TABLE AIS.--Studies concerning the relationship of smoking to infectious respiratory disease in hunms (Actual "umber of cases shown in parentheses) SM = Smokers NS = Nonsmokers Author, Ye*=. Number and Data country, type of collection Results Comments reference population Mills, 118 male and Hospital Cases Controls The author stated that 1960. female patients Interview. Mean age . . . . . . . . 49.6 49.6 there was a U.S.A. with pneumonia NS . . . . . . . 16.26 25.21 significant difference (167). and 472 healthy Cigarettes only . . . . 63.66 62.33 in tobacco "sage individuals fmm Mixed . . . . . . . . . . . . . . . . . . . . . . ..*.. 21.19 22.46 between the "random" sample. two gro"ps. LOW& 620 male and Interview by Males Ft??WltX Cigarette smokers 1966, 135 female trained CCUlt% Controls Cams chtrols include pipe smokers. England tuberculceis social NS . . . . . . . . . . . . . . . 2.6 8.1 37.3 61.4 The author noted a (157). patients and 419 worker. Cigarettes/day: l-9 . . . . 9.2 12.9 20.6 25.7 significant deficiency male and 249 10-19 . . . . . . . . . . 38.1 35.6 30.8 20.5 oi'non- and light female control 20-29 ,,............. 29.4 21.4 smokers and a" outpatienti. 30-39 .,............. 11.3 9.3 11.4 2.4 excess of heavy >ro . . . 9.4 6.7 smokers e.mo"g the cases ~~ Dowling. Individuals Interview and Ezposed to placebo &posed to infeetima agent No statisticnlly et al.. exposed to medical Percent Percent 1967. significant "infectious examination. developing developing differences U.S.A. cold agent" Number "Cow' Number "cold" noted. (76). and placebo. NS . ..t............ 111 10 323 34 SM .,.....,......... `I'8 14 249 36 TABLE A15.-Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.) (Actual number of cases shown in parentheses) SM = Smokera NS = Nonsmokers Author. ye*=, countrY, reference Number and type of population Data collection Results Comments Boake, 1958. U.S.A. (9.7). Parents of 59 families. Interview NS . . . . . . . . . . . . . . . . . . . . . . . ..(24) Cigarettes/day: l-10 (19) 11-20 . . . . . . . . . . . . . . . . . ..(25) >20 (19) Pipe. cigar . . . , ,. (14) Number of No statistically Pl38lXt- reepiratory r11nesse.d significant years iam?sees person-year* differences 120 624 6.2 noted. 99 629 6.3 108 486 4.6 99 424 4.3 12 304 4.2 Shah et al.. 1959, India (205). Tuberculosis Survey, X-ray, institute and emploYee8. interview. Tuberculous Normal or t Numbers in bu X-ray nontuberculous parentheses NS .,...................... t10 (19.7) 178 (168.3) represent figures SM _...,,,............_.... 36 (26.3) 215 (224.7) "expected" by use of 2 x 2 contingency table. Tuberculoua employees were found to have significantly fewer nonsmokers and more smokers. TABLE A15.-Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.) (Actual number of cases shown in parentheses) SM = Smokers NS = Nonsmokers Author. year, Number and countl;y; type of reference vooulation Data collection Results Comments Brown 306 male and et al.. 1961, Australia (4). female tuberculosis clinic pntients, 221 male and female outpatients. Interview Smoking habits prior to diagno& Tuberczdous patients (percent) NS . .._................ ..__... 9.1 Cigarettes/day: l-9 10.5 IO-19 ,,........,.... 34.3 20-29 26.3 30-39 . . . . . . . . 7.2 >ro . . . . . . . ..~~....... 6.2 Pipes ,,..._._. ,..,,_,.....,_.. 5.9 Controls (percent) 19.9 15.4 19.5 25.8 6.4 9.1 4.6 Data presented only on Queensland S8nlplC. The authors noted rhat the significant difference between the patients and controls WBS not present when the groups were matched for alcohol intake. Havnes et *I., 1966. U.S.A. (108). 191 male prep school students. Interview Average number of respiratory illnesses/l0 students (adjusted for age) All 8cucre lower All All smere or combined respiratory respiratory respiratory episodes episodes episodes NS (99) 11.1 1.6 0.36 SM (92) . . . . 20.2 6.7 3.34 P*rIlell et al., 1966 Canada (181). 47 smoking- Interview Median number of illnesses/student The authors noted nonsmoker pairs and health All All that these of student nurses service respiratory other differences were matched for age records. disaasest illnesses stntistically und parents NS (47) . . . . . 2.08 2.99 significant. occupational SM (4'7) . . . . . . . 2.64 5.00 t Particularly C&.5. tracheitis, bronchitis, and pneumonia. TABLE AX.-Studies concerning the relationship of smoking to infectious ,respiratory disease in hmans (conf.) (Actual number of cases shown in parentheses) SM = Smokers NS = Nonsmokers Author, year, Number and Data country. type of collection Results Comments reference population Peters 1,496 Harvard Medical his~tory, Number of visita to etudent health unit for rcwimtmy illness/student t p5 .,.,................ 2.60 Finklea 1,811 male Questionnaire Heavy smokers-21 percent more clinical illnesses than nonsmokers: The authors also et al., colll=ae prior to 20 percent more requiring bed rest than nonsmokers noted that: 1969 students. A2/HK/63 Liph't smokers-10 percent more clinical illnesses than nonsmokers; (a) Smokers U.S.A. epidemic and 7 percent more requiring bed rest than nonsmokers. exhibited (83). follow-up on serologic morbidity. evidence of increased subclinical A2/HK/C8 infection. (b) Therewasno difference in the vaccination status between smokers and nonsmokers. .I TABLE AlG.-Complications developing in the postoperative period in patients undergoing abdominal operations Men over 20 Percent Percent Group CCWZS broncho- chest Percent Percent pneumonia t&al Ck&W bronchitis and complicntia" ateleetasis rate Smokera 300 41.7 63.0 6.3 68.3 Light Smokers . 180 68.4 27.7 3.9 31.6 Nonsmokers . . 66 92.6 6.0 1.6 7.6 Women over 20 Smokers . . . . 23 39.1 43.6 11.4 60.9 Light Smokers 62 77.6 20.9 1.6 22.6 Nonsmokers . 518 88.8 8.1 3.1 11.2 SOURCE: Morton. H. J. V. (f7s) TABLE A17.-Arterial oxygen saturation before and after operation Arterial oxygen saturation (percentage) Group CCL% Before number operation Day 1 Day 2 Day 3 1 94 93 94 2 94 93 94 . Nonsmokers . 3 96 93 34 4 95 90 84 . . 6 94 90 33 . . 6 95 91 89 91 7 92 89 81 89 Smokers . . 8 91 89 86 89 9 93 91 88 92 10 90 87 88 92 SOURCE: Morton. A. (171). 230 CHAPTER 4 Cancer Introduction ........................................ Lung Cancer ....................................... Epidemiological Studies .......................... Prospective Studies .......................... Retrospective Studies ........................ Lung Cancer Trends in Other Countries ............ Histology of Lung Tumors ........................ Lung Cancer Relationships in Women .............. Lung Cancer, the Urban Factor, and Air Pollution. ... Lung Cancer and Occupational Hazards ............ Uranium Mining ............................ Other Occupations ............................ Nickel ...................................... Asbestos .................................... Arsenic ..................................... Chromium ................................... Pathological Studies. ............................. Pulmonary Carcinogenesis ........................ General Aspects of Carcinogenesis ............. Polynuclear Aromatic Hydrocarbons ....... Nitrosamine Compounds. .................. Pesticides and Fungicides. ................ Radioactive Isotopes ..................... Inhibitors of Ciliary Movement ........... Experimental Studies ...................... Skin Painting and Subcutaneous Injection. .. Tissue and Organ Culture ................ Tracheobronchial Implantation and Instillation ...................... Inhalation ............................. Reduction in Tumorigenicity .............. Summary and Conclusions ........................ Cancer of the Larynx .................... Epidemiological Studies .............. Pathological Study .................. Experimental Study ................. Summary and Conclusions ............ Oral Cancer ............................ Epidemiological Studies .............. Experimental Studies ................ Summary and Conclusions ............ ........... ........... ........... ........... ........... ............ ........... Page 237 239 240 240 240 244 246 251 252 256 256 256 256 257 257 257 258 258 258 264 264 266 266 267 267 267 267 268 268 275 276 277 277 280 281 281 284 285 288 289 233 Cancer of the Esophagus ............................. Epidemiological Studies .......................... Pathological Study .............................. Experimental Studies ............................ Summary and.Conclusions ........................ Cancer of the Urinary Bladder and Kidney .............. Epidemiological Studies (Bladder) ................. Epidemiological Studies (Kidney) ................. Experimental Studies ............................ Summary and Conclusions ........................ Cancer of the Pancreas ............................... Summary and Conclusions ........................ References ......................................... FIGURES 1. Lung cancer, Finland and Norway . . . . . . . . . . . . . . . . . . . 2. Percent of smoking dogs with tumors . . . . . . . . . . . . . . . . 3. Percent of lung lobes with tumors in smoking dogs . . . . . 4. Effects of chronic cigarette smoke inhalation on the 245 274 274 hamster larynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284 1. 2. A3. A4. 5. 6. A7. 8. 9. 10. LIST OF TABLES Lung cancer mortality ratios . . . . . . . . . . . . . . . . . . . . Lung cancer mortality ratios for males by duration of cigarette smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . Outline of methods used in retrospective studies of smoking in relation to lung cancer . . . . . . . . . . . . . Group characteristics in retrospective studies on lung cancer and tobacco use . . . . . . . . . . . . . . . . . . . . . . . Annual means of total lung cancer mortality and sex ratios for selected periods in Finland and Norway Epidemiologic and pathologic investigations concern- ing smoking and histology of lung cancer . . . . . . . Grouping of pulmonary carcinomas . . . . . . . . . . . . . . Tumor prevalence among males and females 35-69 years of age, by t.ype of tumor and smoking category . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Epidemiologic investigations concerning the relation- ship of lung cancer to smoking, air pollution, and urban or rural residence . . . . . . . . . . . . . . . . . . . . . . Pathologic and cytologic findings in the tracheo- bronchial tree of smokers and nonsmokers . . . . . . P age 289 289 292 292 293 293 293 296 296 299 299 299 299 241 244 323 329 246 247 334 250 253 259 234 LIST OF TABLES (Continued) (A indicates tables located in appendix at end of chapter) 11. Identified or suspected tumorigenetic agents in cigarette smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A12. Autopsy studies concerning the presence of radio- activity in the lungs of smokers . : . . . . . . . . . . . . . A13. Experiments concerning the effects of the skin paint- ing or subcutaneous injection of cigarette smoke condensate or its constituents upon animals . . . . . A14. Experiments concerning the effect of cigarette smoke or its constituents on tissue and organ cultures . . A15. Experiments concerning the effect of the instillation or implantation of cigarette smoke or its constitu- ents into the tracheobronchial tree of animals . . . . A16. Experiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals . . . . . . . . . . . . . . . . . . 1'7. Data on pedigreed male beagle dogs of groups F, L, H,hand N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18. Summary of principal cause of death (days No. 57 through No. 875) in dogs of groups F, L, H, h and N 19. Data on dogs with lung tumors indicating type of tumor and lobe in which the tumor was found . . . . 20. Laryngeal cancer mortality ratios - prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ml. Outline of retrospective studies of tobacco use and cancer of the larynx . . . . . . . . . . . . . . . . . . . . . . . . . ~422. Summary of results of retrospective studies of tobacco use and cancer of the larynx . . . . . . . . . . . . . . . . . . . A23. Number and percent distribution by relative fre- quency of atypical nuclei among true vocal cord cells, of men classified by smoking category . . . . , A24 Number and percent distribution, by highest num- ber of cell rows in the basal layer of the true vocal cord, of men classified by smoking category . . . . 25. Deposition of I%-labeled smoke particles in particu- lar regions of the respiratory tract . . . . . . . . . . . . 26. Classification of the five registered stages of epithe- ha1 changes at the larynx . . . . . . . . . . . . . . . . . . 27. Oral cancer mortality ratios-prospective studies. . A%. Outline of retrospective studies of tobacco use and cancer of the oral cavity . . . . . . . . . . . . . . . . . . . . . A%a. Summary of results of retrospective studies of smok- ing by type and oral cancer of the detailed sites. . Page 265 335 337 343 346 349 270 271 272 278 354 358 359 360 282 283 286 361 368 235 429. 30. A31. A::la. A32. A33. 33. A3.5. A35a. ::6. LIST OF TABLES (Continued) (A Indicate5 tables located in appendix at end of chapter) Experimental studies concerning oral carcino- genesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Esophageal cancer mortality ratios-prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary of methods used in retrospective studies of tobacco use and cancer of the esophagus . . . . . Summary of results of retrospective studies of to- bacco use and cancer of the esophagus . . . . . . . . . Atypical nuclei in basal cells of epithelium of esoph- agus of males, by smoking habits and age . . . . . . Atypical nuclei in basal cells of epithelium of esoph- agus of males, by amount of smoking and age . . . . Kidney and urinary bladder cancer-prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary of methods used in l,etrospective studies of smoking and cancer of the bladder . . . . . . . . . . . . Summary of results of retrospective studies of smok- ing and cancer of the bladder . . . . . . . _ . . . . . . . Pancreatic cancer mortality ratios-prospective studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pngr 371 290 375 378 379 3% 294 381 383 29e 236 INTRODUCTION During the early years of this century, a number* of pathologists and clinicians reported a dramatic increase in the incidence of lung cancer. Autopsy studies and studies of lung cancer death rates re- vealed a significant increase beginning prior to World War I and continuing during the ensuing years. This epidemic of lung cancel continues to the present day, with nearly 60,000 deaths expected from this disease in the United States during 1970. Beginning in the 1920's, a number of reports appeared which suggested a relationship between lung cancer and tobacco smoking (4, 20.3, 278). Since that time, many clinical and epidemiological studies have been published which confirm this relationship. The 1964 Report (291) contains a thorough review and analysis of the data available at that time as well as an excellent discussion of the considerations necessary for their evaluation. Major epidemiological studies have demonstrated that smokers have greatly increased risks of dying from lung cancer compared to nonsmokers. An increased risk of lung cancer has been found for every type of smoking habit investigated, but two character- istics of the risk are particularly evident : The risk is much greater for cigarette smokers than for smokers of pipes and cigars, and among cigarette smokers a dose relationship exists. That is, the more one smokes, as measured by total pack-years of smoking, present level of smoking, degree of inhalation, or age at start of smoking, the greater is the Csk. It has also been shown that the risk of lung cancer among ex-smokers decreases with time almost to the level of nonsmokers; the time required is dependent on the degree of exposure prior to cessation. Pathologists have found that the squamous cell or epidermoid form of lung cancer is the most prevalent one in cigarette smoking populations and that this form accounts for a major portion of the rise in lung cancer deaths (2.5:). Such studies have also indi- cated a lower prevalence among smokers for oat-cell and adeno- carcinomas of the lung than for the squamous form, but in most studies a higher frequency of these tumors is found among smokers than among nonsmokers. Smoking has been implicated in the development of other types of cancer in humans. Among These is cancer of the larynx. A num- 237 ber of epidemiological studies have demonstrated incseased mar- tality rates for laryngeal cancer in smokers, particularly cigarette smokers, compared with nonsmokers. Autopsy studies have re- vealed that a clear dose-relationship exists between smoking and the development of cellular changes in the larynx, including carci- noma in situ. Cancers of the mouth and oropharynx have been found to be more common among users of all types of tobacco than among abstainers. Although smoking is a definite risk factor in the de- velopment of malignant lesions of the oral cavity and pharynx, its relative contribution in conjunction with other factors such as poor nutrition and alcohol consumption has not been fully clarified. Similarly, although smokers are more likely to develop carci- noma of the esophagus than nonsmokers, the relative additional contribution of smoking in conjunction with nutritional factors and alcohol consumption requires clarification. Smokers have been found to be more at risk for the development of cancer of the urinary bladder than are nonsmokers, and there is evidence to suggest that some smoking-induced abnormal meta- bolic product or abnormal concentration of a metabolic product may be responsible for this increased risk. In addition, cancer of the kidney is apparently more common in smokers than in non- smokers, but the epidemiologic evidence for this relationship is not as definite as for bladder cancer. Epidemiological studies have indicated an association between smoking and cancer of the pancreas. The significance of this rela- tionship is unclear at this time. Experimental studies have demonstrated the carcinogenicity of the condensate of tobacco smoke, or "tar." This material, when painted on the skin of animals, leads td the development of squam- ous cell tumors of the skin. Researchers have shown that this condensate contains substances known as carcinogens, capable of inducing cancers. Among these carcinogens are several chemicals which have been identified as tumor initiators, that is, compounds which initiate changes in target cells and also tumor promoters, or compounds which promote the neoplastic development of initi- ated cells. Other, as yet unidentified, factors are presumably also involved because the sum of the carcinogenic effects of the known agents does not equal that of cigarette smoke condensate. Numerous experiments have been performed in which whole cigarette smoke, filtered smoke, or certain constituents of smoke, such as the "tar," are administered by varying methods to animals or to tissue and cell cultures in order to investigate the neoplastic- inducing properties of cigarette smoke. Particular difficulty has been encountered in experiments which have attempted to deliver 238 whole cigarette smoke to the larynx and into the lungs of experi- mental animals. This has resulted in the use of other methods such as the implanting of pellets containing suspected carcinogens and the instilling into the trachea of suspected carcinogens as such, or adsorbed onto fine inert particulate matter as a carrier. The dif- ficulty with the inhalation studies has been twofold. First, the animals, particularly the smaller species such as the rat, frequently die from the acute toxic effects of the nicotine and carbon monoxide in the tobacco smoke. Second, the upper respiratory tract of experi- mental animals, particularly the nose, is much different from anal- ogous human structures, resulting in a more efficient filtration of smoke in the upper respiratory tract. Nevertheless, in rodents and canines, progressive changes apparently indicative of ultimate neo- plastic transformation have been identified in the respiratory tract. Recently, two studies in different species and in different target organs have been reported concerning the development of early in- vasive cancer following the prolonged inhalation of cigarette smoke. Auerbach and his coworkers (II) trained dogs to inhale cigarette smoke through a tracheostoma. After approximately 29 months of daily exposure, these investigators found a number of cancers of the lung. Dontenwill (7'6) in the second of these two studies, exposed ham- sters to the passive inhalation of cigarette smoke over varying and prolonged periods of time. He observed the development of pre- malignant changes and, ultimately, invasive squamous cell cancer of the larynx. LUNG CANCER Cancer of the lung in the United States accounted for 45,383 deaths among males and 9,024 deaths among females in 1967 (289). It is presently estimated that approximately 60,000 people will die of lung cancer during 1970. The alarming epidemic of lung cancer is a relatively recent phenomenon. Death rates for lung cancer (ICD Codes 162, 163) rose from 5.6 (per 100,000 resident population per year) in 1939 to 27.5 in 1967 (289, 290). This rapid increase followed the in- creased use of cigarettes among the United States population. The increase has occurred principally among males, although more re- cently females have shown a similar rising pattern. The converging evidence for the conclusion that cigarette smok- ing is the major cause of lung cancer is derived from varied types Of research including epidemiological, pathological, and laboratory investigations. 239 EPIDEMIOLOGICAL STUDIES Numerous epidemiological studies, both retrospective and pros- pective, have been carried out in different parts of the world to investigate the relationship between smoking and cancer of the lung. These studies are outlined in tables 1, 2, A3, and A4. Prospective Studies The major prospective studies concerning the relationship of smoking and lung cancer are presented in table 1. In all, these investigations have studied more than a million persons from a number of different populations for up to 10 years. These studies show increased lung cancer mortality ratios for cigarette smokers of all amounts ranging from 7.61 to 14.20 among male smokers as compared to nonsmoking males. The one major prospective study of female cigarette smokers reveaIs an overall mortality ratio of 2.20 (118). Also uniformly present in these studies is a dose-related increase in the mortality from lung cancer with increasing amounts of cigar- ettes smoked per day. Other measures of exposure show similar trends. Hammond (118) reported increased mortality ratios asso- ciated with increased inhalation (table 1) as well as with increased duration of smoking (table 2). Ex-smokers show significantly lower lung cancer death rates than continuing smokers. In their study of more than 40,000 British physicians, Doll and Hill (74, 75) noted a decrease in lung cancer mortality rates with increasing time since smoking stopped (table 1). During the past 20 years, half of all the physicians in Britain who used to smoke cigarettes have stopped smoking. While the death rates from lung cancer rose by `7 percent among all men from England and Wales during the period from 1953-57 through 1961- 65, the rates for male doctors of the same ages fell by 38 percent (96). Pipe and cigar smokers have been shown in the prospective stud- ies to have lung cancer mortality rates higher than those of non- smokers, although these are generally substantially lower than those of cigarette smokers (table 1). Retrospective Studies More than 30 retrospective (case-control) studies have been re- ported concerning the relationship of smoking and lung cancer. These studies are outlined in tables A3 and A4. Table A4 presents the percent of nonsmokers and of heavy smokers among both cases and controls as well as the relative risk ratios for all smokers. 240 TABLE I.-Lung cancer wwrtality mtios (Actual number of deaths shown in parentheses)' SM = Smokers. NS = Nonsmokers. Prospective studies Author, Number ye*=. and type COUntrY, of col$;don Follow- Number Regular cigarette Pipe UP of smoking only cigar Inhalation reference pooulation years deaths (cigarettes/daY) Exsmokers CODUll@Xd.9 _ - -_- Hammond 187.783 Qucstion- 31/& 448 Pipe No data Bso7xhogcnic 341/448 and white naire and SM 443 NS ,.., 1.00 (15) NS 1.00 (15) (1Szcluding adenocarcinma) deaths with Horn, males interview. NS 16 20 . ..23.40(117) NS 1.00 (15) Continuing .16.94 eludes those (120). ages All . . .t10.73(397) SM . 1.00 (7) Duration 60-69. of i <1 year .16.50 regular l-10 years (10.44 cigarette cessation >lO years 1.51 smokers who Previously >I pack/day also smoked Continuing .46.21 pipes and Durntion] lO years .17.79 without microscopic proof. Doll and Approxi- Question- 10 212 NS ..I.. 1.00 (3) Pipe and Cigar No data Cigarette smokers Hill, matelv mire and SM 209 1-14 . . . 8.14 (22) NS 1.00 (3) NS ._ ,t ._... . . . 1.00 (3) 1964, 41,000 followup NS 8 15-24 .19.86 (63) Gmmsldw Continuing _. .18.29(124) Great Illale of death >25 ,, .32.43 (57) l-14.. 6.00 (12) Duration 25 .13.71 (3) I cessation lo-20yean 2.57 (3) >zoyears 2.71 (2) Best, Approxi- Question- 6 331 NS . . . . 1.00 (7) Pips No data t Refers 1966. mately naire and tSM 324 <10 . . . 10.00 (67) NS . . . 1.00 (7) NS ,. _, 1.00 (7) toeur- 1966, 78,000 followuP NS . 7 lo-20 .16.41(204) SM .4.36 (18) Ex-smokers of rent Canada male of death >20 .17.31 (63) cigar cigarettes only _. . 6.06 (18) cigarette (21). Canadian certificate. All . .14.20(246) NS .l.OO (7) smokers !z V&3C%C3. SM . ..2.94 (2) only. -- TABLE l.-Lung cancer mortality ratios (cont.) (Actual number of deaths shown in parentheses)~ SM = Smokers. NS = Nonsmokers. Prospective studies Author. Nlllllber Ye*=, and,4'" Data Follow- Number collection Regular cigarette Pipe country, UP d2hs smoking only cigar Inhal&i0n reference population Exsmokers Comme"ts Ye*!3 (cigarettes/day ) Kahn U.S. male Question- 8% 1,266 Pipe (Do="). veterans mire and SM .1,178 NS . . . 1.00 (78) NS . .l.OO (73) Nodata 1966, 2.266.674 followup NS. 78 l-9 . . . . 6.49 (45) SM . . . .1.34 (17) NS . . . . . . . . 1.00 (78) U.S.A. person of death 10-20 . . 9.91(303) Ciga+ Number of eigarettcs/dau: (189). ye**s. certificate. 21-39 . . .17.41(315) NS . , .l.OO (73) l-9 . . . . . . 0.96 (4) >39 . . .23.93 (82) SM . . ..1.69 (6) 10-20 . . . . . . . 3.43 (39) All . . .12.14(749) Pipe and cigar 21-39 . . . . . . . 9.33 (67) NS . . . .l.OO (78) >39 . . . . . . . . 3.24 (19) SM . . . .1.66 (20) Hammond.440.563 Interviews 4 Males Current cigarettes Pipe Males ICD code 1966, III&e by ACS 1.169 OdU NS .l.OO (49) NS . . . . 1.00 (49) 162 only. U.S.A. 662,671 volunteers. srd .l,llO Males SM . . .2.24 (21) Slight . . 8.42(120) (118). females NS 49 NS . . . 1.00 (49) Cigar Moderate .11.46(311) 35-84 FtWtaL% l-9 . . . . 4.60 (26) NS . .l.OO (49) Deep . . .14.31(141) years of 183 10-19 7.48 (32) SM . . ..1.86 (22) FOUL% age in 25 SM . 81 20-39 . .13.14(381) Pipe and cigar NS . . . . . 1.00(102) states. NS . 102 >40 . .16.61 (82) NS . .l.OO (49) Slight . . . . . 1.78 (251 -All .~., . . . . . 9.20(719) SM . ..0.90 (11; F.Z?iWh~ 3.70 (46) NS . . . . . l.OO(l02, J 1-19 . . . 1.06 (20) >20 . . 4.76 (60) All . , 2.20 (81) TABLE I.-Lung cancer mortality ratios (cont.) (Actual number of deaths shown in parentheses)' SM = Smoker%. NS = Nonsmokers. Prospective studies Author, Number Follow- year, andow Dats "P Number count.lY. Eollection Regular cigarette Pipe reference population years de% smoking only cigar Inhalation Exsmokers (cigarettes/day) COllUlWlt5 Bllell 69,866 et al., American `l?$ind 3 1967, Legion- followup U.S.A. naires of death (49). 36-76 certificate. years of age and older. 804 NS , . . . 1.00 <20 . . . . 2.90 20 . . . 3.60 >20 4.90 Hirayama. 266,118 Trained 1?4 43 NS . . . . . 1.90 (3) Preliminnry 1967, male and PIIS SM 40 l-24 . 2.69 (29) report. JC3p8n female nurse >26 . . . 6.68 (6) (1.25). adults interview 40 years and fol- of age and lowup of older. death certificate. Weir and 68,163 Question- 6-S 368 NS . . . . 1.00 DUIIII, males in naire and 5~10 . 3.12 1970, various followup *20 . . . 9.06 U.S.A. OCC"PB- of death >30 . . . 9.66 (SO6). tions in certificate. All . . . . . 7.61 California. 1 Un1ee.a otherwise specified, diaparitiea between the total number of deaths and the hum of the individual smoking categories are due to the exclusion NS include pipe and cigar smokers SN include ex-smokers. E of either occasional. miscellaneous, mixed, or exemokem. TABLE Z.-Lung cancer mortality ratios for males by duration of cigarette smoking (Actual number of deaths are shown in parentheses) Age began cigarette smoking 35-54 25 or older 2.Ti (5) 20-24 5.83 (31) 15-19 8.71(112) <15 12.80 (35) SOURCE: Hammond.E. C. (118,. 55-69 70-84 35-84 3.39 (12) 3.38 (3) 3.21 (20) 11.11 (72) 12.11 (7) 9.72(110) 13.06 (176) 19.37 (27) 12.81(315) 15.81 (57) 16.76 (9) 15.10(101) These smoker-nonsmoker risk ratios range from 1.2 to 36.0 for males and from 0.2 to 5.3 for females. Although not presented in tabular form, the data concerning lung cancer and pipe or cigar smoking are similar to those found by the prospective studies mentioned above. However, a study by Abelin and Gsell (1) conducted on a rural Swiss population noted that an increased risk of lung cancer was present among heavy cigar and pipe smokers (as well as cigarette smokers) to a greater degree than previously reported. The authors suggest that their findings might be due to differences in either the amount smoked or the car- cinogenicity of Swiss and German cigars. The difference might also be explained by the greater use and more frequent inhalation of small cigars in Switzerland as compared to other countries where large cigars are more commonly smoked but rarely inhaled. Kreyberg (15.$), in a review of 887 cases of lung cancer in Norway, noted that pipe smokers showed an increased risk of lung cancer, although this risk was substantially lower than that for cigarette smokers. LUNG CANCER TRENDS IN OTHER COUNTRIES Several studies of particular interest are those in which the changing mortality from lung cancer has been investigated in countries in which cigarette smoking has become popular and wide- spread only in recent years. In those countries where accurate statistics for lung cancer mortality are available for both t.he pre- smoking and post-smoking periods, long-term trends can be studied in some detail, Two such studies have dealt with lung cancer mortality trends in Iceland. Dungal (83) noted in 1950 that lung cancer was a rare disease in Iceland and felt that this rarity could be explained by the relatively late onset of heavy tobacco smoking in the Icelandic population when compared to that of Great Britain and Finland. He observed that the annual per capita consumption of tobacco did not reach one pound in Iceland until 1945, while Great Britain and Finland passed that amount before 1920. In 1967, Thorarinsson, et al. (276) noted a sharp rise in the incidence of lung cancer in Ice- 244 60- 50- 40- 30- 4- 3- 2- -Finland I I -Norway I I 1934-36 1939-41 1944-46 1949-51 1954-56 1959-61 1963-64 Calendar Years FIGURE I.-Lung cancer, Finland and Norway. SOURCE: Kreyberg, L. (154). land after 1950 and found a correlation between that increase and the increasing sale of cigarettes in that country. Kreyberg (154) analyzed the lung cancer death rates of both Norway and Finland in relation to the use of tobacco in those two countries over the past 100 years. Figure 1 shows the substantial difference in lung cancer mortality between the two countries. Kreyberg observed that cigarettes came into use in Norway in 1886 Mile the Finnish population (more closely allied to Russia socio- economically) was consuming more than 100 million cigarettes per Year during the decade of the 1880's. Cigarettes remained scarce in Norway until after World War I, and this 30-year lag in consump- 245 TABLE EL-Annual means of total lung cancer mortality and sex ratios for selected periods in Finland and Norway Year 1936-38 ................... 192 33 34 30 Sex ratio ................ 6.8 : 1 1.1 : 1 1963-66 ................... 1,319 121 366 79 Sex ratio ................. 10.9 : 1 4.6 : 1 SOURCE: Kreuberg. L. (154) tion behind that of Finland is reflected in a similar lag in total lung cancer mortality and sex ratios (table 5). HISTOLOGY OF LUNGTUMORS A number of investigators have focused their interest upon the relationship of cigarette smoking to the varied histology of lung tumors. The major histological types of lung cancer include squa- mous cell (epidermoid) carcinoma, small and large cell anaplastic carcinomas, adenocarcinoma (including bronchiolar and alveolar types), and undifferentiated carcinoma (153). A review of these studies (table 6) indicates a closer relationship between cigarette smoking and epidermoid carcinoma than between cigarette smok- ing and adenocarcinoma (42, 22 3). The work of Kreyberg (153) in Norway, over the past 20 years, provides evidence of a specific histologic relationship. This inves- tigator noted that a clearer association is obtained if the various types of pulmonary carcinomas are grouped. Table A7 presents his groupings of the specific histologic types. Using this classification as a basis for analysis of lung cancer sex-ratios in Norway, Kreyberg has observed that Group I carcinomas are significantly more frequent among males while Group II carcinomas show an approximately equal distribution among males and females. The author considers the recent rise in lung cancer in Norway to be a reflection of the increased prevalence of Group I carcinomas. Table 8 presents a summary of Kreyberg's investigation concerning 793 male and female cases of lung cancer. Among both males and fe- males, the risk ratio among smokers is substantially higher for Group I types than for those of Group II. However, adenocarcinoma among males shows a risk ratio of 2.9, signifying a relationship with smoking. Kreyberg attributes the lower rates noted among females to their significantly lower consumption of tobacco in all forms. 246 TABLE B.-Epidemiologic and pathologic investigations concerning smoking and the histology of lung ca.nce+ (Actual number of cases shown in parentheses) Author, Number of yea=, persons and country. case selection ReaUlt.3 Comments reference method Wynder 644 autopsies on Percent ca8es by histologic type and smoking history The percentage of chain and males with AU lung cance+8 other than smokers in the general Graham, confirmed adenocorcinoma (605) Adenocarcinoma ( 39 ) population (7.6) was 1950, lung cancer. Nonsmokers .._.._............t...... 1.3 10.3 significantly less than U.S.A. Light cigarette smokers . 2.3 7.7 among the patients with (316). Moderate ,.._,........................ 10.1 16.4 adenocarcinoma. The Heavy ,,___.,_........................ 36.2 38.6 authors refrained from Excessive 30.9 10.3 making any definite Chain ,,...._.._____._................ 20.3 18.7 conclusions due to the insufficient number of ease-s. DO11 916 male and 79 Percent patients with lung can.ce~ by average amount smoked daily ower 10 ~a~8 No statistically and female cases Male.4 significant difference Hill. with histologically Oat-cell 07 was found between 1952, confirmed Epidennoid ( 475 ) anaplastie (303) Admocarcinoma (33) the amounts smoked by England lung cancer. Nonsmokers 0.2 (1) 0.7 (2) 6.1 (2) the patients in the (Y3). Smokers: different histological <5 cigarettes/day 2.9 (14) 3.9 (12) 6.1 (2) groups. Number of 6-14 35.6 (169) 36.3(110) 21.2 (7) proven adenocarcinomas 15-25 . . . . . 36.8(175) 34.7(105) 48.5(16) too small for >25 24.4(116) 24.4 (74) 18.2 (6) conclusions. Ft3tWl.e8 Oat-cell 07 Epidermoid ( 18 ) wuzplastic (38) Adenocarcinoma (10) Males-105 unclassified Nonsmokers 61.1 (11) 31.6(12) 50.0 (6) tumors. Smokers : Females -13 unclassified <5 cigarettes/day 5.6 (1) 16.8 (6) 20.0 (2) tumors. 5-14 22.2 (4) 23.7 (9) 10.0 (1) 16-25 6.6 (1) 18.4 (7) . >25 . . . . . . . . . . 6.6 (1) 10.6 (4) 20.0 (2) TABLE 6. Epidemiologic and pathologic investigations concerning smoking and the histology of lung cancer' (cont.) (Actual number of cases shown in parentheses) -~-. --. -~~. Author, Number of Y`ZU, pcrsn': :klld country, case :;e*c c,ion Results Comments reference mc:h~.d Brrslow 493 male and 25 Pcrccnt of patients with specific lung cancers by tobacco umgc during the 20 ye~m prior to study Nonsmokers include pipe et nl., female cabe~ end cigar smokers only. I!#64 with histnloyically All lung cancers other tharl The authors conclude U.S.A. proven lung adcnocarcinoma Adenocarcinoma Controls that cigarette smoking (43). cancer. (472) (46) (518) appears to affect the 51x age and Nonsmokers 6.9 13.0 24.4 development of sex-matched Cigarette smokers _. . . 94.1 87.0 75.6 withelial carcinoma COlll~OlS. more than that of adenocarcinoma. ~--___ SChWElrtZ 430 male and Pexewt of amokers by hi8tdoQic tupe and 8'TllOki?LQ historv et nl., female cases 1957, with histologically Epidermoid Anaplastic Unknown type Cylindrical + Difference FlYLnCe confirmed lung Cases 96.0 97.0 96.0 100.0 significant (247). cancer. 4 matched Controls 79.ot 83.01 79.0t 96.0 et PZO.05 level. control gL'o",,s. -.. __. Hal?Il%Xl 158 female Relative risk for specified tumors (smokers/n~?~~mokers) 134 cases with final et al., CaYPS of histological 1958, lung cancer. Group I (Kreybwg) Adenocarcinoma determination. U.S.A. Adjusted for ege and occuyation. 3.0t 1.19 (ff3). t Difference from unity significant at p~O.01. Hae"s7.Cl 2,191 male Standardized mortality ratios Cases obtained from a and casm of Shimkin. 10 rwcent saml&s of lung cancel Epidcrmoid and mdiffemntiated lung ceneer deaths in 1962, with aderwatc carcinomas Adenocarcinoma U.S.A. doring 1958. U.S.A. histologic data. White males total _, . . . . 100 100 The authors noted an (II?). Never smoked . . . . .._._.. 6 18 Ex-smokers absence of important ..I.................... 34 46 differentials by (1 pack/day _. _, 123 116 histologic type. >l I,aek/day _. .._.....,I...._.....___......_ 499 467 -__ ___-- : ' Dtlta obtained from patient. interview and other sourscs. _---.---.-.----- ~-~~~- TABLE K-Tumor prevalence among males and females 35-69 years of age, by type of tumor and smoking category (Smokers constituted 85 percent of populations studied) Sex and type of tumor Total Smoking category Smoking all methods NO"- smokers Risk ratio among smokers Males Epidermoid carcinoma ............................................ 434 431 3 17.0 26.4 Small cell anaplastic carcinoma .................................. 117 116 1 6.7 20.4 Adenocarcinoma .................................................. 88 83 6 28.3 2.9 B~~,nchiolol-nlvrola~. carcinoma ...................................................... Carcinoid ...... .................................................. 46 39 7 39.7 1.0 Bronchial gland tumor ...................................... .... ................... Total . . . 685 669 16 90.7 7.4 Females Epidennoid carcinoma ............................................ Small cell anaplastic carcinoma ................................... Adenocarcinoma .................................................. Rronchiolol-alveolar carcinoma ................................... Carcinoid ......................................................... Bronchial gland tumor ............................................ 12 9 3 .75 12.0 8 6 3 ,785 6.6 66 14 42 to.5 1.3 . . . . . . 32 I 25 6.3 1.1 . . . . . . . . Total . . . . . . . . . . . . . 108 35 73 18.3 1.9 `Number that would be expected if incidence rate among smokers were SOURCE: Kreyberg, L. (154) equal to that of nonsmokers.