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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