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N Brown et al., 1961, 306 male and Interview female tubercvlosis &makivD habits prior tn dutpnoaia Tnbcreutaua patients (percent) Controls (Pe(cent) Auqtralia clinle NS ......:.......................... 9.1 19.9 (4). patients, Clgarettes/da>: 1-9 ................. 10.5 15.4 221 male end 1U10 .......................... 34.3 19.fi female 2039 .......................... 26.3 25.8 outpatiente. 30-35 .......................... 7.2 5.4 >40 ............................. 6.2 9.1 Pipes .......................... 6.9 4.6 Heynes etal., 191 male prepschool Average number of *eepiratory illncesea/10 students (adiuxted for age_1 1966, etudents. U.S.A. A!1 All acyere Alleeverelomer or combiaqd (10N). reepirutory resyirata.y re9piratory epiaodnn ep'modee epinodre WS (99) .................. 11.1 SM (92) .................. 20.2 l Parnell 0 smoking- Interview at al., nonsmoker pairs and health 1966 ofstudent nuraee service Cenede matched fnr e¢e reeords. (181). and Darenta' supationgl elses. 0.36 3.34 Medinn num6er of illneeeee/etud,mt All All *sepirntory other diecaaee} illneaaea Ns (47) ................... 2.08 -2:59 .. SM (47) ................... 2.64 5.00 Data presented only un Queensland mPle. The authors noted thnt the signifieant diHerenco_ between the p®tienta and controls was not present when the. groups were matched far alcnholintake. The authors noted that these diRerences were statistically significant. } Perticularly tracheitis. - brunchiti., and pneumonie. TT4'as4eo TABI.e A15.-S_Cudies concern_in,q the relationship of smoking to infectious respiratory disease in humans (cont_._) (Actual number of cases shnwn in parenthe.es) SM - Smokers NS -Honsmokere Author, year. Humbex and country; type of Data reference pUpUlit30n cellecf.ion Aesulta Comments

TAt)4H 1,Lung cancer mort¢lity ratios (cont.) (Actual number of deaths shown in parentheses)+ SM =Smoken. NS -Monemnken. Prospective studies Author, Number - -rear, and type Data Follow- Number Resulancigerette eountry, of collection up - of smokiog only teferenee population y¢sYs deaths (ciaeiettes/day) ICuhn U.S. male (]uestion. Bt,tj (Dorn_ ), yeterene neire and 1966, 2,265,674 followup U.S.A. person of death (118). Yeare. cert.ificate. Hemmond.440,568 Inter.eiewe 1966, mal® by ACS U.S.A. 662,671 valunteern. (tla). €emelea 25-84 Years of age in 25 States. Pipe clQar Inhalation 1,266 Pipe SM .1,178 NS ..... 1.00 (78) NS ....1L00 (78) No data NS . 78 1-9 .... 5.49 (45) SM ....1.84 (17) -~ 1Q-20 ... 9:91(303) CIDa.~ 21-89 ...17A1(315) NS ....1.00 (78) 989 ....29.93 (82) SM ....1.69 (6) All .....12.14(749) PipeandeiDar NS ....1.00 (78) SM ....1.66 (20) Maler Current cigarettes Pipe - Male. 1.159 only NS .,..1.00 (49) NS ........ 1.00 (49) SM .1,110 Malee SM .... 2.24 (21) Sli¢ht . . . 8.42(1201 NS . 49 NS ..... 3.00 (49) Cigar Moderate ...1L45(311) Femalee 1-9 .... 4.60 (26) NS ....1.00 (49) Deep .......14.81(Idl) 163 10-19 ... 7.48 (82) SM ....1.86 (22) Femaies SM. 81 20-39 .13.14 (381) Pipeandcigar NS ........ 1A0(102) NS , 102 >40 ....16.61 (82) NS_ ....100 (49) Slight ...... 1,78 (25) All ..... 920(719) SM .,..0.90 (11) Moderate) 390 (45) Females Dee JkD N5 ..... 1.00(102) 1-19 .... 1.06 (20) >20 .... 4.76 (50) All ..... 2.20 (81) Exsmokere NS ..........., 1.00 (78) Number of eigarettee/daV+ 1-9 ........... ... 0.96 (4) 10-20 ......... 8.48 (39) 21-39 ......... 9.93 (67) >39 ........... 8.24 (19) Comments iCD code 162 only. b

Uer of epidemiological studies have demonstrated' increasedi mor- talitiy rates flor laryngeal cancer in smokers, particularly cigarette smok.ers';; compared with nonsmokers. Autopsy studies have re- vealed that a clear dose-relationship~ exists between smoking and t'1re development of cellular changes in the larynx, inclUd'ing carci- noma in sit:a.. 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 sucli~as poor nutrition and alcohol consumption has not been fully clar fied. Similarly, although. smokers are more likely to develop. carci• noma of the esophagus trian 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 dpvelopment of cancer of the urinary bladdcr than: are nonsmokers, and there is evidence to suggest. that some smoking-induced abnormal meta- bolic product or abnormal concentration of ai 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 epidemiologie evidence for this relationship is notas, definite as for bladder cancer. Epidemiological studies have indicated an association between smoking and cancer of the pancreas. The significance of this reia- tionship is unclear at this time:. Experimental studies have demonstrated the carcinogenicityy of the condensate of tobacco smoke, or "tar." This material'„ when painted on the skin of animals„ leads to the developmentl of sqiuam- 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 beeni identified as tumor initiators, that is, compounds which initiate changes in target cells and also tumor promoters, or compound's which promote the neoplastic development of' init'i', ated cells. Other; as yet unidentified, factors are presumablyy also involved because the sum of the carcinogenic effects of the known agents does not.equal that of cigarette smoke condensate. Nnmerousexperiments's have been performed in which wholeeigarette smoke;, filteredd smoke,. or certain constituents of smoke, such as the "tar," are administered by varying method's to animals or to tissue and cell cultures in order to investigate tHe neoplastic- indu:cing, properties of cigar.ettesmoke.. Particular difiicultyhas been encountered in experiments which have attempted to deliver 238 O G7 ~ Cn C'1 , 2v a

TASi_n; A1L.-Shidies concerning ll:c rc(diu2sLip o/ ar ... kirzg (p qlJrctiuliq ...... d'.n, (ALL 1 n,b" i af .hdn Ill : nih„ rn~) Snl ..S,n..lvcrs NSnNun.inu6aia Author. yenr, Numbcrnnd country, type of reier.enie populsGon Data cntle_ctipn Numherl of oiaita to ah:dent hcult/: unit for rrenirot Peters 1,496Harvard Medicelhis2ory1 aryfddneaa/.a et al., and chart review, 1964, 370 Radcliffe und U.S.A. etudents. questionnaire. ~i h¢Imuis (i.mt.l Results aS0.001. (coanmon colda, plary 4l'u'. 6*un .:a. (a, Zne9.monM-+DQt nJ,*yia snO Rar,.-d e. at RadclOde i1891. NS .................... 1.44 (771) 1.44 (192) SM .................... t2.27 (725) 2.27 (177) <2 years smoked ........ 2.00 3-4 .................... 2.30 >s .................... 2.80 Finkles et al., 1,811 male college Questlonnaire prior to Heuvy emokera-21 percent more clinical illnesses than nqnamqkera; 20 percent more reGUiring bed rest than nonsmokers The anthcrs also noted that: 1969 ptudenta. A2(llK/68 Lig h2smokers-l0 pe[eent more clinical illneeses than nonsmokers; (e) Smokers U.S.A. epidemic and _ 7 percent more ropuiring bed rest tban nonsmokers. exhibited ( 85). follow-up on morbidity. serologic evidence of increased subclinicpi A2/HK/68 intection. (b) Therewaepo dirterence,n the vaccinatlon at.w® bet-cen meken and nonsmokers. M<.SnE0

INTRODUCTION During the early-y.ears of this century, a number of pathologists and cIinicians.reported a,dramatic inereasein thei'ncidence oflung, cancer. Autopsy studies and studies of lung cancer death.rates.re- vealed a significant iv crease beginning prior to World R?ar i and continuing dbring the ensuing years. This epidemic of lung cancer continues to the present days with nearly 60,000 deaths expected from: this disease in the United States during19Z0. Beginning in the L920%s, a number of reports appeared which sttggested!a relationship between lung,¢ancer and tobacco smoking (.i; 203, ~?78)~. Since that time, many clinical and epidemiological studies have been published which confirm this relationship. The19fi1Report (291), contains athorougli review and analysi's of thee data availa~ble at that time as well as an excellent discussion of theconsid'erations necessary for their evaluation. Major epidemiological studies have dernonstrated that smokers have greatlyincreasedy risks of dyimgfrom lung cancer eompared'd tononsmokerso An increased risk of lung cancer has been flound'd for ever y type of smoking habit investigated, but- two character- istics of the risk are partiettlarly evident: Thee risk is much.greater for eigarettesmokersthan for smokers of pipes and cigars, and among cigarette smokers a doserelationship, exists... That is;, the more one smokes, as measured by total pack-years of smoking, present level of smoking, degree of inhalationy or agee att start ofsmoking;f thegx•eater is the risk..Ilt has also been shown that the risk ofi'lung canaerr among ex-smokers decreases withh time alrnostt to the ]evell of nonsmokers; the time requ.iredd is dependent onn the degree of exposure prior to cessation. Pat}Sologistss have foundd that the squamouscells or epidermoid form of lung, cancer is thee most preval.entt onee in cigarettee smokingpopulations and that this form accountsfor a majorportion of the rise in.lung cancer deaths Such studies have also indi- catedd a lower prevalencee amungsmokers for oat-cell and adeno- carcinomas of thelung than for the squamous form„ but in most studiesa.higher frequency of these tumors is found.amongsmokersd thann among nonsmokers. Smoking has been implicated i'nthe development of other types ofcancerim humans. Among chese is cancer of the larynx. A num- 437

TAUU:1.-Liug curccar niorda2id(i rutios (cvitt.) (AUtunl , mb.w ur Ju:,ps shuun t.o Va o~hes~sY v ro ... . . .. 56l -- gmokurs NS - Nonsmukers. I'.rust. t swdlus Avthor, Number Follow- year- country. reference andtypP of- noDulation DPtn collection up years Number of deaths Reeulxrci5arette pipe smokina only cicar (cigarettes/dey) Inhalatim. Exsmokers Comments Buell 69.868 Questlon- S 304 Ns .... 1.00 at sl.. American maire and <20 .... 2.30 1967, Legion- fullownp 20 ... a_6U V.S.A. ofJeath >20 .... 4.90 (49). 35-76 certificate. yeara of age an_d_ older. $irayama,Y66,118 Trained 1067, male and pp(S Japan female nuree (1£S). adults interview -- 40yeare andfol- of age and lowup of older. death certificate. 43 N3 ..... 1.OU (3) SM . 40 1-24 ... 2.69 (29) >86 .... 6.68 (6) preliminn_ry report. Weir and 68,158 Question- s~ 888 NS .... 1.00 NS include Dunn, malee in nare and -1-10 .... 3.72 pipe and 1940, varloue fallowup i-20 .... 9.06 ciear U.S.A. occupe- of death >30 .... 9.56 emokers (a08), tionein certificetq. California. All ..... 7.61 Sbf include ex-smokere. r Vnlene otherwise specified, disparities between the total number of deathe and the sum of the individual smoking categories are due to the exclusion of eitber occaslonal, miscell>neoue, mixed, or esemokere.

whole eigarette smoke to the larynx and into the Iungs of experi- mental.animals. This has resultiediin the use ofbther methods such as the implanting of pellets containing suspected carcinogens andl the instilling into the trachea,of suspected carcinogens as such, or adNorbed onto fine inert particulate matter as a carrier. The dif- ficulty with.the inhalation studies has been twofold. First, the animals, pamticularly the smaller species.such as,the rat, frequently die from the acute toxic.effects.of the nicotine and carbon monoxide inthe tobacco smoke. Second~ the upper respiratory tract of experi- mental animalg, particularlythe nose, is much different from, anal- ogous human struetures, resulting in a more efficient filtration of smoke in the upper respiratory tract. NevertheTess; in rodents and canines„progressive changes apparently indi'catinre of ultimate neo- plhstic transformation have been identified in the respirat'orytract. Recently, two studies in different species, and in ditferent.target organs have been reported.concerning the develbpment of early in- vasive cancer flollowingthe prolonged inhalation of cigarette smoke. Auerbach and his coworkers (1,L) trained dogs to inhale cigarette smoke through a traeheostomasAfter approximatel'y 29, months.of daily exposure, these invest'igators'found a number ofcancers of the lung. Dontenwill (76) imthe second of these two studies, exposed ham- sters to~the passive inhalation ofi'cigarette smoke over varying and prolonged periods of time. He observed' the development of pre~ malignant changes and, ultirnatel'.y„invasive squamous cell cancer of the laiynx: LUNG CANCER Cancer of the lung in, the United States accounted for 45,383 deatlisamongmalesand19,024.deathsamongfemalesin1967 (289). It i's presently estimatedd that approximately60,004D people will die of lung cancer during 1970: The alarming epidemic oflung cancer is a relatively recent' phenomenon.,Death, rates.forlu'ng cancer (1iCD Codes 162, 163') rose from 5!6 (per 100,000 resident population per year)~ in 1939 to ?7.5 im 1967(289, 290). This rapid increase followed the in- creased use of cigarettes among the United States populat'iom. The increase has occurred principally among males, although more re- centlv females have shown a similar rising pattern. The converging evidence for the conclusion that cigarette smok- ing is themajor cause of' l:ungcancer is derived from varied types's of research i'ncluding epidemSological, pathological, and laboratory inn•estigations. ]39 7s.

LUNCS(JANCDR AND OCCUPATIONAL HAZARDS E]rQ.9L140Y1Z M&9NiA8q The excess risk for the.development of lung cancer among uran, ium and fluorspar miners has been known for more than 30 years, In a recent review; Bair (17) noted that radon and.radlon-decay products are the only inhaled radionuclides to be epidemiologically related to lung cancer. L.undin„ et al. (178):, in a continuation of the workk initiated by Wagoner, et al. (299, 300; 301),.have re- cently reported on a 17-year follow-up of 3,41'4 white underground uraniumi miners. The authors estimated that smoking uranium miners experienced an excess of lung cancer ten times greater than did nonsmoking, miners, Saccomanno (231)', in recent testimony, analyzed the data of the U'nited States Public Health Service (USPH'S) Study Group asi presented by Lundin, et al. (T78) above. He reported that cigar- ette smoking uranium miners incurred lung cancer rates four ti¢ness great'erthan those of:other cigarette.smokers., Of the 62' lung cancer deaths in this population, 60 occurred in smokers. He alsoo observed that among. 100,000' uranium miners. 700 lung cancer deaths per year would be expected'to occur among cigarette smokers compared with only 4 among nonsmokers. - Other Occupations Nelson (199) has recently reviewed certain environmental and occupational hazards as they relate to inhalation carcinogenesis. He observed that cancer of the respiratory tract has been linkedl epidpmiologically and~~ in some cases, experimentally with occupa- tional exposure to the following materials: chromium„ niekel,, arsenic, and asbestos. Doll (72) andi Goldblatt (100), in earlier reviews, also noted, an association with coal, natural gas„ and. graphite:exposures. . Morgan (194) noted that much of the nasal and; lung eancer at- tributed to nickel exposure may have been due:to arsenical'..impuri- ties found in processed nickel prior to 1925. Doll (69)~ found that the number of excess.deaths among niekel workers under 50 years of age hadi declined following the change in nickeD manufacturing processes..Theexperiments.ofHueper (13+.) and Slanderman,etal.. (267,.268;, 269) fiavee shown that b.othg'uinea pigs'.and rats,develop Iung.cancer foIlowingchronicexposure:tonickel carbonyl or nickel dust:.Sunderman, and Sunderman.(270) also reported that ciga- rette smoke contains nickel and that this concentration of nickel

TSeLE &.-Tumor prevalence among males and females 35-69 years of age, by type of tumor and smoking category (Smoken constituted 86 percent of populations studied) - Smoking category Ezpeeted 6 Ripk $ezandtypepttumor Total Smoking e11 methods Non- smnkers n9 m et -m - ong smokers r ratio fimong smokem Males Epidermoid cercinoma ............................................ 434 431 8 17.0 -- 25.4 Small aell eneplastic carcinoma ................................... 117 116 1 5.7 20A Adenucattinome .................................................. 88 83 5 28.3 8.9 Po~onehiolnl-alveolar cercinnme .......................... ............. .... .... ... .... .... Gercinoid .......................................................... 46 80 7 39.7 1.0 Bronchial eland tumor ............................................ .... .... ... .... .... Total ......................................................... 685 ~ 669 16 90.7 7.4 Females Epidermoid cerciname ............................................ 12 9 9 .75 12.0 Small cell qnepkst_ic carcinome ................................... . 8 5 3 .46 6.6 Adenocarcinama .................................................. 56 14 a_2 10.5 1.3 IIrunchialol_-nlrenlar cerrinumn ..................................... .... .... _ .... ... . 4ereinnld .......................................................... 32 7 26 6.8 1.1 Bronchial gland tnmor ............................................ . .... .... ... .... .... Total ......................................................... 108 35 73 18.3 1.9 t Number that would be expected i( incidence rate among smokers okers were 8ounce: Lcreyberx. L. (154) epual to that of nonsmokers. - ~ EEES9G£0

tion.of various chromium: compounds in rats is associated with the dcvelopment of squamous celll carcinomas and adenocarcinomas. However, Nettesheim~~ et. al. (200) ) exposed mice to,chromium oxide dust and observed that it had no discernible effect on lung tumor incidence:. PATHOLOGICAL STUDIES Investigators who have conductedl detailed autopsy studies on patients who died of lung, cancerhave reported the increased pres- ence, when compared to noncancer patients, of bronchial epitheliall changes which they considered to be precursors of bronchogenicc . carcinoma (:7,. 8.,. 23, .51„104,, 208, 220, 279; 309):. Slachh changes, include squamous metapl'asia, atypical squamous metaplasia (:with~ acanthosis, dyskeratosis,. and numerous mitotic figures), and car- cinoma in situ. Carnes (51) noted that carcinoma,in situ was, pres- ent in. 119: cases of lung cancer but not in any of the 119' controls who were matched for age, sex, and race. Autopsy studies comparing the frequency of these cancer- related changes in the lungs of smokers, and nonsmokers are pre- sented in table 10. Virtually all the studies, noted an increasedi prevalence of these epithelial alterationsamong smokers as com, pared. with nonsmokers. Definite dosage-dependent relationships were evident in the results of many of the reports., ATso, Auerbach, et al. (14), observed that the number of cells with atypical nuclei decreases progressively in the bronchial mucosa. of' ex-cigarette smokers;depending upon the number of years between cessation of smoking, and death, although it usually remains above that found in nonsmokers. The cytologic studies, included in this table (182„ 198, 222) all notedd anincreased percentageof sputum: specimens showing meta- plasia among smokers as compared with; nonsmokers, PULMONARY CARCINOGENESIS GeneraG Aspects o j Careinogenesis Agents found in cigarette smoke which have been identified as, or are suspected of being carcinogenic, are listed in table 11. The list includes certain compounds which most probably contributJe to the pathogenesis of the various cancers discussed in the other sec- tions of this, chapter; Many other agents have been identified in tobacco and tobacco smoke. At the present'.time, they do not appear tobear a direct relationship.to carcinogenesis. Stedman (P62)) and. Wynder and Hoffmann (319) provide detailod listings and discus- sions concerning these materials. 258