TS¢ Taste Al4.—Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tenston Author, year, country, System Method Results reference Miller and Rat lung extracts Cigarette smoke: (1) Exposure to cigarette smoke wag nasoctated with decreased surface tenalon in lung extract. Bondurant, {1) Applied to (2) Surfoce tension of rats (lung extracts) exposed to’ cigarette smoke waa decreadcd 1962, extract. as compared with those not exposed, U.S.A. (2) Exposure (168) of rats. Cook 40 subjects undergoing Surface tension and Webb bronchoscopy: valuce of aurfactant 1966, 14 normal 20 100 Stability index (reflects ? Values algnificantly U.S.A. 7 nonsmokers with percent percent surfactant activity) different from (57) pulmonary disease area area values of normals 19 smokers with and Normal ...esereee 6.5 60.0 1.61 at p<0.02 level, without pulmonary Pulmonary dincase. pationts caeeee $17.0 $60.0 1.00 Chronic smokers .. 16.7 61.0 1.04 Giammona In vitro: Exposed to In vitro: 1967, Surfactant motcrial cigureltte Exponure to clanrette smoke wos associated with w significant decrease in maximn) surface U.S.A. induced from dogs smoke for tenpion, (94) and rats. 3 hours/duy Inatyo: In vivo: for up to Dogs and cats (expored for 1 week)}—no sixnificant change. Dogs, cats, and 3 weeks. Guinen pigs (exposed for 4 weeks) —significant decrense in muximal surface tension. gulnca pigs. Webb, Bronchial Direct Surface tenaion values of surfactant etal. washing, exposure to £0 pereent 100 pereent Ue, from cigarette smoke. Number arca areca Stability index S.A, dog lungs. Control .....6.. 1 ; ; . (2h Smoke on 10 serpincoane {53} (eco. 034 ZSt TaBLp Al6.—Studies concerning the relationship of amoking to infectious (Actual number of cases shown in parentheses) SM = Smokers NS =: Nonamokers respiratory digease in humans Author, year, Number and Data country, type of collection - Results Comments reference population Mills, 118 male and Hospital Cases Controle The author stated that 1980, female patients Interview. Mean age csseececeeecreeeees aneeee ees 43.6 49.6 there was a U.S.A. with pneumonia NS cseeee seoe veers beeeeeennes tae 16,26 26.24 significant uifference (187). and 472 bealtby Cigarettes only cceeesereeeeee surest oe 63.86 62.93 in tobacco usage individuals from Mixed v.cceceeee cece eree tee teeees . 21.19 22.46 between the “random” sample. two groups. Lowe, 520 male and Interview by Males Females Cigarette smokers 1966, 185 female trained Casce Controle Coace Controla include pipe smokers. England tuberculosis social NS iceevree eee peeneenane , 2.6 8.1 37.3 614 The author noted a (157). patients and 419 worker. Cigarettes/day: 1-9 ...05, 9.2 12.9 20,5 26.7 significant deficiency male and 249 10-19 seers eee Vea 38.1 35.6 30.8 20.6 of non- and light female control 20-29 ve rereeeee teens 29.4 27.4 smokers and an outpatients. 30-39 rare eeeee sees 11.3 9.3 11.4 2.4 excess of heavy DAD cece ee eee beveneee 9.4 6.7 smokers among the cnges Dowling, Individuals Interview and Exposed to placebo Exposcd to infectious agent No atatiatically etal, exposed to medical Percent Percent significant 1967, “Snfectious examination. developing developing differences U.S.A. eold agent” Number “eald" Number ‘eold” noted. (7£). and placebo, NS veesee an a M11 10 328 34 SM wee eae veeeeene 18 4 249 36 €SZ Tanie Alb.—Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.) (Actual number of cases shown in parentheses) SM = Smokers NS = Nonsmokera Author, year, Number and Data country, typeof collection Results Comments reference population Boake, Parents of Interview Number of No statistically 1968, 59 families, Person- respiratory Ilinesses/ significant U.S.A, years tlnessea = person-years differences (33). NS co cseer vere recaee seveeeee (24) 120 624 6.2 noted. Cigarettes/day: 1-10 .,....0., (18) 99 529 5.3 W-20 vee eee Sav eenaee (26) 108 436 48 >20 oe . 9 424 4.3 Pipe, cigar 12 804 42 Sbah Tuberculosis Survey, X-ray, Tuberculous Normal or t Numbers In etal, {natitute and by X-ray nontuberculous parentheses 1969, employees, interview. NS beers ete eee et eeee t10 (19.7) 178 (168.3) represent figures India SM bene v eee e eet enens 36 (26.3) 215 (224.7) “expected” by use of (£08). 2x2contingency table. Tuberculous employees wero found to have significantly Cower nonsmokers and more amokers. 7S¢ TABLE Alb.—~Studies concerning the relationship of smoking to infectious respiratory discase in humans (covt.) (Actual number of enses shown in parentheses) SM = Smokers NS = Nonsmokers Author, year, Number and country, type of Data reference population collection Results Comments Brown 306 male und Interview Smoking habite prior to diagnogts Data presented only etal, female Tuberculous paticnte Controls on Queensland 1961, tuberculosis (percent) (percent) sample. Australia clinic NS Fest eee ce eect cesses sees 91 19.9 The authors noted G). patients, Cigarettes/day: 1-9 10.6 15.4 that the 221 male and 10-19 443 19.5 significant difference female 20-29 26.3 25.8 between the outpatients. 30-39 1.2 6.4 patients and DIO cee eevee cece tees aes eans 6.2 9.1 controls was not Pipes ieee ese cece eee eee 5.9 4.6 present when the groups were matched for alcohol intake. Haynes 191 male Interview Average number of respiratory illnessee/10 students etal, prep school (adjusted for age) 1966, students, All severe lower U.S.A. All All severe or combined (108). respiratory respiratory reapiratory episodes episodes cptsodes NS (99) vee eee c cece eee 111 1.6 0.36 SM (92) tee 20.2 6.7 3.34 Parnell 47 smoking- Interview Median number of Wncases/student The authors noted eal,, nonsmoker palra and health Au All that these 1966 of student nurses service respiratory other differences were Canada matched for age records. diseascat incasce statistically (281), and parents’ NS (AT) ccc ccc eters neces 2.08 2.99 significant. occupational SM (47) icc e cece reece eae 2.64 5.00 { Particularly class. trachcitis, bronchitis, and pneumonia. SSC TABLE (Actual number of casey shown in parentheses) SM = Smokers NS = Nonsmokery Alb.—Studics concerning the relationship of smoking to infectious respiratory discase in humans (cont.) Author, year, Number and Data country, tyne of collection Results Commenta reference population Peters 1,496 Harvard Medical history, Number of visite to student health untt for respiratory illness/atudent + p<0.001. etal., and chart review, (comnion colds, pharyngitts, bronchitis, laryngitis, 1967, 370 Radcliffe and preumonia~not allergic rhinitia) U.S.A, students. questionnaire, Harvard Radeliffe (183), NS 1.44 (771) 1.44 (193) SM $2.27 (726) 2.27 (177) <2 years smoked . 2,00 3-4 2.30 >5 2.60 Finklea 1,811 male Questionnaire Heavy smokers--21 percent more clinical jInesses than nonsmokera; The authors also etal, college prior to 20 percent more requiring bed rest than nonsmokers noted that: 1969 students. A, /HK/68 Light smokers—10 percent more clinical [!lnesses than nonsmokers: (a) Smokers U.S.A. epidemic and 7 percent more requiring bed reat than nonsmokers exhibited (83). follow-up on serologic morbidity, evidence of increased aubclinical A,/HK/68 infection. (b) There wna no difference in the vaccination slatus between amokers and nonsmokers, Taste Al6.—Complications developing in the postoperative period tn patients undergoing abdominal operations Men over 20 Percent Percent broncho- Pereent Group Cases chest Percent pneumonia total clear bronchitis and complication atelectasis rate Smokers . 2... 2.2.20 eee ee eee 300 417 63.0 5.3 58.3 Light Smokers .. 180 68.4 27.7 3.9 31.6 Nonsmokergs ....-..--0-0-00- 66 92.5 6.0 1.5 TB Women over 20 Smokers oo... eee eee eee ee 23 39.1 43.5 17.4 60.9 Light Smokers ..........--- 62 WS 20.9 1.6 22.5 Nonsmokers ......06--0-0--% 518 88.8 8.1 3.1 112 Source: Morton, H. J. V. (473) TABLE AlT7.—-Arterial oxygen saturation before and after operation Arterial oxygen saturation (percentage) Case Before Group number operation Day l Day 2 Day 3 1 94 93 94 2 94 93 94 - Nonsmokers ......--- 2-0 eee cree ee 3 96 93 go4 a 4 95 90 a¢ as & 94 90 93 a. 6 95 91 89 91 7 92 89 81 89 Smokers 2... 2.6.0 e cece eee ee eee 8 91 89 85 89 9 93 91 88 92 10 90 87 88 92 Source: Morton, A. (172). 256 Chapter 4 Cancer Source: 1971 Report, Chapter 4, pages 231 - 384, 257 Contents Introduction .........0 cece eee eee ete Lung Cancer .....----e eee eee eee eet ern eettee Epidemiological Studies ......5.----- 0-222 eee ereee Prospective Studies .......-. 2. ee eee eee reese Retrospective Studies ......--- +e eee reece eres Lung Cancer Trends in Other Countries .........--- Histology of Lung Tumors......-..--- esse ee eer eet Lung Cancer Relationships in Women .....-.-.--+-+- Lung Cancer, the Urban Factor, and Air Pollution. ... Lung Cancer and Occupational Hazards ......------ Uranium Mining ........--200ee eee eer eres Other Occupations........-¢ See eee eee eee eeee Nickel... .....2 cece cece cee eee eect eens AsbestoS. 0... ccc eee cee eee ete een aetee AYSONIC. 0 ec ee te eee eters Chromium. ......--00+ cece e seer reeset erete Pathological Studies. ........- +--+ ee eee er eee ret Pulmonary Carcinogenesis ....--6---+ eee ee ere eee General Aspects of Carcinogenesis .........---+ Polynuclear Aromatic Hydrocarbons .....-- Nitrosamine Compounds. .......------++++-: Pesticides and Fungicides.........-..-++-- Radioactive Isotopes .....--- e+e eer eeeee Inhibitors of Ciliary Movement ......-.--- Experimenta! Studies ...-..----++-20 rr rreeee Skin Painting and Subcutaneous Injection. a Tissue and Organ Culture .......----++--> Tracheobronchial Implantation and Instillation ......-.+------eee rere Inhalation ...----- ee eee cree teeter tets Reduction in Tumorigenicity ......--+++--+ Summary and Conclusions ...-.---++-+re er errtett Cancer of the Larynx ....---- eee erect Epidemiological Studies .-.------+++++ sre rrertrtts Pathological Study ....2------ seer cee rere rrnte Experimental Study ...-.-----++++eeereertrst Summary and Conclusions .......---++--+errrertte Oral Cancer ....-.-0-ce cece eee eset eeenereressts Epidemiological Studies ....-.----+-+++serrrrtrtte Experimental Studies ......-----++e++eeerrerctttt Summary and Conclusions .....--.+++-+++serrttrte Cancer of the Esophagus ..-.------+--rrercrctr tt Epidemiological Studies ....---- eee eect ttre Pathological Study ....--.-+-+seeereerrrrrttt Experimental Studies .....--+-+---+errrtrettrte Stummary and.Conclusions .---++++---+sssrrertrts Cancer of the Urinary Bladder and Kidney .......-+---+5 Epidemiological Studies (Bladder) ....-----+--+++>> Epidemiological Studies (Kidney) ...------ eee ree Experimental Studies ....-------++ssrecrrrcrrtt Summary and Conclusions ...-----+++++eesrertttt Cancer of the Pancreas .....----++rerrrrserrrr Summary and Conclusions ....----ssserrrrrrrtt References ..-.----e+ eects eee e eee eee ee eerntee peo me GO OO A3. A4. 10. 260 FIGURES _ Lung cancer, Finland and Norway ..------sre errr? _ Percent of smoking dogs with tumors ..------r errs . Percent of lung lobes with tumors in smoking dogs ....- _ Effects of chronic cigarette smoke inhalation on the hamster larynX .....- cece erect LIST OF TABLES Lung cancer mortality ratios ....-----+ee rere Lung cancer mortality ratios for males by duration of cigarette smoking ..-----+see erect Outline of methods used in retrospective studies of smoking in relation to lung cancer ..-.--++--00 Group characteristics in retrospective studies on lung cancer and tobacco use ..------rree rt 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 ..----+es-+e0 Tumor prevalence among males and females 35-69 years of age, by type of tumor and smoking category .---- eee eee rect Epidemiologic investigations concerning the relation- ship of lung cancer to smoking, air pollution, and urban or rural residence ...---++sssec rrr Pathologic and cytologic findings in the tracheo- bronchial tree of smokers and nonsmokers .....-- 271 300 300 310 267 270 349 355 272, 273 360 276 279 285 il. Al2. A138. Al4. Alb. Al6. V7. 18. 19. 20. LIST OF TABLES (Continued) (A indicates tables located in appendix at end of chapter) Identified or suspected tumorigenetic agents in cigarette smoke .......---5 +2202 eee crete Autopsy studies concerning the presence of radio- activity in the lungs of smokers .:....-----+-++- Experiments concerning the effects of the skin paint- ing or subcutaneous injection of cigarette smoke condensate or its constituents upon animals ....- Experiments concerning the effect of cigarette smoke or its constituents on tissue and organ cultures .. Experiments concerning the effect of the instillation or implantation of cigarette smoke or its constitu- ents into the tracheobronchial tree of animals .... Experiments concerning the effect of the mhalation of cigarette smoke or its constituents upon the respiratory tract of animals ....-...----++ee88 Data on pedigreed male beagle dogs of groups F, L, H, hand N .......- ee eee eee eee eerste Summary of principal cause of death (days No. 57 through No, 875) in dogs of groups F, L, H, hand N Data on dogs with lung tumors indicating type of tumor and lobe in which the tumor was found ...- Laryngeal cancer mortality ratios —- prospective studies . oc. cece eee eee eee ete teense A21l. Outline of retrospective studies of tobacco use and cancer of the larynx .....-.----2 eer cere etree A22. Summary of results of retrospective studies of tobacco A23. A24. 26. 27. A28. A28a. use and cancer of the larynx ........--+---+--+5- Number and percent distribution by relative fre- quency of atypical nuclei among true vocal cord cells, of men classified by smoking category ..... 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. ....- Deposition of '*C-labeled smoke particles in particu- lar regions of the respiratory tract ........---- Classification of the five registered stages of epithe- lial changes at the larynx .......-----2+.-++0-- Oral cancer mortality ratios—prospective studies. : Outline of retrospective studies of tobacco use and cancer of the oral cavity .........--.20 22-2 eee Summary of results of retrospective studies of smok- ing by type and oral cancer of the detailed sites. . Page 291 361 363 369 372 375 296 297 298 304 380 384 385 386 308 309 312 387 394 261 A35a. 36. 262 LIST OF TABLES (Continued) (A indicates tables located in appendix at end of chapter) Experimenta] studies concerning oral carcino- QONESIS 2. eee eee eee Esophageal cancer mortality ratios—prospective studieS 2.0... ee ee eee eens 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 0... eee ee ee eet ees Summary of methods used in retrospective 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 2.2... ee ee ee eee Page 397 316 401 404 405 406 320 407 409 324 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 J and continuing during the ensuing years. This epidemic of lung cancer 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, 203, 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 risk. 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 (154). 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- 263 ber of epidemiological studies have demonstrated increased mor- 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 to 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 earcinogens 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 764. 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 (11) 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 (76) 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 1989 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. 265 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 Studtes The major prospective studies concerning the relationship of gmoking 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 reveals 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 mon- 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. 266 L£9¢ TABLE 1.—Lung cancer mortality ralios (Actual number of deaths shown in Parentheses)? SM = Smokers. NS = Nonsmokera, Prospective studies Author, Number year, and type collection Follow- Number Regular cigarette Pipe country, of Da up of smoking only cigar Inbalation Exemokers Comments reference population years deaths (cigarettes/day) Hammond 187,783 Question- 3% 448 Pipe No data Bronchogenia 341/448 and white Naire and SM. 443 NS ..,., 1,00 (15) NS « 1.00 (16) (Exzeluding adenocarcinoma) dentha with Horn, males interview. NS. 15 <10 .... 8.00 (24) SM . 2.67 (18) Never smoked ......... 1.00 microscopic 1968, in9 10-20 ...10.50 (84) Cigar Previously <1 pack/day proof, Ins USA States >20 ....23.40(117) NS - 1.00 (16) Continuing sree 16,94 cludes those (120) ages AN ....410.73(397) SM... 100 (7) Duration 10 years ., 1.61 amokers who Previoualy >1 pack/day also smoked Continuing ...,....... 46.21 Pipes and Duration 10 years ..17.79 without microscopic proof, Dolland Approxi- Question- 10 212 NS » 1,00 (3) Pipeand Cigar No dota Cigarette amokers Hill, mately naire and SM . 209 1-14 + 8.14 (22) NS.... 1.00 (3) NS wwe. eee eeee 1,00 (3) 1964, 41,000 followup NS . 8 15-24 ...19.86 (53) Grams/day Continuing cere eee 18.29 (124) Great male of death >25 +692.43 (67) 1-14.. 6.00 (12) Duration 25..,13.71 (3) cessativun] 10-20 yeara . 2.67 (3) >20 years =, 2.72 (2) Best, Approxis Question- 6 331 NS + 100 (7) Pine No data t Refers 1966, mately naire and TSM . 324 <10 + 10.00 (57) NS ....1.00 (7) NS voce cece eee 100 (7) to cure 1966, 78,000 followup NS. 7 10-20 .,.16.41(204) SM ....4.35 (18) Ex-amokera of rent Canada male of death £00 ....97.31 (63) Cigar cigurettes only + 606 (18) cignrette (#1), Canadian certificate. All wun. 14,20(245) NS ....1.00 (7) amokers velcrang, SM ..,..2.94 (2) only. 897 TABLE 1.—Lung cancer mortality ratios (cont.) (Actual number of deatha shown in parentheses}? SM = Smokers. NS = Nonsmokers. Prospective studies Author, Number year, andtype Data Follows Number Regular cigarette Pipe country, of collection up of smoking only elgar Inhalation Exsmokers Comments reference population years deaths (clgarettes/day) Kabn U.S. male Question. gy 1,256 Pipe (Dorm), veterans nalre and BM .1,178 NS ..... 1.00 (78) NS ....1.00 (78) No data 1966, 2,265,674 followup NS. 7B 1-9 1... 5.49 (45) SM ..,.1.84 (17) NS viceeveeeees 2600 (78) U.S.A. person of death 10-20 ... 9.94 (808) Cigar Number of cigarettes/day: (236), years. certificate. 21-89 .,.17.41(818) NS ..,.1.00 (78) WD vreeeeeeeee 0.95 (4) >89 ....28.93 (82) SM ,...1.69 (8) 10-20 .......-. 8.48 (89) Al .....12.14(749) Pipe and cigar Z1-89 cree ee es 9.88 (BT) NB ....1.00 (78) S80 cece ee eres 8.24 (19) SM ....1.66 (20) Hammond,440,558 Interviews 4 Males Current cigarettes Pipe Males ICD code 1966, males by ACS 1,159 only NS .,..1.00 (49) NS .....06. 2.00 (49) 162 only, U.S.A. 62,674 volunteers. SM .1,110 Males SM ,...2.24 (21) Slight ...... 8.42(120) (11a). females NS. 49 NS ..... 1.00 (49) Cigar Moderate ...11.48 (811) 85-84 Females 1-9 1... 4.60 (26) NS ....1.00 (49) Deep .......14,81(141) years of 188 1019 ... 7.48 (82) SM ....1.85 (22) Females age in 25 SM, 8% 20-89 ,..18.14(381) Pipe and cigar NS ...c...- 1.00(102) States, NS. 102 >40 ....16.61 (82) NS ....1,00 (49) Slight ...... 1.78 (25) All ..... 9,20(719) SM ....0.90 (11) Moderate Femalea — Deep \ 7+ B70 (45) NS ..... 1.00(102) 1-19 ..., 1.06 (20) >20 .... 4.76 (50) All vices 2.20 (81) 692 TABLE 1.—Lung cancer mortality ratios (cont.) (Actual number of deaths shown in parentheses)? SM = Smokers. NS = Nonamokers. Prospective studies Author, Number Follow- year, and type Data up Number Regular cigarette Pipe eountry, of eollection years of smoking only cigar Inhalation Examokers Comnients reference population deaths (cigarettes/day ) Buell 69,868 Question= 3 304 NS . 1.00 etal, American naire and <20 1... 2.30 1967, Legion- followup 20... 3.60 USA, naires of death >20 .... 4.90 (49), 36-76 certificate. years of age and older. Hirayama, 265,118 Trained 1% 48 NS ..... 1,00 (3) Preliminary 1967, maleand PHS SM. 40 1-24 .. 2,69 (29) report. Japan female nurse >25 . 668 (6) (185), adulta interview 40 years and fol- ofageand lowup of older. death certificate. Welrand 68,153 Question- 5-8 868 NS .... 1,00 NS Include Dunn, males in naire and +10 1... 8,72 pipe and 1970, varlous followup +20 1... 8.05 clgar U.S.A. oecupae of death >30 .,., 9.06 amokers (506). tlona in ' certificate. AN uo... 7.64 SM Include California, ex-emokera. 1 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, or exsmokers. TABLE 2.—Lung cancer mortality ratios for males by duration of cigarette smoking (Actual number of deaths are shown in parentheses) Age began cigarette smoking 35-64 65-459 10-84 35-84 25 or older 2.17 (6) 3.39 (12) 3.38 (3) 321 (20) 2024.6 eee rere -+ §.83 (31) Zi.11 (72) 12.11 (7) 9.72(116) YHS-19 wee eee . 8.71 (112) 13.06 (176) 19.37 (27) 12.81(315) CUB cee eee ere wee 12.80 (35) 18.81 (57) 16.76 (9) 16.10¢101) SOURCE: Hammond,E. C. (118). 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 (154), ina 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 the 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- 270 60—~ ee Fintand Pd Cy ce Be mem Norwazy 50— 40-4 304 20—4 6—4 Annual Death Rate per 100,000 = 7 - 7 - - 1934-36 1939-41 1944-46 1949-51 1954-56 1959-61 1963-64 Calendar Years Figure 1.—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 while 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- 271 TABLE 5.—Annual means of total lung cancer mortality and sex ratios for selected periods in Finland and Norway Finland Norwey Year ~~ TT Moles Females Males Females LOIEBB wo eee ee ere ree 192 33 34 30 Sex ratio ...---.5 essere 68:1 Lisl Oy <3) es 1,319 121 355 19 Sex ratio ....--.e eee cere 10.921 46:1 Source: Kreyberg, L. (154). tion behind that of Finland is reflected in a similar lag in total lung cancer mortality and sex ratios (table 5). HistroLocy of LUNG TUMORS 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, smal] 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, 113). 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 gex-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. Fable 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 orms, 272 £L2 TABLE 6,—'pidemiologic and pathologic inveatigations concerning amuking and the hiatolugy of lung cancer (Actual number of cases shown in parentheses) Author, Number of year, persons and country, caso aciection Resulta Comments reforence method Wynder 644 autopsics on Percent oases by histologic type and smoking Atatory The percentage of chain and males with Al lung cancers other than smokers in the general Graham, confirmed adenocarcinoma (605) Adenocarcinoma (39) population (7.6) wag 1950, lung cancer. Nonsmokers ci sccseccecseeveevteeeeees 1.3 10.3 significantly Joss than U.S.A. Light cigarette amokers .. 2.3 VT among the patients with (316), Moderate wo... .. eee there, 10.1 16.4 adenocarcinoma. The HEavy ice cece ccc ec enc ee ee ereerens 30.2 88.5 authors refrained from Excessive (oo... ccc caevte ere cenenaaeeae 30.9 10.3 making any definite CHAIN ccc cece cence eter entrees . 20.3 18.7 conclusions due to the {nauMelent number of cases, Doll 916 male and 79 Percent patients with lung cancer by average amount amoked daily over 10 ycara No ataltlstically and female cascs Males algnificant difference Hii, with histologically Oat-ecll or was found between 1962, confirmed Epidermoid (475) anaplastio ($03) Adonocarcinoma (#3) the amounts amuked by England lung cancer, Nonamokerg....... Q2 (1) 0.7 (2) 6.1 (2) the patients in the (78), Smokers: different histological <6 clgarettes/day .. 2.9 (14) 8.9 (12) 6.1 (2) groups. Number of 6-14 $6.6 (109) 86.3(110) 21.2 (7) proven adenocarcinoniag 16-26 36.8 (175) 34.7(106) 48.5(16) toa amall for >26 24,4 (116) 24.4 (74) 18.2 (6) conclusions, Females Oat-cell or Epidermoid (18) anaplastic ($8) Adenocarcinoma (10) Males—105 unclassified Nonsmokers 61.2 (11) 31.6(12) 50.0 (6) tumors, Smokers: Females—13 unclassified <5 cigarettes/day .. 66 (1) 15.8 (6) 20.0 (2) tumors. 6-14 seen 22.2 (4) 23.7 (9) 10.0 (1) 15-25 5.6 (1) 18,4 (7) eee eb. 6.6 (1) 10.6 (4) 20.0 (2) 9LE TABLE 6. E’pide miologic and pathologic investigations concerning emoking and the histolog (Actual number of cases shown in parentheses) y of lung ecaricer’ (cont.) Author, Number of year, persons and country, case aclection Results Comments reference method Breslow 498 male and 25 Percent of patienta with specific lung cancers by tobacco usage during the 20 years prior to study Nonsmokers tuclude pipe etal., female cases and cigar amokers only. 1964, with histologically All lung cancers other than The authors conclude USA proven lung alcnocarcinoma Adenocarcinoma Controle that cigarette smoking (i2). cancer. (472) (518) appeore ty ulfyct the 618 age and Nonsmokers reer eeeeenee penne nene 5.8 24.4 develupment of aex-matebed Cigarctte smokers .....6. Levee ere nenee 94.1 76.6 epithelial carcinoma controls. more than that of adenocarcinoma. Schwartz 430 male and Percent of amokera by Aistologic type and emoking history etal., female cases 1957, with hlatologleally Epidermoid Anaplastic Unknown types Cylindrical + Difference France confirmed Jung Cases ... 96.0 87.0 100.0 significant (#67). cancer, 4 matched Controls 79.0t 83.0t 96.0 at px0.05 level. control groups. Heenszel 168 female Relative risk for apecified tumore (emokers/nonemokers)} 134 cases with final etal, cases of histological 1958, lung cancer, Group I (Kreyberg) Adenocarcinoma determination. U.S.A. Adjusted for age and occupation. wieeveeee cues 3.0¢ 1.19 t Difference from (119). unity significant at peo.o1 Haenszel 2,191 male Standardised mortality ratios Cases obtained from a and cases of 10 percent sample of Shimkin, lung cancer Epidermoid and wniifferentiated Jung cancer deaths in 1962, with adequate carcinomas Adenocarcinoma —=o- S.A, during 1968. U.S.A. biytulogic data. White males total .....-- Leen e ee enter net e aes . 100 100 The suthory noted an (112). Never smoked «... 6 18 absence of important Ex-amokers ws... 34 46 differentials by || <2 nock/day 123 a hintulogic type. 4 CDT pack/day versveeeeeeee ee 4g SLe TaBLe 6.—Epidemiologic and pathologic investigations concerning smoking and the histology of lung cancer’ (cont.) (Actunl number of cases shown in parenthoscs) Author, Number of yerr, persons and country, case aclectlon Results Commenta reference method Cohen 417 male and Percent cases by Atatulogtc type and amoking history The authora oluo and female cases of (number of emokers) Noted that: Hossain, lung cancer with 1, Adenocarcinumas 1966, histologic Squamous Undifferentiated Adenocarcinoma Alveolar were 214-3 times U.S.A. diagnosis 1939-63 Nonsmokers ......... 10 (3) 10.0 (17) 23.0 (8) 20,0(1) more common in women (58). at one hospital. Smokers 89.0(183) 90.0(146) 60.0(20) 2. Only l percent of Kreyberg Group | cuaey Were nonsmokers. Ashley 442 male and Percent casce by hiatulopic type and emoking history The authors noted that and female couva of Cigarette smoking Davies, histoloyically Undifferontiated Squamous Adenocarcinom apjears to be as 1967, diagnosed Nonsmokers vie... ss csess 2.8 (4) 2.5 (6) 3.4 (2) strongly related to England lung cancer. PIPE ve eeeee eee eeese ees 9.9 (14) 9.9 (24) 17) adenocarcinoma as to (6), Cigaretle oo... ccc eee 87.3(124) 87.6(211) 94,9(56) the other 2 types. ClO/day we. cee eee 14.1 (20) 22.4 (64) 22.0(13) Agbley’s data on total 10-20 0, 33.6 (48) 41.6 (100) 33.9(20) number of cigarette 21-30 12,0 (17) 21.6 (62) 16.9 (10) smokers are 31-40 14.1 (20) 12.9 (31) 8.6 (5) inconsistent with >40 7A (10) 6.2 (16) 6.1 (3) his breakdown of amokery into groups based on number of cigurctlos smoked per duy, Ormos 118 male and Percent cases by histologic type and amoking Atetory The author nuted that etal, female cases of the amall number of 1969, histologically Group! Group and largocell carcinomas — cuyey ntluws for ne Hungary Proven lung Nonamokers 11. sieve eevee seers eee 24.0 (18) s6.u CO) definite concluyions, (204). cancer with Smokers 79.0 (68) 64.0(16) adequate smoking information, 1 Data obtained frum putlent interview and other sources.