similar but less severe results(109). It seems clear from environmental exposures of man to nitrogen dioxide that definite puhnonarydamage may result from such exposures. Whether nitrogeni dioxide alone, in inhaled cigarette smoke, is capable, ofl producing, such damage in man is less certain. Equal, amounts of nitric oxide and! nitrogeni dioxide in cigarette smoke have been reported (81), but recent w-orkindicates that~ the proportion of nitrogen dioxide is much lower (108)1. These divergent results and theuncertainty as to the level of nitrogen dioxide exposure necessary to produce pulmonary damage make it very difficult tol assess the role of nitrogen dioxide in cigarette smoke. Formaldehydegasispresent' in cigarette smoke in concentrations of 300 ppmL Chronic exposure to 50 ppm. of forma.ldehyde gas produces an irritant cellular response in mice similar to t'hat produced by tobacco smoke. These changes are found mostly in the trachea; higher levels of exposure are.asso- ciated with more severe reactions and! extension of the involvement to thee major but not the smaller bronchi (102)',. Exposure of guinea pigs to lowconcentrations of acrolein, which is also~ present in cigarette smoke, caused! an increase in total respiratory flow re- sistance accompanied by decreased respiratory rates and increased tidal 266

volumes (143). It has been found also that acroliein is a potent ciliary depressant (80). Inhaled vapors of phenol are readily absorbed into the pulmonary circu- lation and, at 30 to 60 ppm~, have produced an organizing pneumonia; the effects being most marked in guinea pigs, less severe in rabbits, and wholly absent in rats (42, 43). Data concerning the metabolism and toxic proper- ties of other constituents of tobacco, such as the polycyclic hydrocarbons, do not suggest that they have a significant role in the development of non- neoplastic respiratory disease in man. Clearance o f Smoke Deposits Little direct evidence pertaining to clearance mechanisms for smoke de- posits is available. There is little reason~ to believe, however, that smoke deposits are cleared through routes different f'rom~ the normal self-cleansingg mechanism of the lung described in the section om"Pulmonary Hygiene and Ciliary Activity" of this chapter. EFFECTS' OF TOBACCO SMOKE ON DEFENSE MECHANISMS OF THE RESPIRATORY SYSTEM Pulmonary Hygiene and Ciliary Activity The cleansing mechanism of the mammalian respiratory system is depend~ ent upomthe efflcient,,integrated functioning of a complex sy.st'em. Froni the nose to the terminal bronchioles, a mucous layer in which impacted! particles and dissolved materials reside is propelled over the surface and' removed from the respiratory tract by the rapid, rhythmic; and purposeful beat of cilia. The mucus is supplied' byy deep: glands in the walls of the airways and by goblet cells. Clearance distall . to the terminal bronchioles has be- come more clearlyy understood in recent years. Fine particles and gases de- posited in the lining of! the acinus are removed by several mechanisms. Even relatively insoluble particles dissolve in the lung because of the large surface area-mass ratio of small particles and the high reactivity of body fltrids (2). Aft'er solution, absorption into the blood stieam~ or lymphatics may result in removal. Remaining particles may undergo phagocytosis or remain free. Some phagocytes enter the alveolnr~ lumen, become laden with foreign material, and are transported to the ciliated air passages tb be ex- pelled intact. Some disintegrate along the way and deposit their products on the surface lining. Still other phagocytes may enter interstitial tissues and' become sequestrated or be removed to regional ly.mph~ nodes. Foreign material which remains free in the fluid lining of the alveolus is transported onto ciliated mucosa by a relatively slow process. The transport results from effects ini the fluid lining produced by the mechanics of respiration andl re- plenishment, of the alveolar fluid lining. Inhibition of ciliary motility following exposure to: t~obaccot~ars; cigarette smoke, or it's constituents has been demonstrated frequently with experi'. mental use of respiratory epithelium from a«•ide variety of animal species (17,22; 39, 59, 79; 80, 96, 97, 98; 111, 112, 131, 147, 157, 158, 167,,178). 267 A"

Similar results have been obtained with ciliated human respiratory epi- thelium (17, 22). Although all investigations have been conducted in vitro, the uniformity of! the inhibitory effects in a numberofl different experimentali modela is impressive. Positive ions are present in cigarette smoke. Each cigarette yields about 1010 positive ions; negatively charged particles are also present (121). These thermally produced gaseous ions have considerable: energy and may pr~odtice effects in cells (190). In air free ofl cigarette smoke, positive ions decrease or abolish ciliary activity. The redtrction in ciliary motility which occurs after exposure to cigarette smoke is augmented and sustained by additional exposure to positive ions (112). Nicotine in high concentrations inhibits ciliary motility although eon- centrations of nicotine similar to those in tobacco smoke d'o not affect rabbit, chickeny or human ciliary function (22, 121). In addition, tobacco smoke from low-nicotine cigarettes produced no significant difference in ciliary response from that obtainedl with cigarettes whose nicotine content had not: been altered (1211. Hydrogen cyanide, ammonia, acrolein. fbrmaldehyde, nitrogen~ dioxide, all components of cigarette smoke, possess potent inhibi- tory activity (40). There seems to be little d'oubt that eigarette smoke is capable of producing significant functional alterations of ciliary activity in vitro. Such alterations could interfere markedly with~ the self-cleansing mechanism of the respira- tory tract. These in vitro results cannot be fully extrapolated! to the effectss of cigarette smoke on ciliated respiratory tissue of man because of the many variables present in the complex experimental methods,, including, dosage of the particular agent. Ciliary depressant activity in the environment of man~ is not limited to the components of tobacco smoke; agents such as ozone and! sulfur dioxide, which are important air polllutants but are not found in si'g- nificant amounts in tobacco smoke, are also potent ciliary depressants. Morphologicalteration of cilia~~ of smokers has been described (31, 32, 104). The length, of cilia in the trachea and bronchial epithelium was meas- ured at autopsy and found to be shorter than in~ non-smokers. In addition the percentage of cells remaining ciliated is lower in smokers than in non- snrokers (~9;~ 10, 104Y. Mucus Secretion Definitive studies on the effect of cigarette smoking upon the quantity and quality of human respiratory tract mucus have not been performed. Alteration in, the appearance of mucus after exposure to cigarette smoke has been noted severali times. Followingexposure to sulfur dioxide, a g~s not present in cigarette smoke, changes in the physical properties of mucus have been observed ( 40):. Whether suchi changes resulti after exposure to gases present in cigarette smoke has not been, established. MorphologFcal changes observed in the goblet cells and mucous glands at post-mortem examination, however, support the possibility that mucus production may have been altered during life. In essence, little has been contributed in this regard since the observation about 11001 years ago; that a marked increase in mucous secretions in the trachea andl larger bronchi of the cat occurred after large doses of nicotine. 268' ~:

Atropinization blocked this effect, indicat'~ingthat thisaction of nicotine was mediated by stimulation of the mucous glands since goblet cells are not under nervous control (185 ). An increase in~ mucus-secreting cells af'ter exposure of rats to cigarette smoke has also been observed recently (130). Alveolar Lining The alveolar surface is covered by a secretion which stabilizes the alveoli' and is produced by the alveolar epithelium (79, 151). Little: is known of, the influence of cigarette smoke on this alveolar lining. The application of cigarette smoke to rat lung extracts, considered to represent the alveolar lining, cause& a decrease in surface tension and an increase in surface comr pressibility. Lung extracts prepared from rats exposed to cigarette smoke during life also showed lower surface t'ension and increase in surface com- pressibilfity,. These findings differ markedly from results in non-exposed animals. Such changes during life would be expected t'o result in a de+ crease in the ef$cacyy of' surface forces stabilizing, the alveoli (134). Fur- ther interpretation of the results of this single study does not appear war- ranted; however, because of the great potential significance of thealterat'ion described, further studies should! beencouragedL Phagocytosis The importance of phagocytosis as a mechanism, for clearance of deposits in the acinus has become more clearly established' in recent years. The uptake of tobacco tars by phagocyt'es is well' documented in~ experimentall studies. On the basis ofl solubility, fluorescence, and pigment characteris- tics ofl the phagocytized material, and its resemblance to the fluorescence of tobacco smoke condensate, this phagocytized material would appear to con- tain polycyclic hydrocarbons. The accumulation ofl exogenouspigment'ed material in mice has been shown to be directly proportional to both the leveli and' duration of cigarette smoke exposure (119, 121). Similar fluorescent materiial was observed in rats exposed to cigarette smoke (130) and in the respiratory lining of the white Pekin duck after application of tobacco smoke condensate (166). Impairment of the efficiency of the phagocytic clearance mechanism after long-term exposure to cigarette smoke apparently occurs in mice (121). Ear1y in the exposure period, the clearance mechanism of the lungs is ade- quate to the task of aggregating andl removing pigmented material and pigment-laden phagocytes; in the final' stages of the 2-year experiment, especially at the high dose levels, the phagocytic mechanism appears to: be overwhelmed since: large areas of parenchyma are flooded: with pigment in the absence of phagocytes. A si¢nilar suppression~ of the effectiveness of the phagocytic clearance mechanism for the human lung has been~ described in pneumoconiosis (41). Fluorescent histiocytes have been found in thesputum of cigarette smokers but were not detected in the induced sputum of non-smokers (188). The intensity of fluorescence and the number of histiocytes were in~ direct propor- tion to the number of cigarettes smoked. These fluorescent histiocytes pre- 269

sumably represent the phagocytic cells of the acinus which are delivered intact to the sputum. Phagocytosis appears to serve an important! function as a concentrating, localizing, and transport mechanism fbr redistribution of injurious constit- uents of cigarette smoke. The full significance of phagocytosis of cigarette smoke constituents in the pathogenesis of disease has not been clarified. Impairment ofi this, fhinction, however, cannot be dismissed since it might be expected to result in lung,injury. Other Mechanisms Little is known about the role of lymphatics in the removall of tobacco smoke deposits. The eval uation of the effects of smoking on pulmonary function tests will be considered in this Chapter in the section on, "Chronic Bronchopulmonary Diseases." Because the several defense mechanisms of the respiratory system are af- fected in various ways by tobacco smoke, it may be useful to recapitulate the. evidence presented in this section. Substantial experimental evidence indi- cates that tbbacco smoke and certain of its components, like many other substances, can reduce or abolish ciliary motility, ati least temporarily, and can slow mucus flow. Impairment of this mechanism in man has not beeni demonstrated under conditions of cigarette smoking; although it seems,lbgi- cal to assume that alterations would occur. If the removal of noxious agents were slowed, the protracted contact might be expected to result in respira- tory tract damage. Decreaseini the number ofl ciliated cells and! shortening of remaining, cilia have been described in post-mortem examinations of bronchi' from smokers, with implied functional impairment. Alterations in bronehial' mucus havee been suggested by changes in goblet cells and mucous glands after cigarette- smoke exposure. Increased amount! ofl secretions in the tracheobronchial tree is a frequent observation afterexposur~eto cigarette smoke. Alterationoftheflnid lining of the alkeoli ini rats as ai consequence of ciga- rette smoke exposure has been~ reported in the only study of this aspect. The dccrease in surface tension and the increase in surface compressibility obd served in this studycouldihave great potential significance in terms of human respiratory disease. That tobacco products are ingested by alveolar phagocytes of the experi- mentat animall and of man seems fairly welldocument'ed. Ezperimental data from animals indicate that the phagocytic mechanism fails under stress of protracted high-level exposure. The potential implications of these observa- tions again, appear to loom 14arge for respiratorv disease in man but further definition of these effects and qµantitatiion willlbe necessary before their full significance can be understood. HISTOPATHOLO(;IC ALTERATIONS INDtiCED IN THE RESPIRATORY TRACT AND IN PUL1t0\:4R7pARE1CIdY17A BYTOB:ACCO: SMOKE A variety of histopathologic studies from diverse points of view indicate clearly that smoking is associated with abnormal changes in, the st'~ructure of 270 .;t ,~.. .. ~. .~.

both the surface epithelium and wall of the airways,, including the mouth. Many of the studies are open t'oi criticism because of inadequate numbers, lack of proper controls, and defects of experimental design, but specific criticisms, are different for each study, an& the sum of the evidence points unmistakably to the reality of deleterious consequences upon the respiratory tract from tobacco smoke. Several reports implicate smoking,, in particular pipe smoking., as an im. portant etiolbgic agent im the development of a condition of the hard palate, and'less often the soft palate, known as stomatitis nicotina (34, 70, 172, 181). This condition is associated with excessive proliferation of the surface epi- thelium and overproduction of keratin; the hyperplasia frequently involves the stbmas of the salivary g)ands, leading to blockage andisubsequent dilata- tiom of the ducts. Epithelium lining the ducts commonly shows squamous metaplasia. This condition is believed to be very common in pipe smokers but usually disappears upon cessation of smoking. A somewhat similar morphologic change has been described in the lhrvnx that correlates closely with the cigarette smoking history (45, 170). Epi- thelial hyperplasia with liyperkeratosis and variable degrees of chronic in- flammation and' squamous metaplasia are present ini the true vocal cord's, false cords, andlthe suhglottic area. The trachea and bronchi show many morphological changes inithecigarette smoker as compared to the non-smoker (9'; 10;,11i, 31, 33, 35. 38, 1711). Var- ious degrees of hyperplasia, with and without overt atypical change;, and metaplasia ofl the surface epithelium have been described. Deviations from the normal have also been found in the goblet cells, cilia, and mucous glands of smokers. Significant, increases ini the number of goblet cells and in the degree of mucous distension of the goblet cells were present in whole mounts of bronchiall epithelium of smokers (31). Hyperplasia and' hypertrophy of mucous glands andi a higher proportioni of cells with shorter cilia also were observed more frequently in smokers (33, 171). The hypertrophy and hyperplasia of mucous glands from miners correlated much better with the degree of smoking than with exposure to silica ( 35). Even though the num- ber of non-smokers among the miners was small, the relationship between smoking and mucous gland' alteration was very striking. The studies on~goblet cells and mucous gland's in smokers and non-smokers are especially important when considered in the light of current concepts of the pathology of chronic bronchitis. It is now apparent that one of the commonest morphologic alterations in the bronchi' in chronic bronchitis is an increase in goblet cells, and hypertrophy and hyperplasia of the mucous glands (69, 163, 164). Similar findings have been noted in examination of patients with chronic bronchitis in the U.S.A. (182, 183, 1$-1)1. Althoughi manyy cases of chronic bronchitis show other morphologic signs of acute andi chronic inflammation, these are not as constant as are the glandular changes.. Provided further investigation of the pathologic anatomy of chronicc bronchitis in other countries indicates that the disease is essentially identical pathologically, the few British studies on goblet cell's and mucous glands in smokers offer the first anatomic support~ for the relat'~ionshipbet,~veen srnokina and chronic br~onchitis suggested by several epidcmiologic reports. Con- ceivably, one or more components of cigarette tobacco: smoke have the prop- 714-422 0-64-19 271

erty of stimulating mucous cell hypertrophy and hyperplasia in a; manner similar to: that of other unknown factors which appear to be important in the pathogenesis of chronic bronchitis (cf. 64i). This mucous cell activity, accompanied by excessive mucus production, may increase the susceptibility of the tracheobronchial tree to secondary infection wit'h various micro- organisms which in turn may lead to acute and chronic inflammation and their consequences. Although this hypothesis (64i) has many attractivee features, especially in reconciling the epidemiologic and anatomic findingss in regard to smoking and chronic bronchitis, it must be emphasized that the anatomic data relating to smoking are still essentially preliminary in~ nature and require confirmation by more extensive and thorough~ studies. Experimental studies on chronic cigarette smoke exposure in animals, al- though acutely massive compared to human exposures, confirm some of the above morphological findings in man (118, 119, 121)~. In mice exposed for long periods to cigarette smoke;, changes observed in the bronchi and peribronchial tissues were characteristic of severe bronchitis; purulent bron- chiolitis severe enough in some instances to cause massive atelectasis, bron- chiectasis with organization, and compensatory emphysema were also observed as a response to long-term cigarette smoke exposure: These changes are similar to those described in advanced cases of human bronchitis. In addition to the hypertrophy of mucus-secreting elements already men- tioned, scattered areas of purulent bronchiolitis, small abscess cavities, bronchiolar dilatations and alveolar changes also have been observed. The studies ini animals therefore support a conclusion that cigarette smoke is irritating to the t'racheobronchial tree and' is capahle of inducing severe acute and chronic bronchitis. It must' be emphasized that the traeheobronchiall tree makes only a lim- ited number of histopathologic responses to: a: large number, of different types of injuries. This restriction, perhaps a reflection in part' of our methodo- logic limitations, makes it difficult to identify with any certaint'yy the basic nature of the etiologic agent in any given disease process. It is therefore important! to be aware of this element of uncertainty when attempting, to compare histopathologic findings in the respiratory system under different environmental conditions and' in different species ofl animals. Recent studies indicate that changes in the pulmonary parenchyma are associated with cigarette smoking (12, 136). Formalin fume-fixed lungs from 83 patients over 40 years of age, from which coal miners were excluded, were examined in a preliminary analysis of a: continuing study ofl the: rela- tionship of smoking, parenchymal pigment,, and emphysema (136)~. The causes of death included "diffuse obstructive bronchopulmonaryy disease." The quantity of "'d'epartitioning',' (Le., emphysema) and the amount of! black pigment were graded from zero to three. The pigment was not! analyzed but was considered to be anthracotic. A close correlat2on~ was observed between the quantity of snioking, the quantity of pigment deposited, and the amount of departitioning, At this early phase of the study, the potential etiologic relationships, if any, between the: anatomic changes and smoking have not been defined (Figurc 1). Histologie examination of peripheral lung sections has revealed changes in~ pulmonary parenchyma, the severity of which was proportional to the 272

BLACK PIGMENT AND EMPHYSEMA IN LUNGS OF 83 PATIENTS DEPARTITIONING BLACK PIGMENT I 1 1 ..•O •OOQ 0 AAA A00 • •• 0 • ~ •. 00 000 *00 00 AQ .O •O 0 • 000 00 ~ NON-SMOKERS ~ - 0 _ >15 CIGARETTES PER DAY < 15 CIGARETTES PER DAY FIGURE 1. Source: Mitchell, R. S. (136) 8v8Sme0

0 i intensity of cigarette smoking as well as to its duration (12)'. One section fromi each of four major lobes of the lung was obtained at autopsy from 1,340 patients for whom a careful smoking history was available. Non- smokers were matched with various categories of smokers by age, race, and occupation and then placed in random order for microscopic examina- tion. The pulmonary abnormalities, measured by arbitr~ary gradations, included the: following: (a)', fibrosis or tliiekening of albeolar septa,, (b)' rupture of alveolar septa; (e)' thickening of the walls of small arteries and of arterioles, and (d) pad-like attachments to alveolar septa. The association of increased pulmonary fibrosis an& cigarette smoking was apparent in all age groups (less than 45, 45-49, 60-64, 65-69, 70-74, 75+ ), eveniin, those who smoked less than one pack per day. The increase in fibrosis was most marked in heavy smokers. Whereas the degree of fibrosis rose slightly with advancing age (160+ ) in the non-smokers, the rise was far more dramatic in smokers. The findings were similarly dra- matic for the degree of rupturing of alveolar septa, the most severe changes being detected in smokers in the older age groups. The same association was found for the degree of t'lrickening of walls of arterioles and small arrteries. Findings in matched pairs of subjects, who differed in respect to one fac+ tor but who were alike in respect, to another factor, were compared. The degree of pathological change was significantly greater in three categories ('pulmonaryy fibrosis,,rupture of alveolar septa, thickening of the walls of small arteries and arterioles) for the following groups: (111) The older cigarette smoker greater than the younger cigarette smoker;, (2) The one-two pack cigarette smoker greater than "never smoked";. (13) The one-half pack a d'ay cigarette smoker greater thani "never smoked" ; (4) The one-two pack smoker greater than one-half~ to one pack cigarette smoker ; (5), The current cigarette smoker greater than ex-cigarette smoker whoo had stopped 20 years. In addition, the degree of fibrosis (but not the otherthree indices) was significantly greater : ('1) In one-half' to: one pack a day cigarette: smokers than in less than one-half per day cigarette smokers;. (2) In two pack per day cigarette smokers thani one-two pack a day cigarette smokers; (3)' In current cigarette smokers than in ex-cigarette smokers stopped 3-4 years. Degree of fibrosis, rupturing of alkeolar septa, and thickening ofl walls of the small arteries (but not arterioles)was significantly greater in current cigarette smokers than in ex-cigarette smokers who had stopped 5-19 years. All the changes above were statistically significant at the five percent level. The degree of fibrosis among,men over 60~years of! age was studied further by relation wsmoking habits in an "age standardized" percentage distribu- tion. Increased fibrosis over that found in non-smokers was striking, for current cigarette smokers but some trends in this direction were also~noted for current smokers of cigars, of pipes, and of cigarsand pipes. 274 4b

After review of the design of the study with~the investigators and the micro• scopic sections on which judgments were made, some concern remains about two of the four pulmonary abnormalities. Increased thickness of the walls of' arteries or arterioles is difficult to interpret on microscopic section; as contraction with decrease in lumen size may simulate an increase in, wall thickness. The pad-lfke attachments are puzzling and the possibility of'~ arti- fact has been discusse& repeatedly. The conclusions drawn~ from this study are based in large part upon the findings pertaining to fibrosis or thickening of alveolar septa and rupture of alveolar septa. In summary, histopathologic alterations in the mouth, larynx, tracheo- bronchial tree and pulmonary parenchyma, associated with smoking, have been documented in~ man. The alterations in~ the bronchi support the hypothesis that cigarette smoking is al cause of human chronic bronchitis. Whereas definite pathologic changes in the lung parenchyma: of man also are clearly associated with cigarette smoking, the abnormalities observed in thee lung parenchyma: cannot be related with cert'ainty to recognized di'seasee entities at the present time. RELATION OF SMOKING TO DISEASES OF THE' RESPIRATORY SYSTEM EFFECTS OF SMOKING ON TI7IE NOSE, MOUTH, AND THROAT Edema, vascular engorgement', dryness, excess mucus production and epithelial changes have been attributed to cigarette smoking on the basis of clinieal' observation. Rhinitis, angina, and! laryngitis, also observed fre- quently in cigarette smokers, are reversible on cessation of smoking. Aggravation and prolongation of' sinusitis are also attributed to smoking. These observations have become clinical tradition, yet surprisingly little documentationi of predictable changes in these tissues as a conseqpence of smoking is available(129). Changes in the palatal mueosa("stomatitis nicotina") and in the laryngeal epit'helium(45)elosely associated with tobacco smoking have been cono sidered in the earlier discussion of histopathological alterations. Thus, evidence of progressive non-neoplastic disease in the upper res- piratory tract, induced by smoking, is lacking. Only in studies of "stomatitis nicotina"' and of epit'heliall changes in the larynx has there been adequate pathological substantiation of the clinical opinion that~ alterations are induced by smoking. SbIOKING AND ASTHMA The definition of asthma of the American Thoracic Societyy will be used for the purposes of this report (4) : "Asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli and manifested by a wide- spread narrowing of the airways that changes in severity either spon- taneously or as a result of therapy. 275 I

"The term asthma is not appropriate for the bronchial narrowing which results solely from widespread bronchial infection, e.g.,, acute or chronic bronchitis; from~destructive diseases of the lung, e.g., pulmonary emphysema;, or from cardiovascular disorders. Asthma, as here defined'y may occur in vascular diseases, but in these instances the airway obstruc- tion is not causally related to these diseases." In rare instances, allergy to tobacco products has been ascribed a causa- tive role in asthma (99, 105, 168, 169,, 189). Support for this association comes largely from the presence of skin test' reactions to tobacco products and passive transfer tests (168,,169). In the "Tokyo-Yokohama Asthma"' studies, a severe asthma-like disease, presumed to be caused by air pollution; affected cigarette smokers predomi- nantly (155). The absence of smoking data on unaffected members of the same population leaves the question of an additive effect of cigarette smoking, unanswered: One study suggests that non-smokers may have a: slightly greater prevalence of asthma than smokers; the possibility of' bias due to self-selection of the base population could not, however, be excluded in this study (84)1. Apart fromi the exceptions noted above, it is clear that cigarette smoking is of no importance as a: cause of asthma. A hypothetical contraindication to cigarette smoking can be postulated for asthmatics on the basis ofl the physiologic alterations induced in the tracheobronchial tree by tobacco smoke. Nonetheless, substantiation of worsening from cigarette smoking im asthmatics has not been reported'frequently. A cause-and,effect relation- ship between cigarette smoking and asthma; as defined above, is not support'ed by evidence available. RELATION OF SMOKING AND INFECTIOUS DISEASES The category, influenza and pneumonia (ISC 480-493), contributed to the excess mortalityof'~ smokers observed in six of seven prospective st'udies (Chapter 8, Tables 19 and 26)'. Details sufficient to warrant conclusions about the nature of this association are not presented in these studies, nor has the apparent association been evaluated further by careful epidemiologi- cal researchL Studies adequate for examination of this association are available for only two categories of infectious diseases, upper respiratory viral illness and tuberculosis (301. Experiments on transmission of common cold's f'ailed to demonstrate increasedy susceptibility in volunteers with a; history of ciga- rette smoking (50). Moreover, common colds were detected among, 5,500 employees over a 2-year period! with approximately the same frequency, in smokers and non,smokers (110). In a study of illness ima group of families under close observation, for several years, the frequency and severity of common respiratory diseases, such as the common cold, rhinitis, laryngitis, acute bronchitis, and nonbacterial pharyngitis, were the same in cigarette smokers and non-smokers (21). Similar results were obtained by ques- tionnaires in an analysis of the frequency of common cold's in a group of college graduates followed over a 20-year period (85). 276

A number of studies have suggested a substantial relationship between smoking and puhnonary tubercul'osis (55, 124,,133„ 175). The possibility that the relationship is not a direct one needs further careful examination. Certain social factors, important to epidemiological assessment in tubercu- losis, have not been considered in detail in these studies. Of particular interest in this regard is a study (i29): in~ which both cigarette an& aleohol consumption were found to be in excess in tuberculosis patients as compared to the matched controls. The number of cigarettes consumed in the two ;roups was the same, however, at each Ievel of alcoholl intake. Matching by cigarette consumption failed to weakenithe association between alcohol con, sumption and tuberculosis (29). Thus, the relationship between tubercu- losis and smoking in, this study was only an indirect one; the association was found to occur between smoking and aleohol consumption and between alcohol consumption and tuberculosis, rather than between, smoking and tuberculosis. Thus the association between smoking and the infectious diseases is con, fined at present'to a single cause-of-death category: Influenza and pneumonia contribute to the excess deaths in cigarette smokers, but the data are insuffi- cient to evaluate this observationi In the limited number of studies avail- able, cigarette smoking has not been shown to contribute to the incidence or severity of either naturally acquired or experiment'ally induced upper respir- atory viral infections. CHRONtC BRONCHOPULMONARY DISEASES .Mbrtality for certain respiratory diseases (bronchitis, bronchiectasis, chronic pulmonary fibrosis, chronic interstitial pneumonia, and' emphysema) increased in the decade 1949-1959 (48)and'eontinues to show an upward trend (132, 1411). In 1955, cancer of the lung was certified as the under- lying cause of death in 27;133 persons and chronic bronchopulhnonary dis- eases in 11,480 persons. A tabulation of all diagnoses, both contributing as well as underlyi'ng causes of death, however, showed that cancer of the lung was entered upon a total of 28,123 death certificat'es, whereas the chronic bronchopulmonary diseases were certified as cont'ributing, t'o 32,041 deaths 147). The possibility that mortality data, as presently recorded, may under- estimate the role of chronic bronchopulnionary diseases through incorrect listing, by the physician as contributory rather tham the principal cause has also been suggested! (115) . Social security records in 1960'show that chronic bronchopulmonary dis- eases, particularly emphysema, ranked high among the conditions for which disability benefits were allowed''l to male workers 50 years of age or older in the United States (186). Chronic bronchitis and emphysema are the chronic lironchopulmonary diseases of greatest public health importance in the United States. They contribute to the excess mortalitryof cigarette smekers, but there is little information about the effects of smoking on the other~ chronic broncho- pulmonary diseases. The scope of~ the subsequent remarks is limited there- fore to the possible relationship of smoking, to chronic bronchitis and liI 27,7~ _.4 --47"~s-___... =V'

emphysema. Since descriptions of both~ were published long before ciga- rette smoking became commonplace (13, 14, 114)~„ it seems reasonable to suggest at the outset that cigarette smoking alone is not the only cause of chronic bronchitis and emphysema. Chronic Bronchitis and Emphysema DEFINITIONS Many definitions of chronic bronchitis and emphysema have been sug- gested. For the purposes of this report the definitions proposed' by the American Thoracic S'ociety (4) will beuse& "Chronic bronchitis is a clinical disorder characterized by excessive mucous secretion in the bronchial tree. It' is manifested by chronic or recurrent productive cough. Arbitrarily, these manifestations shoul& be present on most days for a: minimum of three months in the year and' for not less than two successive years. Many diseases of! the lung, e.g., tuberculosis, abscess, and of the bronchial'tree: e.g., tumors, bronchiec- tasis, as well as certain cardiac diseases, may cause identical symptoms;, furthermore, patients with chronic bronchitis may have other pulmonary or cardiac diseases as well. Thus, the diagnosis of chronic bronchitis can be made only by excluding these other bronchopulmonary or cardiac disorders as the sole cause for the symptoms." This definition and classification of chronic bronchitis later considers complications, listing, three: infection, airway obstruction, an& pulmonary emphM1•sema:. "Emphysema is an anatomic alteration of the lung characterized by an abnormal enlargement of the air space distal to the terminal, nonr respiratory bronchiole, accompanied by destructive changes of the alveolar walls." DIAGNOSIS The diagnosis of chronic bronchitis isbase& essentiallyon~ descriptions of clinical manifestations and is achieved by exclusion. Recollection and int'erpretatiom on~ the pam of the subject are necessary. There is no simple sensitive pulmonary function test that will indicate which person has chronic bronchit'is. A clinical diagnosis of! emphysema, based on the clinical syndrome and certain changes in pulmonary function, is even less exact. The clinical features usually encountered in emphysema tend to be very similar to those found in chronic bronchitis. Most of the symptoms and signs and many of the physiological' changes usually thought to indicate the presence of emphysema may result from airway obstruction due to bronchitis (66, 180). There is no completely satisfactory method of detecting emphysema by pulmonary,functiontestingand nopulfnonary function test is specific for the detection of patholbgic lesions of'emphyserna: . (52). The clinieall detec. tion of emphysema is therefore not a simple matter, especially in the presence of' chronoc bronchitis. 278 Ow ~ ~ ~ 00 cn

The following, adapted from the American Thoracic Society's statement (4), , epitomizes the situation for emphysema: Clinicopathologic correlations have demonstrated that certain per- sons who have this morphologic alteration at autopsy have symptoms of pulmonary insufficiency during life and die of this disease. Others show- ing qualitatively similar pathologic findings had no respiratory symp- toms during life and' died of unrelated causes. In some persons, em- physema may be strongly suggested by the patient's symptoms and its existence predicted om clinicall grounds with considerable accuracy. On the other hand, clinicallmanifestations identical with those of patients with emphysema may occur in persons who are not fbund' to have this disease at autopsy but who, have some other hing disease. Emphysema may exist without any clinical manifestations, and its elinicaland func- tional alterations are not unique but occur in other pathologic conditions. RELATIONSHIP BETWEEN CHRONIC BRONCHITIS AND EMPHYSEMA Chronic bronchitis and emphysema frequently coexist, although one can be present without the other. A clhnicall continuum appears to extend from bronchitis at' one end„through a mixture of the thvo conditions in the major- ity of cases,, to emphysema at! the other end (123). An alternative method of assessing the relationship is by study of patho- lbgical change. A close relationship is found between chronic lironchitis and emphysema on purely morphologic grounds. Although emphysema occurred more frequently in patients with chr~onic bronchitis than could be accounted for by chance, the two conditions also occurred independently of one another (183). Three of the possible reasons why chronic bronchitis and emphysema aree found in association more often thani would be expected by chance are the presence of a common, cause and causation each by the other. The protective mechanisms for the upper respiratory tract are eilia: and a mucous sheath, and the lower respiratory tract mechanisms involve macrophages, the lymphatic system, and possiblyy the fluid lining of the alveoli. Although not yet proved, failure of' the protective mechanisms of the upper respiratory tract might be expected to lead to chronic bronchitis and failure of the pro- tective mechanisms for the lower respiratory tract to emphysema; On this hypotheticall basis, a common cause would not seem unlikely; noxious en- vironmental agents in gaseous or aerosol form would be likely to affect upper and lower respiratory tracts simultaneously, perhaps with potentiation of the injury in the lbwer tract, by particles. Severall ways in which chronic bronchitis might cause or aggravate emphysema have been suggested, such as through trauma resulting from pressure changes induced in the:thorax by cough (138) and by airway obstruction (114). Clinical evidence of hron« chitis preceded clinical evidence of emphysema in over 50 percent of cases in one continuing study (137). Others suggest that emphysema: may be a cause of chronic bronchitis (53). It seems likely that a common cause, eausat'ion of emphysema by chronic bronchitis, and causation of', chronic bronchitis byy emphysema are all operating mechanisms, with varying importance in dfifFerent populations an& different individlials (12.3). 279 O W ~ ~ CJ1 ~ C11 6A f

Evidence Relating Smoking to Chronic Bronchitis and Emphysema Experimental' and pathological' evidence bearing on the possible rela- tionship of smoking to chronic bronchitis andl emphysema has been pre- sented in an earlier section of this chapter. Epidemiological and clinical evidence relating smokina to these diseases will be considered here. EPIDEMIOLOGICAL EVIDENCE Chronic bronchitis and emphysema probably represent disorders of multi~ pie causality. Such problems are particularly suited for analysis by the epidemiological methods especially with regard to the identification of causes and the disentanglement of their relations (140). Two types of studies, prevalence studies and prospective studies, will be considered. PREVALENCE STtrntes.-The most important epidemiological evidence available relating smoking to non-neoplastic respiratory diseases is found in the prevalence studies which concern the number of cases in a population at one point in time. The definitions and criteria for diagnosis of chronic bron- chitis and emphysema are not ideal for the purposes of these epidemiological surveys. The absence of standardieed! diagnostic methods in chronic bron• chitis and the non-specificity of clinical diagnost!ic criteria for emphysema have resulted in the use of prevalence of symptoms and signs of! the respira~ torydiseases under study as a basis for the surveys. Studies of the prevalence of chronic bronchitis and emphysema in the United Kingdom and in the United States over the last decade have developed highly reliable epidemiological methods. Because of the nature of the diseases in question, these surveys present results by the prevalence of specific symp- toms and'signs, or combinations, rather than diagnostic labels of disease en- tities. Various levels or grades of severity of the symptoms or signs are defined andl the data are obtained and handled in a standardized manner, permitting comparisons between different populations and communities;, thus it becomes feasible to evaluate whether smoking is associated with cer- tain signs or symptoms to a greater extent than with other findfngs. (1.) Smoking and Respiratory Symptoms-(',a.) Chronic Cough`The common phrase "smoker's cough" suggests that this symptom is popularlh- be- lieved to be associated with smoking. Several workers have investigated the relationship betweeni smoking and cough; Table 1 lists surveys that tabulate the frequency of cough in smokers as compared with non-smokers. Several different types of populations have been surveyed; the purpose of presenting the findings together is to demonstrate the variation found among the differ- ent populations. The 1,45&mi11 workers studied by Balchum et al. (116)' constituted the ran- dom sample of those who volunteered for chestl X-rays and pulmonary f'unc- tion tests. Of 1,198 smokers, 233 percent reported cough;, of the 253' non- smokers, 10!2 percent reported cough. When the percentage of smokers re- porting cough is considered in each of several categories described by pack- years of smoking experience, a gradient was foundl for those reporting cough~ ranging from 1l1 percent': of those who smoked less tham one pack-year of cigarettes up to 50 percent of the subjects with 60' or more pack-years of smoking experience. 280

TasLE1.-Summary of' reports on the prevalence of cough in relation to smoking Refer- Number of subjects Percent with coueh Atithor Year ence Smokers ' I Non- 'smokers Smokers Non- smokers Ralchum -------------------------- 1962 (16) 1}798 253 23.a 10.2 I Roucot--------------------------------------- 1962 (25) 5,331 8os 31.5 13.0 i RoiCer________________________ ______ 1961 (26) 76 49. 27.6 4.1 i DenPn --------------------------------------- 1963 (44) 2,530 514', 21.2 7.8 Fletcher: Londnn Transport'------------------------- 19fi1 (67) 272 30. 20.0 0 Post Office---------------------------------- 1961 (67) 166 10 18. 7 0 I Flick----------------------------------------- 1959 (68) 157 51 54.8 9.8 i 0lsen: United Kingdom~-------------------------- 1960 (148) 162 11 32.1 0 Denmark° _________________ 196(1 (148) 132 241 19.9 8.3 Rhort----------------------------------------- 1938 (176) 1! 292 496 6.4 1.6 Liebesohuetz ________________ 1959 (120) 83 52 6.0 a Boucot and others (25) considered the relationship in older men of smok- ing andchronic cough in a self-selected population 45 years of age and older. Chronic cough was defined as cough, existing for months or years. Againa a considerably higher percentage of the smokers, reported cough, and a clear- cut gradient was established according to amount of smoking. Bower (26) ) studied 172 men and women employed, in a bank. This study is one of the few which included men and women working under similar con~ ditions. Eighteen percent of 95 men and 17 percent of 77 women adinitted to cough "more or less every day." Of the smokers, 27.6 percent adhnitted to daily coughi (12 of 42 men; 9 of 34 women), whereas 4.1 percent of non. smokers admitted to this symptom (0 of 13 men, 2 of 36 women). Densen and others (44)' presented findings in transit and postal employees. Persistent cough was reported by 21.2 percent of 2;530'smokers and 7.8 per- cent of 514 non-smokers. Flet'cher and. Tinker (67) studied male workers agedl 30 to 59 in the British Generali Post Office and in the London Transport Executive. In the G.P.O., 118.7 percent of 166 smokers reported cough during the whole ofl the day in the winter, compared with none of 10 non.smokers. Among smokers ofl the L.T.E., 20.6 percent, of 272 admitted to a comparable cough pattern whereas none of 30 non-smokers described such a cough pattern. Flick and Patoni (68) in a study of patients excluding those with cardiac and respiratory disorders,, found 55 percent of 157 smokers admitted to habitual cough compared withi 10: percent of 51' non-smokers. After the first hundred patients, the admission to the study was weighted in the older age groups. The questioning,was not as st'andardized'as in some of! the more recent surveys. Olsen and Gilson (148), in their study comparing findings in population samples in Biitain with those in Denmark, found cough~ in 32.1 percent of 162 British smokers and! in 18.9 percent of 132 Danish smokers;, the cor- responding figures for non~smokers was 0 percent of 11 and 8' percent' of 24. Schoettlin (173) studied a group of veterans in a domiciliary and medi- cal-care center, mostly in the age group 45 to 74. The results for cough ("constantly present for two years or more")' are presented in terms of 281 J O W ~ C!1 aD CN1 M

years of smoking, although the original figures were not~ published and are not included in Table 1. By recalculation, it appears that of those who smoked more than 10 years, 4.3.9 percent of 2,153 subjects had cough whereas 18.0 percent of 718 who had smoked' less than 10 years lia& cough. In the population samples quoted thus far, the percentage of smokers admitting to cough ranged f'rom, 17.3 percent to 55 percent, whereas the range for non-smokers was 0 percea to 13.0'percent. Two other studies show a considerably lower prevalence of cough both among smokers and non,smokers in two~ unusual types of population. Short and others (176 )~ reported the frequency with which unselected policyholders admitted to cough~ on periodic health examination, a time when they would be expected to minimize their symptoms. Of 1,292 smokers, 6:4 percent admitted to cough whereas 1.6 percent of non-smokers admitted to cough. In a study of a parachute brigade, Liebeschuetz (120)' found 6:0 percent of 83: smokers an& none of 52 non-smokers admitted to cough. The study of members ofl this unit with particularly high fitness standards was con- ducted at the time of discharge. Hammond (82)~ has presented the frequency of cough in smokers, and has compared this with the frequency of cough among non-smokers. The subjects were asked to st'ate whether they had a cough at, the time of the questionnaire. They were also asked the question: "Have you had a cough over a period of many years?"' They also were asked to estimate its severity as slight, moderate, or severe. The analysis of complaints has been reporte& so far for 43,068 questionnaires; 18;697' for men and 24,371 for women. For each age group and! for both sexes; cough was significantly more common~ among those who smoked cigarettes. The percentage with~ cough (and the percentage with more than a slight cough) increased rapidly with the num- her of cigarettes per day iniboth sexes and in all four age groups. Except for ex-sinokers, the relationship betweeni "chronic cough" and smoking habit was very much the same as the relationship between "present cough" and smoking habits. The proportion of male smokers with the complaint of cough was almost three times as great as might have been, expected on the basis of coughi prevalence among, non-smokers. For women, the ratio of observed-to-expected smokers with the complaint of cough was 2.5 to~ 1. The ratio of observed-to-expected numbers complaining of' coughi "more severe than slight" was 4.09 for males an&2.74:for females. The difference in frequency ofl the complaint of cough or of cough "more severe than slight" bet«een smokers and non-smokers is statistically significant at the 0.001 level. The study sample was not a random sample of the populat2on; but~ it' provides information about the relationship~ between smoking and various complaints for larger numbers of subjeetsthan d'oes any other study. The results again make it' clear that! a larger proportion of cigarette smokers are aware of cough than are non-smokers. I!n~ each of the surveys, smoking, wasfbunds to be associated with the symptom of cough defined in a variety of way,s: The studied populationss varied considerably-from hospital patients, workers in dusty trades and clean offices, urban and rural population samples to members of a parachute brigade. Despite the diversity of these groups, it is surprising to note the consistency of the difference between smokers and non-smokers ini regard 282

to~cough. In each of the surveys, a larger propo rtion of the subjects ad- mitt2ng to cough were smokers and about twice the proportion of smokers admitted to cough as non-smokers. ('b.) Sputum.-Table 2 lists surveys in which the frequency of sputum pro- duction has been tabulated separately for smokers and non-smokers in preva- lenee surveys. Most of the studies were considered in the section on cough and in Table 1. It is interesting that in most of these studies non-smokerss report sputum production more frequently thamcough. j TABLE 2.-Summary of' rePorts on the prevalence of sputum in relation to j ~ smoking' Author Year Reer- Number of subjects Percent with sputum ence Smokers Non- smokers~. Smokers Non- smokers Balchum ------------------------------------- 1982 (16) 1,198 ' 253 30.4 11.1 Bower---------------------------------------- 1981 76 49 I 3'4. 2 20. 4 Densen-------- ------------------------------- 1963 (44) 2,530 514 21i9 13.8 rris: Males------ --------------- ----------------- 1962 (61) 340 125 I 140.3 I 1 13.8 ~ Females------------------------------------ 1962' (61) 209 379 1 19.8 I I 119.4 F1Ptcher: London Tr,3nsport.------------------------- 1961 (67) 272 30. 18. 9 7.01 Post Office-- ------------------------------- 1961 (67) 166 10 18.7 10.01 Flick --------------------- 1959 (M) 156 49. ('rl. 7 24.5 O1sen: United BinFdom-----------__-_---_--_ 1960 (14R) 162 11 27.2 0 Denmark----------------------------------- 1960 (14s') 132 24 11. 4 R:Z I Percentages standardized for age. Ferris and' Anderson (61)i studied a sample of the populationi of a town, their results are presented as percentages, standardized for age. The sample sizes were 542 males and 695 females. Among males -10:3 percent of smokers and 13:8' percent of non-smokers admitted to sputum production with the corresponding' figures for females being, 119.8' percent for smokers and 9.4 percent for non-smokers. Thus, sputum product'iom in each of the diverse populations was found associated with smoking and ai consistent difference between smokers and non-smokers was present in regard to sputum production. ('c:)Cougk, andSputum.-The clbseiy , associated symptoms of cough and, sputum have been combined in:the results of a number of epidemiologic sur- veys. Table 3 showsthe prevalence of cough and sputumi in smokers and ini non-smokers among samples studiedL Of partlicular interest is the series of comparisonsmade byHig;ins and his colleagues (88, 90; 92; 93, 95), on samples drawn from contrasting pop- ulations, selected for their different backgrounds. Lapse rates, were low,, and a high degree of uniformity was achieved im the collection of informa- tion. In the disparategroupsstudied-incl'uding male and flemalesubjeets,, older and younger, and varying, in degree of dust exposure andl exposure to: rural or urban environment-the consistent direction and extent of the dif- ference between prevalence rates in smokers and non-smokers demonstrates a strong relationship between smoking andl productive cough in a variety of different situations, and the predominance of smoking as a determinant of these symptoms. 283

i TABLE 3.-Summary of reports on the prevalence o f cough and sputum in relation to srnokzng Author Year , Refer- Numbeno[ subjects PercenVwith cough and sputum ence Smokers, i Non- smokers Smokers Non- smokers Higgins: Males.-------------------------------------- 1957 (88), 222 28 23.9 7:1' Femalcs------------------------------------ 1957 (88)' 93 176 17:2 4.5 Higgins: Male~~s.-------------------------------------- 1958 (93) 75 6 24.0 0 Females ------------------------------------ 1958 (93) 20 64 30:0 3:1'1 Higgins: Males--------------------------------------- 1959 (90) 315 33 29:8 6.1 Hieeins: '-5-34-------------------------------- Males, 1959 (92) 282. 56 29.1 8.9 . Males,.55-64-------------------------------- 1959 (92) 293 29 44.7 3:4' Payne: Males--------------------------------------- 1962 (153) 1, 400 304 11.0 1.9 Females------------------------------------ 1962 (iS3) 888 1,468 6:0 1.9 Pliillips--------------------------------------- 1956 (156) 823 451, 51.0 2.0 Read: Malhs--------------------------------------- 1 1961 (159) 91 46 23.1 4.4 Females--- -------------------------------- ' 1961 (159) 43 81, 18.6 4.9 - Liebeseiiuetz---------------------------------- I 1959 (120) R3 52 7.2 0. The percentages of symptoms noted by Oswald' and Medvei (150) are unusually high because occasional cough~ or sputum is includ'ed; in addi- tion to more frequent or persistent symptoms. The results are not shown in Table 3, which considers only smoking and cough with sputum ; among males, 63.7 percent of 2,617' smokers and 47.7 percent of 985 non-smokers in Oswald and Medveis study had cough or sputum: Among females, 63.2 percent of 970 smokers and 47.7 percent of 1,27'2' non-smokers admitted to either or both of these symptoms. Payne and Kj elsberg (153 )' presente& data on respiratory symptoms, lung function, and smoking habits in the. adult' population of Tecumseh, Michigan, where a: comprehensive epidemiological study is being made of the entire community. Cough and~ sputum were graded in severity as Grade 1'or Grade II, the latter being, defined as both cough and phlegms of whi& at least one was present throughout': the day for three months in the year or longer. The prevalence of Grade II symptoms is notedl in Table 3. Dur- ing an interview period continued for 18 months, authors were able to show that the prevalence ofl symptbms did! not vary significantly with thee season of the year. Cough and sputum at~ the Grade II level were admitted to by 111 percent of 1,400 cigarette-smoking males, and 2 percent of 364 non- smoking males. The corresponding, figures for, females were 6 percent of 888'smokers and Zpercent of 1,468 non-smokers. These Grade II symptoms increased in prevalence with advancing, age in men, and in women up to 49 years. It is interesting, to note that, lesser degrees of cough and sputum, classed as Gr~adeIsymptoms, showed little ehangein frequency after 19 years of age in either sex. In both sexes, Grade I symptoms of cough and sputum were considerably more prevalent among smokers than among non- smokers-45 percent of 1,400, smokers and'~ 19 percent of 364 non-smokers among,the males, an& 29 percent of! 888 smokers and 17 percent of 1,468 non- srnokers among the females. 284

4 Phillips and' his associates (156) studied two' groups: one of male em- plovees in a steel-making, plant, examined as part of an industrial hygiene program, and containing sub-groups with different' types of industrial ex- posure, and a second group consisting of 30D patients in a Veterans Ad- ministration Hospital who were chosen at random, except for exclusion of cases of specific pulmonary diseases such as tuberculosis or tumor and cases. of congestive heart failure. Chronic cough was defined as daily cough with sputum for a period of one year or more. Various possible environ- mental factors-geographic area, air pollution, specific work environment, and smoking-were considered. Fifty-one percent of 823 cigarette smokers were recorded! as having cough, and 2 percent of 451 non-smokers. Im a tabulation of chronic: cough by age in decades, for cigarette smokers and nomsmokers, it was shown that the increasing prevalence of chronic cough with age was much greater in the cigarette-smoking group. Read an& Selby (159) in a mixed group of 302 subjects, some of'~ them clinic patients, some patients' friends, and some hospital staff, found! that male smokers admitted to cough or sputum ten times as often as did male rton-smokers. and to cough and sputum five times as often. In their femalee subjects the ratios for these categories were eight to one and' four to one. Liebeschuetz(120)~ in his study of parachute brigade members found, as might be expected,, a much lower proportion of subjects with cough and sputum; these do not include subjects previously, noted in Table 1 as having cough alone. Considering these surveys as a group: it appears that the presence of cough, sputum,, or the two symptoms combined, is consistently more frequent among smokers than non-smokers, in a variety of samples drawn from populations differing so widely' in other respects that this association may he taken to be a general one. TABLE 4.-Summary of,reports on the prevalence of'breathlessness in relation to smoking Refe'r- ence Author I Year Number of subjects Smokers Non- smokers Percent elth breathlessness Smokers Non- smokers Balchum - 1962 (16) 1 198 253 14!.5 9.8 - ----------------------------------- Dpnsem -------------`------------------------- 1963: (44) , 0 2,530 514 25.3 16.9 Fletchen: London TransRort-____-_-__________________ 1961 (67), 272 30 8.5 0 Post Oirice------------------ --------------- 1981 (67) 166 10 9.0 10.0 HigRins: Dtales -- ----------------------------------- 1957 (88) 222 I 28 19:8 7:1i Females------------------------------------ 1957 (88) 93' 176 9.7 19.9 HSKvins: bfales.-------------------------------------- 1958 (03) 75 6 29:3 33.3 Females------------------------------------ 1958 (93) 20 1 64 20.0 45.3 Higeins: Sfales -------------------------------------- 1959 (90) 315 33 31. 7' l 19:2 HiR¢ins: Males, 25-34-------------------------------- 1959 (02) 282' 56 9:.9~.. 5:4~, Males, 55-54------------------------------- 1959 (92) 293 29 42.7 7 ~ 17.2 . Pa5•ne: Males-- --------- - ------------------------- 1962 (153) 1,400 364 24. W I 12.1 Females------------------------------------ 1962 (153) 888. 1,468 29.1 29,0 ~. Short----------------------------------------- 1938 (176) 1,292 496 11.51 4.8'. 285 99 IMENUMM f 1

Some of these surveys are limited in one respect, and some in another. The degree to which bias has been avoided varies; several of the surveys quoted are open tocritacism in thisregard„ but in others considerable pains have beeni taken to avoid! any possibility of suggesting a relationship, which may not truly exist. It would be wrong to extrapolate from; say, a hospital population to the general public, but the groups surveyed vary enough that the evidence demonstrates clearlk- that cigarette smokers more often report symptoms of cough, sputum, or both, tban do non-smokers. (d.) Breathlessness.-Table 4 summarizes the prevalence of breathlessness as reported in surveys of various populations. Balchum and others ('16) in their survey of mill workers: reported a greater prevalence of breathlessness among the smokers in, their sample. Tabulation of the frequency of this complaint byy pack-years of smoking experience showed a less smooth gradient than for prevalence ofl cough~ and sputum. Densen and others (44), who studied respiratory svmptoms in transit workers and postmen in New York City, foundi that 253 percent of 2,530 smokers and 16.9 percent ofl 514 non-smokers admitted to breathlessness of Grade II or worse (indicated by positive answers to specific questions on the questionnaire). Fletcher and Tinker (67), in a study of Transport Executive employees and Post Office employees: had only one non-smoker out of 40 complain of breat'blessness, and 38' smokers out of 438. These figures are for workers complaining of dyspnea (a positive answer to the question, "Do you have t'o walk slower than most people on the level?" or "Do you have to stop after a mile or so on the level at your own pace ?") . In the four studies by Higgins listed in the table, the difference in prevalence of breathlessness between smokers and non-smokers is more variable. In his study (88) in the agricultural district of the Vale of Glamorgan, the author presents prevalence figures for the various symptoms among females in two age groups, those under age 45, and those over age 45. His reason for doing so is the considerable difference in frequency of the smoking habit between women in these two age-groups. In both the age groups of females, the prevalence of breathlessness is greater amona the non-smokers, but the difference is not statistically significant. Female smokers ini the over 45 age groups have rather more cough and sput'umi and wheeze than the non-smokers;, but apparently have less breathlessness. In his study in Annandale (93) the prevalence of breathlessness among all men and all women studied was greater in the non-smokers than in the smokers, although the numbers of non-smoking men and! of smoking womeni were small. Wheni males aged 55 to 64 are considered, from the three surveys 190Y, breathlessness is more prevalent among the smokers; and the same thing applies t'o flie two~ different, age ~groups of~~ males stud ied' in Staveley~ (92). ~ Payne and Kjel?;berg (15U, in their survey of a totali community, have stated that among, t'he men, cigarette smokers were affected more often with breathlessness at alUages. Among the wornen,,cigarette-smokers had a higher prevalence of breathlessness than non-smokers below the age of 40, and above this age the non-smokers had a higher prevalence. Considering all ages together, twice the proportion of male smokers admitted shortness of breath 286

I I compared torion-smoking males; the.prevalence of shortness of breath among females was the same for smokers and non-smokers. Short et al. ('176), in a study of' answers to a questionnaire on routine medi~ cal examination for insurance purposes, obtained a larger percentage of com+ plaints of breathlessness among smokers than among non-smokers. Hammond (82) also presents figures for the frequency with which breath- lessness was noted in answer to a questionnaire by' 18,697 meni and 24,371 women. The relationship between breathlessness and smoking, is less clear than the relationship between cough and smoking. A sigpificantlyy greater proportion of complaints of breathlossness was encountered among male and female cigarette smokers, both for total complaint of breathlessness and complaint, of'~ breathlessness "more severe than slight." The: ratio of ob- served-to -expected' complaints of breathlessness among male smokers was 1.97 for the total number with this complaint', and 2.62 for those complain- ing ofl breathlessness more severe than slight. The ratios for females were 1.36 and 1.49. A considerationi of the frequency of complaints of shortness of breath in smokers and ini non•smokers, by age group andl by sex,, shows that'.the excess ofl breathlessness among cigarette smokers is greater and more consistent for men than for women. The older age groups of women show only a slight excess. Thus, the relationship between smoking and the symptom of breathless- ness is less general than the relationship between smoking and cough or sputum, which is found in all, age-sex groups in a variety of different' pop- ulations. For males the associationi is clear; male cigarette smokers com- plain of breathlessness more often than do non-smokers, particularly in the older age groups. Females present a less uniform pattern. In several sur- veys„ females show a higher prevalence of breathlessness ini non-smokers than in smokers, particularly in the older age-groups. The reasons for this sex difference have not! been explained. (e.), Smoking and Chest Illhess.-The percentage of smokers and non- smokers who reported chest illness in the three years prior to the interview TABLE 5-Summary of reports on history of chest illness in the past 3 years in relation to smoking Author 'Year Refer- Number oGsubjeats Percent with chesti illness ence Smokers Non- smokers Smokers Non- smokers ~~. Fletcher: London Transport---_--------------------- 19fi1 (67) 272~ 30 9.2~ 4.3 . Yost Offiloe --------------------------------- 1961 (67) , 166~. 10 I 33:7~ 211.0~. llivgins: Sfales'--------------------------------------- 1957 (88) 222' 28 17.1 ~ 3:fi Females------------------------------------ 1957 (St3) I 93 176 15. 1 I 13: l Iiigcins: Siales.-------------------------------------- 19:iF (93) 75 6 FemalOs------------ ------------------------ 1958 (93) 20 6.1 10!0'.~ 10:9~. IliReins. Males------------- ------------------------- 1959 (4M)) 315 33 23. 8 s: 0 ~. HiReins;. Males, 25-34-------------------------------- 19.59 (y2). 282 56 72.~5~~ - .1 Males, 55-fi4'-------------------------------- 19:i9 (92) 293 29 27.3 I G.:9 ~~ P.rcne: h4ales.-- --------- -------------------------- 1962 (153). 1„400. 364 . 11.0 I 9'1 Femssles'------------------------------------ 196'2 (153). 888 . 1,468 16.0 i 13.0: 714-422 0-64-20 287, s

date is presented'in Table 5. For men, the prevalence was consistently higher among smokers, and in one study (',93'), the associatiom of smoking and chest illness was apparent for the younger (25-34), as well as theold'er males (55- 64). For female smokers and non-smokers, the prevalence of chest illness was about the same. (If.)~ Combinations of Symptoms.-A number ofprevalencestudies. (7; 54, 61, 62, 77, 150) have reported results, either totally or in part,, under diag, nostic headings which cannot be translated into sing]e symptoms. The symptom combinations and the names applied to them varied; some of the studies gave the percentages of smokers and' non-smokers with "any" signs or symptoms rather than specified combinations. The results are presented in Table 6. TABLE 6. Summary of reports on the prevalence of combinations of certain symptoms in relation to smoking Number of subjects Percent wit symptoms h Author Year ftefer- ence Sm okers Non- smokers Smo kers No smo n- kers Ashford ------------------------ ------------- 1961 (7)'~ 3,214 677 21.7 ' 10J3'. F.d«ard4s.-------------------------------------- Ferris: I 1959~ (54), 779! 524 29.4 19: 5 bfales~---------- ----------------- 1962 (61) 340 125 24. 9 1 7.3 Females------------------------------------ 112 ~i (61) 209 379 17.5 ~ 9.4 Ferris: tifales -------------------------------------- 1962~ I (6'2). 54 20 42.6 15:0 Females------------------------------- ----- 196'2 (62)~. 10 60 20.0 10.0 (]oldsmith ------------------------------- --- 1962 ~ (~7 1,2311 744 43.0 31.4 Osw'ald: Males - ------------------------------------ 195':5 ' (1W)~, 2,617 9S5 16.1 9.7 Females ------------------------------------ 195.5. ~ (i150)~, 970 1, 272 15.4 9.1 'Percentages standardized for age. 60 percent of the total fbreedl expiTat'ory voltime. According to this d'efi• 11it'iorn male smokers showed' a 24.9 percent prevalence of irreversible expiratory volume in the first second of expiration (F.E.V. 11.0) of less than Ashford and his colleagues (7) found twice the proportion of "respir~a. tory symptoms"' among Scottish coal mine workers who smoked than among those who did rlot smoke. "Respiratoryy symptoms" were regarded as pres, ent in those who have cough or sputum all da}-y for more than three monthsper year and walk slower than others on the level, or wheeze, or if the weather affects their chest, or if they have had' a chest illness in the last three years. Those who had wheeze an& who claimed the weather affected their chest were also classed under "respiratory symptoms." Edtvards and others (3-4) presented the percentage of smokers and non- smokers with bronchitis, according to clinical assessment by one of 11 general practitioners coouerating in the survey. No attempt to standardize the diagnosiswas reported. Of 779 smokers, 29.-1i percent had "'bronchitis" comparedl with 19!5 percent of 524 non~smokers. Ferris and Anderson (61) presented the prevalence of "irreversible ob- structive Iting disease," which was defined as the report that wheezing or whistling in the chest occurred most daysand nig)lts, that the subject had to stop for breath when walking at his owm pace on the level; or had a forced 288

obstructive lung disease, compared with 7.3 percent of male non-smokers. The corresponding percentages for females were 17.5 percent and 9.4 per- cent. These percentages were age-standardized. In a study conducted in a flax mill, Ferris, et all.(62) presented the prev- alenee of "chronic respiratory disease," defined as productive cough on f,,urdays of the week, for three months of the year, forthreesuceessive vears;, or wheezing in the chest most days and nights;, or breathlessness, of Grade III or more, in the winter; or asthma diagnosed by the physician at t'iie time of the survey; or F.E.V. 1.0 less than 60 percent of forced vital ,I,pacity. Under this definition, 42.6 percent of 54 male smokers and 15.0 percent of 20~ male non-smokers had! "chronic respiratory disease." Forfemalesr the figures were 10.0 percent of 10 smokers and 10.0 percent of 60 wn-smokers. Goldsmith andi others (77), in their study of longshoremen, classified the lubject as having a "respiratory condit'ion" if he had ever had asthma or hrionchiti's, or currently was "troubled by constant coughing." Withi this ciefinitioni 43.0 percent of 1,238 moderate or heavy smokers had a respira- tory condition, compared with 31.44 percent of 744 non-smokers. Oswald! and Medvei (150)!, defining"bronchi'tis" as disability f'romi acute t,xacerbations of chest symptoms, or breathlessness,, or both, found a prev- alence of 16.1 percent, among2,617' male smokers, and of 9.7 percent among ')35 non-smokers. In their female subjects, 15.4 percent of 970 smokers compared' withi 9.1 percent of 1,272 non.smokers had "bronchitis." Although t'hese various combinations of symptoms are not comparable, the consistency an& extent of the differences between, prevalence of symp- tom combinations in smokers and non-smokers are striking. (g.) Relationship~ between Symptoms or Signs and!Amount Smoked.-In several surveys, smoking categories were based on the daily consumption or total lifetime consumption (16,, 61, 67, 82, 90; 153). In the majority, the prevalence of cough and sputum increased with amount smoked. A recent study (82) showed that those who smoked cigarettes of.low nicotine content tended to cough less than those who smoked cigarett'es of high nicotine con- tent. Other symptoms and measurements of pulmonary function show a less clear relationship between prevalence and amount smoked. (hL)Relationsh'ip betw•eenSymptoms andSignSandRleth;od of Smoking.- The numbers ofl pipe and cigar smokers in many prevalence studies are so small that conclusions about the effects of these methods of smoking are not reliable, but they all tend to show that pipe and cigar smokers are likely to be intermediate between non-smokers and cigarette smokers in prevalence: of symptoms and! signs. , (i.) VentiltrtoryFunction.-Pulmonary test's and the method of! presenting results, though varying widely, are important features of the prevalence surveys. In the study by Ashford and others (7) of 4,014 coal miners, the forced expiratory volume in the first second ofl expiration (F.E.V. 1.0') of non. smokers wasslightlyhigher thani that of the smokers, and! a smalli but sta- tistically significant difference was fbund even after correction for differ- ences attributable to physique. No consistent relationship was reported between the amount smoked and the average F:E.V. 1.0: 289

Balchum and others (16) reported that 14:3 percent of 1,194 smokers and 7.8 percent of 243 non-smokers had' an "abnormal" test, an F.E.V. 1.0 of less t'han70percent. When the "abnormal" test' was compared with the number, of pack-years of cigarettes smoked, a steady increase in the proportion of, men with decreased F.E.V. 1.0~ was found with increasing, pack-years. Ferris an& Anderson (61) showed a progressive decrease in the mean F.E;V. 1.0 in successive age groups for male smokers, male non-smokers;, and' female non-smokers. Im, males, there was also a regular decrease in F.E.V. 1.0 within each age group with increase in the number of cigarettes age group over 45, the peak flow was lower in smokers than in, non-smokers, but the numbers were small. These differences are not explained byy differ- ences in age, social class, or occupation. The difference between smokers and non~smokers in peak flow measurement was not seen in tests of women. Higgins• (00=); summarized the dif£'erencein F.E.V. 0.7,5in a variety of different samples of the populat9onL Tabulations for 16 different groups included miners and ex-miners in varying pneumoconiosis categories and non-miners in the same district, and agricult'ural.' workers in two different areas in Britain. In the 13 groups in which comparisons weree feasible, non-smokers recorded a higher F.E.V. 0.75 than the smokers. The small over-all difference in means was recorded' (as indirect Maximum Breathing Capacity) as 50 liters per minute; which was significant at the one percent smokers, and also between ~ non -smokers and light smokers. In each 10-year grams or more of tobacco per day, compared with non-smokers and with those who smoked less than 15 grams a day. For this test, there was no significant difference; between non-smokers and, the lighter smoking, gGoup: Peak flow measurements indicated a difference between heavy and light Higgins (88) showed a decrease, in F.E:V. 0.75 among smokers of 15 w.orkers; foun& the; mean expiratory flow rated'uring the third quarter of maximal forced expiration to be approximately 20 percent less in "heavy smokers" than in "light smokers." "Heavy smokers" were defined as those who had, smoked 30 pack-years or more, and "light smokers" less than 10 pack-years: Franklimand Lowell (73), in a study of 1,000 apparentlyy healthy factory expiratory flow rate showed a decrease with age and a decrease within the age groups with cigarette smoking. Chiv.ers (36)' showed that smoking, age: an& height werecorrelat'ed sig- nificantlv with the expiratory flow rate: The older and, shorter meni had greater impairment associated with, smoking.. Flick and Paton (68) demonstrated a distinct decline, beginning at about 40 years of age, in expiratory flow rate among smokers, but no apparent change among non-smokers until 70 years of, age. Fletcher and, Tinker (67), measuring expiratory flow rates liy the Peak Flow Meter„ found one group, of smokers, but not another, had lower values than the non-smokers. In a later paper (58)'., Fairbairn, Fletcher an& Tinker reported that the Peak Flow Meter appeared to be a less satisfactory sereen- ingtest than the forced expiratory volume. currently smokedi In females, there was little difference in the F.E,V. 11.0 between smokers and non.smokers except in one age group. The peak 290 -L- t

level. By pooling, subjects with different occupations in the older age groups, differences between light and heavy smokers were apparent, though not statistically significant. Higgins commented om a strong trendl in the prevalence of persistent cough and sputum, with amount of tobacco smoked, without a significant trend in,ventilatory capacity. His possible explanation of the difference is that smokers are more likely to give up smoking or re- duce the amount smoked, once their lung, efficiency becomes impaired; than they are when their only symptoms are cough and sputum. In t'heirstudy of miners and foundry workers in Staveley (92), ;, Higgins andUs colleagues showed a decrease in the F-E-V. 0:75 in smokers. Non- smokers, light smokers, and heavy smokers (15 grams per day and over)~ ranked in that order for decreasing F.E.V. 0:75, both in men aged 25 to 34 andl in those aged 55 to 64. The difference between the non-smokers and the light smokers was smaller than the difference between the light and the heavv smokers in the younger age group; in~ the older age group the dif- fcrence was larger between non-smokers and light smokers. Olseni and Gilson (148) measured the F:E.V. 0.75 in a: sample of a pop- ulation in Denmark for comparison, with British population samples. Cig- arette smokers ha& a lower mean F.E-V'. 0.75 than cigar smokers or pipee smokers who in turn had a higher mean than non-smokers, but these differ- ences were not statistically significant. If non-smokers, cigar smokers,, and pipe smokers are groupe& together, non-cigarette smokers had a: significantly higher mean F.E.V. 0.75 than the cigarette smokers. Payne and Kjelsberg (153),,who presented mean values oflF.E-V. 1.0 for men and women by age group and by smoking category; found a lbwer mean value for cigarette smokers than for non-smokers in each age: group of men over 19. In the 16-to-119 age group, cigarette smokers had' a slightly higher mean value than non-smokers. A comparison of the mean values by age group for non-smokers and for cigarette smokers shows a decline with advancing years in both, but more rapid in the cigarette smokers. Women also show a decline of F.E:V. 1.0 with advancing years, but this is no more marked and no more.rapid in the cigarette smokers than in the non.smokers The reduction in F-E.V. 1.0' in cigarette smokers amounted! to 7 percent and 3 ' percent of! the meam values in non.smoking men and women respectively wheni values adjusted to the over-all mean age of 40 years were compared. Read! and! Selby (159) measured peak flow rates in smokers with coughk and in smokers with cough and sputum. Tn a statistically significant extent, male smokers without cough or sputum showed'a more rapid fall in peak flow rate with age than expectedl Male smokers with cough showedl a still more rapid fall with age, and tbosewibhi coughi and sputum, the most napi& fall. Amount smoked ha& no obvious effect. Result's were similar fbr women. Revotskie,and his colleagues (165)i, who grouped smokers in, Framingharn as never smoked, light smoker, medium smoker, and heavy, smoker, found that the F.E.V. 11.0 measurements show a gradient from never smoked to heavy smoker in the "normal" subjects, both for males and females; in the other groups this gradient is not clear. The "Puff meter" ratios tended! in the same direction, but in less clear-cut fashioni thani the F.E.V. 1.0 measurements. 291

Goldsmith and others (77), showed that smokers, regardless of amount smoked, have a slight diminution in the pulmonary function test results, even in the absence of respiratory symptoms. The total vital capacity was much less sensitive in this regprd! than the F.E.V. 1.0 or the "Puffmeter" reading. Longshoremen with "respiratory conditions;" and particularly those with ~ shortness ofi breath, had a more marked decrease in pulmonary function. Cough was associated with the greatest diminution of; pulmonary function measurement. The relationship between cigarette smoking an& abnormal results of pul- ~ monary function tests is more difficult to evaluate from the published surveys than is the relationship between symptoms and cigarette smoking: Pul- <' monary function test results are influenced by severali factors, among which ~ are age, physique, and perhaps occupation. When allowance is made for % these factors, there appears to be a clear difference in the ventilatory func- ' tioni between smokers and' non-smokers. ~ Inithe majority of prevalence surveys, the subjects were not forbidden to smoke prior to pulmonary funetion, testing. Since acute alterations due to smoking might be mis- interpretedias due to a permanent abnormality, it is important to examine the magnitude and significance of the acute effects of smoking on pulmonary function. Biakerman and Barach (20)' found no consistent alterations in vital capacity or in maximum breathing capacity before and after their patients and normal subjects smoked three cigarettes. Simonsson (177) found a smalL decrease in the F:E.V. 1.0 in 13 of 16 young subjects after smoking, and the difference for the group was statistically sig- nificantL No significant change was found in the total eapacity. Severall authors have studied more sensitive tests of airway resistance and lung com- pliance. Eich, Gilbert and Aucltincloss (56) made compliance and' airway resistance measurements, using an esophageal balloon technique, onia group of nine healthy adults, five of whom had respiratory symptoms. No difference was detected after one:cigarette. Ih a group of emphysematous patients, a statistically significant increase in airflow re- _ sistanee was found, but withouV significant change in compliance. Attinger and others (8) reported no statistically significant difference in expiratory airflow resistance or compliance, but in a later study of subjects with~ pulmonary disease, significant, physiological changes-increased mechanical resistance and increased'work of breathing-were noted after smoking one or two cigarettes. Motley and Kuzman (142)', studied the hing volumes, spirometry, blood gas exchange, and pulmonary compliance in 141 subjects, before and after smoking two cigarettes. Not all of these measurements,were made on all subject's: There was no,significant change in a the meam values of vital capacity performed after smoking, some subjects showing a: decrcase,, and others an increase. Six of the normal subjects showed a decreased com- '1 pliance after smoking. Ih 33 subjects with cardiac or respiratory di'sease, 17 had a sig• ` nificant decrease in compliance after smoking: The authors felU that' a decrease in pul- ,~ monary compliance was the only notable abnormality which followed smoking acutely: :' Forced expiratory volume and airflow resistance studies were not included. Miller (134aY, who constructed pressure-volume work loops, demonstrated increase& airflow resistance and uneven ventilationi resulting in increased' work of breathing, ` This author conclUded that inhalation of cigarette smoke gives rise to a significant ; degree of uneven ventilation, which is responsible for the observed decrease in dynamic .' compliance and increased elastic work of breathing.. Nadelland Comroe(Q46) showed a mean decrease of 31 percent in, the ratio of airwayconduetance to thoracic gas volume after inhalation of cigarette smoke, the changes being ' highly significant statistically, and similar for smokers and non-smokers. Repeated test- ~ ing,after smoking showed the response to last for from 10 tu 80 minutes. Without inhala- ' tion{ no significant uhange in the conductance to thoracic gas volume ratio occurred. Inhalation of Ikuprel aerosol before smoking preventedl the increase in airway resistance, ' and when givemafter cigarette smoking it counteracted the increase. 292

b Zamel, Youssef, and Prime (194) found thaUthe,smoking of one cigarette increased airway resistance in smokers and non-smokers, and that'the inhalation ofl Ikuprel reduced airway resistance in both groups. The authors comment that the difference in airway resistance between non-smokers and cigarette smokers is apparent only when the actual estimates of airway resistance are compared with predicted values based on lung volume, because of a reciprocal relationship between airway resistance and lung volume. They add that the experimental values for airway resistance in two groups of persons are not comparable unless allowance is made for the volume of the lungs in each. 'Do sum up this point, the acute effects of cigarette smoking, upon pulmonary function are expressed mainly through increase in airway resistance, which is not severe enough to produce clinically evident manifestations. The smoker is not immediately aware of any increased! difficulty in breathing nor are the pulmonary function tests used in surveys -uffioiently sensitive to detect the acute effects. The differences in results of pulmonary functiow tests between~ smokers and non-smokers, therefore, are greater than cam be accounted for by acute effects from a recently smoked cigarette. PROSPECTIVF. STIIDIES.-In six of seven prospective studies, chronic bron- chitis and emphysema contribute markedly to the excess mortality among cigarette smokers; in the remaining study the mortality ratio was increased but to a lesser extent. In aI11 these studies, mortality ratios for chronic bronchitis and emphysema have been calculated (see Tables 19, 23, 26 in Chapter 8, Mortality). Cigarette smokers in these studies died of chronic bronchitis and emphysema 6.1 times more frequently than non-smokers. In the large study of U.S. veterans (49) the observed number of deaths among smokers attributed to chronic bronchitis was 26 whereas,the expected number based on deaths among non-smokers was 5.6, or a mortality ratio of 4.6. For emphysema, the observed number of deaths among smokers was 1115„ whereas the expected! number was 8.8, or a mortality ratio of! 13.1. In a recent study (82), informatfioni is available on the first 22 months of follow-up of 447;831 menibetween the ages of 35 and 89, of whom 11,612 have died. The observed number of deaths attributed to emphysema in cigarette smokers was 1115 whereas the expected number was 15.4; the mortality ratio was 7.47. For other pulmonary diseases the mortality ratio was 1.65, with 1185 observedldeaths in smokers as compared with 112.7 expected deaths. The duration of follow-up is na yet sufficiently long to allow one to expect deaths from chronic bronchopulmonary disease in, persons who were not afflicted at entry. The paucity of published morbidity studies is striking. Very little iss known of the progression in population samples of symptoms or signs related to chronic bronchitis or emphysema, or found in smokers more frequently than in non-smokers. And very little is known of the incidence rates of such symptoms and'signs in the different categories of subjects constituting popu- lathion samples. This is unfortunate, as prospective studies of morbidity in population samples can best measure.the possible health hazard of smoking. Several studies are under way, but some of the important' informationi will concern changes oceurring, over a period of five years or more. The only study of this type reported! so far is by Higgins and Oldham (94), who measured the F.E.V. 0.75 in a five-year follbw-up study on ventilatory capacity in a population sample in, a mining dlstrict, in Wales. In non- miners this measurement fell more over the five years in smokers than in non~smokers, and within the smoking group there was an increasing fall with amount of smoking. When the miners and ex-miners were considered, 293

the pattern was less clear. In~ three of the four groups, t'he F.E:V. 0.75 of the smokers fell more than that of the: non-smokers or ex-smokers; but the fall was usually greater in the light than in the heavy smoking, group. The authors pointed out that when the original sample was selected, no follow-up was intended, and that! the sample was not very suitable for this purpose: Thus, morbidity data are insufficient at present to be of value in the estimation of the possible health hazard of smoking. Prospective studies in populations followed over long periods offer the best opportunity for filling the major gaps in knowledge about the relationships of smoking,and chronic bronchopulmonary diseases. CLINICAL EVIDENCE Several' studies concerned with individual patients rather than defined populations form the basis for the clinical evidence. A current and continuing study of an "emphysema registry" with entry based on clinical and physiolbgical evidence, has been~ reported(',138) . Of 131 patients with diffuse pulmonary emphysema, 20 had findings at necropsy of widespread alveolar destruction. Clinical differentiationi was made into three groups : a"bronchitic" group in whom a history of cough was present years before onset of d'yspnea on exertion, a "dyspneic" group in whom cough and! dyspnea occurred at about the same time or in whom dyspnea occurred first, and an "asthmatic" group who gave a history of episodic dyspnea or asthma for years before the onset of uninterrupted dyspnea. When the sample of patients was adjusted for age and sex, 95 percent were smokers as compared with an expected 80 percent based on smokina, habits of Americans. In a later reportl (137)', the number of patients had in- creased to 150; 99 percent of the "bronchitic" group, 98 percent of the "dyspneic" group, and 79 percent of the "asthmatic" group were cigarette smokers. Improvement occurred' in 70 percent of the 60 patients who stopped smoking, as: compared! with 1 percent of the 84 patients who con- tinued smoking. Studies of series of patients by others (4, 125) have also notedl the fre- quent association of cigarette smoking with emphysema. A number of clinical studies indicate the frequent association of cigarette smoking, in chronic bronchitis (1:06;, 11,7; 149). Fewer non-smokers were among, the bronchitis patients than in~matched controls in two of the studies (117, 149). Of' interest is a comparison of 127 cases of chronic bronchitis with a similar number of eontrols (,7~5) ; no difference in smoking, habits was found in the men, an& very little difference in the women. On the basis of such studies, with varying diagnostic criteria,, several authors have concluded that cigarette smoking may be an etiologic factor in chronic bronchitis and emphysema; Most but not alll of! the studies have shown smoking to be a more common habit among the bronchitis or emphysema: patients than among the controll groups. Such evidence can~ do little more than provide a basis for hypothesis and indicate the effect of continued smoking on established disease; it does not, of course, establish~ or exclude a causal relationship. 294

t Relationship o f Smoking, Environmental Factors, and Chronic Respiratory Disease. ATMOSPHERIC POLLUTION BASIS FOR INTERRELATIONSHIP AND RELATIVE MAGNITUDE OF EXPOSURE- (1. ) Ezperimental, Evid'ence: The threshold level below which chronic ex- posure to a toxic:agent fails to produce damage to the respiratory system has not been established even for many of the known components of tobaeco smoke and atmospheric pollution. It is known, however, that the mechanism, by which inhaled substances produce an irritant response in the lung, is not a simple one. Physical, chemical, and biologic interaction may result from multiple, simultaneous exposure t'o a wide variety of' the components. Poten- tiation of the irritative actiom of certain gases when inhaledl together with an aerosol of small particles has beem demonstrated (5, 113~ 152)~. A possible example of potentiatiom may be found by contrast of two natural atmospheric pollution disasters; the 1962 London smog episode had lbw-er particulate levels, approximatelyy equivalent sulfur dioxide levels, and fewer deaths than the 1952 London smog. Innumerable components with potential biologic effects are present in tobacco smoke and as atmopheric.pollution,, some components are common to both. At present, information concerning the effects on the respiratory system is available for relatively few of these components. In an earlier chapter ofthfls report (Chapter 6)~„ the toxic actions of the particulate phase and major gas constituents of'cigarette.smoke are discussed; nitrogen dioxide, and to a much lesser extent, formaldehyde, are the gas componentscapable of producing, pulmonary lesions related to respiratory disease of man. The components which constitute pollutants in ambient' air vary wid'ely, largely because of differences in source, meteorologic variables, and photochemical interactions. The effects of some of; the majpr gas const'ituents in air pollu- tion uponAhe respiratory system are knowni and willl be presented briefly. Sulfur dioxide is rapidly absorbed into the lung butl removed slowl~-, per- sisting for one week after a single exposure (115). Interference with the clearance mechanismi is produced through effects upon the mucus, rather than by inhibition of ciliary motility as seen withi cigarette smoke. Sulphur dioxide usually exerts: its effects uponithe upper bronchial tree but intensive, protracted exposure may result in damage to the more distal air- ways. In animals, short4erm, high-level exposures result in increased air- flow resistance, and hypersecretion of mucus has been suggested' by changes ini the mucosa after moderatelyy high, intermittent! exposure of guinea pigs for six weeks (162). Chronic 1bw,level sulfur dioxide exposures have pro- duced'fibrotie bronchitis (86). Experimental human exposures confirm the increased airflow resistance which may occur without symptoms; augmenta- tion of the effects of sulfur dioxide, ini the presence of particulates also has been observe& in humans but it was less evident than in guinea pigs (72, 76, 193). Ozone produces irritant actions on the respiratory tract much deeper in the lung than sulfur dioxide. Repeated ir.halationi of 1' ppm. produces chronic bronchitis and bronchiolitis in rodents, especially rats, but no detectable ef- 295

c fects are produced in dogs (179). Under conditions of acute exposure, somewhat more than 1 ppm. of ozone produced increased airway resistance and decreased diffusing capacity in mani (76). It is not known whether chronic low-levell exposure to ozone produces lung damage in man. The ingredients of motor vehicle exhausts most' likely to have biologic effects are aldehydes, hydrocarbons, oxides of nitrogen, and carbon monox- ide. Guinea pigs exposed to ultra-violet irradiated exhaust gases have enhanced susceptibility to infection and bronchospasm (2, 144)'. No d'ata are available on the long-term inhalation of low concentrations of irradiated exhaust gases or photochemical smog and its effects on human pulmonary tissues. At present, it has not been demonstrated that other components common in air pollution are associated with pulmonary lesions similar to those found in the chronic respiratory diseases of man. (2.) Relative Magnitude of the Exposure.-Estimates of the relative mag- nitude of exposure to constituents common to bot'h, cigarette smoke and atmospheric polltrtion are made diffcult by the complex nature of the char- acteristics of the exposure, such as the relationship between concentration and' durationi and! by the paucity of studies specifically designed to evaluatee this aspect. In general, levels are likely to be high, brief, and frequently repeated! in the discontinuous exposure to: cigarette smoke; air pollutant exposure may be considered to be relatively continuous but with~ wide varia- tion in concentration and composition, particularly in the United' States. The relative magnitude of each type of exposure cannot be accurately calculated at present. Ibsi€ht may be gained, however, into the relative magnitude of exposure to two components, carbon~ monoxide and the oxides of nitrogen, common to cigarette smoke and atmospheric pollution. The smoking of 30 cigarettes per day is estimated to provide a 2(1- to 25-fold gFeater exposure to carbon monoxide than wouldl be experienced in the ambient air of Pasad'ena by non-smokers (76)'. The effect of smoking on carboxyhemo- globin levels in man has been determined in studies utilizing carbon monox- ide in air expired byy cigarette smokers and non-smokers with similar high level community atmospheric pollution exposure. The effect of cigarette smoking on carboxyhemoglobin levels in~ man was more than five timess greater than the effect of atmospheric pollution, even, when the studies were performedl in a relatively heavily polluted area (76)'. The relative magnitude of exposure to the oxides of nitrogen may also be estimated for cigarette smoking as compared with atmospheric pollution. The average concentration of nitrogen oxides in, ambient air is 0:3 ppm. in the Fall quarter in downtown Los Angeles. The oxides of nitrogen present ini cigarette smoke vary from, 145 to 665 ppm. ; moreover, virtually complete absorption occurs after inhalation (23). During periods of cigarette smok- ing, therefore, a substantially greater exposure to nitrogen oxides would be expected (76). Since cigarette smoking is likelyy to occur on every day of the year an& periodically throughout the dayy and evening, and community air pollution~ is likely to be relatively less common or persistent, therelatfive magnitudeof the effect of cigarette smokins, for the bulk of the United States population is certaini to be, greater than indicated above. The exact magnitude is per- 296

haps less important than the finding that it is substantially greater (76). Thus, using exposure either to oxides of nitrogen or carbon monoxide as an index, substantially gFeater exposure results from cigarette smoking than from atmospheric pollution, even when studies are conducted in a highly pallute& atmosphere in the United States. WAereas estimates of exposure to many other constituents of both types of pollution will be necessary before the relative hazard can be calculated more fully, the experimental evi- dence at present is consistent and' indicates that cigarette smoking affords the greater exposure for the bulk of: the population of the United States. EPIDEMIOLOGICAL EVIDENCE.-Most investigations of epidemiologic design have not been directed toward determination of the relative importance, or the combined effects, of cigarette smoking and atmospheric pollution in chronic respiratory disease. Discernible effects of cigarette smoking, such as cough and sputum production, have been observed and documented in the presence or absence of atmospherie pollution. A detailed considera- tion of the epidemiological data is available (76) ; onlyy selected studies wiR he considered here. The prevalence of cough and sputum in the United States appears to be determined much more by the amount and duration of cigarette smoking than by atmospheric pollution. Incomparable samples of cigarette smokerss in New York, Baltimore, Los Angeles, and' San Francisco: no major differ- ences were found in the prevalence of cough and sputum (76, 101) ; it is interesting that similar results were obtained' comparing cigarette smokers in; London, England and Bergen; Norway (139). Atmospheric pollution had little or no detectable effect on the prevalence of respiratory disease among residents of a New Hampshire town; a substantially greater preva- lcnae of! chronic nonspecific respiratory disease was present; however, in cigarette snlokers than, in non-smokers ofl similar age and! sex (6; 61). In veterans pairedl by age and smoking history; the frequency of respiratory symptoms and alterations in pulmonary function tests correlated well with past cigarette smoking history; in contrast, study of these men during the season in which~ Los Angeles atmospheric pollution was high did not result in detectable response attributable to the atmospheric pollution (173)1. In studies in areas withi varying severity of atmospheric pollution, the effects of cigarette smoking have been observed (16, 77; 165). Pulmonary em- physema is relatively rare in a population of non-smokers who live mostly in the areas of California with greatest atmospheric pollution (51). In the Uklited Kingdom, cigarette smoking and' atmospheric.pollution both contribute to the development and progression of chronic bronchopulmonary disease (28). Chronic bronchitis results in a mortality rate 30 to 40 times higher in both sexes and at! all ages than is seen in the United States. The excess mortality remains even, after removal of possible differences in clas- sification and misinterpreted! diagnosis (63). Moreover, differences in to- bacco consumption do not appear to be sufficiently large to account for the excess mortality due to bronchitis in the United Kingdom. In producing,simple, uncomplicated bronchitis, cigarette smoking appears to have the,same result in the two:countries (63). Although recurrent chest illness and evidence of airway obstruction are more frequent in cigarette smokers, the frequency of more advanced forms of chronic bronchitis does 297 >.,-, WA>: ~.:w !

not increase with increasingly heavy smoking (65). Atmospheric pollu- tion in~ the United Kingdom exerts its effects primarily among chronic bron- chitzcs ('117) almost a111 of whom are cigarette smokers (64) ; it also is a major factor in the urban-rural differences in prevalence and mortality (37, 65, 154, 160). Wheni those findings are considered together with other evidence documenting the:role of atmospheric pollution inichronic bronchitis (28;, 76, 161), it seems probable that atmospheric pollution and cigarettee smoking in the United Kingdomi are at least additive and possibly synergis- tic in their deleterious effect on the respiratory tract. Thus the epidemiological evidence oni the relationship of cigarette smok- ing, atmospheric pollution, and chronic respiratory disease clearly indicatess that the dominant association in the United States is between cigarettee smoking and chronic respiratory disease. In the United Kingdom, disabling respiratory conditions and' d'eath are more likely to occur among persons who smoke cigarettes and are exposed! frequently to atmospheric pollutants than in those exposed to either alone. 1' OCCUPATIONAL FACTORS Occupational exposures provide other possible etiologic factors in the production of chronic bronchitis and emphysema. There is little convincing evidence on specific relationships. Nevertheless, epidemiolbgical studies. (,reviewed in 123, 128) provide information on the relative import'ance of cigarette smoking and occupational exposures in selected groups. In a study of 4,014 Scottish coal miners (7), the prevalence of respiratory symptoms among non-smokers was appreciably lower than among smokers of the same age, and the ventilatory function of' non-smokers in all age groups was significantly higher than~ that of the smokers. Among, smokers of 50 years of age andl above, the prevalence of pneumoconiosis tended to be lowest among the men who smoked the most and highest among men who smoked the least. However, the prevalence of pneumoconiosis was higher in ex-smokers than, among smokers and non smokers, except in the oldest' age group, suggesting that men with pneumoconiosis tend to reduce their tobacco consumption. The possibility that factors of selection eliminate some persons with symptomatic pneumoconiosis from study groups should also be considered in the evaluation of these studies. In a; sample of 1,317 men aged 40 t'o 65 who worked in a variety of non- dusty and~ dusty environments, a: greater prevalence of bronchitis (daily cough for at least the preceding six months; productive of! one teaspoon of sputum per day) was found in moderate and heavy smokers (27). Between~ the non-smokers an& the heavy smokers, a significant difference was foun& at all age levels, and also between non-smokers and moderate smokers except in the oldest age group. Although effects from dust exposures could be noted, it appeared that cigarette smoking was the dominant etiologic factor in "chronic bronchitis" in this selected group. Among alkaline dust workers it was found that the dusts in the working, environment did cause some increase in respiratory illness but the sig- nificance of the dusts in the production of respiratory disability,, either functional or pathological, was not! as important as the number of cigarettes smoked daily(36). 298

i I ; In a stu4 of 1,274 steel workers, non-smokers had a comparatiieelq low incidence of chronic cough, regardless of their job classificatiom or condi- tions of work or residence. There was a direct relationship between chronic cough and the number of cigarettes smoked daily in each occupational category (1I56):. Cigarette smoking was of greater importance in deter- mining the prevalence of chronic cough than was the occupational exposure. In a study of New England flax mill workers,, 161 subjects were subjected to a questionnaire and measurements of pulmonary function to determine the presence of "chronie non-specific respiratory disease." The prevalence of such a syndrome, based om a certain combination of symptoms or signs, was related to age;, sex, smoking habits, years of exposure to dust, and estimated inhaledl quantity of dtrstl The effect of smoking`°'far out'~shadows any effect due to age or occupational exposure to dust" (62)'. The studies by Higgins and his colleagues (87; 88, 89, 91, 92) show that smoking and occupational exposure are bothi relatedl to the prevalence of chronic respiratory disease but do not allow quantitative assessment of their relative importance in the populations defined. As this series of studies was undertaken to demonstrate any effect from industrial exposure, and the popu~ l'ations surveyed', were such that exposure to occupational dusts was more varied than in the general population, the importance of the effect of! smoking inithis group of studies on the production of respiratory symptoms is rather convincing (123)1. The authors comment in one of the papers in this series: "So important is the influence of tobacco smoking that it is essential to alloww for differences in smoking,in comparable groups before drawing conclusions about the importance of other factors." In a recent study of bituminous coal miners (103), ex-smokers had pul- monary function results and prevalence of respiratory symptoms comparable to~those of non-smokers; no impairment was attributed to pure pipe or cigar smoking. Cigarette smokers had' the most symptoms of respiratory disease and„except for vital capacity, they had the lowest pulmonary function; The authors comment: ". . . although smoking definitely impairs pulmonary funetion, the impairment of pulmonary function by years worked under- ground is clear and separate from the effect of smoking." In a st'udy of 7,404 metal mine workers, aged 35 years and older, a com- parison was made of'the effects of 20 years' aging and smoking on, pulmonary ventilation, as measured! by the F.E.V. 1.0 in individuals without X-ray evi- dence of silicosis. A decrease of 23' percent occurred with the process of aging 20 years. For heavy smokers (those who smoked for 25 years or more and now smoke more than 20 cigarettes a d'ay)', there was an additional d'e- cline of 1!0 percent over that of aging, alone. "The decline in, pulmonary function associated with heavy smoking, was equivalent to the decline that comes about by the process of aging 10 years. For the entire group of metal mine workers, the reduction in pulmonary function associated with smoking was equivalent to half the effect of heavy smoking, or about five years of aging"'(128). The population at risk from occupational exposure is relatively small com- pared to the population of cigarette smokers. Among occupational groups, cigarette smoking is an important variable that must be considered im all 299

i studies of chronic bronchopulmonary disease. In most studies, but not all, the relative importance of cigarette smoking, is greater than occupational ex- posures in~ the production of symptoms and signs of chronic bronchitis or emphysema. SUMMARY I Tobaeco smoke is a heterogenous mixture of a vast number of compounds, several of which have the ability to produce d'amage to the tracheobronchiai tissues and lung parenchyma. Retention of inhaled cigarette smoke particles in the respiratory system of man is about 80-90'percent complcte with breath holding of two-to-five seconds. Particles penetrate deeply into the respira-- tory tract andl are deposited on~ the surface of the terminal bronchioles, respiratory bronchioles, and pulmonary parenchyma. Little information is available concerning the specific toxic properties of the particulate phase components. Gas phase components probably have a diffuse though not uniform pattern of distribution. It seems likely on the basis of the physical characteristics of gas absorption and distribution, that a substantial portion is retained along, the upper bronchial tract'. Certain of the gases known to be present in cigarette smoke are capable of' producing pulmonary damage in experimental animals and'man. Cigarette smoke produces significant functional alterations in the upper airways. Like several other agents, cigarette smoke can reduce or abolish~ ciliary motility in experimental animals. Post,mortem examination~ of bronchi' from smokers shows a decrease in the number of ciliated cells, shortening of the remaining, cilia, and changes in goblet cells and mucous glands. The implication of these morphological observations is that func- tional impairment would result. Cigarette smoke is also capable of interference with functions in the lower airways. Ini animal experiments, cigarette smoke appears to affect the phy- sical characteristics of the lung lining layer and to impair alveolar stability. Alveolar phagocytes ingest tobacco smoke components and assist in their re- moval from the lung. This phagocytic clearance mechanism decompensates under the st'ress of protracted high-level exposure to cigarette smoke and'tb- bacco smoke components accumulate in the pulmonary parenchyma of' experimental animals. The acute: effects of ci'garette: smoking result, in an increase in airway re- sistance but clinical expression of this change in pulmonary function is not common. The chronic effects of cigarette smoking upon pulknonary fune- tion are manifest'ed mainly by a reduction in ventilatory functioni as measured by the forced expiratory volume. Histopathologieal' alterations occur as a result of tobacco smoke exposure in the tracheobronchial tree and in! the lung, parenchyma of man. Changes regularly found in, chronic bronchitis-increase in the number of goblet cells, and hypertrophyy and hyperplasia of bronchial mucous glands-are more often present in the bronchi of smokers than non-smokers: In experimental animals, cigarette smoke consistently prodUces significant functional! altera. 300

tions in the upper and lower airways. Such alterations could be expected to interfere with the cleansing mechanisms of the lung, Pathological changes in pulmonary parenchyma, such as rupture of al- veolar septa an& fibrosis, have a remarkably close association with past his- tory of cigarette smoking. These changes cannot be related with certainty to emphysema or other recognized' diseases at the present time. Chronic bronchitis and pulmonary emphysema are the chronic broncho- Pultnonarydfiseasesofgreatesthealtlh, significance. Epidemiologicallevidence provides the most important information relat2ngcigzrettesmokina~ to chronic bronchitis and emphysema: All seven of the majpr prospective studies show a: higher mortality rate f'or chronic bronchitis and' emphysema among, -cigarette smokers than among, non-smokers.In the few studies that have examined mort'alfity rates separately for the two~ conditions, chronic bronchitis or emphysema, both rates are higher among, civarette: smokers than among non-smokers. In one of the studies, the risk of mortality from chronic bronchitis was four times greater among cigarette smokers than anlong non-smokers: Emphl sema was listed as a cause of death 13' times more frequentlvy among smokers in one study, and 71/~ times more frequently among smokers in another study. Extensive prevalence studies, based largely on prevalence of specific svrnptoms and signs rather than imprecise diagnostic labels, show a consis- tently more frequent occurrence of! cough, sputum, or the two symptoms aombined. in cigarette smokers than in non-smokers. These manifestations are theclinicale expressions found in, chronicbr~onahitis. The resultsofl the prevalence surveys, however, offer less direct evidence relating cigarette smoking to pulmonary emphysema. as clinical diagnosis of this disease is less exact. Breathlessness, which may result from emphysema or airway obstruc- tion in chronic bronchitis, is associated with cigarette smoking in males, particularl}'y in the older age groups, but not females. Similarly, a:consistent association of cigarette smoking and chest illness is more evidenti for males. In the prevalence surveys ini which various combinations of respirat'ory manifestations have been studied, a greater prevalence of these conditions is found consistently among cigarette smokers. The majority of clinical studies have noted a: relationship betweeni ciga- rette smoking and chronic bronchitis and emphysema. Cigarette smoking is a more common habit in the United States among, patients with~ chronic bronchitis or emphysema than in the control groups studied. The clinical stodies also show a decrease in clinical manifestations of chronic broncho- pulmonary disease after cessation ofl smoking. Examination of' experimental evidence shows that the lung may he dam~ aged by noxious agents found in either tobacco smoke or atmospheric poh lution. In the United' States; the noxious agents from cigarette smoking are much rnore important't ini the causation of chronic bronchopuhnonary disease than are those present as community air pollutants. In the. United Kingdom, persons who smoke cigarettes and are exposed frequently to at- mospheric poll~tants are at greater risk of developing disabling respi'ratory disease and d'eatlhithan those exposed to either, alone. 301

The relative: importance of cigarette smoking, also appears to be much greater than occupationali exposure as an etiologic factor for the chronic bronchopulmonary diseases. Cigarette smoking does not, appear to cause asthma; in, rare instances, allergy to tobacco products has been ascribed a causative role in asthma, like syndromes. Evidence does not support' a direct association between smoking and in« fectious diseases ofl the respiratory system. The category, influenza and pneumonia, contributes moderately to the excess mortality of cigarette smokers but other data are not available to extend' this observation. The association of cigarette smoking and tuberculosis does not appear to be a direct one,,but both are associated with the use of alcohol. Only for "stomatitis nieotina" and the epithelial changes in the larynx is there sufficient documentation to substantiate the clinical opinion that non- malignant alterations in the mouth, nose, or throat are indticed by, smoking. The changes in the mouth are more often associated with pipe smoking but disappear after cessation of! smoking. CONCLti SIONS 1. Cigarette smoking is the most important of'~ the causes of chronic bronchitis in~ the t'nited: States, an& increases the risk of dying from chronic bronchitis. 2. A relationship exist's between pulmonary emphysema and cigarette smoking but it', lias not been~ estkblished! that the reldtionshipis causal: The smoking of cigarettes is associated with an increased risk of dying from pulmonary emphysema. 3. For the bulk of the population of the United States, the importance of cigarette smoking as a cause of' chronic bronchopulmonary disease is much greater than that of atmospheric pollution or occupational exposures. -1. Cough, sputum production, or the two combined ar~econsistently more frequent among cigarette smokers than among non-smokers. 5. Cigarette smoking is associated with a reduction in ventilatory func- tion. Among males, cigarette smokers have a greater prevalence of breath- lessness than non+smokers. 6. Cigarette smoking does not appeart6cause asthma. 7. Although death~ certification shows that cigarette smokers have a mod-erately increased risk of death from inHluenza and pneumonia, an association of'cigarettesmoking and infectious diseases is not otherwise substantiated. REFERENCES 1. Abbott, C. A., Hopkins, W. A., Van Fleit, W. E., Robinson,, J. S. A new approach to pulmonary emphysema. Thorax 8: 1ll(-32; 1953. 2. Albert, R. E.,, Nelson, N. Special report to t'he Surgeon General's Advisory Committee on Smoking and Health.. 302

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Chapter 11 Cardiovascular Diseases f. ,

Contents Page INTRODUCTION .................... 317 PERTINEN T PHARMACOLOGY . . . . .. . . . . . . . . 317 GENERAL OBSERVATIONS ON' CORONARY HEART DIS- EASE . . . . . . .. . . . . . . . . . . . . . . . . . . 320. SMOKING AND CORONARY HEART DISEASE ..... 322 SMOKING AND NON-CORONARY CARDIOVASCULAR DISEASE. . . . . . . . . . . . . . . . . . . . . . . 325 CHARACTERISTICS OF CIGARETTE SMOKERS . . . . 326 PSYCIIO-SOCIAL FACTORS OF' S11iOKING IN RELATION TO CARDIOVASCULAR DISEASE' . . . . . . . . . . . 327 SUMMARY . . . . . . . . . . . . . . . . . . . . . . . 327 CONCLUSION . . . . . . . . . . . . . . . . . . . . . . 327 REFERENCES . . . . . . . . . . . . . . . . . . . . . . 328 List of Tables TABLE 1. Death rates per 100,000 from arteriosclerotic and degenerative heart disease by sex and age, United States, 1958-60 . . . . . . . . . . . . . . . . 321 TABLE 2. Ratios of mortality rates for coronary heart disease, male smokers to non-smokers, by age and amount smoked, in selected' studies . . . . . . . . . . . 324 316

Chapter 11 INTRODUCTION 0 It has been suggested repeatedly that smoking may have adverse effects on thc eardiovascularsystem. Recently, studies of large groups of people have ,hown that cigarette smokers in particular are more prone to die early of' (.,rtain cardiovascular disorders than non-smokers. Chief among these dis- ''rd'ers is coronary artery disease, and the present chapter deals mostly with subject. The chapter begins with a summary of information about the .wute effects of smoking on the cardiovascular system. This is followed by a ;,; ief account of coronary disease, its frequency in different, kinds of people, :rnd the many factors known or thought to aff'ect the likelihood of its develop: ; mt. The aim here is not to: review critically our knowledge of coronary ~ii~,ease buti only to give baekground'for what follows. Next! is summarized information currently available fromi studw ofl large population groups the association of cigarette smoking with an increased tendency to have ,>ronary disease. There follows a; brief discussion of smoking and non« ~oronarv cardiovascular disease. Finally, there is a short, review of evidence rolatinl- to the questioni of whether cigarette smokers may; as a group, differ 'rom non-smokers in ways not caused by smoking itself. Mortality ratios -howing the associationi between cigarette smoking and deaths from cardio- ascular disease, especially coronary disease, do not indicate the magnitude ,41 t'he burden. This can, be better appreciated from considerationi of the foiloicing, facts: cardiovascular disease deaths now, total more than 700,000 .urnrually in the United States. Of these more than 660,000 were due to heart di'sease;, with more than 500,000 due to arteriosclerotic heart't disease inelud- ingcoronarydisease. The remaining approximately 40,000 were ascribed to disease of other parts of the cardiovascular system. Deaths from lung rancer total approximately 39;000! A mortality ratio of 1.7, for coronary heart disease among cigarette smokers in the seven prospective studies repre- sents from 32:9' percent to 51.7 percent of all excess, deaths, whereas thee much higher lung cancer mortality ratio of 10:8 from the same studies repre- sents only 1I3'.5 percent to 24.0 percent of total excess deaths (Chapterr 8, Tables 19, 25). PERTINENT PHARMACOLOGY The acute cardiovascular effects of smoking in man and experimental ani- mals are like those caused by nicotine alone. A smoker who inhales gets usually 1-2 mg of nicotine from a cigarette (5f, 57). Low concentrations of nicotine stimulate sympathetic ganglia„ and high concentrations paralyze them: Parasympathetic ganglia respond in the same way but are less sensitive. Nicotine can also have a: sympathomimetic effect 317

by causing the.discharge of norepinephrine and epinephrine from chromaffin cells in various tissues, including heart, vessels, and skin (10, 11, 9)'. In addi- tion, nicotine produces effects reflexly by stimulating the chemoreceptors of the carotid andi aortic bodies. When nicotine is given intravenously in in- creasing doses to dogs or cats the first effects, at about 1 mierogram,/kg body Weight, are increased' breathing an& sympathetic stimulation, with predomi- nant vasoconstriction, cardiac acceleration, and rise im blood pressure, re- sulting from stimulation of the aortic and carotid bodies (17). Doses of 4 to 8 micrograms/kg can stimulate pulmonary and coronary chemoreflexes which produce opposite effects. If all these receptors are inactivated, much higher doses are needed to evoke the cardiovascular effects of sympathetic stimulation, presumably through action on sympathetic ganglia or chromaffin tissue. Intravenous administration of nicotine in the experimental animal causes a discharge of epinephrine from the adrenal' medulla, and in man~ heavy cigarette smoking produces an increased urinary excretion of catechol6mines (84, 99). Smoking 1~--2 cigarettes causes in most persons, both smokers and non- smokers, am increase in resting heart rate of 15-25 beats per minute, a rise in blood pressure of' 10-20 mmHg systolic and 5-15 mmHg diastolic (76, 78, 85, 86), and an increase in cardiac output of about 0.5 1/min/sq~m (75). There is a decrease im digital blood flow and a consequent dFop in finger and toe temperature (31, 78, 103)~. The decrease in peripheral blood flow which normally follows smoking does not occur in a sympatliectomized lfmb, in- dicating that the effect is mediated primarily by the sympathetic nervous svstem rather than through the release of catecholamines fromi other sites or the direct effect of nicotine upon the smooth muscle of the blood vessels themselves (103). Intravenous nicotine., and probably cigarette smoking as well, can prodtice a slight transitory increase in the blood flow to resting calf muscle (79). In the dog, nicotine and cigarette smoke cause an increase in coronary flow as the blood pressure, cardiac output, and heart work increase (30, 53). These effects resemble those of epinephrine. Nicotine has been found to cause a transient decrease in cardiac oxygen utilization followed by a slight increase (53)!. Relatuvelylittle information is available about the effect of smoking on coronary blood flow in man. In normal subjects it is re- ported that cigarette smoking produces an early increase in coronary flow as heart work increases, but there is little change in oxygen utilization by, the myocardium 2). With continued "steady state" smoking the coronary flow and cardiac oxygen utilization are maintained! at the resting level in both normal subjects and persons with coronary heart disease, despite in- creased blood pressure, heart rate, and heart! work (74). A larger experi- ence must be gatherect in this field before statements about the acute effects of smoking on the human; coronary circulation can be made with assurance. The atherosclerotic rabbit heart, like the normal rabbit heart, shows an initial drop in coronary flow on adininist'ration of! nicotine, but demonstrates less of a: . subsequent increase above the resthng, levell than does the normal heart (97). These effects are said' to be equivalent to those produced by norepinephrine in doses one-tenth as large as the nicotine dose. 318 ,

Little or no change in the electrocardiogram of most~ normal persons or cardiac patients, except for~ an increase in rate, is produeedl by smoking or br the intravenous injiection, of an equivalent dose of! nicotine (82, 98). In sorne persons there:is a slight depression of the S-T segment and a flattening of 1-2 mm in the T wave of the limb leads. These changes are not like those associated with myocardial ischemia. Rarely in persons with true angina. an attack of paim is precipitated by smoking. An ill-defined syn. drome consisting of chest pain, palpitation, and shortness of breath, known as "tobacco angina", has been described as occurring in~ smokers, whodo not have organic heart disease, but it is rarely diagnosed today(73, 82)~. Extras?;stolesand other cardiac arrhythmias have been reported to be caused hv smoking, but! such cases appear to be unusual. The ballistocardiogram obtained from a high-frequency table is some- times,changed by smoking a cigarette from a normal patterm t'o; one said too he typical of coronary disease (78, 91)1.. This phenomenon is rare inihealthy persons belbw 50,, becomes increasingly common with advancing years ini apparentll° healthy persons, but is particularly proneto, occur ati any age inuersons with actual coronary disease. The effect has been used as a "stress roat" to help uncover coronary disease; but false positive and negative results a--e commom The ballistocardiographic changes on smoking have been ariously interpreted as resulting from impaired myocardial contractility 781, from changes in the peripheral circulatfion (82), or from uncertain au~ .es related to the physicall properties of the high-frequency table as well aS changes in the circulation. Cigarette smoking causes an increase in the concentration of! serum-free fatty acids in man (50),, apparently mediated by stimulation of the sympa- thetic nervous system (51). Although continued administration of epine- phrine to dogs over many hours can produce substantial increases in serum rholcsterol, phospholfipids,, and triglycerides, such an effect has not yet been reported from nicotine or tobacco smoke (48, 92). The clotting time of the blood can be decreased 50 percent or more in ex- perimental animals by stimulationi of' the sympathetic nervous system or by administration ofepinephrine(1I2, 13, 14), but att'emptsto demonstrate that ci=arette smoking alters the clotting,properties of the blbod in man have been unsuccessful (5, 68). A decrease in platelet! survivaU in viwo has been found after smoking (68). Cigarette smokers have been reported.to show substan- tial decreases in hematocrit, hemoglbbin, and platelet counts after abstinence of 1I-2 weeks (25), but hemoglobin concentrations are alike in smokers and non-smokers of the same population group (4). Attempts have been made to induce atherosclerosis in, rats by the chronic administration of nicotine for periods up to a year without success (93). Tobacco has antigenic properties (29, 93'). Rats can be sensitized to to- bacco extracts by intraperitoneal injection. Over a third of smokers demon~ strate a positive "immediate" skinireaction to such extracts while only about 1V'r of non-smokers are said to give positive tests. The presence of serum reagins in persons with positive skin tests has been demonstrated by passive transfer techniques. Persons with thromboangiitis obliterans and smokers with occlusive vascular disease of other types are said to show a much higher incidence of positive skin tests than healthy smokers. The cardiovascular 319

diseases which have been related to smoking, however, do not in general resemble those usually ascribed to an immune mechanism. In man and experimental animals smoking or the injection of nicotine causes increased' secretion of antidiuretic hormone. The renal effects of this are easily demonstrable but the quantity of hormone secreted in response to smoking is probably too small to have significant vascular effects (17). In summary, the acute cardiovascular effects of smoking and of nicotine closely resemble those of sympathetic stimulation, and to a considerable extent are mediated by excitationi of the sympathetic nervous system. No additional or unique cardiovascular effects have been demonstrated whieh. in, the light, of our present understanding, seemilikelyto account for the observed association of eigarettesmoking with ani increased incidence of coronary disease. GENERAL OBSERVATIONS ON CORONARY HEART DISEASE Hearrt' disease is the most common cause of death in our population, and coronary disease is the commonest variety of fatal heart disease (59)i. In 1961 there were 1,701,522 deaths from all causes in the Unite&States.Heartdisease deaths numbered 663,391 of which 502.351 were due to arterio- sclerotic heart disease. The disorder consists of obstruction or narrowing of the coronary arteries, redtrcingtheblood supply to the.heart muscle. The underlying cause of the obstruction is coronary atherosclerosis, but an acute coronary artery occlu, sion is often eaused! by theformat~ionof a~ blood clbti in a dfisease& artery. The common manifestations of coronary disease are angina pectoris, recur- rent brief attacks of chest pain caused by inadequate blood supply to the heart' muscle; my,ocardiali infarction, or necrosis of a portion of the heart muscle due to acute loss of blood supply; congestive heart failure,,a chronic state caused! by inability of the heart to pump enough blbod to satisfy the demands of the body;, and sudden death resulting from cardiac standstilll or ventricular fibrillation. There are considerable differences in the prevalence of coronary heart disease in different countries, and'ofteni in different ethnic and socio-economic: groups within a particular country (4fi; 62). The reported death rate of arteriosclerotic heart disease, which is primarily coronary disease, is hiaher in the Unite& States thani in other countries. It is also quite high in New Zealand, Australia, South Africa; Canada, and Finland; and moderately high, in Great B'ritain. The death rate in Norway,,Sweden, and Denmark is roughly half that in the high death ratecountries115/., The death rate in Japan appears to be about one-sixth that in the United States, although persons of Japanese origini living in the United! States are said to have a-death rate similar to that' of the general population of this country (52). Because ofl changing diagnostic skills and revisions in nomenclature of disease, it is difficult tobe certain, of the change in incidence of coronary disease inithe United States over the past few decades, but there is a general opinion that the incidence is increasing in this country and in England, 320

part'icularly in the younger male group (59, 62, 65, 83). In 1955 the nnortalitv rate from arteriosclerotic heart disease was reported to be about 240 19, r 100.000: Although this is an increase of more than 50% over the rate in 1940, it has been estimated that less than, 15% of the increase represented a real change in incidence of the disease, the remainder depending upon Ohan=es in diagnosis, in nomenclature and in the age of the population (59). ince 1955 the death rate from coronary disease (ISC 420) and from :!rteriosclerotic and degenerative heart disease (ISG420 and 422) has con- ±inued to increase gradually. In~ 1960 the age-adjusted death rate from 420 and 422 was 330 per 100;000 for white males and'150 for white females (55). Although the basic cause or causes of coronary heart disease are obscure, ertain f'actors other than smoking,are known or thought to predispose to the ()ndition or tobeassociated with an increased incidence. The incidence of coronary heart disease in men under 45 is about 5 times sgreat as that in wonien (Table 1) (15„20, 59, 62). In both sexesthe inci- ~ience increases with advancing years. After the menopause the incidence increases rapidly in women, and at age 80 the death rates from coronary ,'isease are about the same for the two sexes. Coronary thrombosis plays a relatively more important role in precipitating myocardial infarct2on in young ,cen than it does in old men (105Y. In studies of large population groups , :~ronarv disease has been associetedlwith elevation of the serum~cholesterol„ npertension„and marked overweight (19, 20; 24, 36, 46, 59, 62). Some individual characteristics have been said'to be associated with coro- ~~.rrv disease. Thereisa: significant familial tendencytbdeveiopit (36, 69, erahlet'ban endomorphs and! ectomorphs (136, 62, 88). A coronary-prone ; ier onality has been described as the aggressive, competitive person who takes time for the perfbrrnance ofhis work (33, 34, 35)~. r%a:I,F 1. Deatli rates per 100,009 from, arterioseleroticand degenerative heart disease* by sex and' age, United States, 1958--W e,Group Malfs FemalesBoth Sexes Under 35------------------------------ 3.3 1.2 2.2 35-44, --------------------------------- 90.2 18.3 53.3 -15-54 --------------------------------- 353.7 79.3 213.5 55-64 --------------------------------- 928.5 314.5 610.2 65-74 --------------------------------- 2129.2 1082.0 1569.5 75 or over------------------------------ 4765.1 3738.4 4179.7 k tnclhdes ISC numbers 420 and 422. ~ource: WHOO.I Epidemiologioal and Vital Statistics Report, Vol. 16, No. 2, 1963. Certain occupations have been said particularly to favor the development! of coronary disease, notablly those which feature responsibility and stress 1' )4, 81, 871~, and' which are sedentary in nature (7). Others (58, 7~2, 90) have not found that executives are more prone to coronary disease than non- executivepersonnel. Physicians have been said to have 3 or 4 times as much coronary disease as farmers or laborers (87), and generall practitioners to

have 3 times as much as dermatologists (80). Occupations involving much physical activity are said to be protective (66, 67, 77)~. City life has been~ said to be more closely associated with coronary disease than suburban life,, and menwho drove more than 12,000 miles a year seemed, in one study, moree prone to the disease than those who drove less ('64)1. It has been widely held, and occasionally denied, that a diet high in saturated fat predisposes to the development of coronary disease (46, 52, 69, 81)1. A correlation between the national incidence of coronary disease and the percentage of food calories available as saturated f'at~ has been re- ported'among those countries for which adequate data exist (46) . The serum cholesteroli tends to rise when saturated fat is added to the diet, and it! falls significantly when unsaturated fat is substituted' (46). It has also been sug- gested that general over-nutrition, rather than excess saturated fat predis- poses to coronary disease, on the grounds that the correlation of coronary disease with total available calories or sugar consumption~ per capita is as good as that for percentage of calories in fat (106). In general, it is apparent that multiple personal and'environment'al factors can markedly affect the incidence of coronary disease. SMOKING AND CORONARY HEART DISEASE Over thelhst two decades a considerable number of' epidemiologie studies om diflerent populations, employing different techniques, have shown with remarkable consistency a sigpificant relationship between cigarette: smoking and an increased death rate from coronary heart disease in males, par- ticularly during, middle life. There has been little dissenting evidence. The association of coronary disease with the use of tobacco: in other forms has not been striking. The documentation for these statements is given in the following paragraphs. Particularly important is the information in Chapter 8;, Mortality. English et! al: (26), found the incidence of coronary disease: in male patients at the Mayo Clinic about 3 tirnesgreaterincigarette smokers than in non-smokers in the 40-59 year age range, but found little relation to smoking above 60. Russek (81)~ reporte& a similar relationship; but less striking, in young men~~ with coronary disease. Mill's (64)iii a study of reported mortalit'yy in a Cincinnati population foun& that heavy smokerss in the30a-59year age range had'twice as high a death rate from coronary disease as non-smokers. Male Seventh Day Adventists, who are non, smokers; were found by Wynder and Lemon (104)~ in a stlidy based on hospital admissions to have significantly less coronary disease and! to de• velop it later in life thani the general male hospitali population. Haag and Hanmer ('37) reported that employees in the tobacco industry, who tend to smoke heavily, hadi a lower death rate for cardiovascular disease than the generali population in their geographic region, but no report' was made of mortality rates within the tobacco-worker group, divided by smok- ing,habits. The study has been criticized on thisand otherrrounds (16). Large-scaleprospect'ive studies of mortality in British physicians (Doll arid Hilly 21), Unit'ed States males 50-69 recruited by volunteer workers

li (Hammond andl Horn, 3$; 39; 40;,42) and V.A. Life Insurance policyholders Dorn, 22) have confirmed the association of death froml coronary disease ~sithl cigarette smoking, In the British study, a step-wise association was found between the amount of tobacco consumed (not entirely,cigarettes) and the mortality from coronaryy disease. The association occurred in the : .,)-54 year age range, but not in older men. Hammond and Horm found a similar grad'ed' relationship between coronary deaths and cigarette smok- in,,,: the death rate being more than twice as great in men who smoked ,ver a pack a day as in non-smokers. Men who: had stopped smoking for nore than a year at the start of the study had a coronary d'eathl rate lower tlian those who continued. Studies on special groups of men, suchl as longshoremen (Buechley et al. t; i members ofl a fraternal order (Spain and Nathan, 89;)l andl industrial employees(Paull et al. 71)whieh, in the latter two instances: incorporated clinical coronary disease, as well as coronary deaths, also have shown a relationship between coronary disease andl smoking. The relationship was cl'oser forr menl under 51 than for older mens and closer for myocardlal 'nfarcts anddeath than for angina pectoris (70, 89). The long-term, prospective studies of cardiovascular disease in Framing- i.anr(19) andl in Albany (24)! which have: featured a painstaking searchl at regularintervals for clinieall manifestations of disease: have, on pooling the. ,11{ta (Dor1e et al. 23) shown a threefold increase in the incidence of myocardial infarction and coronary deaths in men who are heavy ciga- rette smokers as comparedl to non-smokers, pipe and ciaar smokers, andl former cigarette smokers. In the pooled data the incidence of angina liec- toris did not show a significant association with cigarette smoking. The lack of this particular relationship hadl beeni suggested on the basis ofl clinicallexperience (White and Sharber, 102). r1ni apparent intcrplar-y of factors relat'~ingto smoking and occupation turned up in al short-term studv of' the development of coronary heart dis- easein a general North Dakota populationi (Zukel et alL, 107)i. Farmersharl about half the incidence of myocardial infarction experienced by others. ln farmers. smoking had no appreciable effect on the incidence of infarc- tion. but' ini others the incidence of' infarctioni was twice as high among smokers as among the non-smokers. The farmers who smoked cigarettes smoked less heavilv than males in other occupational groups. In Chapter 8, Mortality, there is summarized the: most recent infbr- mation av.ailablefrom 7 large completed or current prospective smok~ingand death rate studies (Doll and Hill; Hammond arid Horn; Dorn; Dunny Linden and Breslow; Dunn; Buell and Breslow; Best, Josie, and'W'alker; and Hammond ). The median mortality ratfio for coronary disease of current cigarette smokers to non-smokers is 1.7 (range 1.5-2.0~). Table 2 presentsdatai from some of the large prospective studies onl the ratio of mortality rates due to coronary heart disease of male smokers to nonl-smokers, by age and amount smoked. The ratios tend in general to increase with amount smoked and to, decrease with advancing a,e: The data froin the first 22 months of Hammond's (41)cur~rent studyhell> to~ show the size of the eoronar~yproblem. For this purpose, actual numhersof deaths may,he more informative than mortality ratios. Of nearly 32:; . .r 1 I

TABLE 2: Ratios o f, mortality rates /,or coronary heart disease, male smokers to'non-smokers, by age and amount smoked, in sel'ectedstudies HAMAfO>ID~AND HORN-1958 (42) Cigarettes smoked per day Age ~. Group Less than 10~~ 10-19' 50-54----------------------------------- li 4 2:0 55-59---------------------------------------- 1.4 2.0 60-Fr1~..--------------------------------------- 1.2 1.9 65-69.- ------------------------------------- 1.3 1.6 Total (age adjusted) ----------------_----- 1.29 1.89 20 and over BUECHLEY, DRAKE, BRESLOW-1958'(8)' I 35-d4---------------------------------------- 45-54---------------------------------------- 55-84---------------------------------------- 65-7C --------------------------------------- L ------------------------------- --------------------------------- --------------------------------- --------------------------------- 2.0. 2.8' 1!8'. 0.9 FRAMINGHAM STUDY-19fi4 (47) 30a-62---------------------------------------- (less than 20) 1.5 (20 and!over)3.2 D ORV-1959 (22) Total (age adjusted)------------------------ ~ 1.321 1.76 1 1.75 DOLL AND HILI-1956 (21) Age Group Grams of tobacco smoked per day 1-1i Grams 15-24 Grams~~ 25.or more Grams 35-54---------------------------------------- 2.2 ' 3.3 4.2 55-fr1------------------'-------------------- 0.9 0.6 1.0 65-74---------------------------------------- 1.0 0: 9 1.3 75+F _ ---------'--------'--------------- 113 115 1.6 Total (age adjusted).- ---------------_-----_ 11 l i 1:1' 1.4'. ' Persons smoking 1 pack per day or more compared with those smoking less than t Ipack per day (including non-smokers). 10;000 deaths of men aged 45--79, 46 percent were ascribed to coronary. disease. 51.7 percent of the 2,630 "excess deaths" associated with cigarette smoking were caused by coronary disease: In approximate terms, nearly half of middle-aged and elderly males in the Uhited States die of coronary disease. About half of these males smol:e cigarettes. Cigarette smokers hacebeenfounJ in several studies~to have1.7 times as high a: coronary death rate as non-smokers. If cigarettes actually caused the additional coronary deaths of smokers, they would account for many deaths of middle-aged' and elderly males ill this country. Like other studies (19; 21, 22,, 23, 42), this one shows that the ratio of snlokers' coronary deathrat'es to those of non~ smokers inc.reases progre_,siAclyw•ith the daily cigarette consumption. In add2t'ions at each level of consunlptionvthcratioihcreases with theanlount of'inhalation reported by the smokers. Others (21„23; 26, 89) , have indicated 324

that the risk of'~ death from coronary disease:in male cigarette smokers relative tn that in non-smokers is greater in~middle age than old'age, and Hammond's rurrent study supports this. The mortality ratio was 3,09 in the age range h)---19, and in successive decades was 2.20, 1.58; and 1.38. Mien who stop smoking, have a lower d'eath rate from coronary disease t}lanthose who continue (23, 42, 47). In the study of Hammond and Horn 1 -1'l) the decrease in death appeared only after a year. Angina pectoris is less closely related to cigarette smoking than myocardial infarction and sudden death. In the combined Albany-Framingham expe- rience (23), angina pectoris showed no over-all relationship with smoking,. snd the association has not been strong in other studies (71, 89)i. In surmnar}: a significant association has been established between cigarette -Wc~king and the incidence of myocardial! infarction and sudden death in ;ale~. especially in middle life, in population groups whose members appear far to be similar except for smohinghabits. The question of whether they re. in fact, similar except for smoking is, of course, basic to.the problem of' ~.%-hethercigarettesmoking, actually promotes thedevelopment~ of coronary ,iisea~e or whether it is closely associated witLsome other factor or factors -., hich promote the development of eoronarydfisease. It has been pointed out .hat angina pectoris, which indicates advanced coronary atherosclerosis, is. ~ closely associated with cigarette smoking than is myocardial infarction, .:::d that this suggeststhat any etiologic role of~smoking inmyocardialinfarc- ti,~n shoulde reiate more to~acute occlusive mechanisms, such as intravasculariirombosisor coronary spasm, than to the development of chronic art'erial I', <ea se. SMOKING AND NON-CORONARY CARDIOVASCULAR DISEASE In survevs of large groups cigarette: smoking has not been found to be a"ueiated with an increased prevalence of hypertension (,3, 4, 19,, 47, 49). The study of Hammond and Horn (140; 42) did not showani increased death rate f'sorn hypertension in smokers: However, Dorni {221f~ound that thecleath rate of cigarette smokers fromi hy,pertensionwith heart disease was 1.53' times that of non-smokers, and from hypert'ension without heart dis- ease. 1.41 times that of non-smokers. Harumond's current study shows:, -iinilar figures141 I~. Sinoking~ has not been found to be associated Ntiith an increased' mortalitiyrate flromchronic nheumaticheart disease (22, 41, 42). Ilammondl and Horn1-12)found a modierateincrease in the mortalityrate from: cerebral vascular disease in cigarette smokers as compared to: !iwn-mokens 1 ratio 1.301. Dorn (22)reported a ratio of 1.33, and Ham- nannd (41 i a ratio of 1.43. Although non.s.-philitie aorticaneurysm is arel<iti% ek infrequent causeofl death, the mortalfityy ratio, for smokers to non-sniokers inthi~diaf;nosticcategory is large in relation t'othe ratiosin, other cardiovasc.ular disorders, In, the study ofH'ammond and Horn (42~) ~ it was 2.72. and'in Hammond's-current study (41)l it, is 3.10. 3 2 J

It has been reported (100) that diabetic males who smoke: have a 50'r/ogreater incidence of clinically detectable arteriosclerosis obliterans in the legs than those who; do: not smoke. In general, however, there is little inflormationi about the relation of smoking to peripheral arteriosclerosis. Most experienced clinicians advise patients with obliterative peripheral arte- rial disease to stop; smoking (45). Buerger's disease, or thromboangifitfis obliterans, has been traditionally associated with smoking, anJ the literatureI contains numerous clinicall re- port's describing the arrest of Buerger's disease when smoking is stopped! and its reactivation on resumption of smoking. The existence of Buerger's disease as an entity separate from arteriosclerosis obliterans has been re- centlychallenged, (1©1), but welli defended! (61). It is apparent that! much more work will have to be done to determinee what relationship may exist between non~coronary occlusive vaseular dis- ease, aneurysmal disease, and smoking. CHARACTERISTICS OFCIGARETTE SMOKERS If it could be shown, that': cigarette smokers and non-smokers had signifi- cant constitutional differences apart from any differences that might be cause& by smoking itself, then a; possibilityv would exist', that some predisposition of smokers to a parrticular disease might also be of constitutional origini and not caused by smoking, Cigarette smokers have, ini fact, been foundl to differ as a group from non~smokers, but the differences, such as serum cholesteroU concentrationi and resting heart rate, could have resulted from the smoking habit itself, so far as present knowledge indicates. The concentration of serum cholesterol has been foundlto be slightly higher in smokers than in non-smokers by a number of investigators (6, 18, 49, 63, 95), but others have found no relationship (1, 54). Dawber (19) found not' only thab serumi cholesterol was higher in smokers thani in non~smokers but also that it'remained higher in those who~stopped smoking. Smokers tend to be leaner than non-smokers, but to gain when they stop~ smoking (3, 18, 49). A few personality differences have been reported between cigarette smokers and non.smokers. Friedman's type A men (the coronary type) tended to be heavy smokers (33):. Smokers are said to be more easily angeredi and to eat more when under stress (i94)~. They havebeen reported to marry oftener, to change jobs more frequently, to be more often hospitalized, and tb~ par- ticipate more actively in sports than non-smokers (60). Thomas (94, 951 has reported that the parents of inedicat students who smoke have a significantly higher incidence of arteriosclerotic and hyper- tensive cardiovascular disease thani parents of non-smokers. Clearly, this findinn is open to more than one interpretation. Smokers tend to have a higher heart rate than non-smokers (3, 94) . The matter of constitutional predisposition tosmokinghas been inves- tigated' in twins. It has been found (27, 28. 321 that the smoking habits of monozygotic twins are significantly more alike than those of dizygotic twins, even when members of a twin pair are brought up separately. 326

In spite of some bits of suggestive evidence the existence of basic consti- tutional differences between smokers and non-smokers is not presently est'ablished. The constitutional hypothesis, which links smoking, and predis- position to disease, is discussed in,detaillin Chapter 9, Cancer. PSYCHO-SOCIAL FACTORS OF SMOKING IN RELATION TO CARDIOVASCULAR DISEASE' Even less conclusve information is available on the rolo of psycho-social factors of smoking in relatfiomto cardiovascular disease. Studies which have focussed onithis are limitediin number according to Heinzelmann (44). Even fewer, he founds are those which have specifically examined the relative „•eight of, these variables or their interaction. Reviewing those available,, lie observes that the evidence is highly fragmentary and uncertain. The findings sungest that the relationship between smoking behavior an&coronary. !ieart di'sease may reflect the influence of stress factors and/or personality mechanisms. However, they permit no definitive statement's with respect to~ the relative role of pyscho-social factors and smoking in relation to etiolo~y of the disease. SUMMARY Smokinr and nicotine administration cause acute cardiovascular effects. ,irnilar to those induced by stimulation of the autonomic nervous syst'em, but these eff'ects do not account well for the observed association between cigarette smoking and coronary disease. It is established that male ciga- iette smokers have a higher death: rate f'rom~ coronary disease than non- smoking males. The association of smoking, with other cardiovascular disorders is less well established. If cigarette smoking actually caused the hiorher death rate from coronary disease, it would on this account be responsible for many deaths of middle-aged and elderly males in the Unite& States. Other factors such as high blood pressure, high serum cholesterol, andl excessive obesity are also knowm to be associatedl withi an unusually high death rate from coronary disease. , The causative role of' these other factors in coronary disease, though not proven, is suspected strongly enough to be a major reasoni for taking countermeasures against them. It is also more prudent to assume that the established association betweeni ciga• rette smoking and coronary disease has causative meaning than to suspend iudgment until, no uncert'ainty remains. CONCLUSION 1'Iale cigarette smokers have a hiaher deathi date from coronary artery disease than non-smoking males, but it is not clear that the association has causal significance: 327 O W ~ ~ Cl1 CD O N

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Contents RELATIONSHIP OF PEPTIC ULCER TO TOBACCO USE . Conclusion . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . TOBACCO AMBLYOPIA . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . SMOKING AND CIRRHOSIS OF THE LIVER ...... Conclusion . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . MATERNAL SMOKING AND INFANT BIRTII WEIGHT . Conclusions . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . S'_1IOIxING AND ACCIDENTS . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . List of Tables 337 340 340 341 342 342 342 342 343 343 343 344 344 345 345 TABLE 1. Summary of methods used in retrospective and cross- sectional studies of peptic ulcer and smoking . . . 338 TABLE 2. Summary of results of retrospective and cross-sectional studies of peptic ulcer and smoking ....... 339 TABLE 3. Expected and observed deaths and mortality ratios for ulcer of stomach and duodenum among current cigarette smokers, from seven prospective studies . 339 336

u Chapter 12 RELATIONSHIP OF PEPTIC ULCER TO TOBACCO USE There are five retrospective studies on the relationship of peptic (gastric and duodenal) ulcer to smoking, in which data have been obt'ained about the smoking habits of peptic ulcer patients and various kinds of control! groups (1, 2; 7, 14; 18). Al;o, in one cross-sectional study, the frequeney of peptic ulcer has been determined in a population of individuals with varying smoking habits (11). Tables 1 and 2 summarize the methods used and the results of'these studies. These studies demonstrate an associatiom between cigarette smoking and peptic ulcer which appears to be greater for gastric tham for duodenal ulcers. The proportion of' non-smokers is higher among t'he controls than among the ulcer patients in every one of these studies. No differences were noted with respect to the frequency of heavy smokers in the study of Dolli (7)! and no consistent relatfionshipwiChi amount smoked was observed' by Trowell (18). In, the cross-sectional study of Edwards, et al. (11) „a larger proportion of peptic ulcer cases was found among the cigarette smokers, and this proportion increased with amount of cigarette smoking. The heavy cigarette smokers had a frequency of peptic ulcer twice that of those who had! never smoked (12 percent as compared to 6 percent)'. No association with pipe smoking was noted (1, 11, 14, 18). In three prospective st'udies (Table 3) gastric ulcer has been classified separately from duodenal ulcer. The mortality, ratios of cigarette smokerss from gastric ulcer are high in all three studies (46/0; 5.1 and 4.3). For duodenal ulcers the mortality ratios are more modest (2.2. 2.3 and 1.1). In the remaining four prospective studies only the combined mortality ratios for gastric and duodenal ulcers are available: their results being based om small numbers of deaths, are erratic but their over-all average mortality ratio is about the same as for the three large studies. Consequently; it ap- pears likely that t'he excess mortality of cigarette smokers from peptic ulcer can be attributed primarily to gastric ulcer. A breakdown by amount smoked (Chapter 8, Table 23) shows no trend. For cigar and pipe smokers the peptic ulcer mortality ratio (total over fivestudies)~ is 1.6 but in view of the small number of deaths this elevation is not statistically significant. Doll, et al.,, (7)conducted a clinical trial of the effect of stopping smoking on the healing of gastric ulcers. The results were assessed by measuring radiologically the reduction in the size of the ulber niche. Patients advised to stop smoking had an average 78~'1c reduction in the size of the ulcer, com~ pared to 57q for those who continued to smoke. In view of the probable existence ofl other factors which may have concomitantliy beem introduced in the approach to the smokers, an& the complex nature of the healing proc- ess, it is difficult to interpret' this observation. 337

TABLE L-Sttmmary o f methods used in retrospective and cross-sectional studies o/ peptic ulcer and smoking ~ Cases Controls In vestigator and Year Country S ex Collection ollection of data _ No. Dlethod ot Select.ion Nu. ~ 34Mhod of Selection ~ Barnett, (2) 1927 U.S.A. M /i6 (Iastric; 178 Patients adtnitted between 5ftp Selected at random from the 1. Retrospective review of -- 1)uodenal. - _ 191aand 1926. Only c,lscs -Fcni~ruladuiissions-In~Aes, records at Peter Bent --"-- «~ith cuutpletc smoking his- tiged 211-SO. Brigham Hospital. tory selected. 2. Ulcer diagnosis probably well established. - Troµell, (18) 1934 England M 50 Duol3enal - Not stated 400 Selected at random from wards 1. Interviewed by irrcestiKator. - __ -- oIa general hospital. 2, Ulcer diagnosis eontirinoi3 by X-ray und/or sur(',ery. Mills, (14) 1950 U.S.A. M 55 Not stated 275 . Sample of population in No details given. Columbus, Ohio. - - Allibone and Flint, (1) 1958 England M&F 107 Consecutive admissions to hos- 107 Matched by age, sex, and Patients and controls inter- pitlA of patients with j;astric tintc of atlmissioti from acute viewed by same observer. and duoiGvnal hemorrhage general surti icalemergency --- or/mrforationr _ adnlissions. - I)oll, Jones, and Pygott (".), England b4kF 327 (}astric: 338 Ulcer paticnts in Doll and 1,143 Patients with non-ule.er dis- 1. S amc interviewers and Rucs- 1958 - 1)uodenal. IIill Lung Cancer-Study cases. Etsch casc mntched _ tionnairein cases and plus additional piCtients in with 2 control patients of controls. Central Middlesexiiospi- swnc sex, 5-year uko group, 2. Ulcer diagnosis probably tal. and same type of place of w'ell established. residence. :Vlale patients niatched by social eLass. Edwards, McKeown, and Fngland M 1,737 men aged CA and over on il (7eneral Practioners' lists weree exiunined and inter- Of 143 eonsidered to have a WhitHeld (11), 1959 ----- - vie.wed by these practitioners. Reptosents about 84% of Isll such men on these lists, peptic ulcer, 53 were con- (9% non_response Ilue to death and/or untraced.) - fduted by X-rey. ...~....~,.r ET6S94E0

TABLE 2. Summary of results of retrospective and cross-sectional studies of peptic ulcer and smoking Percent Non-smokers Percent Heavy Smokers or Average Amounts Used Investigator . - Cases Controls Cases Controls Barnett (2) Total 18 25 Gastric 1.5 IDuodenal 20 Trowell (18) IDuodT enall 8 17 Ciearettes: 12.0 per day 11!1 per day. Pipe: 1.6 oz. per week 2.15 ,oz..per week. Slill i s (14). 18 } -- 35- Allibone and Flint (1) 38 I 54' Doll et al; (7) Gastric ~ Gasdric. Ei 1.3 417 M 10.6 1113 F 51.1i 66.8 F' 1.1 111 DxndenaL. Duodenal, M 2,11 5.8 M 10. 2 12.7 ; F 53:7 82.0 F 1.9 1'.9 Pldwardsetai. (11) Percent'of Peptic Ulcer bySfioking Category~ Never smoked----------------------------------------------- 6.0 Formerly~snioked-------------------------------------------- 6.7 Cigarettes: ~1-9:perday----------------------------------------------- 9.4 10-19 per day---------------------------------------------- 9.8 20 plus per day~------------------------- ------------------ 12..0~ Pipe-------------------------------------------------------- 6.5, Pipe and,cigarettes ----------------------------------------- 8. 5 TcsLE 3.-Expectedand: observeddeatlts and mortality ratiosfbr ulcer of stomach., andduod'enum*amongcurrent cigarette smokers, from seven prospective studies InvestiRator Typeof'UIE~er Number of Deaths ~ Observed Ekpected', -- n ~ Mortality Ratio ~--- - Tlammonrl and TTorn (13)"------------ Gagtr,c:- ----------------- Duodenal_________________ 46' 54 0 25 ~_____--____ 212 Roth types~.--------------- 100 425 I 4.0 Dorn (8)"----------------------------- Gastric'.------------------- Duodenal----------------- 31 36, 6.1 15.4 5:1 2:3 Both types:.-------------- 67 21.5 3:1 Hammond (12):------------------------- Ga.ctric-------------------- Duodenal_________________ 42. 32 9.7 28.9 4.3 1.1 Both types---------------- 74 38.6 1.9 Doll and 11111 (G)----------------------- Botlt types'--------------_ 14 0 ------------ Dwin et al., Occupational (9)----------- ' Both types.--------------- 12 23. 1 0.5 Dunn et al., Legion (10)~---------------- Butlh types~--------------- ~, 12~ 1.8~ 6:R Best et al. (5)-------------------- ------ Both types- --------------I 54 7.9, fi:9 •Inclurles,ISC numhers 540~ 541- "'I'he Ifamruond and 1Ibrm dataa are from their origimt] puirili'slied'report; the other results listed includc. more recent data as tabulated forthe Committe(seeChapter 9). 339.

Numerous investigators have studiede the clinical and physiologicat effects of smoking on gastric motility and acid secret'iom im humans with and with- out peptic ulcer. Great variation of gastric motility and secretion was observed in response to cigarette smoking. Some workers found inhibition of gastric motility (15, 17). Batterman (3) showed three types of response in normal subjects and uleer patients after smoking one cigarette. In one-third no effect was observed„ another third complete inhibition of motor activity for a time, and in the rest a period of hypermotility was followed by normal! or subnormal activity. Smoking appears t'o produce variable effects also on gastric secretion. In a few studies, gastric secretion increased, while in others no change was observed or there was depression of secretory activity (4, 15, 16, 17), Ad- ditional studies of the effect of smoking on gastric secretory activity and motility are needed to explain the biological meaning, of the statistical asso- ciation between, cigarette smoking and peptic ulcer. CONCLUSION. Epidemiological studies indicate an association between cigarette smoking an& peptic ulcer which is greater for gastric than for duodenal ulcer. REFERENCES 1. Allibone, A., Flint, F. J. Bronchitis, aspirin, smoking and other factors in the etiology of peptic ulcer. Lancet 2: 179-82, 1958. 2. BarnettS C. W. Tobacco smoking as a factor in the production of peptic ulcer and gastric neurosis. Boston Med Surg, J 197,: 457-9, 1927. 3. Batterman, R. C. The gastro•intestinal tract. In: Wynder, E: L. ed, The Biologic Effects of Tobacco. Boston, 1955. Chapter 5, p. 133-50. 4. Batterman, R. C., Ehrenfeld, I. The influence of smoking upon the management of the peptic ulcer patient. Gastroenterology 12: 575-85,. 1949. 5. Best, E. W. R., Josie, G. H., Walker, C. B. A Canadian study ofl mor- talityy in relatiom to smoking habits, a preliminary report. Canad J Pub Health 52: 99-106, 1961. 6. Doll, R., Hill, A. B. Lung cancer and other causes of! death in relation to smoking: A second report on the mortality of British doctors.. Brit Med J 2: 1071-811,,1956. 7. Doll', R., Jones, F. A., Pygott,, F. Effect, of smoking on the production and maint'enance of gastric and duodenal ulcers. Lancet 1: 657-62,. 1958. 8. Dorn, H. F. Tobacco consumption and mortality from cancer and other diseases. Public Health Rep 74r5£11'-93, 1959. 340 .._..... ... _.~;,~~

9. Dunn, J. E., Linden, G., Breslow, L. Lung cancer mortality experience of men in certain occupations in California. Amer J Pub Health 50: 1475-87, 1960: 10. Dunn, J. E., Jr.,, Buell, P., Breslow, L. California State Department of Public Health; Special Report'. to the Surgeon General's Advisory Committee on Smoking and Health. 11. Edwards, F., McKeown, T.,, Whitfield; A. G. W. Association between smoking and disease in men over sixty. Lancet'. 1: 196-200, 1959. 12. Hammond, E. C. Special report to the Surgeon General's Advisory Committee on Smoking and Health. 13. Hammond, E. C., Horn, D. Smoking, and death rates-Report on forty-four months of foll'ow-up of 187,783 men. II. Death rates by cause JAMA 166: 1294-1308, 1958. 1-1. Mills, C. A. Tobacco smoking: Some hints of its biologic hazards. Ohio Me& J 46: 1165-70, 1950. 15. Packard, R. S. Smoking and the alimentary tract: A review,. Gut 1: 171-4, 1960. 16, Schnedorf, J. G.,, Ivy, A. C. The effect of tobacco smoking on the alimentary tract. JAMA 112: 898-903, 1939. 17. Steigmann, F., Dolehide, R. U.,, Keminski, L. Effects of smoking tobacco on gastric acidity and motility of hospitall controls and pa- tients with peptic ulcer. Amer J Gastroent 22: 399-409, 1954. 121. Trowell, 0. A. The relation of tobacco smoking to the incidence of chronic duodenal ulcer. Lancet 1: 808-9, 1934. TOBACCO AMBLYOPIA For more than a century clinicians have attributed certain cases of amblyopia-dimness of vision unexplained by an organic lesion-to the use of tobacco. The distinguishing characteristic of tobacco amblyopia is a specific type of centrocecal scotoma. Since this disease was defined as a distinct clinical entity for the first time in 1930~ (4), the medical literature prior to this date is,of relatively little value in~the critical evaluation ofithe problem (3). No epidemiological studies with adequate controls are available to: establish for this disease, a: relative risk among, smokers and nonsmokers. Clinical impressions associate tobacco amblyopia with pipe and cigar smoking and very rarely with cigarette smoking. It has been suggested that this disease, which is now rare in the United States, occurs mainly in individuals with a nutritional deficiency which presumably renders the retina or optic nerve unduly sensitive to tobacco (1, 5). Objective attempts at experimentation have been extremely rare and most of the literatures is related to uncontrolled clinical impressions (2). 341 N a I

CONCLUSION Tobacco amblyopia had been related to pipe and cigar smoking by clinicall impressions. The association has not': been substantiated by epidemiological or experimental studies. REFERENCES. A 1. Heaton, J. M., McCormick, A. J. A., Freeman, A. G. Tobacco Amblyopia: A clinieal manifestation of vitamin B-12 deficiency. Lancet 2: 286- 90; 1958. 2. Potts, A. M. Special report to the Surgeon General's Advisory Commit- tee on Smoking and Health. 3. Schwartz, J. T: Special report to the Surgeon General's Advisory Com- mittee on Smoking and Health. 4. Traquair, H. M. Toxic Amblyopia, ineluding retro-bulbar neuritis. Trans Ophthal Soc U K 50: 351-85, 1930. 5. von Sallmann, L. Special report to the Surgeon General's Advisory Committee on Smoking, and Health. SMOKING AND CIRRHOSIS OF THE LIVER Epidemiological studies have noted an association between cigarette smok- ing and mortality from cirrhosis of the liver. The mean~ mortality ratio for cirrhosis of the liver calculated from all prospective studies was 2;2 (Table 19, Chapter 8)'. The individual ratios in six of these studies ranged from 1.3 in the Canadian veterans study (11) to 4:0 in the California occupational study (3). The earliest prospective study, by, Doll and Hill (I2) reported! no deaths from cirrhosis of the liver among non~smokers. The small amount of information on the biological effects of nicotine and tobacco:smoke on the liver of experimental animals is contradictory (5). In several studies (4, 6, 7) it has been reported that heavy smokers also tend to drink alcoholic liquors excessively. It is well established that heavy consumption of alcohol and nutritional deficiencies are associated with in- creased mortality from cirrhosis of the liver. The increased death rate from cirrhosis among smokers may reflect the consumptioni of alcoholl and! asso, ciated nutritiional' deficiencies rather than the effect of cigarette smoking. CONCLUSION Increased mortalfityy of smokers from cirrhosis of the liver has been shown in the prospective studies. The data are not sufficient to support a direct or causal association.

REFERENCES 1. Best, E. W. R., Josie, G. H., Walker, C. B. A Canadian, study of mort'ality in relation to smoking habits, a preliminary report. Canad J Pub Health 52: 99-106, 1961. 2. Doll, R., Hiil,, A. B. Lung cancer and other causes of deathi in relation to smoking;. A second report on the mortality of British doctors. Brit Med J 2: 1071-811, 1956. 3'. Dunn, J. E., Linden, G., Breslow, L. Lung cancer mortalit'yy experience of inen, in certain occupations in California. Amer J Pub Health 50: 1475-87, 1960. 4. Heath, C. W. Differences between smokers and non-smokers. AMA Arch Int Med 101: 377, 1958. 5: Larson, P. S., Haag, H. B., Silvette, H. Tobacco-experimental and clinicali studies. A comprehensive account of the worldl literature. Balliere, Tindall & Cox, Lond'on, 1961. p: 319-321. 6. Matarazzo, J. D., Saslosv, G. Psychological and related characterist'acss of smokers and non-smokers. Psychol Bull 57: 493, 1960. 7. McArthur. C., Waldt-on, E.. Dickinson, J. The psychologyof smoking. J Abnorm Soc Ps}'chol 56: 267-275, 1958. MATERNAL SMOKTNG' AND INFANT BIRTH1 WEIGHT Fi've retrospective and two prospective studies have shown an association between maternal smoking during pregnaneti- and birtL weight ofl the infant!, (2, 4, 5, 6, 8,, 9„ 10). Women smoking during pregnancy have babies of lower birth weight than non-smokers of the same social class. They have also a significantlyy greater number of premature deliveries (defined as birth weight of12,500 grams or less) than the non-smoking controls. While several studies reported a slightly greater neonatall death rate of the children of smokers (2, 5)!, others did not demonstrate any significant difference in the fet'all and neonatal death rates of the two groups (6, 7). Studies on alterations of placental morphology and function as a response to smoking are insufficient for judgment. The difference ini infant weight may be due to vasoconstriction, of the placental blood vessels (1), or to toxic substances such as CO in the circulation of the smoker and fetos (3:)l. It is not known whether the lower birth weight of the infants of smokers has anyy clinical significance. In one of the groups studied (5) there was less needi for surgical induction of labor among, mothers who smoked. CONCLUSIONS 1. W'omenwhosmoke cigarettesduring pregnancy tend tb~ have babies of lower birth weight. 2. Information is lacking on the mechanism by which this decrease in birth weight is produced. 3. It is not known~ whether this decrease in birth weight has any influ- ence on the biologieal fitness of the newborn. 343

REFERENCES 1. Essenberg, J. M., Schwind, J., Patras, A. The effects of nicotine and cigarette smoke on pregnant female albino rats and their offsprings. J Lab Clin Med 25: 708-17, 1940. 2. Frazier, T. M., Davis, G. H., Goldstein, H., Goldberg, I. D. Cigarette smoking and prematurity: a prospective stud'y. Amer J Obstet Gynec 81: 988-96, 1961. 3. Hadd'on, W. Jr., Nesbitt, R. E. Smoking and pregnancy: carbon mon- oxide in blood! during,gestation and a term. Obstet Gynec 18: 262-7, 1961. 4. Herriot, A.,, Billewicz, W. F., Hytten, F. E. Cigarette smoking in preg- nancy. Lancet 1: 771-3, 1962. 5. Lowe, C. R. Effect' of mother's smoking habits on birth weights of their children. Brit Med Ji 2: 673-6, 1959. 6. O'Lane, J. M. Some fetal effects of maternal cigarette smoking. Obstet Gy,nec 22: 181-4, 1963. 7. Savel. L. E., Roth, E. Effects ofismoking on fetal growth, Obstet Gynec 20: 313-6; 1962: 8. Simpson, W. J. A preliminary report oni cigarette smoking and the in- cidence of prematurity. Amer J. Obst'et Gynec 73: 808-15, 1957. 9. Villumsen, A. L. Cigarette smoking an& low birth weights: A prelimi- nary report. Ugeskr Laeg 124: 630-1, 1962. 10. Yerushalmy, J~ Statistical considerations and evaluation of epidemio- logicall evidence. In: James, George and Rosenthall Theodore eds. Tobacco and Health. Springfield, 111, Charles C. Thomas, 1962, p. 208-30; SMOKING ANDACCIDENTS Sinoking has beeni associated withi a variety of accidents. Among these,, fires have the most obvious and important consequences. In a speciall studyy cnfl homeaccident f'atal'atiesin~ 1952 through 1953; the Public Health Service and the National Safety Council reported that 231! (18~c )~ of 1,274: deaths from fires of known origin were due t'o, cigarettes, cigars or pipes (1). The Metropolitan Life Insurance Company reported that of 352 deaths in 1956 and 1957 among their policyholders from fires and burns with known causes in and about thehome, 57 (16jo), were due to smoking (12). Of physiologicaliresponses related to driving. smoking degrades detectably only the differential brightness threshold and this effect increases with amount ofl smoking (4) . The epidemiolbgical data available on the effects ofl srnokingon traffic accidents are inconclusive. It has been shown that a level of carboxyhemoglobin of 5 percent-a level which is not uncommon among heavq cigarette smokers (3, 6)--depresses visuali perception to as great an extent as anoxia at 8,000 to 110,000 feet altitude (4, 5). 344

CONCLUSION Smoking is associated with accidental deaths from fires in the home. No conclusive informatron~ is available on the effects of smoking on traffic accidents. REFERENCES 1. Home Accident Fatalities: 1952-1953. National Office of Vitali Statistics, U.S. Public Health Service, 1956. Mimeographed report. Table 12. 2: How fatal accidents occur in the home. Metrop Life Insur Statist Bu114.0; 6-8, Nbvember-December, 1959. 3. Larson, P. S., Haag, H. B., Silvette, H. Tobacco: Experimental and Clinical studies. Baltimore, Williams and Wilkins, 1961. Carboxy- hemoglobin, p. 107-110. 1. 1lcFarland', R. A., Moseley, A. L. Carbon monoxide:in trucks and busess and informatyon from other areas of research on carboni monoxide, altitud'e and cigarette smoking. In~: Conference proceedings: Health, medieall and drug factors in highway safety. National Academy of Sciences-Nationall Research Couneill Publication 328, 1954. Sect. 4..L7-4.33, McFarland, R. A., Roughton, F. J. W., Halperin, M. H., Niven, J. I. The effects of carbon monoxide and altitude on visual'thresholds. J Aviat Med 15: 6, 381-94, 1944. ~. Schrenk, H. Hl Results of laboratory tests. Determination ofI concen, tration of carbon monoxide in blood. Pub Health Bu111 278: 36-49, 1942. 345 0

03765921

Chapter 13 Characterization of the Tobacco Habit and Benef icial Ef f ects of Tobacco

Contents Page CHARACTERIZATION OF THE TOBACCO HABIT .... 349 Nicotine . . . . . . . . . . . . . . . . . . . . . . . 349 Distinction Between Drug Addiction and Drug Habituation . 350 Tobacco Habit' Characterized as Habituation ....... 351 Relationship of Smoking to Use of Addicting Drugs .... 352 Measures for Cure of Tobacco Habit . . . . . . . . . . . 354 Summary . . . .. . . . . . . . . . . . . . . . . . . . 354 BENEFICIAL EFFECTS OF TOBACCO . . . . . . . . . 355 Summary . . . . . . . . . . . . . . . . . . . . . . . 356 References . . . . . . . . . . . . . . . . . . . . . . 356

Chapter 13 CHARACTERIZATION OF THE TOBACCO HABIT NICOTINE Of the known chemical substances present in tobacco and tobacco smoke, 0nly nicotine has been given serious pharmacological consideration in rela- tirn ship to~the tobacco habit. Lewin (17) stated, "The decisive factor in~the r-irect's of tobacco, desired or undesired, is nicotine . . . and it matters little ,.dtecther it passes directly into the organism or is smokedl" Support for this >!:aement isbase&mostly on rationalizations from smoking behavior, analogy ti, ,thcr hahits irvolving pharmacolbgical agents and, to a much lesser extent, ,,n established scientific fact. The latter may be summarized briefly as (''Iihws: 1. Only plants wit'hi active pharmacological principles have been employed !iiihatually by large populations over long periods; e.g., tobacco (nicotine) ; -0 1ee. tea, and cocoa (caffeine) ; betel nut' morsel (arecoline) ; marihuana ~-annibinols)'; khat (pseudoephedrine);opium (imorphine);coea leaves ocaine);, and others (see Lewin; 17)~. ?'. lleniaotinized tobacco has not found general public acceptance as a -:,i'stitute (16y, pp. 531-532). l: Chewing tobacco andiusing snuff, although providing oral gratification,, l+~ furnish nicotine for absorption to produce systemic effects (134). 1. NTany but not all, smokers cani detect a reduction in nicotine content of (i~!aretltes (9),. ~ The: adininistrataon of nicotine mimics the subjective effects of >1,nking (13). In uncontrolled experiments Johnston administered nicotine !!vpodermically, intravenously, or orally to smokers and non-smokers. Nbn- Fmokers found the effects "q;ueer," whereas many smokers, including John- ston himself, claimed the subjective effects to be identical to those obtained by inhaling cigarette smoke and found that the urge to smoke was greatly reduced dttrring nicotine administration. In spite of the anecdotal nature of most of this information, the facts are tl3at nicotine is present in tobacco in significant amounts, is absorbed readily from all routes of administration, and exerts detectable pharmacological efft:cts on many organs and' structures including the nervous system. The classicali pharmacological characterization of nicotine-cellular stimulation followed by depression which is note& in isolated tissue and organ systems- has been invoked to explain the widely differing subjective responses of smokers, many of whom describe the effects as stimulating ("smoking relieves tbe depres.sion of the spirits"), while others obtain a soothing and tranquilie- ing effect (16, p: 533):. Wilder (33): summarized the literature by noting ". .. observations that cigarette smoking obviously serves a dual purpose: it will mostly pick us up 349

when we are tired~ or depressed and will relax and sedate us when we are tense and excited." In order to ascribe such biphasic effects solely to the direct action of nicotine it would be necessary to discount psychological re- sponses and alterations in mood from alll other types of stimuli associated with smoking or the use of tobacco, an obvious impossibility. Although Knapp and' Domino (15) have shown nicotine in small amounts to exert potent arousal effects in the electroencephalogram in animals, this evidence is difficult to interpret as it relates to smoking in man. A consensus among modern authors (27) appears to be that smoking, and presumably nicotine, exert a pred'ominantly tranquilizing and relaxing effect. The act of smoking is of such complexity that the difficulties associated with objective analysis of whether smoking induces pleasure by creating euphoria or by relfievingd`•sphoria renders objective analysis virtually impossible. The anecdotal literature suggests that sed'ation plays a more important subjective role in~ pipe and cigar smoking than~ with cigarette smoking. Since most pipe an& cigar smokers do not inhale, this suggests that bronchial and pulmonary irritation from cigarette smoke after inhaling may contribute an important sensory input to the centrali nervous system which could modify the sedativee effects of nicotine, so that some individuals w.oul& describe the experience ass stimulating rather than sedative. Ileavy cigarette smokers who inhale often describe the act as a pleasant sensory experience which constitutes for them one of the prime drives to continue to smoke. Fieedmani (10) used the term "pulmonary erotism." Mulhall (19) and! Ilobicsek (22) have commented on this concept. An interesting psychoanalytical approach by Jonas (14), which postulates central nervous system eounteririritation to constant pul! monary irritation from smoking, is based upon this concept. If' pulmonary irritation isal pleasure factor it probably is not related to nicotine al'one but to other irritants in smoke and could represent' a non-specific increase in afferent'sensory discharge from the whole respiratory tract. A gap:in knowl- edge exists in this area. Furthermore, until car~efully controlled experiments withi nicotine are conducted in man, the literature will be burdened further withi anecdote and hypothesis rather than fact. DISTINC'PION IfF?Tw.EEN DRUG ADDICTION AND DRUG HABITUATION Smokers and users of tobacco: in other forms usually develop some degree of dependence upon the practice, some to the point where significant': emo- tional disturbances occur if they are deprived of its use. The evidence indi- cates this dependence to be psychogenic in origin. Ln medical and! scientific terminology the practice should be labeled habituation to distinguish it clearly from a.cldietion, since the biological effects of tobacco, like coffee and other caffeine-containing beverages, betel morsel chewing and the like, are not comparable to those prroduced by morphine, alcohol, barbiturates, and many other potent addicting, drugs~ In~ fact, to make this distinction, the World Health Organization Expert Committee on Drugs Liable to Produce Addiction (35) created the following definitions which are accepted throughout the world! as the basis for eontrol! of potentially dangerous drugs. 350

Drug Addiction Drug addiction is a state of periodic or chronic intoxication produced by the repeated consumption of a drug (natural or synthetic). Its charac- teristics include: 1) An overpowering desire or need (compulsion)' to continue tak- ing the drug and to obtain it by any means; 2) A tendency to increase the dose;. 3) A psychic: (psychologica4 and generally a physical depend- ence on the effects of the drug; 4) Detrt-iment'ali effect on the indi- vidual and on society. Drug Habituation Drug, habituation (habit): is a con- dition resulting from the repeated consumption of a drug, Its charac- teristics include: 1) A desire (but nota compulsion) to continue taking the drug for the sense oflimproved well- being which it engenders; 2)Littdeor no~tendencytb~increase the dose;, 3) Some degree of psychic depend- ence on the effect of the dEug, but absence of physical de- pendence: and hence of an abstinence syndrome; 4)! Detrimental effects, if' any, pri- marily on the individual. TOBACCO HABIT CHARACTERIZED A9 HABITUATION Psychogenic dependence is the common d'enominator of all drug habits and the primary drive which leads to initiation and relapse to chronic drug use or abuse (25). Although a pharmacologic drive is necessaryy it does not need to be a strong one or to produce profound subjective effects ini order that habituation to the use of the crud'e material becomes a pattern of life. Besides tobacco, the use of caffeine in coffee, tea, and cocoa is the best ex- ample inithe American culture. Another example, the chewing of the betell morsel, exists on a world scale comparable to tobacco and involves several! hundte& million individuals of both sexes and of all races, classes, and! religions (17). The morsel contains arecoline from the areca nut, an ingre- dient of the mixture. It is a very mild stimulant of the nervous system which is ordinarily no more detectable than nicotine subjectively. The morsel iss chewed from morning to night, from infancy to death, and creates a craving, more powerful than that for tobacco. As with tobacco, oral gratification plays an important role in this habit. Thus, correctly designating the chronic use of tobacco as habituation rather than addiction carries with, it no implication that the habit may be broken easily. It does, however, carry ani implication concerning the basic nature of the user and this distinction should be a clear one. It is generally accepted among psychiatrists that addiction to potent drugs is based upon serious personality defects fromi underlying psychologic or psychiatric dis- orders whichi may become manifest in other ways if the drugs are removed l32)- Even the most energetic and emotional campaigner against smoking, and nicotine could' find little support for the view that all those who use tobacco, 714-422 0-64-24 351

coffee, tea, and cocoa are in need of mental care even though it may at some time in the future be shown that smokers and non-smokers have different psychologic characteristics. RELATIONSHIP OF SMOKING TO USE OF ADDICTING DRUGS Undoubtedly, the smoking, habit becomes compulsive in some heavy smokers but the drive to compulsion appears to be solely psychogenic since physical dependence does not develop to nicotine or to other constituents of tobacco nor does tobacco, either during its use or following withdrawal, create psychotoxic effects which lead to antisocial behavior. Compulsion exists in many grades, fromi the habit pattern of the cigarette smoker who subconsciously reaches into his pocket for a cigarette and may even light his lighter before he realizes thati he is already holding a lighted cigarette in his lips, to the heroin addict who becomes involtied in crime, sometimes in murd'er, in his searchi for drugs to satisfy his addiction. Clearly there is a significant difference, not only in the personality involved but also in the effects upon the user and his relationship to society. Proof of physicall dependence requires demonstrationi of a characteristic and reproducible abstinence synd'rome upon w-ithdrawal of a:drug or chemical! which occurs spontaneously, inevitably, and is not under control of the sub- ject. Neither nicotine nor tobacco comply with any of these requirements (26)'. In fact, many heavy smokers may cease abruptly and, while retaining the desire to smoke, experience no significant symptoms or signs on with- drawal. On the other hand, it is well established that manyy symptoms and a few signs which may be observed objectively byy others may occur follow- ing cessation of smoking, but no characteristic abstinence syndrome occurs. (16„p. 539). Rather, a gamut of mild symptoms and signs is experienced and observed as in any emotional disturbance secondary to deprivation of a desired! object or habitual experience. These may be manifest in some per- sons as an increased nervous excitability, such as restlessness, insomnia, anxiety, tremor, palpitation,, and in others by diminished excitability, such as drowsiness, amnesia, impaired concentrathon and judgment, and dimin~ ished pulse. The onseti and duration of these withdrawal, symptoms are reported by different authors in terms of days (20), weeks (30), or months (12, 28)1, obviously an inconsistency if one attempts to relate these to nicotine deprivation. In contrast tb, drugs of addiction, withdrawal from tobacco never constitutes a tlireat to life. These facts indicate clearly the absence of physical dependence. This view is supported further by consideration of the diversity of methods which are reported (116, pp. 540-546) to be successfull in treatment of smok- ing withdrawal. Most methods have been based strictly on symptomatic treatment;; for t'hose «•ho~ are depressed, stimulants such as caffeine,, theo- bromine, and metrazol; and for those who are excited, sedatives, barbiturates,, and the like. Flansel (11i) treated his patients bystimulating, them in the daytime with 110 to 15 mg of dextroamphetamine and putting them to sleep at night with a sedative. At, least this treatment has the advantage that it does not interfere with the usuall patterns of diurnall and' nocturnal behavior. 352

In contrast to addicting drugs, the tendency to continue to increase the dose of tobacco is definitely self-limiting because of the appearance of nicotine toxicity. Undoubtedly there is a considerable variation among individuals in inherited capabilities to tolerate nicotine. In some individuals this may completely deprive them of the pleasure of using tobacco (30). Although some tolerance is also acquired with repeated use, this is not sufficient too permit the nervous system to be exposed to ever-increasing nicotine concen- trations as is the case with addictfing drugs. This in itself may militate against the development of the adaptive changEs in~ nerve cells which create physical dependence. It is a well-known fact among smokers and other users of tobacco that certain toxic effects such as nausea and vomiting, which accompany the initial use of tobacco, disappear wit6 repeated use. This tolerance is only relative and excessive use may at any time initiate these signs and symptoms even in the heavy smoker or other user (6):.. Acquired tolerance may take two forms: (a) A low grade tissue tolerance in mucous and pulmonary membranes to the irritants in tobacco or tobacco smoke (8)'. This probably involves adaptive changes in cell membranes, similar to those which.occur with other local' irritants; and a reduction in sensory nervous input permitting moree prolonged exposure to those irritants wit'hout unpleasant subjective manifestations. (b) Specific organ tolerance to nicotine which is also relatively low grade and' comparatively short-lived. This tolerance, which may permit the ad- ministraton of nicotine in quantities several times larger than those which~ would induce toxic signs and symptoms initially (13), varies with age (17), . sex (30, and duration of exposure. Differences in metabolic dispositioni are not enough to account for tolerance (7, 29, 31)~. Animal studies indicate considerable tolerance tb small but little if any to convulsant or lethal doses (2, 4). Another form of! adaptat7oni to tobacco which is psychologic in origin is also common to many other drug„ habits. It might better be termed tolera- tion than tolerance; the user "puts up with" symptoms of' irritation and nicotine toxicity which are unacceptable to the novice. Many smokers accept persistent cough, bouts of nausea, and other unpleasant manifestations of irritation and' toxicity. Much controversy concerns the relationship of smoking to other drug habits especially to those agents which are addicting like alcohol, the opiates, and others: Since the motivating factor in, the habitual use of drugs of any typee is the desire to change the status quo in order to: achieve pleasure, to relieve monotony, to abolish tension or grief, etc:, it is not unusual that many in- dividuals in search of such gratification will habitually rely on several sub- stances. Attempts to establish cause and effect relationships among the several habits have not been meaningf'ul. A more plausible explanation iss that the personality characteristics which lead to the search for change may find mild expression in smoking„coffee and moderate alcohol drinking, and in arrexaggerated form by abusing the narcotic and stimulant drugs of addiction. 353 I CtiF: ^'

MEASURES FOR' CURE OF TOB:4CC0 HABIT Measures directed at' the cure of the tobacco habit havebeeni designed! principally to modify or abolish the psychogenic, sensory. or pharmacologic drives(16, pp. 540-5=I6) . In the psychotherapeutic area these include psychoanalytic technics, hypnotisni, antismoking campaigns based upon fear of health consequences, reliaion, group psychotherapy (similar to Alcoholics Anonymous~)~,an& ,. : tranquilizing or stimulant drugs. ~ Modification of tobacco tastebv astringent mouthwashes (silver nitrate and copper sulf'ate), bitters(quinine. quassia ) , loeal' anestbetics (benzocaine lozenges). substitution of other tastes (essentiad oils and flavors), and pro-duction of a: dry mouth (iatropine or stramonium) are all measures ~~~hichi have been aimed'at dimioishing, the sensory drives. Administration of oral lobeline. a substance from Indian tobacco; with weak nicotine-like: actions as a nicotine substitute has had rather extensive tr~iall (5, 21, 36), andl commercial preparations are available. Carefully controlled studies have failed to establish the value of lobeline (1, 18, 24)~. Of the methods cited above, those which deal with the psvchogenic drives: have been the more,successful sinceult'~imate realization of the goal involves the firm mental resolve ofi the individual to stop smoking, There is no acceptable evidence that this goal can be achieved solel'y by modifying sensory d'rives or using tobacco substitutes. SUIINIARY The habitual'use of tobacco is related pr~imarilytopsychologicalland social drives, reinfloree& and! perpetuatcd by the pharmacological actions of nico- tine on the central nervous system, the latter being interpret'ed subjectively either as stimulant or tranquilizing dependent upon theindividual response. M eot~ine+fre eine+free tobaeco~orother plant~ materials do not satisf'ythe needs of those: who acq;uire the tobacco habit. The tobacco habit should be characterized as an habituatioa, rather than an addiclion, in conformity with accepted World Health Organization d'efini- tions, since once established there is little tendency to~ increase the dose; psychic but not physical dependence is developed; and the detrimental e$ectss are primarily on the individual rather than society. No characteristic absti- nence syndrome is developed upon withdrawal. Acquired tolerance, even though comparativelk• low grade, is important in~ overcoming nausea and other mild signs of nicotine toxicity and is a f'actor in continued use ofl tobacco: Discontinuation~ ofl smoking: although possessing~ the difficulties attendant upon extinction of any conditioned reflex, is accomplished best by reinforc- ing factors which interrupt the psychogenic drives. Nicotine substitutes or supplementary medications have not been proven to: be of major benefit in breaking the habit. 354

BENEFICIAL EFFECTS OF TOBACCO Evaluation of the effects of smoking on health would lack perspective if no consideration was given to the possible benefits to be derived f'rom the occasional or habitual use of tobaacoL A large list oflpossible physical benefits can be compiled from a fairly lhrge literature, much of which is based upon anecdote or clinical impression. Even in those circumstances where a substantial body of fact and experi- ence supports the attribute, the purported benefits are comparatively inconse- quential in, a medical' sense. Examples are: (a) maintenance of good intestinal'tone andi bowel habits (23), and (b) an anti-obesity effect upon reduced hunger and a possible elevation in blood sugar (3)1. Insofar as these are supported by fact they represent tangible assets and cannot be tot'allvdismissed. On the other hand, it would' be diflicult' to~ support the position that these attributes would carry much weight in counter-balancing, a significant health hazardl Btrt't it is not an easy matter to reach a simple and reasonable conclusion concerning the mental health aspect's of smoking. The purported benefits oni mentall health are so intangible and elusive, so intricately woven into the whole fabric of human behavior, so subject to morall interpret'ation and censure, so difficult of medical evaluation and so controversial in nature that few scientific groups have attempted to study the subject. The drive to use tobacco being fundamentally psychogenic in origin has the same basis as other drug habits and in a large fraction of the American popu- lation appears to satisfy the total need of the individual for a; psychological': crutch. An attempted evaluation of smoking on mental health becomes more realistic if one is willing to confront the question, ridiculous as it may seem. Whab would satisfy the psychological needs of the 70,000,000 Americans who smoked in 1963 if they were suddenly deprived of tobacco? Clearly there is no definitive answer to this question but iU may be illuminated by analogy with the past. Historically, man has always found and used substances wit'h, actual or presumed psychopharmacologic effects ranging in activity from the innocuous ginseng root to the most violent poisons. In China, traditions and custom endowed the ginseng root with remarkable health-giving properties. The strength of this belief was so strong and the supply so short that the root often became a medium of exchange. The value of the root increased in direct proportion to its similarity in appearance to the human figure. The remarkable aspect of this situatiom is that the ginseng root is his- torically the world's most renowned placebo, since science has failed! to es- t'ahlish that it contains any active pharmaeologic principle. It would be redundant t'orecount here all of the potent substances at thee other end! of the scale. It will suffice to note that this human drive is so uni- versal and may be so powerful that man has always been willing, to risk and accept the most unpleasant symptoms and signs-hallucinations andl delusions, ataxia and paralysis, violent vomiting and' convulsions, poverty and malnutrition, destructive organic lesions, and' evem d'eathi 355

If'. the thesis is accepted that the fundamental nature of man will not change significantly in the foreseeable future, it', is then safe to predict that man will continue to utilize pharmacologic aids in his search for contentment. In the best interests of the public health this should be accomplished with sub• stances which carry minimal hazar& to the individual and for society as a whole. In~ relat'ing this principle to tobacco it may be reemphasized that the hazard, serious as it may be, relates mainly to the individual, whereas the in- discriminate use of more potent pharmacologic agents without medical'super- vision creates a gamut of social problems which currently constitutes a major concern of government as indicated! by the recent (111962) White House. Con- ference on~ Narcotic and Drug Abuse (32). SUMMARY Medical perspective requires recognition of significant beneficial effects of smoking primarily in the area of mental health. These benefits originate in a psychogenic search for contentment and are measureable only in terms of individual behavior. Since no means of quanti- tating these benefits is apparent~ t'he Committee finds no basis for a judg}nent which would weigh benefits versus hazards of smoking as it may apply to the general population. REFEREN!CES 1. BartlctN, W. A., Whiflehead, R. W. The effectiveness of ineprobamate and lobeline as smoking deterrents. J Lab Clin Med 50: 278-81, 1957: 2. Behnend, A., Thienes, C. H. The development of tolerance to nicotine by rats. J Pharmacol Exp Ther 48: 317-25, 1933. [Abstract] J Pharmacol Exp Ther Proc 42: 260, 1931. 3. Brozek, J., Keys, A. Changes in body weight in normal men who stop smoking cigarettes. Science 125: 1203, 1957. 4. Dixon, W. E., Lee, W. E. Tolerance to nicotine. Quart J Exp Physiol 5: 373-83, 1912. 5. Dorsey,, J. L. Controf of the tobacco habit. Ann Intern~ Med 110: 628- 31, 1936. 6. Edmunds, C. W. Studies in tolerance, 1-nicotine and lobeline. J Phar- macol Exp Ther 1: 27-38, 1909. 7. Edmunds, C. W., Smith, M. I. Further studies in, nicotine tolerance. J Pharmacol Exp Ther 8: 131-2, 1916: Also: J Lab Clin Med 1: 315-21, 1915-16. 8. Farrell, H. The billion dollar smoke. A working truth in reference to cigarettes and cigarette smoking. Nebraska Med J 18: 226-8, 1933. 9. Finnegan, J. K., Larson, P. S., Haag, H. B. The role of nicotine in the cigarette habif. Science 102: 94-6, 1945. 10. Freedmani B. ConditSone& reflex and psychodynamic equivalents in alcohol addiction. An illustration of psychoanalytic neurology, with rudimentary equations. Quart J Stud Alcohol 9: 53-71, 1948. 356

i ] l. Hansel; F: K. The effects ofl tobacco smoking upon the respiratory tract. South! M J 47: 745-9, 1954. 12. Head„ J. R. The effects of smoking. Illinois Med' J 76: 83-287, 1939. 13. Johnston, L. Tobacco smoking and nicotine. Lancet London 2: 742, 1942. 14. Jonas, A. D. Irritation and counterirritation. A hypothesis about the autoamputative property of the nervous system. New York Vantage Press, 1962. 368 p. 15. Knapp, D. E., Domino, E. F. Action, of nicotine on the ascending, ret'ic- ular activating system. Int J Neuropharmaeoll 1: 333-51„ 1962. 16. Larson, P. S., Haag, H. B., Sihvette, H. Tobacco: Experimental and Clinicali Studies. Baitimore,,The Williams & Wilkins Company, 1961. 932 p. 17. Lewin, L. Phantastica: Narcotic and stimulating drugs: Their use and abuse. London, Kegan Paul, Trench, Trubner, 19311. 335 p. 18. Miley, R. A., White, W. G. Giving, up smoking. Brit Med J~~ 1: 101, 1958. 19. 14Iu1ha11, J. C. The cigarette habit. Trans Amer Laryng Assn 17: 192- 200; 1895. Alsoc Ann Otol 52: 714-21, 1943; and N Y Med J 62: 686-8, 1895. 20. Ochsner„A. Smoking and cancer: A doctor's report. N Y J Messner, 1954, 86 p.. 21. Rapp. G. W., Olen, A. A. Lobeline and nicotine. Amer J Med Sci 230: 9, 1955. 22. Robicsek, M'~ U. H. Eine neue Therapie der Nikotinsucht oder die Kunst, das Rauchen zu lassem Fortschr Med 50: 1014-5, 1932. 23. Schnedorf, J. G., Ivy, A. C. The effects of tobacco smoking on the alimentary tract. An experimental study of man and animals. JAMA 112: 898-904, 1939. 24'. Scott, G. W., Cox, A. G. C., Maclean, K. S., Price,, T: M. L.,, Southwell, N. Buffered lobeline as a smoking, deterrent. Lancet 1: 54-5, 1962. 25. Seevers, ~1L H. Medical perspectives on habituation and addiction. JAMA 181: 92-8, 1962. 26. Seevers,,M. H., Deneau, G. A. Toleranee and dependence to CNS drugs. In: Root, W. S:, Hoffman, F. G. eds. Physiological Pharmacology,. N Y Acad Press, 1963. p. 565-640. Vol. 1: Nervous system. 27. Silvette, H., Larson, P. S'., Haag, H. B. Medical uses of tobacco past and present. Virginia Med Monthly 85: 472-84;, 1958. 28; Swinford, 0., Jr., Ochota, L. Smoking and chronic respiratory dis- orders. Results ofl abstinence. Ann Allerg 16: 4b5-8;, 1958. 29. Take.uchiy M., Kurogochi, Y., Yamaoka, M. Experiments on the re- peated injection of! nicotine into albino rats. Folia Pharmacol Jap 50: 66-9; 1954. 30. Von Hofstatter, R. Uber Abstinenzerscheinungen beim Einstellen des Tabakrauchens: Wien med Wschr 86: 42-3, 73'-6, 1936, 311. Werle, E.,, Muller, R. Uber deni Abbau von Nicotin durchi tierisches Gewebe. II. Biochem 308: 355-8, 1941. 32. White House Conference on Narcotic and Drug Abuse. Sept. 27-28, 1962. Proc Govt Print Off; 1963. 330 p. 9 357

33. Wilder, J. Paradox reactions to treatment. New York J Med 57: 3348'-52. 1957. 34. Wolff, W. A., Giles, W. E. S'tudfies on tobacco chemistry. Fed Proc 9: 248, 1950. 35. W'orld Health Organization. Expeft Committee on~Addiction-Producing Drugs. Seventh Report., 15 p. (Its Techn Rep Ser No. 1116, 1957.) 36. 1~TdYight, I. S., Littauer,, D. Lobeline sulfate, it's pharmacology and use in the treatment of the tobacco habit. JAMA 109: 649-54, 1937.

Psycho-Social Aspects of Smoking

Contents INTRODUCTION .................... DEMOGRAPHIC FACTORS ............... Age ......................... Smoking by Socioeconomic Level . . . . . . . . . . . . Occupation . . . . . . . . . . . . . . . . . . . . . . Education . . . . . . . . . . . . . . . . . . . . . . Sex . . . . . . . . . . . . . . . . . . . . . . . . . Race . . . . . . . . . . . . . . . . . . . . . . . . . Marital Status . . . . . . . . . . . . . . . . . . . . Religion . . . . . . . . . . . . . . . . . . . . . . . Rural versus Urban . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . PERSONALITY AND SMOKING . . . . . . . . . . . . . Extroversion and Introversion . . . . . . . . . .. . . . . Neuroticism . . . . . . . . . . . . . . . . . . . . . . Psychosomatic Manifestations . . . . . . . . . . . . . . Psychoanalytic Theory . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . TAKING UP SMOKING . . . . . . . . . . . . . . . . . Parents' Smoking Patterns . . . . . . . . . . . . . . . Intelligence and Achievement . . . . . . . . . . . . . . Some Hypotheses on the Beginning of Smoking ...... Status Striving . . . . . . . . . . . . . . . . . . . . Rebellion Against Authority . . . . . . . . . . . . . . Smoking as a Response To Stress and as a Tension Release .. DISCONTIN U ATION . . . . . . . . . . . . . . . . . . SUM MARY . . . . . . . . . . . . . . . . . . . . . . . CONCLUSION' . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . 360 Page 361 361 361 362 362 363 363 363 364 364 364 364 365 365 366' 367 367 368 368 369 370 371 372 373 373 374 376 377 377

Chapter 14 INTRODUCTION The smoking habit~ has been f'ound' to be linked with severall dem.ographicc variables (~such as age, sex, socioeconomic level, etc.), with a number of general behavioral' patterns (such as degree and kind of participation in a variety of social activities), with psychological characteristics (suchasin-tell[gence, school achievement, etc.), and witL certain personality variables. (such as intro- and extroversion, gregariousness, feelings of inferiority, need for status, etc.). A brief general discussion will, be followed by a revieww of empirical evi- dence linking demographie characteristics with smoking. Certain psychol'og- ical-personality variables will then be considereds followed by a review of what is known about the beginning of the smoking habit and about its dis- continuation. Finally, general conclusions will! be drawn about' the present state of knowledge. The term "smoking," unless otherwise specified, refers throughout to cig- arette smoking only, because almost all research in the area has dealt onlyy with cigarette smoking, DEMOGRAPHIC FACTORS A clear and'authoritative demographic description of smokers is not readily available from any one study on the subject. The considerable.differences in the characteristics of the smoking population as reported by various studies can probably be explained by one or more of the following factors: 1. Samples were drawni from populations differing in geographical loca- tion and ini a number of other population characteristics. 2. Data in the several studfies were collccted' during dffferent years be- tween the 1930's and 11962. Therefore, some differences in re- ported data could be due to time trends. 3. Methods of gathering information differed' among the studies. 4. Data were analyzed and/or grouped in different ways. Nonetheless certain trends seem to be well established. AGE As far as is known from actual! data, few children smoke before the age of 12, probably less than fivepercea of the boys and lessthan: one percent ofl the girls. From age 12 on, however, there is a fairly regular increase in the prevalence of smoking, At the 12th grade level, between 40 to 55 361

percent of children have been found to be smokers. By age 25, estimates of smoking prevalence run as high as 60 percent of men and' 36 percent of women. There is a further increase up to 35 and 40 years after which a drop is observed. In the 65 and over age group, prevalence of smoking is only approximately 20 percent among,men and'four percent among women. These distributions are based on cross-sectional rather than longitudinal data and may be subject to considerable change over the years as each gen~ eration of smokers carries its own smoking pattern into higher age brackets. It is also conceivable that increased public attention to possible hazards of smoking within the last few years has led to some decrease in the number of smokers, a decrease not evenly dist'ributed among the several age groups. Since these statistics were collected several years ago, they may not reflect current' age distributions. More recent but limited data suggest that there has been an increment in smoking prevalence at all age levels since the earl} fifties (7, 113, 23, 26, 31). Horni (11)~ estimates that 110 percent of later smokers "develop the habit with, some degree of regularity" before tiheir teens and 65 percent during their high school years. It seems, then, that the years from the early teens to the ages of 18-20 are significant years in exposing people to their first smoking experiences. SAiOKING By SOCIOE(:01031Ic LEVEL Empirically, socioeconomic levell is usually determinedl by means of one or several separate and measurable variables such as income, educations occupation and type of residence. Despite the use of' different determinants of class status., there is rather consistent evid'ence that smoking patterns are related to socioeconomic level in, that the lower or «-orking classes contain both more smokers and earlier starterrs. This has been found in America as well as in England (3; 4, 10. 22, 27)1. As to separate class-linked variables. income does not seem to be related ini a consistent manner to prevalence of smoking either in England 139) or in the U.S,A. (26). Thered'oes appear to be some tendency toward fewer male smokers among those w,itlia yearly income below S2;000(asof 1956) and, ini the older groups only, with an annual income over $5.000: On the other hand, income does relate positiveh-y to the quantity of cigarettes consumed. OGCC'.I'ATtOhP Almost as many different ways of classiNing and grouping occupations have been used as there are studiesdealingwith this variahle: making com+ parisons extremely difficult., Moreover, most groupings are not very meaningfull since they used broad and comprehensive job classifications which obscure some of the most'' important occupational characteristics. For example, the category "professional" encompasses (as do other cate- gories) a t'remendous range of occupations. These vary widely among 362

themselves with respect to many characteristics that may be significantltiy associated with smoking, habits. For these and other reasons it is not sur- prising that data reported on the relationship between occupation and cigarette smoking are anything but easy to interpret. 1Nonetheless, if occu- pation is used' merely as a class-index, these data are in accord with those obtained in reference to other socioeconomic indices: whitecollar, profes- sionals manageriali and technical occupations contain fewer smokers than craftsmen, salespersons, and laborers. Unemployed! have been found to be somewhat more likely to smoke than employed (23). According to Lilienfeld (19), smokers change jobs significantly more often than non-smokers. Specific data as to reasons for such changes are not given, however, making this variable difficult to interpret. Repeated job changes may be indicative of neurotic traits as the author proposes, but they may also be due to other reasons which create psychological pressures to which smoking is one possible response. The relationship between smoking and educationi is unclear. Lilienfeldl (19) failed to:find educational differences between smokers and non-smokers in his 1956 probability sample of: adults ini Buffalo, New York. Matarazzo and' Saslow (23) also concluded that educational attainment, ini terms of highesti . grade completed, does not differentiate smokers f'romi non-smokers. Hammond (8):, on the other hand, reported a curvilinear relation among men between 45 and 79 years of age. Smokers werc under-represented among those who never attended high school and among college graduates,, and over-represented in all the categpries between. Because of the~ strong relationship between education, and occupation, the trends found ini regard to occupation may reflect those found in reg-ard! to education: those occupations normally associated with high education show, by and lar~e, a smaller prevalence of smokers. SEX Fewer women smoke than men and their smoking is almost entirely restricted to: ci-,arettes. However, the proportion of women smokers has increased! faster than that of men smokers in recent years. Horn (11) reports that a recent American Cancer Society survey showe& an increase since their 1955 survey of five percent (from 31 to 36 percent). Salber and Worcester (28) suggestion the basis of a sample of senior students at Newton, Mass., high schools that "k'omen, particularly Jewishi women; may soon, overtake men in the number who smoke." RACE The proportion of smokers is roughly the same among whites and non- whites (7) and relations of smoking to sex and age alsoi were comparable 363

in the two groups. But many more heavy smokers (more than one pack per day) were f'ound among whites, as compared with non.whites, in the case of both men and womenL Since, as was reported earlier, income was found to relate to amount, though not to prevalence,, of smoking, this racial difference could reflect economic differences between, whites and non-whites, t-~ MARITAL STATUS Smoking (lof any kind) is most prevalent among the divorced and widowed and least among those who have never been married, except that among persons over 45, never-marrieds arne as likely to be smokers as the married. (7). RELIGION There is evidence ofi lower smoking rates within some religious sects which condemn smoking ('16)1 and among persons who1old devout religious beliefs. For example, less smoking was foun& among Harvard students who were religious and whose parents were devout;, and non-smokers seem more inclin4 toatrtend church than smokers (;3; 22, 37). Bothi Horn (ill) and Straits and Sechrest (37) report over~-representation of smokers among Catholics, a churchi ini which more tolerance is shown towards smoking than among some Protestant churches. As in all suchi correlational studies it is impossible to say whether there is a direct causal linkbetweeni religion and abstention, or whether some other factors account both for the religious convictions and the abstention from smoking. RURAL VERSUS URBAN There are proportionalls~• fewer smokers in rural than in urban areas, but the smallest percentage of smokers is within the rural farm populatiom The rural non-farni population is more like the urban population with only slightly fewer smokers than in the latter. No relationship ofl smoking to size of community has been established. No convincing, interpretation can be offered in view of the lack of! additional data. SU111MARY OF DEbZOGRAPI$IC FACTORS No single comprehensive theory to explain smoking is suggested by these demographic data taken by themselves. In fact', the only know•ni attempt at formulat'~inga theory whichis; at least partly, related to or based on, such data revolves aroundl a hypothesis relating smoking or not-smoking, to introjected culture standards linked to social class norms in our society (21, 22),.. Nonetheless, there are many, though not always clear, relationships be- tween smoking and a variety of social and economic variables. Taken al- 364

together, there emerges the picture of smoking as a behavior that has over many years become tied clbsely to many of the complexities of our present society. There can be no doubt that! smoking as a habit is determined in some measure by a variety of such social forces as are reflected in demo- graphie data of the kind reviewed above. But it will be some time before the specificinterrelatyons can~be disentangledl Since man is not a passive target of such forces but an active participant,, no possible explanation can omit consideration of the way in which he reacts to and, in turn, creates such forces, in short, a considerationi ofl personality factors. PERSONALITY AND SMOKING All research studies on the relation between smoking and personality select one or several, more or less distinct personalit'yy traits or characteristicss for scrutiny. For example, they may try to test hypotheses on the interre- l'ationi between smoking, and introversion, smoking and neuroticism, smoking, and anxiety, etc. A few students have tried to describe personality syn- dromes by a synthesis of severall such traits. At the present' state of knowl- edge. however, it is more fruitful and more valid to speak not in terms ofl a "smoker personality," but' rather in terms of discrete personality charac- teristics which may he found: tobe associated with smokers. Certain difficulties are encountered in reconciling findings fh~omi the sev- eral studies: Sometimes authors use identical terms even though there is some doubt that they refer to the same concept. For example, the term "neuroticism"in" one study may refer to a personality trait as measured by certain psychological tests, in another to a classification of observed so-called nervous behavior. When data from studies using the one are at variance with data from studies using the other, it is difficult tb say whether these studies really are yielding cont'radictory findings, or whether differences in such data are due to the fact that they reflect different variables. In addi- tion, psychological techniques for the assessment ofl personality are still of uncertain validity, some possibly ofl little or no value. For example; in a number ofl studies the investigators have made up a priori scales, tests or questionnaires without any reported attempts at establishing their reliability or validity. EXTROVERSION AND INTROVERSION One of the best-designed studies (1, 6) was carried out in England using representative samples and objective techniques using questions previously developed by Eysenck and claimedi by him to "have been found to be ... reasonably valid measures of three personality traits, extroversionL neuroti- cism„and rigidity:"(6). Ifoneaccepts the author's claim that t1he question- naire rneallb did'measure these traits, a very significant relationship was found between extroversion and smoking. Heavy smokers were more extroverted than medium smokers; these were more extroverted' than light smokers and 365

ex-smokers; and both non-smokers and pipe smokers were least extroverted. Two consecutive studies with different representative sampl'es yielded! the same results, and the association of smoking with extroversion was also supported' by several other investigators, such as McArthur et al (22) and Schubert (34)~. Another study by Straits and Sechrest (37) using the Social Introversion Scale from the Minnesota Multiphasic Personality Inventoryy on ' a rather small and probably biased sample did not support' this finding. ' The: generallpicture which emerges from Eysenck's stud'}ry and from others is one of smokers tending to live faster and more intensely,, and to be more socially outgoing. Several studies; using behavioral rather than psychological test data, sup- port this picture. Davis (4) describes young smokers as "more gregarious and socially advanced" tham non-smokers. McArthur et al' (22) report similar findings. However, a compilation of' actual participation of smokers and non- smokers, respectively, in a nurnberof specific:social activities as reported by several investigators (4, 13, 19, 30) yields conflicting data. Smokers are reported to participate more in suchi social activities as dancing, courtship, and fraternities-in line wit'hwhat would be expected of extroverted indi- viduals. As to participation in sports, findings in some studies favor the smoker, in others the non-smoker. Non,smokers were found by one investi- gator to show greater social participation in organizations and to hold moree offices-activities more associated' with extro- thani withintroversion. Smokers show greater interest in TV and movies, non-smokers in reading books. Studies an& cultural activities are over-represented among non- smokers. These conflicts in the data as collected do not necessarily reflect reali con- flicts, however. Some sports may be of a less gregarious or extroverted nature than others (for example, swimming or tennis as compared to foot- ball). Offices in college organizations also may range from president of a cultural club tbl classpresident. It is altogether possible that this range can accommodate introverted as well as extroverted students. Lumping together heterogeneous activities under one broad descriptive term, as donee in, so, many studies on smokers' behavior, may obscure real relationships. In any case, while the association between extroversion and smoking is fairly well supported by available evidence, less certainty exists as, to the exact nature of this association. It is possible that extroversion is directly related to smoking as a habit pattern, that is, that smoking is an expression, of this kind' of personality, as most authors seem to imply. It is equally plausible that the extrovert, by virtue of his greater partScipationi ini various social activities, exposes himself more to social stimuli to pick up ond re-enforce the smoking habit. He may also be: more susceptible to social influence. NEL RoTlctsal Several studies, using a variety of'~ methods, have investigated variables related more or less vaguely with what may be subsumed under the term neuroticism~ Such variables include neuroticism as a personality trait in- 366

>d. ferred from such varied indices as psychological tests, existence of anxiety :he: states, "nervousness," somatic symptoms, unusual restlessness ini terms of lso job and residence, an& others. nd Most studies support the contention~ that neuroticism, in this wide sense, ial is indeed associated with the smoking habit (16, 18, 19, 24, 25). on A few studies faili to demonstrate any relationship of smoking behavior with one or another of these neurotic characteristics. Straits and Sechrest ~rs (37)' found no significant difference in anxiety as measured by Taylor's re Manifest Anxiety Scale (in contrast to Matarazzo who did). Eysenck et al. (1), using a neuroticism-scale, did not find any significant relationship of p- neuroticism either to type or degree of smoking. He does suggest, however, us that "inhaling may be more prevalent among the more: neurotic and irt emotionally disturbed." The state of our knowledge in respect to the smokin-neuroticism syn- n- drome can be best summarize& this way: 1v Despite the individual deficiencies of many of the studies, despite the re great diversity in conceptualization and research methods used, and despite p, certain discrepancies im reported findings, the presence of some compara- i• bility between them and the relative consistency of findings lend support e to the existence of a relationship between the smoking habit and a person- i• ality configuration that is vaguely described as "neurotic." However, there. 'e are no acceptable studies that help decide how this relationship arises, to 1. what degree (if at all) neuroticism l'eads to the beginning andVor to the g continuation of smoking, or to what degree if at all, it accounts for habitu- i- ation and resistance to discontinuation. PSYCHOSOMATIC MANIFESTATIONS i 4 In a study by Matarazzo and Saslbw (23)1, smokers report more psycho. somatic symptoms than non-smokers in responses to the "Saslow Psycho- somatic Screening Inventory." However, differences were significant in only one of three groups tested. In the English study by Eysenck (1): heavy, medium and ex-smokers of cigarettes were found to have the largest number of psychosomatic disorders, non-smokers the least, light cigarette and pipe smokers being intermediate. None of these differences, however, were statistically significant. There is no persuasive evidence that smoking, and psychosomatic ailments are associated to any important degree. PSYCHOANALYTIC THEORY I Psychoanalysts have advanced the hypothesis that smoking, like thumb- sucking, is a regressive oral activity related to the infant's pleasure at his mother's breast (36). It is claimed that male thumbsuckers are: very likely to smoke and drink in later years. The frequently observed fact that those who stop smoking show increased food consumptiony weight gains and use of chewing gum also supports the oral hypothesis. However, Kissen (15) argµes that this could be explained in terms of purely physiological responses. 714-422 0-64-25 367

McArthur et al. (22) found a positive statistical relationship between the ability to stop smoking and~the number of months of breast feeding. He also reports that thumb•sucking in childhood was more common~among men who continued to smoke. The data provided are insufficient to assess these claims, but they do at least suggest that the oral hypothesis warrants further investigation. SUMMARY OF PERSONALITY AND SMOKING Some investigators have attempted to synthesize many of the differences in personality characteristics, as they have been found or suggested by a variety of studies, int'o a comprehensive "smoker personality."' What emerges in each case is an artifact. "While smokers do differ from non-smokers in a variety of characteristics, none of! the studies has shown a single variable which is found exclusively in one group and is completely absent in the other" (23). Nor has any singlee variable been, verified in a sufficiently large proportion of smokers and in sufficiently few non-smokers to consider it an~ "essential" aspect of smoking. "While this is true for all of the variables ... it is especially true for thee variables measuring personality characteristics ... a clear-cut smoker's personality has not emerged from the results so far published in~ thee literature" (23). Nonetheless, there appear enough differences between smokers and non- smokers to warrant the assertion that there are indeed different psycholbgical dynamics at work. However, in what ways these differ, and to what extent these differences are cause, or effect, or both, is not yet known. TAKING UP SMOKING All available knowledge points towards the years from the early teens to the age of 20 as a significant period during which a: majorityof later smokers began to develop the active habit. For this reason, many, studies have focused om, smoking, among youths, almost exclusively selecting high school and college students as their subjects. The trend~ to an inverse relationship between smoking and socioeconomic level is more pronounced when~ smoking among children is examined in the light of parents' socioeconomic status. For example, Salber and MacMahon (27) report significantly fewer smokers among Newton; Mass.,, public school students (grades 7 through 12) in the upper than in the lbwer socioeconomic levels. Horn et al. (i13) found a significant inverse positive relationship between parents' education and children's smoking behavior in students in the Portland; Oregon, high school system, althoughi this relationship diminr ishes with grade,, becoming negligible by the senior year. Several other studies, with more narrowly selectedl samples, yielded! similar results. Smoking patterns among children could be influenced by their parents' smoking patterns whieh„in turns are affected by the latter's social class-linked characteristics. On the other hand, the social class level of children them- 368

selves is associate& with a number of factors that could' influence their behavior. For example, children from better homes may go to different schools, may show higher learning,ability and motivation, may associate with different kinds of peers, may engage in~ different kinds of social activities, an& so forth. All these factors could have a bearing on their smoking, inde- pendent of, or in~ addition to influences exerted by their parents. There can be little doubt that all of these observations must be considered in any attempt to answer the question of initiation of smoking. PARENTS' SMOKING PATTERNS Horn etal. (13) found a strong,association bettveen parents' and children's smoking habits. There is a consistent increase in the number of high school smokers from their freshman to their senior years, regardless of sex or parental habits. But within each~ year there are significantly more smokers in families where both parents smoke than in families where neither parent smokes. Various combinations of smoking practices of father and mother respectively, also affect children's habits differentially. Horn's findings aree supported by those of Salber and MacMahon (27)' obtained from Newton, '11ass., high, school students. This congruity between parents' and' children's smoking habits has led some investigators to ascribe, explicitly or implicitly, simple and direct causal properties to parents' smoking behavior. It has even been asserted that' the most effective way to diminish smoking radically among children would be to~ decrease smoking among their parents. However, such con- gruity could be due to several factors. Parents could exert direct and force- ful influence on their childFen~;, the attitudes and practices of smoking parents could create a general atmosphere of permissiveness in~ the home; conflict between parents' exhortations and their actual behavior could influ- ence children's perception of the pros and cons of smoking. Selection of social associates on the basis of similar attitudes and behavior norms may lead to a social life on the part of the parents involving other families (and their children) who smoke, thus providing additional social smoking stimuli for their own, children. Then, there is the availability of cigarettes in a home where parents smoke which could facilitate the child's first'~ steps to- wards smoking, Finally, the possibilities of similarity in personalities of parents and children cannot be ruled out. Even in families where neither parent smokes there is a striking increase with age in~ smoking among children. Moreover, congruity betweeni the two generations diminishes with each year from freshman to senior year. That this trend of diminishing congruity continues into college is suggested by the findings of Straits and Sechrest (37) who report f'rom, a sample of 125 male college students that smokers are not more frequently from families in which both parents smoke. The most plausible (though not necessarily the only) interpretation is that, as children grow older, they themselves, as well as their relationship to the home, change. With approaching adulthood and its associated new social patterns, other influences supplant those of the parents. The children 369 I

spend increasing amounts of time away f'rom~ their immediate families and their direct supervision and are increasingly exposed to other social influ~ ences. They begin to exert their independence more and more: In fact, as will be seen later, hypotheses to the effect that taking up smoking may be a symptom or an expression of striving for self-assertion have been advanced and have received some support from~ various investigations. It is quite possible that parents'' influence affects the age at which children start smoking much more than it affects the ultimate taking, or not taking up of the habit. . With very few exceptions,, the association between parents' andl children's smoking behavior has been investigated only via inferences drawn from statistical relationships. The exceptions offer data that are mostly of doubt- ful validity (mainly because of unsophisticated techniques for eliciting self- reports by children or because of non-representative sampling) or are insufl- ficient for the derivation of' any even moderately firm conclusions. No study employing appropriate and intensive methods on adequate samples has beem found which examined the nature of the psycho-social dynamics. Therefore, all interpretations of the association between parents' and children's smoking habits must remain on the level of' hypotheses, no matter how suaTestive the:data may appear to be. INTELLIGENCE AND ACHIEFEAMENT Children's intelligence does not seem to be related to whether they take up smoking or not. Earp (5), IV1at'arazzol et al ('24)~, Kissen (1I5), and Mat- arazzo and Saslbw (23) all failed! to find significant correlations between in- telligence measures and prevalence of Gmokina. Salber, et al (32) report that among boys fromi the Newton, Mass. public schools, non-smokers in every grade have "a bi gher mean IQ than discon- tinued smokers w-ho; again; have higher mean IQ's than smokers ... thee trend in girls, though similar in direction, is less markedL"' However, no, statistical t'estsare reported andl ani approximate check on the reported data by means of several t-tests does not support the authors' contention. In the same study a: highi relationship was found between achievement scores obtained from school grades andl non~smoking, and the authors con- clude that "the difference in smoking habits results from differences in aca- demic achievement rather thani intelligence:" Earp (5) found that more smokers than non-smokers among Antioch College students failed to graduate. Lynn (;20) claimed that non-smoking adolescents make higher grades (but scholastic averages according to age were found sometimes to favor the smokers). Horn et al. (1I3) present evidence that there is a higher proportion of smokers among high school students who are older than the modall age of their classmates. The authors describe such students who are older than their classmates as students who "tend to be scholastically unsuccessful" implying, that under-achievement may relate to their smoking. However, since smoking is age-linked among high school students, statistical differences between older and younger students within any given school grade can be accounted for by their age differences. 370 ,...31«~,.. ....... r, ,.o '.7

Thomas (38) and Lilienfeld (19) found no differences between~ smokers and non-smokers in academic standing and in number of years of schooling completed, respectively. In general, the evidence seems somewhat to favor a moderate tendency towards less satisfactory achievements by smokers than by non-smokers. Again, the question of "why" is difficult to answer. It is most unlikely that smoking itself could be responsible. It is possible that whatever accounts for poorer classroom performance may also account for the higher smoking prevalence. It is also possible that smoking is an effect of frustration, or of other psychological reactions to such failure to maintain high, scholastic standards. SOME HYPOTHESES ON THE BEGINNING OF' SMOKING Davis (4) deduces from responses to the question "how did you come to start?"t'wo factors that explain the beginning of smoking: a: sociability. imitative an& awish-for-adult-status factor. Support for this hypothesis is seen in the similarity between parents' and children's smoking habits. Other studies (2, 3. 5, 13) also support it. Despite this agreement among several studies, at', least along general lines, and despite the plausible, common-sense nature of the hypothesis, it is not an altogether satisfying one. First, evidence is derived largely from self- reports. These may or may not reflect valid insight on the part of', the respondents. Secondy the similarity between parents' and their children's smoking behavior lends itself to such other, an& perhaps more plausible, interpretations as have been presented earlier. Third, the explanations for first smoking, such as "curiosity," "saw others smoke" or "someone offered me a cigarette" (reported by investigators) come to mind easily and this may account for the frequency with which~ children offer them rather than other possible explanations requiring both deeper insight and more introspective efforts. Considering that during adolescent years the problem~ of becoming an adult! is universal and that smoking has probablyy become a very pervasive symbol of adulthood in our society, the hypothesis fails to explain why so many children, under the very same circumstances fail to become smokers. A collection of self-inspective reports from smokers, even though probably representing valid reasons for those respondents who give them, is not sufficient to explain why these respondents, but not others, become smokers. In order to have greater confidence in this hypothesis, it is necessary to know whether non-smokers do not also have the "wish for adult status"; whether, if they do, they do not see smoking as appropriate symbolic behavior; ifl they d'o not see it as such a symbol, why some do and others do not; and if non~smokers do see it as such~ a symbol, why do they not take up smoking. As to "imitat'ion,"' it is less an explanation than a description of what occurs. Imsomewhat more dynamic terms, one might think of it as conf'orm- ing behavior in the sense that conformity with the behavioral norms of one's social reference groups may be a: means for gaining social acceptance. Although the hypothesis has a persuasive: ring and has some suggestive 371 I

evidence, all that can be sai&is that these two factors, imitation and desire for adult status, may play a role in inducing some, and perhaps many, children to take up smoking. STATUS STRIVING Some students of smoking behavior have looked at t'he d'ynamics of "striving for status" in a broader sense, as a manifestatiow of interrelated basic psycho-social needs. To be accepted by one's reference persons, partic- ularly one's peer groups, to develop self-esteem and an acceptable self-image,, and to cope with painful feelings of inadequacy, are such basic psycho-social needs. Of these, striving for adult status is only one aspect. It' is entirely possible thatS if smoking is related to the latter, it may be more in terms of keeping, abreast' of one's peers than in terms of deliberately wanting to be an adult. H'orn (11) points out that there emerges from a variety of studies a "syndrome of intereorrelated measures that seem to have in common the failure to achieve peer group statvs or satisfaction." The reference is to such reported findings as that smoking is more frequent among students who are older than their classmates, fall behind their peers in scholastic standing, become drop-outs, and choose easier over, more demanding curricula. This relation between under-aehievement and smoking has generally been inter- preted in terms of compensation. Salber et aL (32) suggest, "it may be that children, who do not achieve this desirable state (good standing with family and peers) because of poor academic grades, find in taking up: smoking a way of, demonstrating their maturity and' achieving acceptance in a peer group whose values are some- what different from, those of the academically more successfull student." In a wider sense; Horn (11) regards smoking as a "compensatory behavior, a symptom of other problems of emotional health." Other authors have found evidence of greater participation of smokers in sports (although this evidence is not entirely consistent), of smokers' more daring war records, of their poorer disciplinary records, and of impulsive, rebellious behavior, especially on the part of heavy smokers (20; 22, 33). The findings from anthropometric studies of students' physiques which de- tected an, association betweem physicall masculinity and non-smoking (35) has also been~ cited as support for this interpretatiom Once again there is considerable evidence to render the hypotheses advanced very plausible but not altogether satisfactory. A number of ques- tions can be raised. First of all, the evidence that scholastic underachieve- ment may be to some measure responsible for smoking, (as is more or less strongly implied by some authors): is not very impressive. For example, in all studies reviewed; the fact that a student does not perform as well as hiss peers in the classroom is accepted! as prima-flacie evidence that he feels psy- chologically frustrated'or socially deprived. The underlying assumption iss that children generally see scholastic achievement as an important goal to strive for, and that even partiali failure to achieve this goal is sufficiently dis- turbing to them to lead to compensatory behavior. This assumption is open to question especially among populhtion groups in whose hierarchy of'~ values 372

the pursuit of intellectual goals does not rank very high. Many children from lower socio-economic levels (who contribute considerably t'o the ranks of "underachievers" and among whom smoking is more prevalent) , may be among, those who ascribe relatively little importance to competing, success- fully with their peers in classroom performance. No studies have demon- strated that there is a relation between smoking and' under-achievement as a psychological, variable. The evidence concerning greater participation of smokers in sports is, as stated earlier, not consistea Nor is the evidence on each of the other vari- ables that are presumed to be indicative of status deprivation or status striving. Other questions can be raised. Even if smokers do participate in more sports, do engage in more dating an& courtship behavior (4) an& generally do manifest more "masculine behavior," why need this be interpreted as "compensatory" behavior rather than a reflection of actual masculinity? If these behaviors are mere demonstrations of masculinity, wliyy should smoking, be taken up as an additional; certainly less self-evident, demonstrationi of masculinity? Why is it that smoking, a habit acquired inereasingNy byy women, should persist in carrying with it such a pervasive symbolfc meaning of masculinity? An& again there is the troublesome question as to why some,,but not so many others, choose this part'icular, means of giving evidence of their masculinity? At present, there is persuasive, but not convincing evidence that smoking, among, adolescents may in many cases be related to needs for status among peers, self-assurance, and'strivingfor adult status. REBELLION AGAINST AUTHORITY Since a need for independence, a striving for adult status and' moree stature among one's peers in an adolescent are associated' with rebellion against authority, the hypothesis relating smoking with such rebellion is a logical extension of the foregoing hypothesis. While rebellion may play a role, perhaps an important one, there is not much, evidence for it. Claims in the literature are at best based' on circum- stantial, suggestive evidence, linked to conclusions by a chain of questionable assumptions. SMOKING AS A RESPONSE TO STRESS AND AS A TENSION RELEASE Stress seems to be related to smoking, as it does to a score of other habits. There is some evidence that the experience of stressful situations contributes to the beginning of the habit, to its continuation, and to the number of cigarettes consumed (4,, 14, 22). Kissen (115) concludes that' "cigarette consumption increases in relation to the occurrence of some emotionally stressful, situations. Such situations therefore appear to play a paa in per- petuating smoking. The interpretation of what is emotionally stressful may depend on, its particular significance to the individual, that is, it may depend on the personality traits of the individual." 373

A plausible case can be made that the experience of stress together with social situations favorable to smoking can provide the trigger to initial experiments with smoking as well as a mechanism to reinforce the habit once established. Considerable evidence lends credence to this hypothesis. "Nervous" traits, anxiety, and! over-reaction to environmental stimuli have been found to be very prevalent among smokers as eompared! to non-smokers. Under- achievement, that is failure to live up to one's expected' norms, may produce stress if the experience is relevant to a person's needs and values. Cart. wright eU a1L (3)~ found that men often tended to start smoking when they took their first wage-earning, job. This, could be due to the tensions and anxieties associatedl with the event, together with~ new social influences andy perhaps, the new-found freedom from home restraints. The same explana. tion could be advanced for the observedl increase in initial smoking among young men in military service (7). More direct, but possibly less reliable, is evidence from, self-reports of smokers. With great consistency, investigators have reported that smokers state they tend to smoke, or to smoke more, under temporary stress-pro- ducing experiences. As McArthur et al. (22)' point out, such short,livedl fluctuations in response to brief stress episodes woul& not be detected by survey methods that elicit information on smoking behavior at only one point in the smokers' lives or even, as in McArthur's case, at yearlly inter val§. Here again different and more intensive research methods are called for. Existence of an association between stress and tensions on the one hand, and smoking behavior on the other can probably be accepted with a reason- able degree of confidence. It should' be noted, however, that stress, as heree used, is defined in terms of an inner psychological-physiologicali response to, certain external events. The fact that a number of people may be exposed even simultaneously to the same stressfull life situation does not necessarily mean that! all of them experience stress or experience it to the same~extent andl in the same way. Whether they do, in what way, and to what extent depends, among other things, on the psychological meaning that the situation has for them: This, again, points to the need to supplement broad correlational studies with researchi that morespeeificallyexamines constellations of the several interdependent variables within and without! the individual. Furthermore, the role of smoking,relative to the tension which presumably evokes it is not at all clear. Is smoking merely an expression, of tension or does it serve as a reducer of psychic tension? If the latter, is it effective, that is, would tension actually be less while smoking a cigarette than while not doing so? No, research has apparently dealt with this problem. DISCONTINUATION Consideration of factors invoh'ed' in discontinuation of smoking may help understand the nature of the habit itself.* fBecause the present chapter is concerned only with psycho,social aspects,, discussion of methods of discontinuance or their relative effectiveness has been dealt with elsewhere (see Chapter 13). 374

Even less is known about discontinuance than about beginning of smoking. However, there is good evidence that it is related to the beginning,of the habit, its nature, and its duration. The rate of smokers who discontinue has consistently beerr found to be highest among those who start late in~ life, have smoked the least number of years, and whose average cigarette consumption~has been smallest (7, 11,,16, 22). Most frequent reasons for discontinuing given by children who had been fairly regular smokers but had quit, were lack of enjoyment and dislike for smoking, Interestingly, these reasons differ from reasons given by cliildren~ who have never smoke& for not taking up smoking, These latter are more along health, aesthetic and moral lines (29). Among adult smokers who quit (the 1955 census data list about 11 per- cent, a rate that has probably increased in the intervening years), the most frequent' reasons given were "various health considerations, the expense, moral reasons, andi a test of one's will' power" (9, 16). Relatively few people refer to publicity about lung cancer (17), but this may be changing with increased public attent'ion, to this issue. Also, the surprising lack of reference to fear of disease among respondents may be a functioni of certain inhibitions to admitting such a negative motive for what is generally re- garded as an intelligent and desirable thing to do. A study carried out in 1957 by Lawton and Goldmani (17) yielded some interesting,results that throw some light on, the effects of intellectual elements in relation to discontinuation of smoking and! at~ the same time raise some puzzling questions. Two groups of scientists, matche& for age and sex, and for the scientific nature of their interests forme& the subjects. One consiste& of 72 well- known lung cancer scientists, the other of experimental psychologists. Significantlly fewer of the cancer specialists than of the psychologists were smokers, and the same difference existed in respect to the number of persons in each group who believed cigarette smoking, to~ be ai cause of lung cancer. But there was no difference in respect to the number of persons in. the two groups who had discontinued smoking within the past five years, nor in~ respect to the number of smokers who expressed dissatisfaction with their smoking habits. Most interesting, however, was the finding that when thosee in the two groups who believed smoking, t~o~ be a: cause of cancer were com- pared,,it was the psychologists who expressed more d'assatisfactioni with their own smoking, and who exhibited a significantly lower prevalence of smoking; a higher rate of attempted! discontinuations, and a higher rate of deliberately diminished amount: of cigarettes consumed. There is no readily available convincing explanation for this finding, hut it does demonstrate that the smoking habit is linked with so many aspects of a person's psychological make-up that'mere intellectual awareness of risks involved, even among those with rather intimate and intensive con- tact with the subjpct, is insufficient to overcome other dynamic factors involved. On the other hand, Horn~ (12) related that among several approaches used to modifyy high school children's smoking habits, the "remote" approach involwing a logical appeal to the intelligence of the boys and girls proved 375

~ to be the relatively most effective one. There was evidence, according to Horn, that "this approach was most effective among those who smoked in emulatiom of their parents, and less so among, those who smoked for the N more emotionally tinged reasons of compensation or rebellion." Unfortu- nately, it is not entirely clear from the description of the study how trust- worthy was the id'entification~ of' the motives underlying these children's smoking. Yet, these results agree logically with the position that there is no single cause or explanation of smoking,, but that smokers may start, continue, and discontinue smoking, in response to different inner needs and external influences, social and other. SUMMARY Scientific investigations into the psycho-social aspects of smoking are relatively recent and, except for a few large-scale and systematic studies, leave much to be desired from~ the standpoint of methods and conceptions. However, evidence from~ a few sound studies, and converging evidence from many studies, none of~ which could stand up by itself under exacting serutiny, permit the follbwing statements concerning the relationship between psycho- social characteristics and! smoking behavior: 1. As far as is known from actual d'ata, few children smoke before the age of 12, probably less than five percent of the boys and less than one percent of the girls. From age 12 on, however, there is a fairly regular increase in the prevalence of smoking, At the 12th grade level between 40 to 55 percent of children have been found to be smokers. By age 25; estimates of smoking prevalence runias hibh as 60 percent of men and 36 percent of women. There is a further increase up to 35 and 40 years after which a drop is observed. In the 65 and over age group, prevalence of smokinQ, is only approximately 20 percent among men and 4 percent among women. 2. Smokers and non-smokers differ in a number of demographic character- istics but no single comprehensive theory to~explaim smoking is suggested by the demographic data taken by themselves: 3. Although~ smokers are different from non-smokers psychologically and socially;, there are many differences among smokers and among non-smokers, so that some smokers may be like some non~smokers. 4. Smoking appears to be not one behavior but a range of psychologically diverse behaviors each of which may be indluced by a different combination of factors and may serve different needs. Therefore no single explanation cam suffice: 5. Social stimulation appears to play a majpr role in a young person's earliy, and first experiments with~ smoking. 6. There is suggestive evidence that early smoking may be linked with self-esteem and status needs although the nature of~ this linkage is open to different interpretations. 7. No scientific evidence supports the popular hypothesis that smoking among ad'olescents is an expression of rebellion against authority. 376 VI:

8. No differences in intelligence between smokihg and non-smoking chil- dren have been found, but smokers are more frequent among,those who fall behind in scholastic achievements. 9. No smoker personality has been established but certain personality fac- tors have been reported to be associated with smoking, among them extro- version, neuroticism, and a disproportionate prevalence of psychosomatic manifestations. 10. Stress appears to be less associated with prevalence of smoking than with fluctuations in amount of smoking. 11. The culturatrnilieu seems to have a strong influence, a permissive cul- tural climate tending, to promote and a rejecting, or outright prohibitive one to inhibit smoking. 12. Less is known about discontinuation~than about beginning,of smoking, although~there is good evidence that it is related to the beginning of the habit, its nature, and duratiom CONCLUSION The overwhelming evidence points to the conclusion that smoking-its beginning, habituation, and occasional discontinuation-is to a large extent psychologically and socially determined: This does not'rule out physiological factors, especially in respect to habituation, nor the existence of predisposing constitutional or hereditary factors. REFERENCES 1. A Report on Personality Factors and Smoking. Part 2. [Eysenck supv] Prepared by Mass-Observation Ltd. August 1962. 27, 24 p. 2. Bothwelly P. W. The epidemiology of cigarette smoking in~ rural school children. Med Offr 102: 125-32, 1959: 3. Cartwright, A., Martin, F. M., Thompsony J. G. Distribution and devel- opment of smoking habits. Lancet 2: 725-7; 1959. 4. Davis, R. Cigarette smoking motivation study. Research Services, London, 1956, 5. Earp, J. R. The student who smokes. Yellow Spring$„ Antioch 1931. 64 p. 6. Eysenck, H. J., Tarrant, M., Woolf, M., England, L. Smoking and personality. Brit Med J 1: 1456-60, 1960: 7. Haenszel, W'., Shimkin, M. B., Miller, H. P. Tobacco smoking patterns in the United States. Public Health Monog No. 45: 1-111, 1956. 8. Hammond, E. C. Report t'o ~ the Surgeon General's Advisory Committee on Smoking and Health. 9. Hammond, E. C., Percy,,C. Ex-smokers. N Y J Med 58: 295C-9,1958. 10. Heath, C. Differences between smokers and nonsmokers. AMA Arch Intern Med' 101: 377488, 1958. 377

11. Horn, D. Behavioral aspects of cigarette smoking. J Chronic Dis 16: 383-95, 1963. 12. Horn, D. Modifying*smoking habits in high school students. Childten~ 7: 63-5, April 1960. 13. Horn, D., Courts, F. A., Taylor, R. M., Solomon, E: S. Cigarette smoking among, high school students. Amer Public Health 49:, 1497, 1959. 14. Kissen, D. M. Emotional factors cigarette smoking and' relapse in, pub monary tuberculosis. Health Bull' 18: 38-44, 1960. 15. Kissen, D. M. Psycho-sociall factors in cigarette smoking, motivation. Med 0$r 104: 365-72, 1960. 16. Lawton, M. P. Psycho-social aspects of cigarette smoking. J Health Hum Behav 3: 163-70, 1962. 17. Lawtons M., Goldinan, A. Cigarette smoking and attitude toward' the etiology of lung cancer. J Soc Psychol 54: 235-481 1961. 18. Lawton, ML, Phillips, R. The relationship between excessive cigarette smoking and psychologieall tension. Amer J' Med Sci 232: 397-402, 1956. 19. Lilienfeld, A. Emotional and other selected characteristics of cigarette smokers and nonsmokers as related to epidemiologicallstudies of' lung cancer an& other diseases: J N'at Cancer Inst 22: 259-82, 1959. 20. Lynn, R. b'1. A study of, smokers and non-smokers as related to achieve- ment and various personal characteristics. [Abstract] In,: Res Prog No. 464, p. 164, 1948'. 21. McArthur, C. C: The personal' and social psychology of! smoking. In: James, G., Rosent'hal; T: e& Tobacco and Health. Springfield, Ill., Thomas, 1961. p. 201-9. 22. McArthur, C:, Waldron, E., Dickinson, J. The psycholbgy of smoking. J Abnorm Soc Psychol 56: 267-75, 1958. 23. Matarazzo, J. D., Saslow, G. Psychological and related characteristics smoking: A study of schooU children. Pediatrics. In press as of Sep- 30. Salber, E. J., and others. Recreational activities and attitudes toward Summer 1963. secondary school children. J Health Hum Behav 4: 118-29, No. 2, 29. Salber, E. J., Welsh, B., Taylor, S. V. Reasons for smoking given by In press as of September 1963. 28. Salber~, E., Worcester, J. Change in women's smoking patterns. Cancer. Public Health 51: 1780-9,, 1961. dents, related to sociall class and parental smoking habits. Amer J 27. Salber, D., MacMahony B. Cigarette smoking among high school stu- income. USDA Market Res Rep No. 189, 1957. 26. Sackrin, S:, Conover„ A. Tobacco smoking ini the U.S. in relation to 1957. 25, Moodle;, W. Smoking, diinking, and nervousness. Lancet 2: 188-9, terns. J Abnorm Soc Psychol 56: 329-38, 1958, logical test, and organismic correlates of interview interaction, pat~ 24. Matarazzo, R. M., Matarazzo, J. D., Saslow, G., Phillips, J. S. Psycho- of smokers and non-smokers. Psycholl Bull 57: 493-513, 1960. tember 1963, 378

31. Salber, E. J., Goldman, E., Buka„M., Welsh, B. Smoking habits of high school students in Newton, Mass. New Eng J Med 265: 969-74, 1961. 32. Salber, E. J., MacMahon, B. Smoking habits of high school students related to intelligence and' achievement. Pediatrics 29: 780-7, 1962. 33. Schonfeld, J. Special report to the Surgeon General's Advisory Com- mittee on Smoking and Health. 34. Schubert, D. Volunteering as arousal-seeking. [Abstract] Amer Psychol 15: 413, 1960. 35. Seltzer, C. Masculinity and smoking, Science 130: 1706-7, 1959. 36. Strachey, J., ed. Sigmund' Freud three essays on the theory of sexuality. In: Inst Psycho-Analyt Lib. Lond'on, Hogarth, 1962. No. 57, p. 1-130. 37. Straits, B., Sechrest, L. Further support of some findings about the characteristics of smokers and non-smokers. J Consult Psychol In press; 1963. 38. Thomas; C. B. Characteristics of smokers compared with non-smokers in a population of healthy young, adults including observations on family history, blood! pressure, heart rate, body weight, cholesterol, and! certain psychologic traits. Ann Intern Me& 53: 697-718, 1960: 39. Todd, G. Statistics of smoking. 2d' editiom Research Paper No. 1. The Tobacco Manufacturers' Standing Committee. London, 1959. 379

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Contents PHYSIQUE OF SMOKERS . . . . . . . . . . . . . . . . SOMATOTYPE CLASSIFICATION . . . . . . . . . . . . MASCULINITY . . . . . . . . . . . . . . . . . . . . . BODY WEIGHT . . . . . . . . . . . . . . . . . . . . . PROSPECTIVE STUDY . . . . . . . . . . . . . . . . . CONCLUSION . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . Page 383 383' 383 384' 385 387 387 a_

Chapter 15 MORPHOLOGICAL CONSTITUTION OF SMOKERS' PHYSIQUE OF SMOKERS Several studies deal with the relation of morphological constitution and smoking. In 1929 Diehl (2) reported a study of the physique of smokerss as compared to non.smokers in a group of freshmen at the University of Minnesota. Measurements of height and weight were obtained at the time of the freshman entrance examination, and smoking habit was determined from a questionnaire item based simply on whether the student did or did not smoke. No: significant differences were found in height, weight, and height/weight ratio between the 445 smokers and 441 non-smokers. How- ever, the design of the study limits the reliability of the information. SOMATOTYPE CLASSIFICATION A more satisfactory but still limited study was reported' by Parnell (4)' in 1951. Using Sheldon's somatotyping technique, Parnell contrasted the classifications of smokers and non-smokers of 308 Oxford undergraduates. In smokers the most frequent somatotypes were the d'ominant endomorphs and endomorphic mesomorphs; the least frequent was the dominant! ecto- morph, witL the dominant't mesomorph in the middle. For the non-smokers the most frequent somatotype was the dominant ectomorph, and the meso- morphic ectomorph; the least frequent were the end'omorphs and! the endomorphic mesomorphs, and again the dominant mesomorphs were in the middle. MASCULINITY In 1959 Seltzer (5)1 presented information on the relationship between physieaUmasculinity and'smoking in a group of 247 Harvard Collcge students who had been follbwe& for more than 15 years for smoking habits, as well as other information. From the smoking data, the subjects were classified into: three groups, non-smokers, moderate smokers and heavier smokers. When the subjects were sophomores, they were rated with respect to a body- build complex known as the masculine component, which referred to the element of masculinity as indicated by external morphological features. In measuring, this element, the more the pattern of anatomicall traits tends 714-422 0-64-26 383 I

toward the extreme masculine form, the stronger is the masculine component; the greater the departure from the extreme masculine type towards the feminine build, the weaker is the masculine component. The results of this study showed a statistically significant association between the strength of the masculine component and smoking habits. More specifically, it was found that weakness of the masculine component is significantly more frequent in smokers than in non-smokers, and' most frequent in heavier smokers. Furthermore, it was indicate& that the subjects with weakness of the masculine component showed a constellation of personality and behavioral traits that were, for the most part, not inconsistent with the findings of Heath (3) in his study of the differences between smokers and non-smokers. Although these findings were suggestive, they were recognized' by the author as being preliminary and tentative in nature and requiring further confirma- tion. Furthermore, the series on which these result's were obtained was relatively small and represented a highly selected population. Thomas (7), in her study of precursors of hypertension and coronary artery disease in more than 1,000: students at The Johns Hopkins University School of Medicine compared the group of non•smokers with the group of smokers for body weight among other characteristics. The group of 297 non-smokers included occasional smokers as well, and the 321 smokers in- cluded allismokers except non-smokers, occasional, ex-smokers, and unknown. Pipe, cigar, and mixed smokers were includedi ini the smoker category. The relationship of body weight to smoking habits was analyzed on the basis of percentage of overweight and underweight calculated from standard tables. Thomas found the percentage distribution of overweight and underweight was similar for smokers and non-smokers except at the upper end of' the distribution curve. There was an~ excess of smokers who were 30 percent or more overweight, and the subjects who were 40 percent or more overweight were all regular smokers. The non-smokers had also a greater frequency of individuals with 10 percent or more underweight than the smokers: The difference between smokers and non-smokers with regard'to this body weight classification was found to be statistically significant. The subjects were also compared for the ponderal index (height over the cubesoot of weight), with the smokers showing an excess of the unusually heavy body builds. In the introduction to her paper on the characteristics of smokers com- pared with non-smokers (of which the weight analysis was a part), Thomas wrote: "The finding that smokers, especially heavy smokers, have a higher mortality rate from coronary heart disease than do non-smokers makes it important to determine whether those who smoke are fundamentally different from those who do not smoke, or whether smokers and non-smokers are essentially alike. If alike, then smokers and non.smokers may be considered as a single population with a uniform life expectancy. If, however, smokers have constitutional differences from non-smokers, the two groups might have 384

I inherently different mortality rates, and one group could not serve as a control for the other in statistical studies." After detailing the significant differences noted in her data between smokers and non-smokers, with regard to history of'~ parental hypertension, heart rate, pulse pressure, body weight, and' other variables; Thomas conclnded that "It cannot be determined from the present data whether those individual characteristics which are more often found among smokers than non-smokers represent true constitutionat differences or are due to the effects of smoking. The differences observed' in the parental histories indicate that smokers and non-smokers have a somewhat different heritage, and' suggesti that at least some of the variations foun& in individual traits may be genetic in origin;" In a study of 167' adult male factory workers of Neapolitani parentage but, of American birth and upbringing, Damoni (1) reported' on rnorpho• logical correlates with smoking. The original series contained 2113 volunteers but 46 dropped out for various reasons, and the age range was most' extensive from 20 to 59 years of age. Damon's non-smoker category con- sisted of subjects not currently smoking,and had never been regular smokers. Cigar and pipe smokers were combined with cigarette smokers, and the statistical, analysis was based on the biserial correlation coefficient. As a result of his analysis, Damon found that smoking was associated at the 5 percent level withi bi-ilfiac/biacrominal breadth, subscapular skinf old, ectomorphy, and' physical activity; and at the 1 percent level with weighty height/cube root' of weight, endomorphy and somatotype group. Smokers of all grades had very similar levels of activity. On the other hand'; the most active and the least active men smoked more thani those of average activity-a finding which reflects a curvilinear regression of smoking on activity. Damon concludes: "The results show a consistent and significant tendency ... for lean meni to smoke more than stout or fat (but not mus, cular) men ... higher cholesterol levels among smokers . . . contrary to findings previously reported, smokers in this series were no less masculine in physique, were no more active and consume& no more alcohol than non-smokers." PROSPECTIVE STUDIES Tlie most extensive study of morphology as related to smoking habits is Seltzer's prospective study of 922' Harvard alumnil 13 years out of college, whose physical characteristics were recorded when they were under- graduates (6). The investigation was concerned with the morphological characteristics of' different classes of' non-smokers, cigarette smokers, pipe smokers, and cigar smokers, in a selecte&male population in order to ascertaini the extent, to which different smoking classes are phenotypically and genotypi- ca11w conditioned. The morphological material consisted of a series of anthropometric measurements takeni in the fall of 1942 as part of the routine. Harvard College medical examination. A total of 12 measurements weree obtained of various part's of the body, from which 10 body ratios or indices were computed. When the morphologic data were collected, there was no 385

prior consideration or knowledge of their ultimate use in this eorrelativee study with the subjects' subsequent: smoking histories. Information with respect to the smoking habits of these Harvard men was obtained in the fall of 1959 throug6the medium of a questionnaire (81 percent response),. The questionnaire covered approximately 16 years of smoking history and the subjects at the time of completing the questionnaire averaged 35 years of age, a period of maximum lifetime smoking experience. As far as smoking Of all the morpholbgical studies, this prospectiive study appears to present the best data available. Nevertheless, the Harvard students comprise a highly sel+ected sample. trend of the maximum "2 + packs daily" smokers. into exclusive groupings of cigarette only, cigar only, and pipe only in accordance with the form of tobacco used. All who regularly used more than one form of tobacco were omitted from this particular classification. For the analysis of degree or rate of cigarette smoking, there was a breakdown into five subgroups from occasional to 2+ packs a day. The prospective nature of the study, with the availability of the physical measurements madee during the college years, had the special advantage of representing a level of morphological status undifferentiatedl by individual variations resulting from modes of habit, diet, physical activity, health and disease of the subsequent adult years. The analysis was divided into three parts: comparison of non- smokers and smokers, variations among smokers according,to form of smok- ing, and variations among smokers as related to degree or rate of smoking. The comparison of 234 non-smokers and 688 smokers showed that the two groups were significantly differentiated both in morphologic dimen- sions and proportions: In every instance, the smokers had larger mean dimensions than the non-smokers, and in all'but one instance these differences were statistically significant. Smokers were consistently greater than non- smokers in height, weight, and in~the dimensions of the head„face, shoulders, chest, hip„leg, and hand. Similarly, the smokers of cigarettes only, pipes only, and cigars only, had larger mean dimensions than those of the non-smoker category. In addition, in eight out of ten bodily indices or proportions the smoker types showed mean deviations from the non-smoker that were all in the same direction and indicative of the same t'rendl A consistent graded' pattern of differentiation into a specific order of arrangement of non-smokers, cigarette only, pipe only„ and cigar only smokers, in that order, was found. Thus, for: example, in the case of weight, the cigarette only smokers were 4.37 pounds heavier than the non-smokers, the pipe only smokers 6.59 pounds heavier, and the cigar only smokers 10:41 pounds greater mean~ body weight. Analysis of the data dealing with amount of cigarette smoking did not show a regular significant body build differentiation according to rate or degree of smoking, but there were suggestions of a: positive linear trend from the lightest smoking category to the "1 to 2 paeks daily" followed by a downward categories are concerned, an attempt was made to obt'ain groupings as pre- cisely differentiated as possible. The primary classification separated the subjects into non-smokers and smokers. The non-smoker was defined as a person who had never smoked at all or had attempted an occasional smoke during his lifetime. Individuals who smoked occasionally but not every day were exclude& from~ the non-smoker category. The smokers were subdivided 386 -4

CONCLUSION The available evidence suggests the existence of' some morphologic differ- ences between smokers and non-smokers, but! is too meager to permit a conclusion. REFERENCES 1. Damon, A. Constitution and smoking. Science 134: 339; 1961. 2. Diehl, H. S: The physiquef of smokers as compared to non-smokers. A study of university freshmen. Minnesota Med 12: 421, 1929. 3. Heath, C. W. Differences between smokers and non-smokers. AMA Arch Intern Med 101: 377, 1958. 4. Parnell, R. W. Smoking and cancer. Lancet 1: 963, 1951. 5. Selteer, C. C. llascuiinity and smoking, Science 130: 1706, 1959. 6. Seltzer,, C. C. Morphologic constitution and smoking. JAMA 1'83: 639; 1963'. 7. Thomas, C: B. Characteristics of smokers compared with non-smokers in a population of healthy young adults, including observations on family history, blood pressure, heart rate, body weight, cholesterol and certain psychologic traits. Anm Intern Med 53: 697, 1960. 387 I1.S:6OVERNMEN7 PRINTING OFFILE:1964 U-714-422

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