cigarette, the average length of time taken to smoke a cigarette (except in the highest number of puffs category), and the taking of more puffs at the end of the cigarette. These findings, and those of the study of Auerbach, et al. (11), add further support to the dose-response relationship between lung cancer and total cigarette smoke condensate exposure. SUMMARY AND CONCLUSIONS 1. Epidemiological evidence derived from a number of prospec- tive and retrospective studies coupled with experimental and path- ological evidence confirm the conclusion that cigarette smoking is the main cause of lung cancer in men. These studies reveal that the risk of developing lung cancer increases with the number of cigar- ettes smoked per day, the duration of smoking, and earlier initia- tion, and diminishes with cessation of smoking. 2. Cigarette smoking is a cause of lung cancer in women but accounts for a smaller proportion of cases than in men. The mor- tality rates for women who smoke, although significantly higher than for female nonsmokers, are lower than for men who smoke. This difference may be at least partially attributed to difference in exposure; such as, the use of fewer cigarettes per day, the use of filtered and low "tar" cigarettes, and lower levels of inhalation. Nevertheless, even when women are compared with men who ap- parently have similar levels of exposure to cigarette smoke, the mortality ratios appear to be lower in women. 3. The risk of developing lung cancer among pipe and/or cigar smokers is higher than for nonsmokers but significantly lower than for cigarette smokers. 4. The risk of developing lung cancer appears to be higher among smokers who smoke high "tar" cigarettes or smoke in such a man- ner as to produce higher levels of "tar" in the inhaled smoke. 5. Ex-cigarette smokers have significantly lower death rates for lung cancer than continuing smokers. There is evidence to support the view that cessation of smoking by large numbers of cigarette smokers would be followed by lower lung cancer death rates. 6. Increased death rates from lung cancer have been observed among urban populations when compared with populations from rural environments. The evidence concerning the role of air pollu- tion in the etiology of lung cancer is presently inconclusive. Factors such as occupational and smoking habit differences may also con- tribute to the urban-rural difference observed. Detailed epidemio- logic surveys have shown that the urban factor exerts a small influence compared to the overriding effect of cigarette smoking in the development of lung cancer. 276 7. Certain occupational exposures have been found to be asso- ciated with an increased risk of dying from lung cancer. Cigarette smoking interacts with these exposures in the pathogenesis of lung cancer so as to produce very much higher lung cancer death rates in those cigarette smokers who are also exposed to such substances. 8. Experimental studies on animals utilizing skin painting, tracheal instillation or implantation, and inhalation of cigarette smoke or its component compounds, have confirmed the presence of complete carcinogens as well as tumor initiators and promoters in tobacco smoke. Lung cancer has been found in dogs exposed to the inhalation of cigarette smoke over a period of more than two years. CANCEROFTHELARYNX Cancer of the larynx is a disease which predominantly affects males in the 55 to 70 year age group. In 1967, a total of 2,468 males and 329 females died of laryngeal cancer in the TJnited States. With the development and application of more effective therapy during the past 30 years, the death rate for cancer of the larynx appears to be dropping slightly (282, 289) ; however, the incidence con- tinues to rise. Figures from the Connecticut Cancer Registry (88) show that the age-adjusted incidence per 100,000 population of cancer of the larynx for males rose from 3.0 in 1950 to 5.6 in 1961. EPIDEMIOLOGIC`AL STUDIES A number of epidemiological studies have investigated the rela- tionship between smoking habits and the development of cancer of the larynx. The major prospective studies, as outlined in table 20, show that smokers of cigarettes run an approximately six-to- tenfold risk of dying from this form of cancer as compared to non- smokers. Smokers of pipes and cigars incur a three-to-sevenfold risk. The retrospective studies listed in table A21 uniformly show fewer nonsmokers and more smokers among eases wit.h cancer of the larynx than among matched controls. Table A22 summarizes the relative risk ratios derived from the retrospective studies. The wide variation is due to a number of factors, including type of popu- lation and interview technique. But, in general, the magnitude of most of these ratios is of the same order as in the prospective studies. Wynder, et al. (312) have distinguished between cancer of the intrinsic and extrinsic larynx. Tumors arising on the vocal cords are classified as intrinsic and constitute approximately 70 percent of the lesions. The extrinsic larynx is composed of those sections of the larynx excluding the vocal cords and may also be referred to as 277 TABLn Xl-Laryngeal cancer mortality ratios (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. -___. Prospective studies Number Author, year, cou"tly. reference Number and type of population Data FOllOW- collection UP years Hammond and HOI.", 1958, U.S.A. (fZ0). 187.783 white males 5c-69 years of age in 9 states. Questionnaire and follow- up of death certificate. Doll and Hill, 1964, Great Britain (74). Approximately Questionnaire 10 41,000 male and follow- British up of death physicians. certificate. Kahn U.S. male Questionnaire (Darn). veterans. and follow- 1966, 2.265.674 up of death U.S.A. person years. certificate. (139). ____ Hammond, 440,558 males Interviews 1966, 562,671 fc by ACS U.S.A. males 35-84 vo1u"teers. (118). years of age in 25 states. of laryngeal CanCer deaths Cigarettes/day Pipes, cigars COlIlIll~"t3 24 Cigarette smokers W/24. Cigar Data referring to mortality SM . .24 NS 0 3/24 Mired 4124 l`atio included cancer of esophagus and mouth. 16 SM ..16 NS 0 All smoke+8 by amount in gsame NS . _. . 1-14 1.00 15-24 __ __ __ ._ __. 1.00 >25 _. ._ _. _. ,, 7.60 Pipe and cigart t Includes data on ex- NS . 1.00 smokers of pipes and cigars. SM 5.00 No NS died of laryngeo- tracheal cancer. therefore l-14 gram SM set as 1.00 standard. Data combine laryngeal and tracheal carcinoma. R IL 54 NS ..__.....__. 1.00 (3) Pipe Refers to current cigarette I_ SM .51 l-9 ..__._._..... 3.27 (1) NS 1.00 (3) smokers only. NS 3 l&20 8.45(10) SM .10.33 (6) 21-39 .13.62(11) Pipe and cigar >39 ,............ 18.85 (3) NS 1.00 (3) All ,. 9.95(25) SM .._. 7.28(11) 4 57 NS ._..__._... 1.00 (3) Pipe and cigar Male data only. SM ..54 SM (age 45-64) 6.09(32) NS 1.00 (3) Pipe and cigar data refer to NS 3 SM (age 65-79) 8.99(18) SM 3.37 (4) males 55-84 years of age. TABLE ZO.-Loyi~~gcnl cmccr 7nwtalitjj ratios (cont.) (Actual number of deaths shown in parentheses)' SM - Smokes. NS = Nonsmokers. I'rosyective studies Author, year, country, reference Number and type of population Data collection Number of lawngeal caneel deaths Cigawttrslday Pipes, cigars C""l"lZ?"tS Wrir and Dunn, 1970, U.S.A. (906). 68,153 males Questionnaire 5-8 11 NS - No nonsmokers died of in various and follow- SM ..ll *lo 1.00 Inryn~.eal carcinoma, occupations up of death NS 0 220 ., . 5.00 therefore -cl0 smoker set in California. certificnt~. >30 5.84 as 1.00 standard. NS includes pipe and cigar smokers. SM includes ex-smokers. ' Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, 01' ex-smokers. t.he hypopharynx. These authors noted that the percentage of heavy smokers among the patients with cancer of both the extrinsic and intrinsic larynx was significantly greater than that among controls. However, it is of interest that the excess risk of laryngeal cancer among cigar and pipe smokers in this study could be attributed to the extrinsic laryngeal group. As in studies of oral cancer, it appears that alcohol consumption should also be taken into account in studies of laryngeal cancer. Wynder, et al. (872) reported a significantly increased risk of extrinsic cancer among those with alcohol intake above 7 ounces of whiskey per day. With less than this amount, no increased risk wa,s evident. Schwartz, et al. (&8), noted no effect in relation to alcohol intake. Further research into the interaction of these two variables is necessary. Auerbach, et al. (9) studied histological changes in the larynges of 942 men, age 21 to 95, who were autopsied at a single hospital between 1964 and 1967. Cases of primary cancer of the larynx were excluded from the study. Smoking histories for all cases were obtained from family members of the deceased by trained inter- viewers. The randomized histological sections were graded by one observer. Tables A23 and A21 summarize the findings in the true vocal cord. Of the men who never smoked, 7.5 percent had no cells with atypical nuclei, only -1.3 percent had sections with areas con- taining 60 to 69 percent of cells lvith atypical nuclei, and none had a higher percentage. The 116 ex-smokers had laryngeal histology similar to that of the nonsmokers, as far as atypical nuclei were concerned. HoLvever, disintegrating nuclei \vere found in JO.5 per- cent of the ex-cigarette smokers and in only ()..I percent of the remaining cases. Only one of the 9 1 cigar and or pipe smokers had no atypical cells. Three had carcinoma irl sitrc, and one case had a section showing early invasive primary carcinoma. The highest percentage of atypical cells IVWS found among the cigarette smokers. The proportion of cases with a high degree of cellular change increased with increased daily smoking. None of the pack-or-more-a-day smokers n-as free of atypical nuclei in the laryngeal epithelium. Of those ivho smoked t\vo or more packs per day, 85 percent had 1eGons xvith 60 percent or more atypical cells as compared to -1 percent of the nonsmokers. Between 10 and 18 percent of the cigarette smokers had areas of carcinoma irz sitl(, and .I of the 64-I cases showed early microscopic invasion. The thickness of the basal level of the true vocal cord was also directl! related to the amount smoked. 280 EXPERIMESTAL STUDY Dontenwill (76) has recently reported the development of an effective and practicable method 1)~ n-hi& small rodents (ham- sters. rats? mice) can be exposed to long-term passive inhalation of cigarette smoke in a mannel' nhich circumvents the fatal effects of acute toxicity. which ruincc! earlie:, attempts but allows for a dosage of smoke great enough to induce the development of chronic patho- logical changes. The SJ.rian Golden hamster was found to be the most suitable species for such inhalation experiments for several reasons : its resistance to pulmonar!- infections, its resistance to the effects of nicotine a.5 compared to that of rats or certain strains of mice, and, especially, its susceptibility to develop tracheobronchial cancers after treatment nith carcinogens, in contrast to its almost total freedom from the spontaneous development of these tumors. Dontenwill demonstl*atecl that the concentration of deposited cigarette smoke uas greatest in the hamster's larynx as compared to the other portions of the exposed respiratory tract (table 25)) and that the lar\-ngeal epithelium was the tissue which underwent the greatest smoke-induced histological changes. In studying the changes in the larynx, the author differentiated five stages of epithelial change, using as his reference the Atlas of Tumor Pathology of the Armed Forces Institute of Pathology (5). Table 26, quoted by Dontenwill, describes the five types of change. They range from benign. such as epithelial hyperplasia, to pre- malignant. exemplified by pseudoepitheliomatous leukoplakia. The results of the inhalation experiment are presented in figure -1 in which a dosage-related increase in the severity of the epithelial changes is represented in graphic form. The author also reported, and depicted with photomicrographs, the finding of an early inva- sive squamous cell carcinoma. This form of cancer is the predomi- nant type involving the human larynx. SUMMARY AND CONCLUSIONS 1. Epidemiological, experimental, and pathological studies sup- port the conclusion that cigarette smoking is a significant factor in the causation of cancer of the larynx. The risk of developing laryngeal cancer among cigarette smokers as well as pipe and/or cigar smokers is significantly higher than among nonsmokers. The magnitude of the risk for pipe and cigar smokers is about the same ol.cler as that for cigarette smokers, or possibly slightly lower. 2. Experimental exposure to the passive inhalation of cigarette smoke has been observed to produce premalignant and malignant changes in the larynx of hamsters. 281 TABLE 25.~Deposition of `"C-lubeled smoke pwticies in particular regions of the respimtoq tract' Organ Traced radio- activity 01-g?in CnCi) Head and palate 6.11 Head. palate Tongue 0.41 Oral cavity in total. Larynx (r 39 Trachea 0.26 Lungs 6.35 1 Total 14.12 Eitimated Deposition radio- of activity particles (nCi) ( % 1 Traced Proportional depwsition area of the in relatirm respiratory to the tract ProPortional j-3 1.6 0.1-0.3 X561-187 1 ,Zl.i 0.6 X62.3 1000 Xl 1~11).0 282 TABLE 26.-Classification of the five registeredstages of epithelial charzgcs at the lwynx'.' stage -.-__~ --__~ __-- ~- ~.-. . ~~ - ..--. .~ Drskerntosis (we- mature atypical Acanthosis (thickm- H, ,,erkr,xt<& Pnrakeratosis (in- cornification ing of stratum increased complete cornifica- changes in the Mitosis spinosum multi- cornificntion tion of nuclei in nucleus prolifern- cellular layer) (stratum corneum) the stratum corneum) tion of the basal 1. t'nchvdwmia (epithelial hywrplasia) + + t t t 2. Leuroplakin + +- 1 r t 4. t'apillrnnntou~ kwruplakia + t t +it f TOTAL 146 34 35 8 6 10 7 11 4 5 17 4 5 . . . . . . . . . . . . . . . 5 . . . . . . . 4 . . . . . . . . 3 2 . . . . . . . . . . . . . 52 c " ,I I I I 2 4 6 8 10 12 14 16 18 20 22-28 SMOKE EXPOSURE, months . ZONE ANIMAL &=ANIMAL LIVING O=LARYNX CANNIBALIZED FIGURE 4.-Effects of chronic cigarette smoke inhalation on the hamster larynx. Review of the results of the inhalation experiments: number of smoke-ex- posed animals with and without changes in the larynx, duration of smoke exposure, and number of animals still alive. SOURCE: Dontenwill, W. (7G). ORAL CANCER The cancers included in this category are those of the lips, tongue, floor of the mouth, hard and soft palate, gingiva, alveolar mucosa, buccal mucosa, and oropharyns. It is estimated that 15,000 of these cancers will be diagnosed in the United States in 1970, accounting for about 2.5 percent of the estimated 600,000 malignant neo- plasms reported (289). A variety of histological types of malig- nant neoplasms can affect these tissues, but squamous cell car- cinoma is by far the predominant type, accounting for about 90 percent of the cancers. The incidence of and mortality from oral cancers has remained steady over the past 20 to 30 years. The Connecticut Cancer Reg- istry (88)) which is a fairly reliable index of incidence, noted that the incidence among males remained between 15.8 and 16.3 per 100,000 population during the years from 1950-1961. Examination of mortality rates over the past 20 to 30 years (882, 289) reveals a similar constancy. The apparent lack of change in mortality from oral cancer in 284 contrast to the sharp increase that took place in lung cancer rates in those years is probably due to serreral of the following factors. First, pipe and cigar smoking are both significantly related to can- cer of the oral cavity, and the increase in cigarette smoking among men, noted between 193r and 1955, has been, to a large degree, accompanied by corresponding l,eduetions in the use of pipe.; and cigars. Second, aside from the V:CYiOUS changes which the Interna- tional Classification of Diseases (ICD) had undergone during t.hat period, the diseases discussed above are recorded in ICD Codes 140-148 which include some neoplwms not found to he related to the use of tobacco. The various sites of cancer themselves do not contribute equally to the o\~e~all 1,atc and are subject to nidely dif- ferent cure rates, so that their contl.i1)ution. to the total incidence rate is different from their colltri~Jiltil~ll to the c~vt>rall mortality rate from oral cancer. Although more than 31,000 cancers of the oral cavit)- were estimated ;1~ nelvl:- di:cyno.& ill 1967, the total number of individual5 rcco~~ierl ;is tlJ,ing front oral wncer during that year was only 6,71 x (~8:)). Oral cancer occurs predominantly in people of the middle and older age groups. More than 90 percent of all oral cancers occur in persons over age -15, with the average age at time of diagnosis approximating 60. Although the majority of oral cancers occur in men, there is recent evidence that the ratio of males affected to females affected is decreasing (2.57). ~EPII,E?~~IOI,~)GIC.L\L STUDIES The use of tobacco in various forms has been associated with the development of cancer of the oral cavity and pharynx. The studies in this area of concer1, at-t' ?rul~- international, many having been carried out in Asian :" :ll~ns as well as in the M'est. The major pr(J~im,: ; t' u!~i:lumic~logic~~l htudies have found in- creased rates of fhcw .`::I "`.:rs for cigarette smokers as well as for pipe and cigar sni:)kei~:: (see table 27). Pipe smoking, per se, has long been recognizt:cl :~s a cause (Jf lip cancer (?!I1 ) . The methodol- ogy and results of the numerous retrospective studies are sum- marized in tal,lti:.i X28 ar:d AZ&. These studies almost uniformly show significant relalionships between the various forms of tobacco use and )`.' `::"-c'-: 1,; -1 P c:`.:: ;:t\-ity and pharynx. Studir5 !I; .`$-. :!: ,t' 1;~: h:~~e examined the prevalence or inci- dence of pl'enliijJ~J:,.!.. :i~n& , ,G;lrch as oral lettkoplakia, as well as that of cancer of the oral cavitp. In many of thwe studies, forms of tobacco use not prevalent in lyestern countries have been investi- gated, including reverse smoking (in which the lighted end of t.he cigarette is kept in the mouth close to the palate) and the chewing 285 TABLE 27.-Oral cancer mortality ratios-prospective studies Author year. country, reference Number and type of population Data collection (Actual number of deaths shown in parentheses) SM= Smokers. NS = Nonsmokers. FOllOW- Number UP Years of Cigarettes deaths Pipes, cigars Comments Hammond 187.783 white Questionnaire 3 $6 20/56 Pipe MiXCd Data referring to mortality and males in 9 and follow-up 5/M 21/56 ratio do not include cancer of HOlYI, states 50-69 of death NS ..3 Cigar larynx and esophagus. 195R, years of aEe. certificate. 6/66 t Excludes two occasional U.S.A. only smokers. (110). Doll nnd Approximately Questionnaire 10 19 All smokera by amount Pipe and cigar No NS died of oral CBIICCI', Hill, 41,000 male and follow-up SM .19 in gram.9 NS ....... 1.00 therefore 1-14 gram 1964. British of death NS .. . NS - .............. SM ....... 1.00 smoker set as 1.00 Great physicians. certificate. 1-4 ............. 1.00 standard. Britain 15-24 ............ 0.25 (74). >25 ............. 5.25 - .... ..-- . Kahn U.S. male Questionnaire Xl/, 61 NS .............. l.OO(ll) Pipe Data do not include pharynx. (Darn), wternns. and follow-up SM .50 tCias/day 1-9 .... 0.86 (1) NS ....... l.OO(ll) t Refers to current cigarette 1966, 2.265.674 of death NS .ll lo-20 ............ 2.93(13) SM ....... 3.12 (4) smokers only. U.S.A. ,:cI`:ioll YCBTS. cel~tifirnte. 21-39 ............ 7.34(20) Cigar (139). >39 ............. 5.73 (3) NS ....... l.OO(ll) All .............. 4.09(37) SM ........ 4.11 (9) H~~IllOlld. 410,65;: males Interviews by 4 95 NS .............. 1.00 (`7) t Pipeand/or t Male data only. Pipe and 1966, T,C2,1;71 females ACS volunteers SM .33 SM (age 45-64) ... 9.90(63) cigar. cigar data refer to males U.S.A. :ii-' I ycnrs "f NS .. . SM (sge65-`79) .. 2.!33(25) NS ....... 1.00 (7) 55-84 years of age. (118). apt ill 25 states. SM ....... 4.94(15) Weir and FR,lS:i lN.ales Questionnaire 5-R 19 NS .............. 1.00 SM includes ex-smokers. Dunn, in vat ious and follow-up -10 ............. 3.69 NS includes pipe and 1970, occupations of death -t20 ............. 1.17 cigar smokers. U.S.A. in California. certificate. >3n ............. 6.62 (.W(i). All .............. 2.76 of "pan" or "Nass," which are mixtures of tobacco with either betel nut or lime ash, and other ingredients (241, 2.55, 256). Snuff dipping, a habit in which snuff is placed in the gum and ret.ained there for prolonged periods, has also been associated with the development of oral cancer (1118, 210)) as has the chewing of tobacco (124, 193,211,298). The risk of developing a second primary mouth or throat cancer, after the recognition of the first primary cancer, has been found to be greater in continuing smokers than in those who quit smok- ing. All of the patients studied by Moore (190) were asymptomatic for at least three years following the treatment of the first cancer. Of the 117 patients with adequate smoking histories, only 4 of 33 (9 percent) who quit smoking developed a new primary cancer. On the other hand, 27 of 74 (36 percent) who continued to smoke developed a second primary cancer. However, a study by Castigliano (53) of patients treated fol oral cancer did not show a greater risk of a second primary among continuing smokers. In this study, 5 of 26 (19 percent) of those patients who did not quit smoking developed a second primary cancer as compared to 9 of 51 (18 percent) of those who did quit. The rate of quitting smoking in the two studies is markedly dif- ferent (36 percent in the Moore study and 62 percent in the Casti- gliano study). From the data presented in the two papers, it is not possible to evaluate the other significant ways in which the pop- ulations may have differed. Keller (1~0) studied 408 males with histologically confirmed squamous cell cancer of the mouth or pharynx. This author dealt with the question of recurrent tumors in a somewhat different manner. The patients were observed for the development of a sec- ond or third primary cancer at an anatomically discrete site of the mouth and pharynx within a median period of three years after the first cancer. He found that a second or third cancer (termed a coexisting cancer) developed in 28 of the 408 cases. Among these 23 cases with 32 coexisting neoplasms, 21.7 percent were heavy smokers, but among their matched controls, there were no heavy smokers. Coexisting cancers were most commonly found on the soft Palate, an anatomical site that is in direct contact with the main- stream of tobacco smoke. More recently, Wynder, et al. (S1S) studied 62 male and 23 female patients with multiple primary cancers of the mouth and pharynx. They observed that heavy smoking prior to the develop- ment of the oral cancer was associated with a greater likelihood of developing a second primary. Also, continued smoking after t.he fil'st primary was found to have a significant association with the occurrence of a second primary. 287 With or without smoking, use of alcohol appears to contribute to the development of oral cancer (124, lJ0, 183, 2.97, 322). In a study of male veterans, Keller (110) found that heavy smoking and heavy drinking were associated with cancer of the mouth and pharynx. X:0 studies are presently available which determine the relative contributions and possible interactions of heavy smoking, heavy drinking, and concurrent nutritional deficiencies in the etiol- ogy of these cancers. EXPERIMENTAL STUDIES In 1964, the Advisory Committee to the Surgeon General on Smoking and Health (291) reported that cigarette smoke and ciga- rette smoke condensates had failed to produce cancer when applied to the oral cavity of mice and rabbits or to the palate of hamsters and t.hat the oral mucosa appears to be resistant in general to can- cer induction even when highly active carcinogens such as benzo- [alpyrene are applied. Some of the difficulties in experimental de- sign were attributed to the fact that mechanical factors, such as secretion of saliva, interfere with the retention of applied carcino- genic agents on the tissues of the oral cavity and pharynx. Positive results with certain carcinogens have, however, been obtained in the hamster cheek pouch, but it has also been pointed out that the cheek pouch lacks salivary glands and that its structure and func- tion differ from those of the oral mucosa. The majority of these studies are outlined in table AZ9. Although cigarette smoke condensate acts as a complete carcino- gen on mouse skin, the work of several authors (319) supports the concept that cigarette smoke contains cancer promoters that may be of special importance, particularly in oral carcinogenesis. Elzay (90) has reported that whole cigarette smoke is a promoting agent for the hamster cheek pouch. More importantly, regarding the chewing of tobacco, Bock, et al. (27. .30), Van Duuren, et al. (.Z!1$), and Wynder and Hoffmann ($21) have shown that unburned to- bacco products contain tumor promoters that might contribute to the promoting activity of the smoke. Roth, et al. (d?li , ~27) have shown that the dye-binding capacity of the DNA of oral epithelial cells is significantly enhanced in cigarette smokers in contrast to nonsmokers, probably reflecting an increase in the DXA content of oral epithelial cells in smokers. Smokers had values of dye-binding capacity intermediate between nonsmokers and "1 patients with proven oral cancer. Those smok- ers who refrained from smoking for up to six months showed a significant decrease toward more normal values. SUMMARYANDCONCLUSIONS 1. Epidemiological and experimental studies contribute to the conclusion that smoking is a significant factor in the development of cancer of the oral cavity and that pipe smoking, alone or in conjunction with other forms of tobacco use, is causally related to cancer of the lip. 2. Experimental studies suggest that tobacco extracts and tobacco smoke contain initiators and promoters of cancerous changes in the oral cavity. CANCER OF THE ESOPHAGUS Esophageal cancer accounted for 4,306 deaths among American males in 1967 and 1,321 deaths among females. The death rate from esophageal cancer has remained relatively constant since 1939. EPIDEMIOLOGICAL STUDIES The major prospective epidemiological studies (table 30) have indicated a significant relationship between smoking and esopha- gea! cancer. Overall mortality ratios for male cigarette smokers range from 1.74 to 6.17. There are insufficient data concerning females for establishing firm conclusions. A number of retrospective studies concerning the relationship of smoking and esophageal cancer are outlined in table A31 and &la. Smokers incur risk ratios ranging from 1.3 to 6.6 when compared with nonsmokers. As in studies of oral cancer, the effect of alcohol consumption must be taken into account in studies of esophageal cancer. Because a relationship between alcohol consumption and tobacco use is kno1v-n to exist, Wynder and Bross (310) analyzed the association between tobacco consumption and esophageal cancer after adjust- ing for alcohol intake. They found that in the absence of alcohol consumption, there was no association between the use of tobacco and esophageal cancer but that in the presence of alcohol consump- tion, an increasing relative risk with increasing number of ciga- rettes smoked was apparent, as well as an association between cigar and pipe smoking and esophageal cancer. More recently, Takano, et al. (Z'6), in a retrospective study of `?(I0 patients with esophageal carcinoma, found an increased risk mith smoking which was magnified by increased alcohol consump- tion. Martinez ( 183) analyzed the association of tobacco usage and esophageal cancer after controlling fol. age, sex, and alcohol consumption. Increasing relative risks with increasing tobacco use 209 TABLE 30.-Esophageal cancer mortu& ratios-prospective studies (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. Author, year, countrY, reference Number and type of population Data Follow- collection up years Number of esophageal cancer deaths Cigarettes/day pipes, cigars Commmts Hammond and HOlTl, 1958. U.S.A. (120). 1X7.783 white males in 9 states EDIM!, yenrs of age. Questionnaire and follow-up of death certificate. 3% 34 Cigarette smokers Pipe Mticd Data referring to NS ___ 1 15/33. 2/33 cigarette mortality ratios SM . ..33 Cigar smokers included cancer 2/3.1 13/33 of mouth and larynx. Doll and Approximately Questionnaire 10 29 All smokers bu amount tl'ipe and cigar t Includes ex- Hill, 41,000 mnlc and follow-up in grama NS 1.00 smokers of pipe 1964, British of death NS , ._ 1.00 SM 2.00 and cigars. Great physicians. certificate. 1-14 2.00 Britain 15-24 3.60 (74). >25 5.00 All 3.00 -____- __ Katm U.S. male Questionnaire 8 `A 111 NS l.OO(tl) Pipe t Refers to (Darn), veterans and follow-up NS 11 t1-9 1.76 (2) 1.99 (3) cigarette 1966. 2,265,674 of death SM . ..lOO 10-19 4.71(18) Cigar smoking U.S.A. person years. certificate. 20-39 .11.50(24) 5.33(12) OdY. (139). >25 7.65 (3) All 6.17(47) Hammond, 440.sj5X malrs Interviews by 4 46 NS 1.00 (6) Pipe and Cigar 1966. 562,671 females ACS volunteers. NS . 6 SM (age NS 1.00 U.S.A. 35 a4 years of SM 40 45-64) 4.1'7(32) SM 3.97(14) (118). age in 25 States. SM (age 65-79) 1.74 (8) (Actual number of deaths shown in parentheses) SM= Smokers. NS = Nonsmokers. . Author year. country. reference Number and type of population Data Follow- collection up years HirElYalIla, 265,118 male Trained PHS II/& SM . ..21 NS l.OO(p30 l.f?2 (SUB). All 1.82 ' Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellnncous, mixed, or ex-smokers. Comments Refers to all forms of smoking. NS includes pipe and cigar smokers. were noted. The consumption of very hot beverages was also found to be related to the development of esophageal cancer. PATHOLOGICALSTUDY Autopsy studies of smokers as compared with nonsmokers, spe- cifically observing the pathological changes in esophageal tissue, have been performed by Auerbach, et al. (15). A microscopic study was made of 12,598 sections of esophageal autopsy tissue from 1,268 men who died from causes other than esophageal cancer. The findings were strikingly similar to the abnormalities generally ac- cepted as representing premalignant tissue changes in the respira- tory tract epithelium. Esophageal epithelial cells with atypical nuclei (having an irregular distribution of chromatin) were found far more frequently in cigarette smokers than in nonsmokers. Basal cell hyperplasia and hyperactive glands were also found more fre- quently in cigarette smokers than in nonsmokers. An increase in frequency with amount of cigarette smoking was noted for both epithelial cells with atypical nuclei and basal cell hyperplasia. Tables A32 and A33 summarize these findings. EXPERIMENTALSTUDIES Kuratsune, et al. (156) investigated the possibility that the car- cinogens known to be present in tobacco smoke could penetrate the esophageal epithelium more readily if dissolved in aqueous ethanol. Mice were exposed to several compounds by esophageal intubation. Tissues were then removed and studied by fluorescence microscopy. Deeper penetration and a different distribution were found when B[a]P was dissolved in aqueous ethanol as compared to B[a]P in olive oil. It was also found that benzo[a]anthracene and fluoran- thene dissolved in ethanol solution or aqueous caffeine solution could penetrate the epithelium of the esophagus. Horie, et al. (132) reported on the development of 10 papillomas and one squamous cell carcinoma of the esophagus in a group of 63 mice periodically forced to drink a solution of benzo[a]pyrene dissolved in diluted ethanol. Twenty-six papillomas and one squam- ous cell carcinoma also developed in a group of 63 mice to which 4nitroquinoline l-oxide was administered in the same way. None of the 67 control animals given only diluted ethanol developed neoplasms. Several other authors have reported nitrosamine-induced esopha- geal cancer in experimental animals (56, 79, 80, 81) . As noted above, the presence of nitrosamines in cigarette smoke is still a subject of debate. 292 SUMMARY AND CONCLUSIONS 1. Epidemiological studies have demonstrated that cigarette smoking is associated with the development of cancer of the esopha- gus. The risk of developing esophageal cancer among pipe and/or cigar smokers is greater than that for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly lower. 2. Epidemiological studies have also indicated an association be- tween esophageal cancer and alcohol consumption and tthat alcohol consumption may interact with cigarette smoking. This combina- tion of exposures is associated with especially high rates of cancer of the esophagus. CANCER OF THE URINARY BLADDER AND KIDNEY EPIDEMIOLOGICAL STUDIES (BLADDER) Cancer of the urinary bladder accounted for 6,019 deaths among American males and 2,743 deaths among American females in 1967 (289). Incidence rates have increased from 1949 to 1962 (88)) but the death rates from bladder cancer have remained relatively stable during that period. Improvements in early diagnosis and therapy may have masked the increasing incidence of this disease. A number of epidemiological studies have indicated that smokers have an increased risk of contracting or of dying from bladder cancer (see tables 34 and A35). Certain of these studies include kidney cancer mortality in the results. The major prospective stud- ies, with the exception of that of British physicians, have shown bladder cancer mortality ratios among cigarette smokers ranging from 1.40 to 2.89. Smokers of more than 1 pack per day were shown to incur ratios of 3.42 to 5.41. The study by Doll and Hill (74, 7'5) of British physicians, on the other hand, reports death rates for smokers to be lower than those of nonsmokers based on 38 bladder cancer deaths. The mortality ratios for pipe or cigar smokers are substantially lower than those among cigarette smokers. Pipe smokers were shown by both Hammond and Horn (120) and Kahn (139) to incur ratios approximating 1.20. Retrospective studies (table A35a) have also shown an increased proportion of smokers among bladder cancer patients when com- pared with matched controls. Relative risk ratios for bladder can- cer among smokers range from 1.0 to 7.3 among all smokers and up to 10.3 among heavy smokers of all types. 293 TABLE 34.-Kidney and urinary bladder cancer--prospective studies-Mortality ratios (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. Author, yen=. Number ar.d Data Follow- Number country, type of collection up years of Cigarette/day Kidney Bladder Comments reference population deaths Pipe. cigar Hammond 187,783 white Questionnaire 3 I/(? and Horn, 1958. U.S.A. (120). males in 9 and states. intrrview. 287 NS 1.00(383 Pipe 20 3.42(41) Cigar NS .1.00(38) SM .1.06(19) Data include patients dying of prostatic carcinoma. Data refer to microscopically PlW"Wl carcinomas. Doll and Approximately Questionnaire 10 Hill, 41,000 male and follow- 1964, British UP of death Cl-eat physicians. certificate. Britain (74). Best, Approximately Questionnaire 10 1966, 78,000 male and follow- Canada Canadian UP of death (21). veterans. certificnte. Hammond, 440,66X males Interviews by 4 1966. 562.671 ACS U.S.A. females volunteers. (11X). 35-84 years of age in 25 states. 38 NS ..l.OO SM ..0.41 All SM bg amount in grams NS . ..l.OO l-14 .0.59 15-24 .0.65 >25 .0.76 All .0.`71 114 NS 1.00 Pipe Refers to 20 1.43(16) Cigar group. All 1.40(10) NS ..I.00 SM .1.16 (3) Bladder 138 SM ,115 NS 23 Kidney 104 SM 82 NS 22 Cigarettes Cigarettes Male data onl2/. NS .1.00(22) 1.00(23) Bladderincludes SM (age 45-64) .1.42(64) 2.00(59) other urinary SM (we 65-79) .1.57(28) 2.96(S) tract cancers. `I'ABLE 34.-KicOlc7!y und wimry hladdcr cancer-prospective studies--Mortality ratios (cont.) (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. Number and Data Follow- Number type of collection pom&ition "I) Years de:ftha Cigarette/day Pipe, cigar Kidney Bladder comments Kahn U.S. malt Questionnaire (Darn), vetcrnns and folluw- 13FF, 2,265,G74 up of death U.S.A. person certificate. (138). years. Hirayama, 265,118 male Trained PHS 1067, ana female nurse inter- Japan adults 40 view and (125). yea,? of age follow-up and older. of death certificate. Weir and FR,lRR males Questionnaire DlIIlll. in various pnd follnw- 1070, occupations up of death 1J.S.A. in California. certificate. (sns). -.- .___ S'/, Bladder NS _... .1.00(38) 1.00(52) Bladder includes 224 Pipe .1.32 (6) 1.20 (8) other urinary SM ,112 Cigar .O.W (6) 0.94 (10) tract calleers. NS . 52 Ciaarettes/day: Kidwey l-9 .a.97 (4) 1.10 (6) 141 10-19 .1.34(21) 1.93(U) SM ,102 20-38 l&8(16) 3.20(34) NS 39 >39 .2.76 (5) 2.62 (6) All . .1.45(46) 2.15(82) _.--. -___ l',$ SM 6 NS 1.00 Bladder cancer only. SM . . ..lO.OO (6) Refers to all forms of smoking. 6-8 Bladder 27 Kidney 27 NS a10 ?20 >30 All 1.0" NS . ..l.OO SM include ex- .0.&i .3.30 .2.57 .2.46 ?lO .1.52 smokers. 520 .2.81 NS include pipe >30 .5.41 and cigar A11 .2.89 smokers. ' Unless otherwise specified, disparities between the total number of deaths and thr sum nf the individual smoking categories are due to the exclusion of either wcasional. miscellaneous, mixed, or w-smokers. EPIDEMIOLOGICAL STUDIES (KIDNEY) A total of 5,894 Americans died of cancer of the kidney during 1967. A relationship between smoking and this type of cancer has been suggested by several epidemiological studies. The three major studies which separately examine the relationship of kidney cancer to smoking (table 34), namely those of Hammond (II 8)) Kahn (139), and Weir and Dunn (306)) have shown mortality ratios for all cigarette smokers to range from 1.42 to 2.46. Retrospective studies by Bennington, et al. (18, 19) have indicated a significant association between all forms of smoking and renal adenoma and adenocarcinoma. EXPERIMENTAL STUDIES Numerous experiments have been undertaken by many investi- gators to elucidate the relationship of tobacco smoking to bladder carcinogenesis. The two areas of major concern have centered upon the presence of a known bladder carcinogen, beta naphthylamine, in cigarette smoke and the presence of abnormal tryptophan me- tabolism in patients with bladder cancer. By virtue of data gathered concerning industrial exposure of workers, beta naphthylamine has long been known as a bladder carcinogen. Complementing such data was the work of Hueper, et al. (136) who subjected mongrel dogs to daily subcutaneous injec- tions and oral administration of commercial beta naphthylamine. Thirteen of the 16 animals developed bladder papillomas and car- cinomas of the bladder. Saffiotti, et al. (236) fed hamsters a diet containing up to 1.0 percent beta naphthylamine and observed that 18 of 39 animals developed bladder tumors, almost all typical tran- sitional cell carcinomas. More recently, Conzelman, et al. (5.9) ad- ministered beta naphthylamine to 24 rhesus monkeys for more than 30 months. Transitional cell carcinomas of the urinary blad- der were induced in 9 of the animals, and a dose-response relation- ship was apparent. Pailer, et al. (207') and Miller and Stedman (185) failed to find this amine in cigarette smoke. However, more recently, Hoffmann, et al. (127) identified it in cigarette smoke. The authors, noting the minute quantity present in each cigarette (2.2 x l&`g), hesi- tated to attach a biological significance to the finding. Of more recent interest have been the metabolites of tryptophan present in certain patients with bladder cancer. A number of nor- mal and abnormal metabolites of tryptophan have been found to be carcinogenic when tested by implantation in the bladders of mice. These include 3hydroxykynurenine (OHKy), 3-hydroxyanthranilic 196 acid (OHA), 3-hydroxy-2-amino-acetophenone (all orthoamino- phenols), the g-methyl ether of xanthurenic acid (CHXa) , xanthu- renic acid (Xa) , L-kynurenine (KY), quinaldic acid, and 3-meth- oxyanthranilic acid (3CHOA) (2, 36, 37, 39, 47, $8). OHKy and OHA are frequently present in human urine, as is kynurenic acid (WA). Certain investigators have concentrated their attention on the presence of abnormal tryptophan metabolites and increased amounts of normal tryptophan metabolites in the urine of patients with bladder cancer as compared with selected controls (1, 10, $6, 97, 148, 211, 2;3, 32.9). These authors have observed the increased excretion of Ky, KyA, OHKy, anthranilic acid, OHA, and acetylky- nurenine in such patients. Yoshida, et al. (Jz!?), in a recent study concerning the relationship between tryptophan metabolism and heterotopic recurrences of human urinary bladder tumors, reported that those patients with recurrences showed abnormal metabolfte excretion more often than those without recurrences. The relationship of smoking to these biochemical findings is presently uncertain. Kerr, et al. (123)) in 30 experiments on 3 smokers and 3 nonsmokers who were given large doses of trypto- phan, found that smoking increased the urinary excretion of OHKy and OHA and decreased that of N'methylnicotinamide (an end product of tryptophan metabolism). Kerr concluded that smoking interferes with the normal metabolism of tryptophan. Recently, Brown, et al. (is) studied 15 adults under smoking and abstinence conditions and found that except for the basal excretion of acetylky- nurenine, tryptophan metabolite excretion did not change with smoking or cessation. The authors also compared 13 nonsmokers and 17 regular cigarette smokers under basal and tryptophan- loaded conditions. No differences were observed in the excretion of the measured tryptophan metabolites. However, due to its instabil- ity, OHA was not measured. The authors concluded that the rela- tionship of smoking to urinary bladder cancer was probably not via its effect on the kynurenine pathway of tryptophan metabolism. Another experimental approach to the relationship of smoking and urinary bladder cancer is reflected in the work of Schlegel, et al. (241, 215). The authors observed an elevated concentration of certain ortho-aminophenols in the urine of bladder cancer patients and cigarette smokers, when compared with nonsmokers (241). More recently (215) , the same group compared the chemilumines- cence of the urines of smokers, nonsmokers, and bladder tumor patients. They noted that nonsmokers showed the lowest level of luminescence (which they relate to the presence of aromatic hydro- carbons) and the bladder tumor patients the highest level. The normal cigarette smokers' level was found to be intermediate. 297 TABLE 36.-Pancreatic cancer mortality ratiosqrospective studies (Actual number of deaths shown in parentheses)' S.M x Smokers. NS = Nonsmokers. .____- Author. year, Number and Data I+llOW-UP Number Comments country, type of collection years of deaths Cigarettes Pipes, cigars reference population ___~ Best. Appro\imntelp Queutionnni;~ F SM 35 Currntt ~cigarcttes OnLY) Pipes -- 7x.000 male Canadian vrternns. and folk,w-up of death crrtiiicate. NS 1.00 NS .l.OO 20 .,.. 2.37 (7) NS .l.OO SM .2.63 (1) -~ ~-___ -: Hammond 140,55X male5 Intcrvicms b, 4 262 NS~.. 1.00 (29) Male data only. 19GG St;L'.liil fcmnies ACS SM . ..a233 SM (age U.S.A. .15-x4 )Iw,w v~,ln"tre~.s. NS 29 45-64 ) Z.G9(158) (IIY). of nge in 25 SM (age stntrs. 65-79) 2.17 (75) Kahn (Darn ) 10 c G __ 344 NS 1.00 (88) Pipes ~~~ t Refers to current smokers tSM . ..256 1-9 0x7 (8) NS .1.00(88) of all types. NS X8 lo-20 1.93 (65) SM ..0.74 (8) 1J.S.A. per`s,," yr?ll'b. certifiratc. 21-39 2.18 (43) Cigar8 ( I.79 , >39 1.87 (7) NS .l.OO(SS) All 1.84(125) SM .1.52(27) Both NS .l.OU(RUt SM .0.93;13; Hirasrima, 265.11~ malr Trained PHS 111 SM 14 NS t. 1.00 - l!lCi, and femnle nurse inter- 1 (Pa0 1.44 All 2.43 NS includes pipe and cigar smokers. At present, no definite conclusions can IX: rlra\vn concerning the interrelationships of bladder cancer, abnormal tryptophan metab- olism, and tobacco smoking. Further study is required in this and the other areas of bladder cancer pathophysiology. SUMMARY AND CONCLUSIONS 1. Epidemiological studies have demonstrated an association of cigarette smoking with cancer of the urinary bladder among men. The association of tobacco usage and cancel' of the kidney is less clear-cut. 2. Clinical and pathological studies have suggested that tobacco smoking may be related to alterations in the metabolism of trypto- phan and may in this way contribute to the development of urinary tract cancer. CANCER OF THE PANCREAS Several prospective epidemiologic studies have suggested a rela- tionship between cigarette smoking and cancer of the pancreas (table 36). A retrospective study of 465 cases of pancreatic cancer by Ishii, et al. (137) has shown a dose-related increased risk of pancreatic cancer in association with smoking. Analysis of dietary data revealed that the relative risk for pancreatic cancer from smoking was considerably greater than from dietary factors. No experimental studies relating to this question have been reported. SUMMARY AND CONCLUSIONS Epidemiological studies have suggested an association between cigarette smoking and cancer of the pancreas. 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