Tobacco Documents Online

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LIST OF TABLES (Continued) (A indicat'estables located in appendix at endd of chapter). PageA2J. Experimental studies concerning oral carcino- genesis .................................... 371 30. Esophageall cancermortal.ity ratios-prospective studies .................................... 290 A31. Summary of methods usedl in retrospective studies of tobacco use and cancer of the esophagus ...... 3,75 A31a.. Summary of results of retrospective studies of to- bacco use and cancer of the esophagus ............. 378' A32. Atypical nuclei in basal cell~ of epithelium of esoph- agus of males,, byy smoking habits.and age ...... 379 A33. Atypical nuclei in basall cells ofl' epithelium of esoph- agus of males, by-amomit of smoking and age .... 380 34. Il;idtrteyy and urinary bladder cancer-prospective studies ...................................... 294 A35. Summary of methods used in retrospective studies of. smoking, and cancer of the bladder ............ 381 A35a. Summary of results of retrospective studies of smok- ing and cancer of the bladder ................. 383, 36. Pancreatic cancer mortality ratios-prospective studies ........................................ 298 236

TABLE A15.-Sh/dios omteevlaiup tka rcAetiolestlip aJsnlyd:hif~ fo iu/ c6r usrrsln+Frlnr?1 ctisenesaa )!+.u...n. ( ~.a (ACtum nun,bnr of ca. sLawu !n pm.eutno., S61-Swukers NS=Nnnmaokcrs Author, year, Number and euuntry, type of r;fSrence popnlatiun. Bonke. 1965, U.S.A. (33). 3hah ctaf., 1969, India (E05). Data collection Resulte Contntents Parents of 59 femilies. lnterview Pereon- h`u~nber of raspiratory Iline.ve.! Nn etatistiralb eign!fie.m t yeare sllneeseepsrson-yeors _ d~Rere . nc NS .........................(24) 120 624 5.2 noted. Cig.rettea/day: 1-10 ..........(19) 99 829 5.3 11-20 ...................(26) 108 486 4.5 >20 ......................(19) 99 424 4.3 Pipe, eiger .................. (14) 72 804 4.2 Tuberculosle 3urvey, X-rgg TuLe.culoue Nnrma! nr institute and - by X-ray +ontubcrcu(ove emplarees. interview. NS ........................ }10 (19.7) 118 (168.8) SM ........................ 36 (26.3) 215 (224.7) t Numbers in narentheeea ceprespntfigures --expected" by use of 2 x 2 contingency table. Tuberculoua mPLuYee9 w2re ronnd to have eigniflannety fewee nnsmokere and moker

60 50 40 30-! 20- ~ 10~ 4- 2~ 1934-36 1939~1 1944-46 1949-51 1954i56 1959-61 1963-64 Celentlar Years FIGURE1.-I6ung.cancer, Finland and Norwag.. $OURCE: $'lteybergJ,Ii. (154).. . land after 1950 and found a correlation between that increase and the increasing salee ofeigarettes in.thatcountry. Iireyberg (Y54) analyzed the lung cancer deathi rates of both -N'orn°ay and Finland in relation tothe 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. Kreybergobserved thatcigarettes,came.intouse in Norway in 11886~6 while the Finnish population (more closely allied to Russia socio- economically) was consuming more than 100 million cigarettes per Year dhring the decade of the 1880's. Cigarettes remained scarce in Vorway until after World: War I, and this 30-year lag in consump- us , M

T.tBLE A16.-Comp[ications developing en the. postoperative period in patients undeygoing a7idominal'.operqttions Men over 20 Percent Percent broneho- Percent Group, C4ees chest Percent Pnee.moniea total: clear 6runebitisand complication atelectasis rate Smoken .................... 300 41;1 63.0. 6a 58.3 Light Smukers .............. 180 68.4 2P:9' 3:9 31.6'. Nonsmokers . ................ 66 92.5 6:0I 1.5 9.6 Women. over 20 Smnkers ................... ... 2339.1 43.5' lYd. 60.9 Light Smoken ................ 62' 77,5 20.9~. 1.6. 22.5 Nonsmoken.................. 618'~ 88.8 8.1 3.1 LL2 SOnRCg: Mortbn, D..I. V. (1yY') TaeLE A17:-Arterial oxggen.satur¢tiion before and.after'operatian A[LCrinll oxygen saturetiGn (percentage) Group Case u nber Defore operation Day 1. Day.2 Day.B 1 94 93 94. .. 2 94 93 94 Nansmokera ......................... 3 96 93 94~ ... 4' 55 90 94. ... 5' 94 90 93 ,., 6'. 95 91 89 91' 9 92 89 81 89'. 3mokera ................................ 8 91 89 86 89 9: 93 91 89 92' 10 90 87 88 92 9onRCa: Maxton„ A. (1!2).. 230

Contents Page I'ntrndaction ........................................... 237 Lur.g C:nucer ....................................... 239! F'nfiiaminlnc*i~rtaT Studke9. .......................... ,... ... 240 Prospective Studies .......................... 240 Retrospective Studies ........................ 240 i.i;nm (',imcer Trend4~~ in Other Countries~............. ,. .... 244! Ilistology of Lung Tumors ........................ 246 LungCancer Relationships in Wumen, .............. 251 Lung Cancer, the Urban Factor, and Air Pollution .... 252 Lung Cancer and Occupational Hazards ............ 256. Uranium Mining ............................ 256 Other Occupations ............................ 256 -Nickel ............................................ 256 Asbestos .................................... 257 Arsenic ..................................... 257 Chrnmin~rn.-..--- ..................`---........,...,.. 257 P:ahological S'tudies. . . . . ........... . .......... ,. .. 258 ['nlmonary Carcinogenesis ........................ 258 General Aspects of Careinogenesis ............. 258 Polynuclear Aromatic Hydrocarbons ....... , 264 Nitrosamine Compounds................... ..~,....~ 264 Pesticides and Fungicides ................. 266 Radioactive Isot'opes ..................... 266, Inhibitors of Ciliarg. bZovementl ........... 267 Experimental Studies ................ ........ 267 Skin Painting and Subcutaneous Injection. .. 267 Tissue and Organ Culture ................ 267 Tra ch eo.S ron ch ia1 Imp lantation anrl Tnctillatinn .. 268~' Tnh~alatinn ... ............ 26$~~ 275 R'eduetion in Turnor geni¢ity . .............. ..... 276 Summary and Conclusions . .. ............. ... .. Cancer of the Larynx ................................ 277 Epidemiologieal Studies .......................... 277 P2thological Study .............................. 280 Experimental Study ......................................... 281. Sltmmary.y and Conclusions.. ........................ .. ...281 Oral C'ancer ......................................... 2841 Epid'emiolbgical Studies .......................... 285 Experimental Studies ............................. 288' Summary and Conclusions ........................•. 289. 233 '

Page Cancer of the Esophagus ............................. 289 Epidemiological Studies .......................... 289 Pathological Study .............................. 292 Experimental Studies ............................ 292' Summary and-Conclusions ........................ 293 Cancer of the Urinary Bladder and Kidney .............. 293 Epidpmiological:Studies (Bladder) ................... 293' EpidemiologicaI Studies (Kidney)' ................. 296 Experimental Studies ............................ 296 Summary andi Conclusions ........................ . 299' Cancer ofthe Pancreas ............................... 299 Summary and Conclusions ........................ . 299 References ......................................... 299'. FIGURES 1. Lung cancer, Finland and Norway ................... 245. 21 Percent of smoking,dogs with tumors ................ .. 274 3.. Percent of lung lobes with tumors inn smoking dbgs ..... .. . 274 4. Effects of chronic cigarette smoke inhalation on the hamsterlhrynx ................................. 284 LIST OF TABLES 1. Lung cancer mortality ratios .................... 2411 2. Lung cancer. mortality ratios for males by duration of cigarette smoking ........................... 244!. A3. Outline of inethods' used in retrospective studies of smoking in relation to lung cancer ............. .323 A4. Group characteristics in retrospective studies onihmg eancer and tobacco use .................... ..., 329' 5. Annual', means of total lungca.ncer mortality and.sex ratios for selected periods in Finland and Norway 246 6. Epidemiologic and pathologic investigations concern ing smoking and histology of lung cancer ....... 247 A7. Grouping of pu:lmonarycar.cinomas .............. 334 &, Tumor prevalence among males and~ females 35-69 years of age;, by type of tumor and smoking category ................................... 250 9: Epidemiologic investi'gat!ions ¢oncerningthe relation- ship of lung cancer to snrokingy air pollution, and urban or rurallresidence ...................... 2'53 10. Pathologic and cytologic findings in ttie tracheo- bronchialitree of smokers and nonsmokers ...... 259 234 .;.... _,~...d:..~::~_

TABLE A15s fitudies concemrng the relationship of smoking to infectious respiratory disease in humans (Actual numberof casea ehown in pamnlheses) SM - Smnkece NS = Nonsmokers Author, ycae. Numberand Data cdunCry, type.of " collection Reaulta Comments reference population Mine. _11_8 male end 1950, female patienta U.S.A. with pneumonia (167). and4'I2healthy individuals from d °e l ran om mp e. Hn pital Interview. Mean age ........................~..... Caeee 49.@ C_ one.ole 49.6 NS ............................. ..... 16.26 25.21 Cigarettes only .......................... 63.56 62.33 Mixed ...........................~.... 21.19 22-46 Lnwe. 62Umaleand Inter.cie.wby 1956, 185temale trained England tuberculoeia eocial (i5Yi. petientsand419 worker. male and 249 female control outpatienta. Dowling, lndividuala at al., expased to 1969, "infgctloue U.S.A. oold agent" (YS}L andplacebo. Malea Caeee Cont*ota The author stated that thecewasa eignifcantdiRerenee in tobacco vaage between the two. gmupe. Femnlee Cigarette emakere Caeee C_ ontro7w include pipe smokers. NS ....... ............. 2.5 8.1 37.3 51.4 Cigarettee/dsy: 1-9 ...... 9.2 12.9 20.5 25.7 10-19 ............... 38.1 35.6 30.8 20.5 20 29 ............... 23.4 27.4 30 39 .. 11.3 9.3 1 11.4 2.4 >40 . . ... 9.4 6.7 The author noted s eignificantdeflciency o,non- and light smokers and an e cess of heavy smokers emong the caeea Interriew and Exposed to plaeebo Expoaed to inJectioua o0ent No ortatistteally medical Percent Percent significant examinat/on. developinG deveinpinc diRerenees Number ^cold" Number "co(8" noted. . NS ................. ]11 10 328 ... 34 SM ................. 78 14 249 35

EPIDEMIOLOGIGAL. $TUDIE& Numerous epidemiologicall 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 A4L. those of cigarette smokers (table 1). ies to have lung cancer mortality rateshigher than those of non- smokers, although. these are generally substantially lower than Pipe and cigar smokers have been shown in the prospective stud- ( H~d ) ., England and Wales during the period from 1953'-57 through 1961- 65s the rates for male. doctors of the same ages fell by 38' percent. deathxates,from lung cancer rose by 7 percent among all men from Ex-smokers show significantly lower lung cancer death ratesthan continuing smokers. Tnitheir study of more than 40',000I British physicians, Doll and Hill (9'4, 75), noted a.d'ecrease in lung cancer mortality rateswith 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 thee duration of smoking (table 2)1. ciatedl with increased inhalation (table 1) as well as,with increasedi inithe mortalityfrom ]hngcancer with increasing amounts of cigar- ettes smoked perr day.. Other measures of exposure show similar trends. Hammond (118) reported increased mortalityy ratios asso- 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 of2'.20 (118). Also~uniforrnlypresent.in these studies is a dose.related increase Prospective Studies The major prospective studies concerning,the relationship of smoking andlung cancer are presented in table 1. In allll thesee and. controls as well as the relative risk. ratios for all smokers. ported coneerningthe relhtionship~of smokingand lung:caneer.. These studies are outlined in tables A,' and A4. Table A4 presents's the percent of'nonsmokers and of heavy smokers among both cases. More than 30retrospective(ease-comtrol) 0 studies have been. re- Retrospecta've Stzdies 24'0

LIST OF TABLES (Continued) (A ibdicatestableslocatedlin appendix at.end.of chapter) Page SL Identified or suspected'' tumorigeneticagentsinc cigarette smoke ............................. 265 AT2'. Autopsy studies concerning the presence of radio- activity in the lungs of smokers ............... .335 AL:.,. Experiments cancerningthe effects of the skin paint, ing,or subcutaneous injection of cigarette smoke condensate or its constituents upon andmals ..... 337 Al-4l Experiments coneerning,,thee effect of cigarette.smoke or its constituents.an tissue and organ cultures .. 343 At a.. Experiments concerning the effect of the instillation or implantation: of cigarette smoke.orits constitu- ents into the tracheobronchial tree of animals .... 346 .a7Gi Experiments concernsngthe effect of the inhalatilonn ofi cigarette smoke or its constituents upon the respiratory tract of animals ................... 349 171.. Data on pedigreed male beagle dogs of groups F, L„ 18. H,h and N ................................. 270 Summary of principal cause of death (days No:, 57 through No. 875 ) in dogs of groups F, L,,H, h and NI 271 19. Data, on dogs with lung tumors indicating type of tumor and lobe iin.which the tumor was found .... 272 20, Laryngeal cancer mortality ratios - prospective studies .................................... 278 A'71,. Outline of retrospective studies of tobacco use and. cancer of thelarynx ......................... 354 A22. Summaryy of results of retrospective studies of tobacco~ use andlcancerofthelarynx .................... 358 A2'3: Numtier and percent distribution by relative fre- quencyr ofatypicall nuclei among true vocal cord cells, of men classified by smoking category ..... 359 :a'?4. Number and'. percent distribution, by highest num- ber of'cell rows, in. the basall layer of'the true vocal cord, of men elassifiedd by smoking category ..,. . 360 25:, Deposition of "C-labeled smoke particles in particu- lar regions of the respiratory tract ............ 282 26: Classification ofthe five registered stages of epithe- lial changes; at thelarynx.............. ......... . 283 27. Oral cancer mortality ratios-prospective studies.. 286 A28: Outline of retrospective studies of tobacco use and cancer of the oral'.cavity ..................... 361 A28a. Summary of'results of retrospective studies of smok- ing by type and.oral cancer of the detailed sites.. 368 235

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

TaeLe5.-Annuai meansaf total lung aancermortatit',y and'sex ratios for selBcted periads in Finland and Norway Year Finland Nor.oay Muiee. Females Mafee. Femaiee 1936-88' ...................... 19288. 34 20 Sex ratio .................. 6.8: 1 1.1:1 1908'-65' ................... 1,819'. 121 8667b. Sex retio .................... 10.9 : 1 4.5 : 1 Sountac K,eyberq, L. (75<)., tion behindithat of.Finl'and is reflected in a similar lag in total lung cancer mortality and sex ratios (table 5). HISTOLOGY OF LUNG. TU2a0RS. A number of invesfigators 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 sqaa- mous'cell! (epidermoid) carcinoma„ small and Iarge cell anaplastic carcinomas, adpnocarcinoma (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- ingandg adenocarcinoma (42, 113)_, The work of Kreyberg (1'53) in Norway;, over the past 20 years, provides evidence of a specific histologic relationship.. This inves- ti'gatornoted thatl a clearer association is obtained if the various: types of pulmonary carcinomas are groupedL. 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 maI'e 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.forthose 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 femalesto their significantly lower consumption of tobacco in all forms. 2.6. QO

Finally; analysis of the ratio of male and female lung cancer death rates (283, 284,285;, 286; 287, 288„ 289,. 290) reveals that since 1960 this ratio has shown a st'eadyy decline; reflecting the greater relative rise in. mortality f'rom lung cancer in the female population. I LUNG CANCER,. THE URSANFACTOR, AND AIR POLLUTION A. number of studieshave been concerned with the relative influ- ences of smoking, urban. residence, and air pollution in the etiology of lung can®er.. Table 91ists studies perforrned in the United States, Gbeat Britain, and Jiapan which have dealt with. this question:. Kotin and Falk (149, 150) and more recently the Royal College of Physi- cians (228) have reviewed the literature concerning the influence of atmospheric and environmental factors in the pathogenesis of lung cancer. The studies listed in, table 9 show a number of important trends. Lung cancer death rates,arcefoumd to be higher arnong urban.popu- lations tham among rural populations. It is not known to what: ex- tent this urban factorin the etiology of lung cancer is, due to differences in the levels of aivr pollution. Other factors associated with urban residence which may influence the etiology of lung, cancer are: differences in srnoking habits between the two popula- tions,, occupational differences;, and possible differences, in the re- porting of'.lung cancer deaths (228)',. The studies also uniformly show that within each urban/rural, grouping,lung,caneer death rates increase with.increased smoking., Whether air pollution acts with cigarette smoking to influence lung cancer death rates in a. combined manner is presently unclear (112, 126; 264, 265)yandl thee evidence concerning a~ separate role of air pollution in the etiology of lung cancer is still. inconclusive (228). The recent report of the Royal College of Physicians on air pollu- tion and health (228) concluded that "the study of time trends in. the death, rates.ofl'lung cancer in urban areas demonstrates thee overwhelming effect of cigarette smoking on the distribution of the, disease. Indeed, only the dptailed surveys that have.taken individual. smoking histories,into account have succeeded in.separating the relatively very small inflbence of the 'urban factor' on the over- riding effect of cigarette smoking in the development of cancer of the lwng."' . 252

LUNG CANCER IiDLkTIONSHIiPS INWOMENLu:ng cancer death rates for women are presently much lower thani the corresponding rates for men. In addition, it has been oh- servetl that among certain strains of mice exposed to carcinogenic agents, the male:animals, show a greatertendencytor develop~lung tumors than do the females (200;. 307) altlhough there are strains for iwhich this is apparently'notso. The extent of the influence of endocrine factors in the sex variation in the incidence of lung tu:mors is unknown.. As of 1967 in the United, States, womenlaccounted for only about one-sixth of the tJotad deaths from1ung cancer (289). Hlowever, the lung cancer death.rate in women has, risen by over 400 percent in! the past 40 years. From 1950'to 1967 alone, the rate per 100;000: population doubl'ed, increasing from 4.5 to 8.9 (289', 290). A number of retrospective studfiesconcerning lung,cancer and. cigarette .smoking among women have found tlhat the difference iinn the prevalence of lung cancer between males and females is ac- counted for principally by those tumors classified asKreyberg's Group 1(1S.S, t)'t1)~. These; aswas noted above, are the tumors, par= ticulxirlp in males, which show the closest relationship. with smok- ing„ Haenszel,, etal.. (.113),., in a. study of 1158 women with~ lung cancer, observed: that the sex differential for lung cancer death rates diminishes, but does not fully disappear when only nons smokers are considered. Havnmond' (118) found that the death rate for lung cancer in not smoking males was somewhat higher tham for nonsmoking fe- males. Homwever, the difference in male-female rates was much greater when smokers were compared. It appears that a substantial part of thee di:fferencein deatih rates between male smokers and fe-male smokers can be explained, mainly by differences in their smok- ing habits. These differences in smoking Mabits between males, and females are of two ty.pes.. First,, overall.consumption among.femalesis.stillg significantly lower than that among males, In 1966' (281), 30 per- cent: of rnalesreported that t'hey had never smoked while for fe- males the corresponding.figure was 59 percent. Thisstudy also noted that. nearly three times. as many males as females reported consuming more than.20 cigarettes per day.,Second„it has been sFi.own that wmmenn smoke differently than men (303) : They heginn smok:ing laterr than men (114) '. and do not smoke cigarettesas closee to the end, where.proportionally morenicotine and "tar" arein- haled- Women smoke more filter-tip and.'9ow tar and nicotine"' cigarettes than men. Furthermore, cigarette smoking still tends to be heavily concentratedl among women under the age at which lung cancer is most likely to occur. 251

u P 'CAm t; 7Q-L'µf/tologic and rifttl(ugic fieddanqs m the tlacken-brerzcbial tree of snyoker,v and nonsmokers (so (Actual number (rf ses shown in Parentheses) Authar, Number of --year, nnd nntrr, methodof reterence selection Hesnlts Auerbnch et al., 1962, 92autopekd former eiga- rettesmokers Number of secpions of bronchiad U.S.A. who had been Number spithalium (14). mnkfngfor Nansmukpre ........ 72 3,156 ?10 ycem Ea.emokers ........ 72 S,45ti and had Currentemoke® . . 72 3,63T ceased ?5 yeare aga. .) Comments Pccent sectione 1'crcent acctione Percent eectinn. Each ex-amoker with tilia ahecnt with some atypi- with 50 percent matched with a and entirdv cut ceRe and at&Pieal cetie current emoker atyyicq[ ccfk cilia a6aent and cilia preesns plus nsvsnamoker 0,0 0.1 0.5 forage,oecupa- 0.2 0.9 2.5 tion, and resi- 8.0 19.0 80.8 dence. Therv wae averegeof 60.3 eectione Per. eubject and nune had leee than 18 section..

TAaLe 2'.-Lung cancer nlortalityy ratios far rruales bpt' dttrationo f' cigare t'te smolaing (Actual number of deathsareatiown in Unrencheses) L Ageo be¢an cigarette smakinq3fi-64 55-69 T0.84. 3"4 , 25 or older .............. 2.77, (6) 8139 (12) 3.39 161. 3.21 (20) 20.24......... ........ . 5.83 (31) . 11.11 (72) 12.11 (7): 9.42(Ilp) 15-19 ..... _......... 8.71(112). 13.qG(176) 19:87(27{. 12.81(315) <15 ................... 12.80 (35'). 15.&1 (57) 16.76 (9), 15.10(k01) 8tlueca:,Hammond,II. C. (118). These smoker-nonsmoker risk ratios range from 11.2 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 andl pipe or cigar smoking are similar to those found by the prospective studies mentioned above. However, a study by Abelin and Gsell (',Z)conducted on a,rural $wiss'population noted that an increased risk of lu,ng cancer was present among heavy cigar and pipe smokers (as well as cigarette smokers): to a greater degree thann previously reported.. The authors suggest that'their findings might be due to.differences in either the amount smoked or the car- cinogenicitynf,Swiss and German cigars. The difference might also be explained by the greater use and more fliequentl inhalation of small cigars in SwitzerlExnds as compared to other' countries where large cigars are more commonly smoked but rarely inhaled. Kreyberg (]5w), in a reviewrof 887 cases'of lung cancer iniNorway, noted that pipe smokers.showed an increased risk of lung cancer, although this risk was substantiallyIow,er than that for cigarette smokers. LUNG C',ANCERTRENDS IN OTHER COUNTRIES Several' studies off particular interest are those in which the changing mortality from lung cancer has been investigated in countries in which cigarette'smokinghas become popular and wide- spread only in recent years. In those countries where accurate statistics for lung cancerr 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 im 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 wheni compared to'o that of Great. Eritainn and Finland. He observed that. the annual per capita consumption of tobacco did' not reach one pound'n in Iceland'', until 1945, while Great Britain and. FinIand passed that amount before 1920. In 1967;, Thorarinsson, et al. (276)~ noted a. sharp rise in.the incidence of lung cancer in Ice- 244 f

'fnate 1.-LJniD 9evlscr utmrda_IitU Mfi0g (Actual n ,mber ofd_e_n_tha shown in porentheae_a)P SM -- Smokers. NS - Nonsmukere. Author. Numher yeaednd type collection Follow- country, of Data up reference poBnlatiJn yenre Hemmond 187.783 Question- uestion- 3';' end white naireend Horn, males interyiew. 1968, in9US.A. States (120). egA 50 69. Doll and Approxi- Question- 10 Ifill, mate)v naire an19G4, 41.000 fo8nwup Great mnle of death Britain British certificate. (74). physicians Beat, Approxi- Questfon- 1966, mately nnineand 1966, 78,000 fnllowup Canada male of death (8+). Canadian certificate. veterans. iye stydieg Nomber Regular cigarette Pipc bfsmoking`onlv ciR_ar Inha)ation deaths (cigssrettie/dey) - 448 Pipe Nadata SM . 443 NS ..... 100 (15) NS ... 1.00 (15) NS . 15 <10 .... 8.00 (24) SM ... 2.57 (18) 10-20 ...10.50 (84) Cipar >20 ....23.40(117) NS ... 1.00 (16) All ....t10.43(397) SM ... 1.00 (7) . 212 NS ..... 1.00 (3) PipeandCipn. Nodata SM . 209 1-14 .... &14 (22) NS .... 1.00 (3) N8 . 8 16-24 -..19.86 (53) Crams/day >25 2_5 ....32.43 (67) 1-14.. 6.00 (12) 1g24.. 6.43 (6) >25...13.71 (3) 331 NS ..... 1.00 (7) Yipe Nadata fShf . 324 <10 ....10.00 (67) NS ....1.00 (7) -~ ~~NS. 7 10-20 ...16.41(204) SM ....4.36 (18) >20 ,,..19.31 (63) Cigar All ,....14.20(245) NS ....1.00 (7) SM ...,294 (2) Examokera Commente HvanehoYCnie 341/448 (Szdnding adenornrcinemm) deaths with Never smoked ........ . 1.00 microscopic Previausly <1 pnck/day emuf. In- Continuing ...........16.04 rludesthose Duratienl <I ye r ..16.50 regular af 111( 1-10 yeare .10.44 cigarette ces ation111 >10 ye s-. L61 emokers wbo Premoualy >1 pack/day also smoked Continuing ........... 46.21 pipee end Du tion <1 yea .68.28 engers. of 1-10ye ra .22,82 i WLLhar cess tion >10ye s ,17.78 ithout mroscopic proof. Cigarette emoker. NS ................... 1.00 (3) Continuing ........... 18.29(124) quratiunl <6yeare .. 9.67 (5) of JJ1ff{ 5-9 yeam . 7.00 (7) essation 10-20yeara . 2.57 (3) >20yenw . 2.71 (2) r Refera NS ................... 1.00 (7) to cnr Ex-amokers of rent cigarettes only ...... 6.06 (18) cigarette ---emakern only. ~~:as0c4eo

may be capable of inhibiting the induction of lung aryl hydroxylase, ani enzyme which is able too detoxify aromatic hydrocarbons includ- ing known earcinogens such as benzo[a]pyrene. Asbestos In 11955, . Doll (71) found't that lung cancer was a definite hazard among asbestos workers. In a more recent study,, Selikoff„ et al.. (251, 252) examined the relationship of smoking and asbestos ex- posure to Eung cancer..These authors followed 370 people who had been asbestos workers during the years 1942-1962 Over a 5-year follow-up period[ 94 deaths occurred in this group, of which 24 were due to bronchogenic carcinoma. The authors noted that, according to data obtained from Hammond (118),, only 3.16 deaths from lung cancer would have beem expected among smokers, and calculated'~ a 7.6Itlo 1.00:mortality ratio due to asbestos exposure: None of the 87 nonsmokers or pipe and cigar smokers died of ]hng cancer. When the expected numberofl'nonsmoker deaths (426), is compared with the actual number (24.), which; occurred among, the smoking, asbes- tos workers, amextremely high mortality ratio of 92 to 1 is obtained, thus reflecting the possible:interaction of asbestos exposure and cigarette smoking. . . . Exposure of mice(179). and rats. (106) to asbestos d'ust or the intratracheal injection of ehrysotile asbestos dust has resulted in the production of significant numbers of primary pulmanary car- cinomas, Miller, et al, (184) exposed hamsters to intractracheal injections of benzo[a]pyrene. These.authorsobserved that the addi- tion of the ehrysotile varietyy ofl'asbestos to the injectionsappeared to promote benzo[a]pyrene.carcinogenesis in: the: respiratory tract, as determined by the time of appearance and yield5 of papillomas and carcinomas, Arsenic A recent epidemiologie study by Lee and Fraumeni (163) has indicated an excess.of lung eancerdeaths among,smelter workers exposed to arsenic for more t'han one year. Cigarette smoking was not taken into account in their computations: Experimental work on the i,nduetion of cancer in animals using arsenic has yielded either negative or inconclusive results (133;,135)~. OJaromaf¢ona. - - ' - Exposurete~ industrial bichromate compounds' has; been associ'l ated with an excess of lung cancer deaths (22,255)_ Laskiny et al. (159) have recently reported that intrabronehiall pellet implanta- 257

J a Y -T-AIt1.P: ('i.-F.pirlCtuiolqJjc tPld P,(Ir~d.i Author. Numbcrof ..year. neisovsavd c6untYy. cAS& selectiJn ceference method Wynder 644 autuPSies on and males.with Graham. confirmed 1950, lung cancer. U.S.A. (tt6). Doll end Hill, 1962, England (zs]. Peraent m / li ..ctl.. Nanr..... and a+naktnn hietarV aennlcn!s 'Phe t-evtagc of chai Adenacarcinoma (39) Nonsmokers .......................... 1.3 10.3 Light cigarette amokern ................ 2.3 7.7 Muderate ............................. 10.1 16.4 Henvy .... ................ .......... 36.2 38.5 Ex<essive ............................ 30.9 10.3 Chain ... ............................. 20.3 18.? 916 male and 79 Percert yatievt. with lunQ cr r by avera_8e amount smoked daff i ove. 10 yeara female cases withhistulogically anfirmed lungenncer. onsmokers .---.-.. Epidcc®oid (475) 0.2 (1) Malee Oat-ceU or ¢rm,piktatic (]0}) 0.C (2) Adenoouru(noma (f]) 6.1 (2) Smokers: <5 cigarettesFday -- 2.9 (14) 8.9 (12) 6.1 (2) 6-1a .............. a5.6(169) 361010) 21.2 (7) 15-25 ............. 26.8(346) 84.Y(106) 48,5416) >26 .............. 24.4(116) 24.4 (74) 18.2 (s) Femalee Epidernoid (1 Oat-ceR or 8) ararylaetic ($8) Adenacarmrto+na (10) Nonsmokers ........ . 61.1 (11) 31.6(12) 50.0 (6) Smokers: <5 cigarettes/dsy . . 5.6 (1) 15.8 (6) 20.0 (2) 6-14 ............. . 22.2 /4) 23.7 (9) 10.0 (1) 16-26 ............ . 6.8 (1) 18.4 (7) >26 ............. . 5.6 (1) 10_6 (4) 20.0 (2) . nokcra in the ggnyral yopulation (ZO) was signifiesptly le5y than among the patients with edenncarcinuma. The authors refrnimd from making any definitc conclusions due to the insufficient number of cases. No statistically s+gniflcantdiRerence was found between theamounlnamakedby thnatientsinthe aitferent histumgical grouye. NumLer of yr, . aden n ocare;nomse i mnll [or enndus;ons. Males-lQ6 unelaseified tumors. Females-13 unclnveified tumors. ,

1nlhnr. Nn ue,. „f u9 w,tuy. d ~.f rrfnvuev idn rrr n _- A'.uab, 14 ............................. ..... G:N II 11, Smokers: 1-10 eignrettes/dav ............................. . ......... IKU 47 09 / 11-20 ............. ..................... .................... .14G 51.43 21-30 ........................................................ 9J 61.29 >30 ......................................................... 39 e@.28 Nnsiell, 50 nonsmaking SRPtu+n cUtplogrc_ c_hau0ea PGCrcCtlt with } ftuguxded by 1968. outppvicnts, Nercnnt Percent with a6u»iea! author ns "reW Sweden 39tlsmokers Vumhpr Malc_s MeanaUeu p{et2planin mc_da_g_lnsdat vremnlignant (198). particinnti_ng_ Nonsmnkere ............. 60 42 5].1 18 4changc." in ¢enersl Smokers ................ 398 73 d6.6 62 _ 27 health exem- mation who underwent sputum induction. Malt~mi I,OOOhrnltliY ct ul., iula wFn 19LN, undivwent ItalY .aVnlurn (18.). Ind,nJ.inn. Spain 157 males and Numher Percent with vnetaPlaaia The authors found at nl., 9F femnlex Males: no evldence of 1970, autonaied fol- Nonamnkere .................. ........... ......... .......... .. 36 @0.0 careinomnin aitu V.5 A, lowing sndden Ex-smokers .................. .......... ....... .......... 21 57,7 or preneoplaatie .... . . (258). ar arcidental <1 psck ..................................................... 32 62.6 atYpicalchanges. death for >1 pack .............................. .... _ ................ 68 43s whom smok- Females: ing data were Nonsmokene ................................................. 34 34.1 available (ex- <1 Peck ..............................................._ .... 18 33.3 smokers ex. >1 paek .................................................... 26 46.1 cluded from female data ). 9VCS9GC0

TABLE 9.-Epidemiologic investigations concerning the relationship of lung cancer to smoking, air pollution, and nd urban or raral residence (cont.) - (ACtual number of deaths shown in parentheses) Author. Population year,studledand Couniry, method of reference data collection Haenszel 10 percent of all etal., whitemnlelun¢ 1962, cancer deaths tn U.S.A. U.S.A. for 1958 (1ut). forwhomne:tof kin or physicians suaplied smoking data.2d91 eases with adequate Results Age- and amokfnIDStandardised lung cancer rnorta{ity ratioe (eYidcrmout and urydigerentisE¢d carcinomaa uniy) Metropotitan cuuntiee NaSmetropot(tnn ceuntiee >50,000 ..............119 2.500-60,000 ......90 10,000-60,000 .........151 Rural n_onfarm ....4C 8,600=10,000 ...........99 Farm ............5T information. D_ oll andHip, 1964, 41,000 male British physicians. questionnnire and England (74). follow-up of death ce_rtiHeete. Nunsmnkers .......... Cigarette sm_ okers: 1-14 ................ 15-24 ............... >25 ................ W)cken, 1,90fimaleand 1966, female lung cancer Northern death.r over 95 lre)and rears of aqe from (a08).reqister.Personal Males .intcrview.awith Femeles..... kin or physielana. Standnrdized deatA ratca for lunp caneer Conurbation(49) LaryeTOwnn (a4) Smas Tomna (32) 0.03_ 0.00 0.11 0.48 0.32 0.87 1.31 1.88 1.06 1.90 4.43 2.20 Commenta _Standsrdi¢ed Mortality Ratio = 100 fer U.S. whtte males a¢e 85 and over in 1958. The authors also noted ".. , joint elfecta of resldene¢ and emokinz hiatories in the echedule of hang-caacer rates far ¢reater then those e%pected en the 6a9VTpti9n of additl_vlty of the separete eHects . .. The authors noted that _ rural mortelity data Rura! (18) were affected by a 0.12 sienificant numberof city residents 0.52 retirin¢tothecountyy. Lung cancer death rate per 100,000-ape. and amokivgstandurdined Total n mber of deeths noted under method of Inner Quter Ret/ast Urhau . Small data collmtion include Rel7set Belfast Environe Areaa Towne Rural 954 cantrols. 157(241) 139(157) 22 (38) 17 (2/) 135(45) 118(195) 12 (6) 23 (35) 137(26) 22 (5) 47(149) 12 (43)

In order to facilitate understanding of the relationships of the various compounds to one another,, the third column presents the presently understood relative importance of each of the various groups of compounds. These compounds have been tested only in animalsor tissue cultures, and' it should be stressed that the rela- tive importance ofone compound may not be the same in man as it is in animals. Table 11 is divided into two major sect'ions,. The first section details those compounds which are considered to be or are suspected of being cancer initiators.. These are compounds which induce irreversible changes in responsive cells. In the second section are listed those compounds which are considered to be or are suspected of being tumor promoters. These compounds promote the malig- nant reproduction of cells in which meopl'astic changes have, been i:nitiiated. A number of these initiators may also act as complete carcinogens in their own right. The evidence concerning the two stage initiat'ion-promotion mechanism is stlilll rather limited for respiratory tract careinogenesis,. The polJnuclear arom:atic kydrocarbon:y (P?,II') listedi are pres- ently considered to play a very significant role in pulmonary car- cinogenesis due to tobacco smoking. These compounds act' as tumor, initiators or eomp]ete carcinogens. The particular role of these agents in environmentall andd occupationail carcinogenesis, . hass beenn reviewed by Fallt, et a]: (93)1. That such hydrocarbons are pro- duced. from tobacco during human smoking has been shown by Kiryu andiKuratsune (146). These authors reported the presence of benz[a]anthracene, chrysene;, benzo[a]pyrene, and benzo- [blfluoranthene in the "tar"' produced by normal smoking and' measured in either filters or stubs,Two hydrocarbons which have frequently appeared in the litera- ture on experimental tobacco carcinogenesis may not actually be present in. tobacco smoke. They have been used a& representatives of carcinogenic P'AAI„ a class which. ineludes,many constituents that have beeni identified in cigarette smoke condensate. They are 7,1i2-dimethylbenz[a]anthracene and 3-methyTcholanfhrene andi have been. frequently used as t'umor initiators or complete carcino- gens,. particu]arlyiny skinn painting and. tracheal implantation experiments. The nitrosanGine compounds listed are potent carcinogens affect- ing' many organ systems,., including the respiratory tract (188, 189). Magee and B~arnes (181)') have presentedl a detailed accountt of experiments in. this area. Nitrosamines have been identified in trace amounts in tobacco "tar" and'the conditions required for their' formation (the presence of secondary amines and nitric oxide) are 264' C W ~ WI

TABLE 9c h:pidemiuloyiC imlyBfifPltionm cmlrrnliup fh r rrfu_frnlrship of 1RRJ cn)IC_c_r lm sato5.-ercag, air yolGlEiolp, ¢vud urGal_t o)' rv<anL7csidc:;ce (Aatunl mmnher nf dralhs shown in parenthesw) Author, vcar, CnuntrY, rcfeTence Populatinn ntudiednnd method of datacojlcetion IIesulb, 9nmments DoB, Estimated death retes Laap ra . u mortafita 0050) yer 1.000 Authors nnted that 1953, from lung cancer Malra Nemalce Nonsmokers estimates are based on England in English Lorulmi Other urban Rural London Other urban Rural AfL arcae very few destha. N U Y (y0). populationand among nonsmokers obtained from general rY6ieter. Stocks and Death rates in Campbell. Englandand 1955. Northern Wnlea. England_ Bevlew, of Yatient (265). cLart or interview with kin or physiciana. A 25-44 ...... 0.126 0.095 0.070 0.028 0.028 0.012 0.020 45-64 ..... _ 1.572 1.264 0.851 0.194 0.162 0.120 0.090 65-74 ..---. 3.12d 2.006 1.104 0.440 0.326 0.288 1219 Mala ng cancer death rates l9sa~4 (per 100.000) aGea 5b-Y4 Rura{ (68) Mixed (118) Urbnn (689) Munsmokers ................................ 14 . 131 Pipe ..._ ............................~...... 41 25 148 Cigarettee:Light ............................. _ 87 153 297 Moderate ................................. 183 132 287 HeevY ............ ............... .... ~.... 863 303 304 Hammond and Horn 187,7&8 white m_eles in 9 etntes Age standardized ized death rate6 du¢ 6o 6ronckapen{c carcinuma (males) , 1958, U.S.A. . @ue.tionneire eadinterview. Rural Su6urb ortown Citgof 10,000-s0,000 Citgof >50,000 (tt0). Nonemnkers ............. ... 4.7 (2) 9.3 (3) 14.7 (4) Cigaretteemakers........ fi6.2(52) 51.7(67) 70.9(69) 85.2(83) The authors noted the upward gradient among nonemokera, pipe emokers end light cigarette smokers and d the lack of e similar - gradient among moderate and heavy cigarette emakers. Data excluded _ edenncarcinome.vehen etanderdisedfo.ragcand smoking,ruralratewa_s stillnotedtohe26 percent less than urban. seessc,eo

N a m TAaf.E 6. Epidemio2ogic and pathologic investigations concerning smoking and the histology of lung cancer* (cont.) - (Actual number of cases shown in uarentheeee) Author, Numberaf year. pereanebnd country, case selection Results Comments reference method - Breelow 493 male and 25 Pereent of patiente with epecific tung camcers by tobacco ueago durinp the 20 yeare prior to etudv Nonsmokers include pipe et al., female ce.•qa . ._ and cigur amakere only. 1954, with histologically A I! tunD c¢ncerx uthsr than The authors conclude U.S.A. p_coven lung adenocarcimm¢ Adeovoca.cinoma Controls that cigarette amokin g (4y) eanner. (4>Y) (46) (518) _ _ appearetbaReetthe 618 sge and Nonemokers ...................... .... 5.9 13.0 24.4 development of sex-matched Cigacette smokers ................ .... 94.1 87.0 76.6 epithetlaleercinoms controls. more than that of adenocnrcinoma. teessceo Schwartz 430 male and Percent of arnokere bv hietotogic type anut smoking hietory -_._.....- etsl., femalecaxs 1967, with hiaalogically 6pide*mnid Anaplaetic Unknown type Cul:ndrieal t DiRerenen France confirmcd lung Cases .......... .... 96.0 97.0 96.0 100.0 significant (247). eancen.4matched Centrols ....... .... G9.0t k3.Ot 70.0 96.0 atp~0.051evel. gruuPS. control Haenszel 16k female Refative risk fnr speciBed tumave (emnkere/n.onernokere) 134 ceees with final et al., cases of - hietolugiea] 1953, lungc cerg a n graup!(Krcyberg) Adexacarcinoma determination. U.S.A. _ _ _ -- - Adjusted for age and occupation . ............. 3.0} 1.19 t DiRercncefram ( ll d1. . .. nitr signtficant at . . pc0.0L Heenszel 2,191 male Standardized mortality ratioe Cases obtained from a - and csses of 10 percent aempis of Shimkin, lung cnneer 6pidcrmo_idaaduruiigeroxtinted -------lung csncer deaths in 1962, wwith adequste earctnomae Adenacorcinoma U.S.A. during 1968. U.S.A. histologic data. White males tota l ............................. 100 100 The authare nole_d an (ltyl. --~ -~ Never smoked .. ....... ................... 6 18 absence of important Ex-smokers .... ............................... 34 46 differentials by !1 pack/day .... ................................ 123 116 _-__.._.. . .. hiatdohistologic tYpe. >1 pack/day ... ............................... 499 469

quently located at bifurcations and that the polonium~ levels whichthey found in those regions probably have biologic significance (~216). Other investigators(123;, 217) have not observedd thiss excess at bifiercatlions„and in a recent.disetassion Wyn&r and Hoff- mann. (320) concluded that it appears unlikeythat Po.,„ in thee amounts present in cigarette smoke plays a role in tobacco car- cinogenesis. Although not listed as a separate group, there are a number of agents in.cigarette smoke which are potent inhibitors of ciliary movement. Their importance in carcinogenesis derives from. thee increasedd amount of timee which they afford thee knownn carcinogensto be present on the surface of.the bronchial epithelium. These inhibitors include volatile aSdehydes, hydrogen cyanide,, nitrogen oxides, volatile phenols, and certain volatile acids such asformic and acetic (129). Ea•perirn.entalStzcdies. In some respects, the animal and tissue culture studies detailed below apply to neoplastic transformations, not only in the lung but in other tissues in which tobacco smoke, particularly cigarette smoke„ is believed to plhya role. These general experiments will be presented here; liowever;,with the experiments which bear on lung tissue directly. Skin P'aintingarulSn,bcutanenus Injection Numerous. animal studies on rats, mice„ and rabbits, have been. performed. utilizing known carcinogens, whole tobacco "tar," and'' various tobacco condensate subfractions„ or compounds known to be present in tobacco smoke. These experiments involve the single or repeated painting of shaved or unshaved animal' ski.n. A selected number ofthese studies is presented inn table A13.. Numerous other studies, performedd prior to and following 1953, are reviewedd by Wynder and Hk)ffmann (,319)... The skin painting method is still considered to be a valid pro: cedure for the identification of agents suspected of participating in pulmonary carcinogenesis,, as welb as for thee quantification of'f thee reduction. in tumorgeniicity off specific agents. Z'issu.e andQrga7v CuZture Th.eexposure of tissueand'e organ: cultures too cigarette smoke,, its condensates, or its constituentt compoundss has been shownn tosig- nificantly alter patterns of eell: growthandh reproduction. 1lableA14 presents.an outline of these experiments. Once again~ less.severe effects have been noted when filtered smoke wasused (165)..

TABLE 1Q-F-atholo9ic and cytologic findings in the tracheo-kmoncitial tree of sztwkers and nonsmokers (Actunl n mber of c es shown in parentheses) UYES9ga£O Author. Number of Yenr. eneed and nntry, methodof referenee -8eleetinri C_heng, 105 mele. and 1957. femnles 40-&6 U.S.A. yeers of age. end Hurea (55). Hamilton at al., 1955, U.S.A. (117). Seleeted autoney meteriel. 5a_nderud, 100 melee. 1958, aatopsied et Norway Qadc Inetitute (Y40). pn whnm - emokingdata .wac availsble. Rnudtsnn, 1960, U.S.A, (_14_>). Resultr Perccne of ca.ex witA bronrhial baeuI ceA hyperactivityN.onsmokere ..................................... ................... 23.5 (34) Smokere .................................................... ... . 43.9 (71) Heavy emokera................................ ................. T61.3 (31) Numbe+ 8mokare ................ 15 Nonamokere ............. 20 Age ranpe a9-ai 28-85 Per.cent of colee witb: Bavaiceli Sauamoue hVperptaela me_taplaeia 86.6 20.0 40.0 15.0 Trqnaitionnl metGplael 40.0 36.0 Percent oF caase m(th brone_hial e9uammu eyithelial metuptaNa Nonemokere .................................................. 54.0 (39) Pipe . .......................................................... 80.6 (20) All cigarette ................................................. 79.0 (36) CiBSrettes per day! 8-14 ...................................................... 70.0 (28) 16-26 ....................................................... 90.0 (10) >25 ............................................................ 100.0 (6) 100persone 28-86 yecra No. of Percento/ aaaptoith: No 8aea1 eeR of ege eutopeied et Nonemokers ............. P[rbane (21) ehangc 47.6 hYpe_>plaeia 28.6 Seatfle CI¢erettee/day: Veterene 1-0 ................. (0) 77.8 11.1 Hoepital on 10-16 ................. (11) 18.2 18.2 whom 16-20 ................. (44) 20.4 29.5 emoking >21 ................... - (9) 11.1 89.3 aata w.e :. 100.0 avaRable. Atypical S9uamoue proNjeratfve metaplaaia metantnslo 14.3 9.5 11.1 54.5 8.1 29.5 29.5 44.4 11.1 .. .. Cammenta Smokers included pipe and cigar make i p=e.U1 in corn- yarisqn with nonsmakere. No lung csncer patiente included. Nonsmokers in- cludethese emoking le?s than or eaual to 6 grame per dcY. Age, occapati_o_ n_ . .nd sEte of restden<n were found to hnve no appreciable e8eqc.

TABLE 10.--Pathologic and cytologic findings in the tracheo-bronchial tree of smokers and nonsmokers (cont,) (Actual number of ceses shown in Parenthr~as) Author, Numberot yeai, - cases sad country, method of reference sdection Auerbacb 456 male and et al., 302 female 1962, smokerssnd U S.A. nonsmokers. (IS). sutopsiedand Number matched for Malee: age,occu- Nonsmoken ........... 47 pation. and Cigarette emnkere ...... 75 residence. Femsles; .. Nonsmokers .......,,,. 47 Cigarettesmokem ... .. 75 Malee: Nonsmakere ........... 36 Cigar smokety . 96 Cigarette amokere ...... 35 Robbine._ l0_3 students 1966, 14-24 yeare U.S.A. of age who (RYf). underwent asol sVUtum induction. Reeulta Percenteac- Percenteer- Perc.entaae- Nvm6er of tione with tfona with Nune witJA 50 acctiona of eili¢ a6eenE tome atYPi- p$rcent ¢tYPieal bronJ.ia{ and entirety cal re_(le and eelle and epiEhe7ium atypioalceRa ciliaabeent c7iupreeent 2,346 3,393 6.9 F,379 3,607 2.5 1,'!06 1,'t33 9.8 1-526 12.8 0.1 0.7 21.2 78.6 0.1 0.5 19.8 62.6 0.2 0.5 10.0 10.7 27.3 83.1 Percent in eac_h cytolopic cfaae SliLhNy Muderately Stronyly No*mat ntypicat atLPicu/ atypicat Nonsmokers (46) .................. 86.7 4.4 8.9 .. Smokers (58) ...................... 65.2 32.8 10.3 1.7 Comments Major findings nated: Urban nonemokere shawed more lesion than rural. Roth leslons snd stypical nuclei were much less freauent in non- smokera and less frepuentin piy¢ and cigsr emakers than in ci_garette emokers, 64.1 % of caeea had 60-55 sectiong 31.6%, , of cases had 49-/9 eeatione 7.3% of cases had 30-39 sectlone 4.6% of casea had 16-29 sections Smokere defined as those heving con- sumed =t0 ciga- rettes a day for ?] Yee

Tracheabroncluial 1meplant¢tion and'Institlmt!ion More complex experiments concerning the carcinogenicity of cigarette and tobacco smoke are representediby those whieh involve the direct impl~antation„ instlillation~, or fixation of suspected ma- terials into the tracheobronchial tree of animals. Certain.of these experiments are outlined in.table A1!5. Recent reviews by Saffiotti (233, 23Y;.) Laskin, et al., (1;5R)„and Montesano, et al, (189) as well as that by Wynder and Hoffmann (319) provide more detailed and extensive accounts of these experiments. Of.note among the results outlined in this table are the following : 7Pheenhanced carcinogenicityfound.whenibenzo[a)pyrene (B[a]P) is combined with a,carriier such as hematite dust (!.235)„and tlie definite increase in bronchial epit'helial' preneoplastic and neo- plastic changes among dogs t'reat'ed with.smoke condensate as com- pared with those undergoing only physical bronchial stimul'ation (224). I fnhad'¢tion Various species, including, mice, rats, hamsters, and dogs, have been exposed to cigarette smoke or aerosols ofits constituents. These inhalation experiments are outlined intable A16. It must be noted'd that the majorityr of the studies listed involve the passive inhalation ofi the material presented usualVy in a.chamber. Activee inhalation experiments, exemplified by the work of Rockey and Speer (223) and Auerbach and his colleagues (11, 1.Y.9) involbed' animals which were trained to inhale voluntarily, thus more closely simulating human smoking. Results of note among these experiments include the following: Nluhlbock (185)) observed that cigarette smoke inhalation. en~ hances the alieady substantial rate of spontaneous alveolar cell carcinoma formation in hybrid mice, and various investigators in- duced adenomas in experimental animals(108, 168, 200). Harris and Negroni (121) , found that exposure to cigarette smoke.achieved some enhancement of adenocarcinoma formation in mice but did not observe proven sqiuamous cell carcinoma. Some of their mice had also been exposed' to Swine influenza virus aerosol. In a related study, Boren (32)~ exposed, hamsters to cigarette smoke at set inter= vals overr a.48-hou2°per-iod.. THe: author observedd alterations in pu1- monary cell kinetics (the pattern of DNA synthesis)' as demon- strated by H'-thymidine autoradiography. The pattern of the label- ing response to cigarette smoke was significantlg different from. that of the response to high oxygen concentrations:. Auerbach, et all(11) have reported the development of early 768 oh0

T-AALB 9.-EpidemiuFoqic irurcxtigntLnts co.nclrriinD DIIr rrlotiousLig of !t{np caucer to Author 1'unnlstiun renr, s_ludiqland ConntrY, nlethiul,ef refrrancd dntu rullevtinn 1)ue]I etal.. 1`J67, U,S.A. (49). Hitoeugl, 1968, Jegan (186). sersokeng,aie pal6ttio>I, and etr3ult or ntrat resideRCe (emtlt.) (Art,inl nnmh,r,,f d-ah, ahvwn in parcntheses) Rcsults Comments 10, hmg anncer A9qadiYetcd 1unF cancer de¢th rqtee yer 100,090 man yeare and mOrtality Tatioe - ~ dcnthsnmong --- --- - --- American l.eaionnaires LnaAnaefee San Fren .eco/ SanDiego Afi other Catqorn(acuunties nged25andaver. Rate ate Ratio RaEe Ra[fo Rate Itatio QuesUonnairesLe next of kin. Nonsmekers ................ Smokers: 2_8.1_ 2.5 43.9 8.9 11.2 1.0 E1 uack/day 63.6 5.7 77.1 6.9 61.02 6.4 21 ....................... >1 ....................... 126.0 241.3 11.5 21.6 134.5 12.0 226.0 20.8 124.9 137.6 11.2 12.8 185 male and femalc lung can r Lung cancer death mte per 100,00 0 ce deaths and 4,191 matched cantxols Maiee FoUvtrnnT¢gson Low lntermcd:afe High eked 36-74. Data from Questionnaires and interviews. Nonamokers ................................... 11.6 8.8 4.9 Smokers: ~1-14 ciearette./day ........................... 10.6 14.2 28.6 >15 ......................................... 21.8 18.6 81A Femnlee Nonemokeea ....~ .............................. 4.6 6.9 8.8 Smokers: 1-14 cigarettee/dey ........................... 19.7 16.5 16.8 >15 ............................................... 12.4 20.5 17.1 ~ ~-~- Age- and amaking-adjueted tung eaneer death rate ner 100.000 Low Internud:ate High hlates .......................................... 16.1 . 22.4 28.4 Femelee ....................................... 7.6 11.6 8.7 The authors noted the lack ofdeath-ratediRerence between Los Angeles and SanFrenciscoregions andconclpdedthat photochemicalsmog is nat related to long cancer. - The authors yastulated a_ elieht eynergistin eRecthetweenamokivg and air pollution.

u V Y TABLE 19: Data on dogs with h<ng tunaors indicating type of tontoz and tQbe in which the tuinrzr was found (crzut.) Number Age at Early squamous Group Day of of de;ab Lobes wilh bronchlolo-alveolar tumors eelltironchfal drnth rignrettes (yenrs) Non-invnsive Invusive GrouD h(ne 61ter) ......................h 696 ,A,469 4,6 T.A h 626 3,926 4.4 h 649 4,143 5.0 RI h ]94 5,400 5.1 LA, RA - - LA, RI - LA. RA - -~ - LA, left apleal lobe; LC, left cardiac: LD left disphregmatic; RA, right start of smoking. The letter "a" or °b" follews the day of death of dogs apieal; RC, right eardiac; RI, right intermediate; RD, right diepbrsgmatiq . crificeH after day .jj946. LAHE, left apical branch bruncus; LMR, left m n bronchus. Fur emoking dog& the day of death indicate.5 the number of dqys since Squace: Auerbach, O. et el. (tt).

Tpnf.B 18. Sum?nary of principal cause of death (days No. 57 through No. 875) in dogs of groups F, L, H, h, and N I>wneh death classified according to most severe cocd,4on some d as ~liad u[ a cimbinnt, n o[ causes listndl Filter No No No tip filter Iittez filter Nonsmoke r s Principal cauxe of death .. . . Group E' Group ..L Group. H Group -h _ _ G n _T~. Total Pulmunery emPhyeema and fibrosis ..................... - - 2_ - - 2 Gm~ pulmonule (]mlmunary emnhyxeme uvd fbrusig with right heart enlaraement) ~....~ ...................... - -- 2 5 - 8 Puimonary infarction ................................... 1 1 2 5 - 9 Branrhopneumonia .................................... - - A 1 - 4 Aspiration of food ..................................... I I - - ° 2 Uncertain ............................................ - - 2 1 - a Number of deaths ..................................... 2 2 12 12 - 28 Number surviving 875 days ..... ....... .......... 10 10 12 26 A 66 .... .. . Total number of do8s .................................. -_- ... ....-.--.- 12 12 24 38 8 94 $mrxc&: Hemmnnd, E. C. et al. (119). MS9GE0

TAtlIP: G_ li~~ideniz¢lqgic axd pa-Iltniopte ita"esllUalipua i iroi<ef! -.t [iu.q uoil Nir Ll,ybnio Author, Numbernf year, pci-.9oi19 9lld country, nClCeliun refPrenee method Cohen 417 male nnd and femnlecas_esof Hus. , lun6c cr wlth 19C6P1T histidiryic U.S.A. din¢nosis 1939-63 (58). at nae hyahlfal. Ashley 442 male and and fe.malecaseso_f Davles, histolaxically 19Gi, diagnosed England lungeencer. (6). No nemoker.. .... . . . . . Smokers .......,.... Nunsmokers ............. 1'ine ................. . (%iSPreCte ............... l10,idar ................ 10-£0~ .................... 21-80 ........ _ ......... 31.40 ................... >40 ..................... i j fuug c2w er' (ctln(.) I[-ulLC Colnments Porotrvt rasce (n hasto[oq(e tyyc eud smoking hiytory The authors also __- Imuz¢6 ruJmnokera) noledthat puamuua Uudifjcruntioted Adenocordno_ma Alveolar 1.0 (3) 10.0 (14) 23.0 (8) 20.U(1) 89.0(189) 90.0(145) 60.0(20) ... 1. Adenocarcinomas . e2V~-,itimcs are common in women m 2. Only 1 percencof Kreyherg Group I ceseaweren .makers. Percent cueca by hietoio.oic type and smoking historv The anthors noted that cigarette smoking Undigcentiuted SOUOmoua. Adxnorarcinem appears to be as 2.8 (4) 2.6 (6) 3.4 (2) stronglyrdutMto U.9 (14) 9.9 (24) 1.7 (1) edenoeurcinomaasto 87.3(124) 87.6(211) 94.9(66) the other 2 types. 14.1 (20) 22.4 (54) 22.0(13) Ashley'sdatamo tatel 83.8 (48) 41.5(100) 35.9(20) numbero[cigarette 12.0 (17) 21.6 (52) 16.9(10) nmokersare 14.1 (20) 12.9 (31) 8.5 (6) inconsictentwith 7.1 (10) 6.2 (16) 6.1 (3) hisbreakdowno_f amokers into eroups based on number of etgurettes smoked per day. Ormos 118 male and Percent caa_ee by hietoiopic typc aM smokinV Aietory The author noted that I` etal., fe.maleeascsof th mallnumberof ': 1969, histologicaily Group I Group II aud larye cd( carcinorw:. c s allnws for no Hungary pravenlung Nonsmokers .......... ....... 21.0(18) 36.0 (9) defnitecondveions. ------cencer with Smokers ........ .................. 49.0(G8) G4.0(16) adepuate smnking , informatinn. r Data obtained from patient intervierv and other sources.

dV 1 e6£SJLCO TABLE 10. Pathotogic and cytologic findings in the trttcheo-bronchiat tree of smokers and nonsmokers (cont.) (Actual number of cases shown in parentheses) Author, >car, couutry, reference Number of cases end metfiod of selection HCeVlts Auerbaeh et al., 339 persona 22-89 resra Number Numbez of eectionw 1961, of ago uj of bconchial U.S.A. (12). autopsied at East Orange Nonsmokere: peraona epithdiu?n Vcterana <40 rears of age ................. 8 883 Hoanital 40-59 ............................ 11 560 (eacludee 60-69 ............................ 28 1.463 lung >70 ............................. 18 918 cancer). Smokcre <1 packlday: <40 yeera of age ................. 14 727 40-59 ..... ......... ....... 24 1,240 6P59 ............................ 35 1,772 >70 ............................. 22 1,101 Smoken. >1 psck[day: <40 years of age ................. 17 880 d0-69 ............................ 63 3.027 60E9 ............................ 84 4_.IB6 >70 ............................. 15 756 Commente Percene sectinns Pexcent eectione The authoca nateA a with citia abaent with some dos esponae re- and entire(tt atypica! reiie latiaa of amoking atvpicaP ccten and ci7ia absent to: ,. 0.3 a. luss nf cilia. h. increase in number of „ 0.1 atxMeel . . 0.5 eells, , 0.1 4.7 carcinoma c in sifu. 1.0 16.9 Avera¢e number of 0.6 10.8 eections per ceen 0.s 9.4 eQwaSoa 5e.s.---- 1.6 12.6 4.5 17A 6.9 20.6 9.8 23.7 Cross 140 persons ~ Pe.cent sections showing changee in bronchial epithedium (number of ~tions) et al., autoyeied at Squamous Atypical Carcinoma 1961, IowaCity No.ra.e1 Hppcryla.ia metavlueeo metup£asia insitu Careinoma U.S.A. Veterans Nonemokem (31) .......... 61(662) 36(137) 8(33) 115 (58) .... .... (64). Hospital 3mokers (109) ............. 44(570) 43(562) 16(197) 20(263) 1(12) 2.6(34) on whom smokin¢ data was availeble. t Th. authors noted that the diRer- ence between smokersand non- smokeeo was rtatistically significant.

TAECE.11., Identiffed:orsuspeotedtumorige-nic ¢gents.in.cigare'tte smoke' (cont.) AmponentS Estimated concentra- tion in 100: [ig9rettk5 (85mm5 nonfiltenl. Presently understood relative rmpnrl9neelnexeerimental tobaeco earcinogeneeis II..TUmor promotin¢ apenta: Neutrallpromotera(polymers). Nodata. Of pos.vibleimportsnce: (unknowaattuetures ) . Vulatile uhenols .......................... . 20-30 mg. Of possible.importance. I. Phenol 2. Ckeanl Nonvolatile fatty eelds ....................... 20-100 mg: Of minor importance: 1. $tearie acid 2. Olek acid N-alkylheterocyclita<. Of; poasibleimportance: 11.9-methylearbazole ...................... Piesent', 'bTodified and: expandedfiom' (SL9. 220) with reference lti (5P,.60, ee; I}}, 129; @0P. 282. £95; 491, 295). ° Has not.been 4sted.as an initiator, but G~ a known complete cnrrinaqem. aSeeNeuratb, (P0f). ' 9he (1I1:.12d)'. found in tobacco smoke (38)~. However;, nitrosamines may be arti- facts dependent on the method of smoke collection (2i01)... Neurath (202) considers the nitrosamines liatediin table 11 as being present in fresh cigarette smoke (253',.254:). However„ con- clusive confirmation of their presence in fresh smoke is not availabde (38.,138,155,.319)., Certain of the pesticides and fungicides presently in use on tobaeco have.been found to be carcinogenic (91, 273„280).. A num- ber of these, such as DDT, are now being phased out of regular domestic use. The compounds listed have been shown to be present in trace.a¢nountsin mainstream tobacco smoke: (111, 128). A recent, extensive review by Guthrie (111) provides more detailediilforma- ti:on.concern3ng,these agents.. Radioactive isotopes can be found, in tobacco and tobacco smoke (',105).. Potassium-40', while presentt in tlobacco leaf„ is not trans- mitted in any substantial amount to~ mainstream smoke (230)i. Polonium: 21'Q (Pb_le), however, is transmitted intothe mainstream smoke (9!6, 123,.142;.1K5;, 215, 21'7)..A number of autopsy studies (tableA12). have shown thatthe: bronchial epithelium, ofsmokers contains significantly more P'a_,n than that off nonsmokers. Litt(le;., eti.al. (172, 173, 17,J) have also noted that the concentration of polonium was markedly higher at sites of bronchial bifurcation. These,aut'hors stress the importance of this finding for pulmonary carcinogenesis by noting that bronchogenic'careinomas are fre- 266

GROUP N: NONSMOKING TUMORS COGS FIGtiRE'.2.,-Peraent of smuking.g dogss with tumors. SOURCE: Adahtedd from Auerbach, 0.,.et al. (11.).. 60 w m O J w O F 2' w U K w n ' 40 20 0 GROUP Nr. NONSMOKERS (B4 as. menv 'cigarettes) az Grap H TUMORS 2 LUBES 56 GROUP F: FILTER-TIP GROUP L: NO FILTER (%r as mrvy cicarettes): as Gsuup H GROUP H: NO FILTER 4' 7 19 12 12 24 GROUP F: FILTERTIP 4 64 GROUP L: GROUP HI NO FIGTERI NO FILTER'. 12 80' 35 T68 FIGURH 3-ParceuG of Iung'lolies.}vith tumors is smoking 'dogs: SaassEe Adapt'e& f rom Auerhaeh, (1~, et al. (11). 274

T.tu1.E 111.-Ldent'sfied or suspected tumoripenic'.agents 4n cigarettesmoket omponents Estimated concentra. tion in 100 ciga[ethes (85 mm. nunfilter) Preaentlyunderstood relative imGortancein.erzperlmenttl tobacco cercinoyeneaie L Comulete carcinoaens snd tumor initiatare: Polynuclcar.aramatichydrocarbona ........ 10-30 ug Tumor.iaitiatore. 1..Ben2n1a1p1ien2 .................>.. 3.9'. ^_: Dibenz(a,hjanthrseene ............... 0.4 5!.Benralb)fluoranthenec ................ 0.3' 4. IIenzn (j)ftuoranthene~ .................. O..Dibenza(a,i)PVrene ................. 0.6'. Traoe ri. Benela)enttirac'me ............ ... 0.3'. ]', Chrsaene ......- .................... 2.0 . S.Indeno(1,2,3'-cd).ayrerre .............. 9. Eenrn('c)phensnthrenec............. 0.6 Trace. 10, 1fetbplbenzo(e)AYrenes' ............. 0.1 ll. MetMylfhrYsenes ..................... 2.0'. S-hcccrocyciic hvdrocarbons~. .....,.....~.... 1-2: Tumorinitiators. h Dibenz(a,h)acridine .................. 0.01 ^. Dlbenn('~a,j)acrldine .._.......... ...... 3.iH-dibenzo(qg)carbazole.... ,...... 1& O.GY S'-sitcosamihes" ............................. 1-1.0 Suspected earcinogena of yossible importhnce.(presenco.in fresh amokepossibie. l. Dlmechylnitrosaminc _ ............... 0.4'. 2'. Dieth>lnitrosamine~ ...... _............ 3: blethyl-rvbulvlnitrosamine ........... Trace Trace .. 4.NicrosoPyrrolidine.... ............... 51 Aitrosupiperidine. .,.,.~ .............. 0.4 Trace l:poxides,.peroxycompound3, and Iactones: L1 Epoxidee ............................. 2. PeraxidEs ............................ 3. l.aecunes .._............. .............. a. a llewantenalidE ................... b. g-6evant'enalide ................ No data Certain of these compounds are Present kno. aroinogens: presenae.in . smoke.condensatenoteateblished. 20.0 2.0 ti~a:kyl-her rocgclioa: 1. C-metByBndolA ...................... Pesticides end fhngicides:` Pvesent Possihleinitiator. No.essential.contritiution.suspected.. 1..TDE I ...... .... _ .................. ... 10 10a ... 2..o,P-DDD ............................. 10-100 3:.DDT' ........ 10-100 4.Nialeie:hrdrazide: ..~..........._....-. 10-lo0 Bcta-naphthrlamine ....................... 23 5uspected bladder esrcinnaent Polonium 210 ............................... 1-60. of doubtfullsignificence at reportedlevels. Of'someimportance onlNin the picocutves caseofrel'etiYely.highcancen- tration; butmot important atl reported levels. Kickelcompaunds ................. .... Present Suspected careinogene of aome, mportance. 265'

0 TABLE 17.-Data on pedigreed tttade beagiee dogs of groups F, L, H, !t, and N (Some of the figuree apply only to dogs surviving 875 days or Innger) Filtcr group F No filter grullll -L No filter group II No filter group h N_ onsmokerg group N- Number of dogs on day No. 6T' ......................... 12 12 24 38 g Weight at start (day No. 1) mean weight (pounds) ...... 25.0 25.1 86.0_ 31.9 80.4 Cigarettes per dog in 8V6 days .......................... 6,143 3,103 6,129 6,129 none Mamn nunWer of cigerettes nev day .................... 7.02 3.54 7.0 7.0 -_ Equivulentnumheru£cigarettespedayfor150poundman 42.1 - 21.2 42.0 32.9 - Type nf ciSarettes:° Milligrams of tar Per cigarette ........................ 37.8 36.8 34.8 84.8 - 81i11{grame of nicotine per nigap¢pe ................... 1.17 1.85 1.85 1.85 - Total dosage in 875 days: Grams of tar per dog ................................ 109.3 103.5 207.8 207.8 - Grams of nleotine per dog ........................... 7.19 6.66 11.12 11.12 - Dusage in 876 days relative to atarting weight: Gonms yrFpannds weight ............................ 4.37 4.12 8.31 6.61 - Grams ni[otine!puunds weight ........................ 029 0.22 0.4_4_ 026 r The smoking dogs were divlded into groupa F, L, H, and b on day No. 67. ~ s Dogs of groups L. H, and h smnked filtce-tip cigarettes_ during a training period at thee start of the experiment, but smoked nonfilter cigarettes thereafter. SocxCe: Adapted £rom Hnmmond, E. C. et al. (11v). ESES94£0

d i TABI.D 19. Data on dogs with h<ng tlcmors indicating type of tesneur and lobe in wtaichh the tumor was found Number AReat Earlyspuamoue Gruup Dsyof ~of drnth Lobes w1tL bronebinloalveolar tumors vellbironchisl death cigarettea (Years) Nun- usire Ivvaaiye barcinoma - Graup N(nonsmokers) .................N 901. _ 5.1 LA N 0041: _- 4.9 RA Group F(filtenlip) ..................... F 878. 6,161' 6.] LA - - F 87@a 6,170 99 LA - - F 885. 6,224 5.2 LA - F tl90s 6.269 5.4 LA - - Group L (no filter) ..................... L L L L L L Group H (no filterl ..................... H H ~ H 347 1,055 812 2,Y4'I 974. 31103 P74e 3,107 AN2a 3,127 896. 3.183 899. 3,10u 135 259 563 716 753 760 868 876. a 977 8]Xa 882a 883. HNSa 8N9e 890. 892. 852b 897. 89'!b &16 1,343 3,404 4,689 5.030 5.088 5,970 6.129 s.i5a 6.147 6,183 6,192 6,210 6,246 6,255 6,273 6,273 6,318 6,318 5.1 5.2 5.2 63 5.4 2.6 3.3 4.7 6.0 3.8 4.2 5.3 4.9 6 4 5.3 5.4 4.7 5.0 5.0 4.9 5.7 5.3 62 4.5 LA. LC_ RA LA, RA LA,LC LA, I.D LA,RD LA RC - _ LA, RA, RD - - LH, RA LA - RI LA, RA, RD - LA - - LA_ - -. LA,LD,RA LA RA LA LA - RA,RD,RI LA LA LC, RA RA LC LA, RA LA LA, RA LA a SSES94E©

invasive squamous cell bronchogenic carcinoma in dogs following a period of direct inhalation of cigarette smoke. These investiga- tors trained beagle dogs, to inhale cigarette smoke through a. tracheostoma (?0) and,dilvided the animals into groups according to dosage as detailed in. table 17. A number of'dogs died during the course ofi'the.experiment which ran for 875 days, orapproximately, 29 months. The causes of death are listed im table 18. All of the remaining, dogs, with the exception of group "h" (high exposure,. heavyy weight)„ were sacrificed shortly after day 875; the survivors, among the heavier dogs are continuing to smoke. Examination oftthe respiratory tree of.the animals revealed a. number of tumors (table 19). Most of these were similar to the type of tumor which in man is referred to.as bronchiolb-alveolar. This tumor arisesin the bronchiolar and alveolar epitheliuQn and tends to lie muIticentric..Twostriking characteristics of these bronchiolo- alveolar tumors were the existence of a histolbgic spectrum (from. aa tumor resembling the benign condition of' adenosis to franklymalignanty tumors. with invasion of the pleura and surroundingp.u•enahyma) and the marked tendency'to squamous change. Inva- ~ive bronc6iolo-alveolar tumors were found in, 12 dogsin the group %vhich had been exposed to the largest dosage of cigarette smoke. `everad had tumors of more than one category. Ten of these dogs had inn~asive bronchiolb-alveolar tumors which did not.extendlilnto the pp'eura, one dog had an.invasive bronchiolo-alveolar tumor which extended to the pleura, and four had invasivebronchiolo::1lVeofar tumors extending, into the pleura beyond the pleural-pulmonary junetions. In addition, two bronchogenic squamous,cell .urrinomas were found in this group (table 19). The dosage de- pendence of tumor formatliomils shown in figures 2 and 3. JLtj tr findings of the study were twofold.. First, that smoking tilter-tip cigarettes was less harmful, both im terms of pulmonary parenchymal damage and lung tumors, than smoking identical cigaretteswit'houts fiSters. This supports the generally held view that total partiiculate matter is a~ meaningful indicator of the car- cinogenic potential of a cigarette. Second, lung cancer of two typesfound irt man was. produced by the inhalatiom of cigarette smoke. Tivo of the dbgs were found to have early invasive squamous cell. carcinomai of the bronchus, and both belonged to the high-dosage group: These carcinomas were indistinguishablle from early invasive sq.tuamouss celll carcinomas.found im thee bronchiall tubes of' humann bei.ngswho: smoke eigarettes.. The majorityof1 tumors found inn thee dogscrere of a bronchiolo.alveolar type;: which although not.ascommun as selctamous cell cancer in man, is not rare in humans.. This tvpe is often included in the category of adenocarcinoma. A number of studies have shown an excess of these tumors among 269 0 W ~ ~ W

TABLE 20.-I,ar7lnpeai canner nmrtafaty ratios (cont.) (.Aclu_al number of demhe sho,n in pvren[hesesl' SM-Smokerx- NS-Nnnsmnkc'a.- zsess1'Eo Prnsnec Number Author, of year, Numlus and Datx Follow. _lexynz_eal country, typeof eollectfnn up - r reference noqulation years devf3s Cigaretteslday Weirand 68,153mulee questionneire 6-9 11 NS Dunn, in verinue nnd follow- S11f ..11 190 ............. 1.00 1970, uecueations up of death NS .. Fl -! ZU ............. 6.00 U.S.A. inCnlifornia. nertificate. >30 ............. 5.84 (80®). ' Unless otherwise specified, disparities between the total nnmber of deaths end the sum of the indiridual smnking cetegoies are due tn the exeluxion of either occasional, miscellaneous, mixed, ar ex-emokers. Pipee, ciKGrs fommente No nonsmokers died of laryngenl earcinoma. therefore 210 smoker set as 1,00 standard. N$ includes_ pipe and ciRee mnkers. SM includes ez-smnkerp. w

Tnn[E: 25.-Depaaitionn o/r'C-I¢beled~ smoke particles in.partfattlarveginns of theres7riratary t4'actt Traced radio- Estilnated~ Deposition radin of PrunorRionail area of the: Traced dEpasitiono in relation Organ activitu• OrBan activity parttlNea espitatoryto.rthe (nCi) (nCl) (:%r,) tYact proportional area Head and palate ._. 6.11 Hcad palate 5.5 3] 4 Tongue. ........... 0.41 Oralcavitr 105 n4utal. La~~rwnx ............. 0.39 I 0,1-0.3 X501-187 Tinchea .......... 0.26 7:6Iltrsoed1 51.7 0.6 '. X62:3', Lungs ............. 6.95 ! 1000' XI:. Total ..........14.12 '14~..4. ]:00.0 t Cigarettes labeled with "C-t-m Ile.xaAeovn:.. data represent mean valuesftom: 10 animali, celhulated frnm surface distrihution in thehez.l. 'Ttre ~'alueof ]4V'mntainm 05s.nanneuriea as eslimnted fFum quaruity of'depusition.in the nontraced oralcaviu• reajons (calculated as tn nroportionxl area.). 30L'np&: Dontenxill. W. (rc)., 282

TABLS 26.-Ctassiftcatiwx of the five registered stages of epitGeEiaE changes at the (arUnx'~- Acanthosis (tbicken- S.age ing nf stratum - spinn5um multi- cellulnr layer) Hyperkerutnsis increased cnmifie,atinn (strntum corneum) Parakeratosis (in- complete corniflea- tinn of n.utei in the strhtum earneum) Drskeretosis (Ure- _inatuEe etanlenl nifewtinn r changess in the p]itosie nuclcna prulifern- tinn of the basal layer) 1. Pachydermia (epithelial hYPerplosia) ............ ... + + t t t 2. Lcucoplakia ........................................ + + I E k &. Yerrucuus leucoPlxkia ............................... + } + t # 4. Pnpillometous lcucoplakia ........................... + t t ++ $ 6. Pseudoeuithelimnatous levcnplekie ................... + + + }}} + iSymbols: i=negntive; I=minimal; }-weak;}}=mellum; }}}=strong. 2 From Atlas of Tumor Pethology of the Armed Forces I_nstitute of Pathoingy. SOURCE: Adapted trom Dontenwill, W. (76). 99ES94,E0

TAE6F 30-h'fiePhaprn0 rmlr<r murtulitil cstiux-pt xapctirr shrdiec (cont.) IActua number of dcaths s'hUwn in parenthe.eal SM-. Smoners, NS -Nunsmukers. N VGC994c0 Author year, _Numherand Data Follow- cauntry, -~typeof collection upyeirs xeferenee populution _Hirayxma, 2f5.Il8male 1967, and female ?a4an adults 40 (125). years ufage and nd older. Weir and 66,153 mnles Dunn, in earioua 1970, occupnticns U.S.A. in Ca3iforniaa (sn6). Trained]'HS 1?r_ SM ...?I NS ......1,p0(pG0.03) Referstoall nunseinter- cima and follow-up of death certificate. SM ...... 2.4q(21) formpof smoking. @_ uestimmaire 5-8 32 N9 ....... 1.00 NS ineludes pipe and follow-up +10 ...... 1.27 end eigar efdenth 12U ..,... 1.60 amoke_r_s. - certifiente. >30 ...... 1.82 All ....... 1.82 ' Unless otherwise specified, disparities between the total number of deaths and the sum of the indixidual emokin¢ catcg_ori¢s a[e due to the exclusion of either occasional, miscellaneoue, mixed, or es-smnkcis. ,OiWl

With or w.ithout.smoking„ use of alcohol appears to contribute to the develbpment of oral cancer (T24:,. 140, 183, 23~.7,..322)~. In a study ofi' male v.eterans, Keller (140) found that heavy smoking and heavy drinking were associated with cancer of'the mouth and pharynx. No studies are presently available which determine the relative contributions and possible interactions of heavy smoking, heavy drinking, and concurrentnutritional deficiencies in the etiol- ogy of these cancers. EXPERIMENTAL $TUDIES In 1964, the Advisory Committee to the Surgeon General on Smoking and.I-I'ealth. (291) reported.thatd cigarette smoke and.ciga- rette smoke eondbnsates, had failed to produce cancer when applied to the oral cavi6yy of mice and rabbits or to the palate of hamsters and.thatl the orall mucosa appears,to be resistant in general to can- cer inductionn even when highly active carcinogens such as benzo- [a]pyrene are applied. Some of the difficulties in experimental de- sign were attributed to the fact that mechanical factors, such as secretion of saliva, interfere with the retlention of applied carcinoc genic agentls.on the.tiss'ues of:the:oralf cavity.and pharynx. Positive results with certain carcinogens have, however, been obtained in the hamster cheek pouch, but it,hasalso been pointed out that the cheek pouch lacks salivary glands and that its structure and func- tion differ from those of the oral mucosa. The majority of these studies are outlined in table A29. Although.cigarette smoke condensate acts as a complete carcino- gen on mouse skin, the work of several authors (.319)~ supports the concept'thatcigarette smoke.contains cancerr promoters that may be of speeialimportance, particularly in oral carcinogenesis. Elzay (.90)) hasreported that whole cigarette smokeis a promoting.g agent for the hamster cheek:pouch. More importantly, regarding the chewing,of'tobacco, Rock;.et a]. (27,30), Van Duuren,. et.ai. ('2.9+):, and Ft'ynder and Hoffmann (321) have shown that. unburned to- bacco products contain tumor promoters that might. contribute to the promoting activity of the smoke. Roth,. et al. (226, 227). have shown that the dye-binding capacity of the DNA of oral. epitiheliall cellE; is significantly enhanced in cigarette smokers in. contrast to nonsmokers, probably reflecting an increase in the D.NAcontent of oral epitheliali cells in smokers. Smokers hadi values of d$,e-binding capacity intermediate between nonsmokersand'. 21 patientss with proven oral cancer... Those smok- ers who refrained from. smoking for up. to six months showed a significant decrease toward more normal values. 288

the hypopharynx. These authors noted thatthe percentage of heavy smokers among the patients with cancer of both the extrinsic and intrinsic larynx was significantly greater than that among controls. However, it i's of interest that the excess risk of laryngeal cancer among cigar and pipe smokers in this study could be attributed to the extrinsic laryngeal group. As in studies of oral cancer, it appears that alcohol consumption shouldl also be taken into account in studies of laryngeal cancer. Wynder, et al. (.112) reportedl a. significantly increased risk of' extrinsic cancer among those with. alcohol intake above 7 ounces of whiskey per day. With less than this amount„ no increased risk was evident. Schwartz, et al, (.2418), noted no effect in relation to alcohol intake. Further research. into the interaction of'thesetwo variables is necessary. PATHOLOGICAL STUDY Auerbach, et al.. (9)studEed histoIogi'cal changes in the larynges of'942' men, age 21 to 95, who.wrere autopsied at a single hospital between 1964 and 1967.. Cases of primary cancerof the lkrynx were excluded from the study.. Smoking, histories for all cases, were obtained from family members of the deceased by trained inter- viewers. The randomized h.istol'ogical sections were graded by one observer. Ti ables A33 and A24 summarize the findings in the true vocal cord. Of the men. whoo never smoked, 75 percent had no cells with atypical nuclei, only 4.5 percent had sections with areas con- taining 60'to 69pereentofTcells.with atypical nucleil,l andd none had a higher perccntage. The 7116 ex-smokers had laryngeal histology similar to that of the nonsmokers, as far as atypical nu'sleii were concerned. However,.disintegrating'nttciei were found in. 40',5 per- cent of the ex-cigarette smokers and in only 0.4 percent of the remaining cases.. Only one of the 9'1 cigar and; or pipe smokers had no atypical cella. Three had carcinoma in situ, and one case had a section showing early invasive primary carcinoma. The highest, percent!age of atypical cells was found among the cigaret,te:smokers. The proportion of cases~ with.a high.degree.of cellular ehange increased with i'ncreased daily smoking.. Nlone of the pack-or-more-a-day smokers was free of atypical nuclei in the laryngeal epithelium.. Off those whosmokec] twoo or more packs per day, 83pereent had.lesions with60pereent.or more atypical cells as compared to -1' percent of the nonsmokers, Between 10 and 18 pereent of the cigarette smokers.had areas of carcinoma inn sztu, and. 4 of:the 644 casesshonti^ed early microscopic invasion. The thickness of the basal level of thetrue vocal cordl was also directly related to the amouu t smoked. 280

TOTAL 146 5 4 3 Y 0 e + 7~ 111 4'. 5 17~ 4 5 t i l T 1, . . ~ . . ' ., . ;y` ~ ..}. I. ' 2 4 6 8 10. E2' 14 16 SMOKE EXPOSURE, months 18 20 22-)t28 . -ONE'.ANIM'AL +-ANIMAL LIVING d-LARYN% CANNIBALIZED F3cuaE 4,-Effec.tsof'ehronic cigarette smoke inhalation on the hamster.lar}?nx.. Revicw of the results of.the inhalationn experiments: number of smoke-ex-posed animals with~and without changes in the larynx, duration of smoke exposure, and number of animals stillaliue. SOURCE: DontenwilC„W: (75)',.. ORAL CANCER The'.cancersincluded'.in this aategory,as•ethose.of the ]ips, tongue, floor of the.mouth, hardd and soft palate;, gingiva, alveolar mucosa, buccai.mucosa, andoropha'ryns.It is estimated that 15,000 of these cancers will be diagnosed in the'United States in 1970„ accounting for about 2.5 pereent'' of the estimated 600,000 malignant neo- plasms reported ('289). A variiety of histological types' ofl ma11g- nant neoplasms can affect these tissues, but squamous cell car- cinoma is by far the predominant type, accounting for about 90 percent of the aancers. The incidence of and! mortality from oral; cancers has, remained steady over the past 20 to 30 years. The Connecticut Cancer Reg- istryy (88), which i's a fairly reliable index of incidence, noted that the incidence among males remained between 15.8 . and 1!8.3 per 100,0000 population during the y'.earsfrom 1950-1961. Examination of mortality rates over the past 20 tJo 30' years (282, 289) reveals a similar constancy. The apparent lack of change in mortality from oral cancer in 284

N b G Author, yea:, Number and uiitry, tyneof refer. e populatfon Hammond 187,783 white and mules in 9 Hnnn, Statcs 5tr69 1958, Yeors of egc. U.S.A. (t2a). Doll and Approximately Hill, 41,000 male- 1964, Kri4ish Great uhyeicians. Britain (74). Kahn U.S. male (Dorn), veterans 1966. 2,265,674 U.S.A. person years. (139). Hammond, <40,55F inaley 1966. 662.671 femeles II_S.A. 35-84 yeu_rs of (]t8). a¢ein 25 States. T_A_BI.E 30.-Esophagea6 cancer mortality ratios-progpeetiva studies (Actual number of deaths shown in parentheses)' SM = Smokere. NS = Nonamokers. Number ul ~.. -. . Data Follow- esophageal eollection .upyears --eueced~ Cigarettes/day Pipe.s,ciRars Cnmmenta .. . .. .. . dcntAs Questionnaire 3t6 34 and fallow-up NS ... 1 of death 8M ... 33 ceetifieate. Cigarette smokers 15/33. Piyc Mixed Data raferring to 2/33 cigarette mortality ratioa Ciga.r ¢mokera Includedcancer 2/38 13/33 of mouth snd larynx. 0uestionnaire 10 29 A(IpmokcnbYamount fPiPeandcipa. }Includeae.- and follow-up in 4rum.e NS .... 1.00 smokers of plpe of death N_ S...... 1.00 SM .... 2.00 and cigara. centificate. 1-14 . . 2A0 15-24 .... 3.60 >25 ...... 5.00 All ...... 3.00 Questionnaire and follow-up of death certificete. Interview- by ACS volunteers. ill NS ...... 1.00(11) Pipe tRefersto NS ... 11 il J..... 1.76 (2) 1.99 (8) cigarette S_M ... 1_00 10-19 .... 4.P1(18) Cfpnr smoking 20-39 ....11.50(24) 5.33(12) only. >25 ..... 7.65 (3) All ...... 6.17(47) 46 NS ...... 1.00 (6) Pina nnd Cipar NS ... 6 SRt (age NS .... 1.00 SM ... 40 46-64) . 4.1Y(32) SM .... 3.9Y(14) SM.(nge 65-79) , 1.74 (8)

cigarette„ the average length of time taken to smoke a cigarette (except in the highest number of puffs category)„ and the taking of more puffs at the endl ofl the cigarettie.. These findings, andi those of the study of Auerbach, et all ('Z2), add further support to the dose-response relationship between lung cancer and total cigarette smoke condensate exposure: .SUBT2vI:1RY AND CONCLUSDON6. 1. Epidemiolbgical evidence derived from a number of prospec- tive and retrospective studsescoupled with experimental and path-otogical'evidence confirm the conclusion that cigarette smoking is the main cause of lung:cancer in men. These studies reveal thatthe risk of developing lung cancer increases with the number of cigar- ettes smoked per day, the duration of smoking„ and earlier initia- tion, and diminishes with cessation of smoking, 2'.. Cigarette smoking is a cause of'lung,cancer in women but accounts for a smaller proportion of cases than. in men. The mor- tality rates for women who smoke,, although significantly higher than for female nonsmokers, are lower than for men who smoke. This difference may be at least.partially attributed to difference in exposure; such as, the use of fewer cigarettes per day, the use of filtered and!low "tar"'cigaret'tes, and lower levels of inhalation. Nevertheless, even when women are compared with men who ap- parently have similar levels of. exposure to, cigarette smoke, the mortality ratios appear to be lower in women. 3.. The risk of developing lung cancer among pipe and/or cigar smokers is.higher than for nonsmokers but significantly Iower than for cigarette smokers. 4. The risk of developing lungeancer appears to be higher among smokers who smoke high "tar" cigarettes.or smoke in such a man- ner as to produee higher levels of "tar" in the inhaled smoke: 5. Ex-cigarette smokers have significantly lower death rates for lung cancer than continuing, smokers. There is evidence to support the view that cessation of smoking by large numbers of cigarette smokers would be followed by lower lung cancer death rates. 6. Increased death rates from lung cancer have been observed among urban populhtions, when compared withh populations from rural environments. The evidence concerning the role of air pollu, tion in the etiology of lungcancer i's presentlyinconclusive. Factors such asoecupational and smoking habit differences may.also con- tribute to the urban-rural difference observed. Detailed epid'emio- logic surveys have shown that.the urban factor exerts a small influence compared to the overriding effect ofcigarette smoking inn the development of lungcancer. 276

TABl.p 20.-Laryngeal caneer mortality ratio2 (Actual number of-deaths sh.wn in parenthe_rer)r SM = Smokers. NS = Nonsmokers. a Author, rq year, Number and Data f nee refere type of population cnll_et5an Hemm_o_nd 1_87,783white Q tionnaire and males 50-69 and Sollow- ~ Horn, years of age up of death 1958, in 0 states. certificate. U.S.A. (t80). Dolland_ Approximately Questionnaire Iiill, 41,000 mnle and follaw- 1964, Bcitish vp of dcath Creat physicians. certi6nate. - Britain (74). Kahn U.S.male Questionnaire (UOrn), veterans, endfnllow- 1966, -- 2,265,674 upo[death U.S.A. person Yeare- certificete. (139). Hammond, 440,668 males -- Intcrviews 19G6, 562,@71 fe_ by ACS U.S.A. meles 35-x4 volunteers. (118)_ year0of age la 25 atatey. Number of Folloa- IarxuBeal up cancer years deuths 3F• 24 SM ..24 NS .. 0 16 SM ..1s NS .. 0 6'F_. 54 SM ..51 NS .. 3 Prospective studies Cigarettes/dey Cigarette smokers 17/24. A!L smakere bp amovnt .... . .. ,n. .n sra NS .............. 1-14 ............ 15-24 ............ >25 .............. NS .............. 1-4 ............. 10-20 ............ Com en(s Cipar Data referring to mortelity 3/24 ratio included cancer of Mixr.d esoohngusendmauth. 4/24 Pipe and ciDarf 1 Includes date on e a- .. 1.00 1.00 7.60 NS SM .... .. 1.00 6.00 smokers of pipes and cigars. No NS died of ]nryngeo- trachea) eaneer,therefore 1-14 gram SM set as 1.00 standard. Data combine laryngeal and tracheal csrcinoma. 1.00 (8) Pipc Refersto current cigarette. 3.27 (1) NS ... 1.00 (a) emokersonly. 8.45(1U) SM ....10.33 (6) 21-39 ..........,,13.62(11) Pi_pa and cigar >39 .............18.86 (3) NS .... 1.00 (3) AII .............. 9.95(25) SM ..,. 7.28(11) 4 57 NS .............. 1.00 (3) Pipe and cigar Male data only. SM ..54 SM (pge4"4) .. 6.09(32) NS .... 1.00 (9)Pipeandcigerdatare[erto NS..3 SM(age65-79) ..6.991181 SM .... 8.37 (4) meles56-84yearrofage. , ,T.;1c:Wb„

Cetlain occupational exposures have been found to be asso- ciated with an increased risk of dying from lung cancer. Cigarette ~nioking interacts with these exposures in the pathogenesis'of Iung, cancer so as to produce very much higher lung cancer death rates ii those cigarette smokers who are also exposed to.sueh.substances., r.. Experimental studi'es on animals utilizing skin painfling„ tracheal instillation or implantation, and inhalation of eigarette .moke orr its component compounds, have confirmed the presence of completecareinogens.as.wel7 as tumorinitiators and promoters in. :,,imcco smoke. Lung.cancerhas beenn found in~dogs exposed to theiuhalation of cigarette smoke over a periodlotl more than two years. CANCER OF THE LARYNX Cancer of the larynx is a disease which predominantly aftectls, ntalhs.ini thea`5 to 70 year age.group. In 1967„ a.total of.2,A68 maless andl ;'29 females died of laryngeal cancer in. the Un.ited$tates.,With~ !he develbpcnent andl application: of more effective therapy duringI iie past:ED ,lrears„ the death rate forcancer of the larynx appearato~ bedroppitsg slhghtly(282,. .289) ;however, the incidence eon- nneo to rise. Figures from the Connecticut Cancer Registry (88). <ho v that tlhe age-adjusted incid'enee per 100,000 popul'atibn of' c.muer of the larynx for males,rose from 3.0 in 1950 to.5.6in 1961.. EPIDEMIOLOGSCAL STUDIE9'. _1number of epiderniological studies have investigated the rela-rionship betlween smoking habits and the development of cancer' of'the larynx.. The major prospective studies,., as outlinedd in table. 20, show thatsmokers of cigarettes runn an approximately sixrta- tenfolkl risk ofdyi'ngfromthisform of cancer as compared to non-smolters.. Smokers of pipes and cigars incur a three-to-sevenfold risk. The retrospective studies listed in table A271 uniformly show fce,,er nonsmokers and more smokers among cases with cancer of' the larynx than among matched controls. Table A22' summarizes the relative risk ratios,derived from the retrospective studies. The wide variation is'dueto a number of factors, including type of popu-. lation and interview technique. But, in general, the magnitude of' mosU of these ratios is of the same order as in the prospective studi'es. Wynder, ett aI.. (3Y2) have: distinguished between cancer ofthef intrii sic and extlrinsic larynx: Tumors arising on the vocal cords are classified as intnilnsic and constitnte approximately 710.percentof'thelesions. The extrinsic larynx:is composed ofthose sections o11 the larynxexcludingthe.vocalicords and mayalso.be referred to as 277

were noted. The consumptlion of very hot beverages was also found tobe related to,the development of esophageal cancer. PATHOLOGICAL STuDY Autopsy studies of smokers as compared. with nonsmokers, spe- cificallyy observing' the pathological changes in esophageal tissue, have been performed by Auerbach, et aI. (15). A microscopic study was made of 12,598 sections of esophageal autopsy tissue from, 11,268 men who.died from causes other than esophageal cancer..Thefindings were strikingly similar to. the abnormalities generally ac- cepted ass representing premalignant tissue changes in the respira-tory tract epithelium, Esophagead epithelial. cells with atypieall nuclei (having am irregular distribution.of chromatin) were found far more frequently in cigarette smokers than in nonsmokers. Basal cell hyperplasia and hyperactive glands were also found more fre- quently in cigarette smokers than. in nonsmokers:. An increase in frequency with amount ofi' cigarette smoking was noted for bofh epithelial cells with atypical nuclei and basal cell hyperplasia.. Tables A32 and A33 summarize these findings. EXPERIMENTAIL STUDIES Hturatsune„etal. (156) investigated the possibility that the car- cinogens known too be present in tobacco smoke could penetrate the esophageal. epithelium.more readily if dissolved in aqueous ethanol. Mice wereexposed to several compoundE3 by esophageal intubation.. Tissueswere t;henn removedd and studiediby fluorescence microscopy. Deeper penetration and' a different distribution were found when B.[a]P' was dissolved in aqueous ethanol as compared to B'[la]P in olive oil. It was' also found' that benzo [a] anthracene and fluoran- thene dissolvedlin ethanol solution or aqueous caffeine solution could penetrate the epithelium, of the esopltagus: 131orie, et al. (132) reported on the development of 10 papillomas and one squamous cell carcinoma of the esophagus in a group of 63 mice periodically forced to drink al solution of benzo[a]pyrene dissolved in diluted ethanol. Twenty-six papiIlomas and one squam- ous cell carcinoma also developed ihrn a. group of 63, mice to which 4-nitroquinoline 1-ottide was administered in the same.way. None of the 67 control animalsgiven onlydil.utedl ethanoldeveloped neoplasms. Several other authors have reported nitrosamine-induced esopha- geal.cancer in experimental animals (56, 79, 80,. 81).., Asnoted above; the presence of nitrosamines in cigarette smoke is still a subject of debate. 292

SUMIdARYANDCONCLUSIONS 1. Epidemiological studies. have demonstrated that cigarette smoking, is assoeieted with the dcvelopment of caneerr of the esopha. gus. Theriske ofdevelopiing, esophageal cancer among pipe and/or cigar smokers is. greater than that for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightl,y lower. 2. Epidemiological studieshave aNo indicatledian association be- tween esophageal cancer and alcohol consumption and tthat alcohol cwrsumptlion, may interact wuthh cigarette smoking, This comkbina~- tion of exposures is associated with especial9y.high rates of cancer of the esophagus. CANCER OF THE URINARY BLADDER AND KIDNEY EPIDEMIOLOGDCAL S!fUDIES ('BLADDER) C'ancer of the urinary bladder accounted for 6,019 deaths among American males and~ 2,743 deaths among American females in 1967 (.8fL). Itru,cidence rates have increased from 1i949to 1962. (88), but the death rates from bladder cancer have remained relatively .table duringg that period. Improvementsins early diagnosisand therapy may have masked the increasing incidence of'this disease,. A raumber of epidemiologieal studies have indicated thatsmokers have ani increased risk.of contracting or of'dying from bladder cancer (see tables 34 and A35). Certain of these studies include kidney eancermortaCity in thexesult's, The major prospective stud- ies, with the exception of that of Britishi physic'cans,, have shown bladder cancer mortaSit!y ratiosamong cigarette smokers ranging, from, 1.40 to ?.89. Smokers of more than I pack per day were shownn to incur ratios of 3.42 to 5.41. The studyy by Doll andl Hill (74,. 75) of British physicians, an the other hand, reports death rates for smokerss to be lower thanthose of nonsmokers based on 38 bladdereancer dleaths. The mortality ratios for pipe or ei'gar smokers aresubst'antirally lower thann thosee amongcigaretteg smokers. Pipe smokers were shown by both Hammond and Horn (120) and Kahn (:13:9)) toincur ratios, approximating,1.20:. Retrospective studies (table A35a): have also shown an,irttcreased proportion of'smokers among bladder cancer patients when com- pared with rnatched controls:. Relative risk ratios for bladder can- cer among smokers range from 1.0 to. 7.3' among all smokers and up to 10.3 among heavy smokers of all types. 2A3'

TASf,f7 24.--0rad canaer-msorta6iby ratios--prospective stxtdies (Actual number nt deaths shown in parentheses) SM- Smokers, NS - Nnnsmokera. Author ye6q Nnmberand Data Follow- countrr, tyVe of collection up years reference poPUlation Han md 187,783 white Questionnaire S~G end males in 9 and }ol7ow-up Horn, States 50-69 of death 1958, Yesrs nf age. cErtificate. U.S.A. ( Cn). Doll and Approximately Questionnaire Hill, 41,000 melc and €ollow-up 1964, Dritish of death Great physicians. certificate. Britain (>4). Kahn U.S. male Questionnaire e?§ ~ (DOrn), 1966, veterane, 2,265,G]4 and follow-up of death $ S.A. (139). person yeara. cettiflcete. Hammond, 440,659 males Interviews by 1966, 562,671 females ACS volunteers U.S.A. a5-34 qsars of (118). age in 25 States. 4 Weir and 68,153males Questionnaire 5-8 Dunn, in vnMOus and follaw-up 1970, occupntiona of death US.A. in California. certificate. (5061. Number -of--- Cigarettee Pipee, cigars Comments deaths 56 20/s6 Pipe Mized Data referringto mortality iSM ..51 5/56 21/56 ratio do not include can_eer of NS .. 3 ' Cigar larrnxandesophagua, 5/56 t Excludes two oecasianal smokers. only 1B AfLxmokerahunmuunt P4peandcipar No.NSdied-afornlcaneer, SM ..19 in. grams NS ....... 1.00 the ~e€are 1-14 gram NS .. 0 NS ,,,,,,,,,,,,,, - SM 1-00_ emokersetas1,00 ~~ -~ - L-4 ,,,,,,,,,,,,, 1,00 standard.16-24 ........... 0.25 >25 ............. 5.26 61 NS .............. 1.00(11) Pipc Data do not include pharynx. SHI ..60 }CigeLdny 1-9 .... 0.86 (1) N9 ....... 1.00(11) t Refers to current cigarette .__ - NS ..11 ]0-20 ............ 2.93(13) SM ....... 3.12 (4) smokeraonly. zl-a@ ............ 7.34(20) Cigar >s0 ............. 5.58(3) NS .....,. 1.00(13) All ... _ ......... 4.09(3V) SM ........ 4.11 (9) 95 NS ,,,,,,,,,,,,,, 1.00 (7) YPipeand/nr iMeledataonly.Pipeand ..88 SM (aee4G-64) ... 9.90(G3) cigar. - cigerdataraferto.malee ..7 SM(age65-79) ..2.93(25) NS ..,.... 1.00(7) 55-84ycarsafage. SM ....... 4.94(15) 19 NS .............. 1.00 SMincludese:-umokers. il0 ..... ........ 3.69 NS includes pipe and ±20 ............. 1.17 riqarsmokers. >30 ............. 5.62 All .............. 2.45

SUMMARY AND C'oNCLIISLObIB. 1. Epiulemiologicall and experimental studies contribute ta, the conclusiom that smoking is a significant factor in the development of'cancer of the oral cavity and that pipe smoking, alone or in conjunction with other formsof tobacco use, f.scausaldy related to cancer of the lip. 2. Experi'rnentlal studies suggest that tobacco extracts and tobacco smoke contain initiators and promoters of cancerous changes in.the oral cavity. CANCER OF THE ESOPHAGUS Esophageal cancer accounted for 4,306 ' deaths among Americann maless in 1967 and L,:32D deaths among females,. The death rate f'rom esophageal cancer has remained relatively constant since 19 19. EPIDESiIOLOGICAI: STUDIES. T}iema,jorprospective epidemQologicall studies (tablb 30) have indicated a significant relationship between smoking and esopha- geal cancer. Overall mortality ratios for male cigarette smokersr.uogefrom 11.'71' to 6,17.. There are insufficient data concerning ;emales for establishing firmconelusions~ A number of retrospective studiesconcerning,the relationship of smoking and esophageal cancer are, . outlined in table A31 and _V;la.. Smokers incur rii;kk ratios ranging, from 11.3 to 6.6 when: c:ompared v: itK nonsmokers. As in studi'es of oral cancer, the effect of alcohol consumption n:ust be takenn into account inn studi'es of esophageal eancer: Because a. relationship between alcohol consumption and tobacco use is kuc>ccn to exist, Wymder and Bross (310) analyzed the association between tobacco consumption andl esophageall cancer after adj,ustl- ing for alcotlollintake. 11he7found that in.the.absence of.aleohol'f con,ttmptiom there was no association between the use of tobacco and esophageallcancerbut that.inthe presenceof albohol consump- tion,.an i,ncreasing relative risk with increasing number of ciga- retles~ smokedd was apparent,, aswells as, an association between. cigr,rand pipesmokimg and esophageal cancer., ,llo re recently, Takano,. et al. (272), in a retrospective study of °06 patientswith esophageal carci:noma,, found ani increased'd risk with smoking which was magnified by increased alcohol consurznp• tion. tidartinez (:Y8,4)~ analyzed the association of' tobacco usage and esaphageal cancer after controlling for age, sex, and alcohol conanntptiionL Iincreasing relative risks withh increasing tobaceouse 289

- I 'I'AIS1.K 3-1. ICfd Aul6nr, year, Ntmubr, and inLry, tqnr of refprenee pnpnlation clevr~ yiliJ'. .-]1pE'I!t(it,f 9tio.v (euiiL) lhI - ~~ ~ N) N~ lluta Follow- Number uollaetinn uP yrnry of Cignrctlr(dny Kahn U.@. mnle Questionnnitx LDOrn), veterans undfnllaw- 196G, Y,206,f.74 up nf death U.S.A, person certilieute. (tS9). Seers. denths______ 8';~ Hiwfdur 224 SM .192 N5..62 Airlncy 141 SM ..i02 N6..38 Hirayama, 265,11({ mnle Trained PHS 1 F SM 6 NS .... 1.00 I967, and femole nurse inter- SM ....10.00 (6) Japan udnlts40 icw and ( tE3 ). years nf age_ follow-up and older. of death certificnte. Weir and 68,153mnles Questionnetre G-8 BlaAdcr Dunn, . various end follow-. 27 1970, occupetions up of death Kfdncy U.S.A. in California. reetiRCSte. 27 LJO6). 'Unleeq other... xpeei0ed, disnurities betwcen the total number of deaths and the m uf the mdividuul smoking enteguries n e due to the . . ¢xelu.inn of either nccnsronnl, m,srepaneous, mixed, ov ex-smokere. f'ipr, cigar Kidnry Bladder Comments NS ...............1.00(39) 1.00(52) Bladder includes 2ipe ..............1.32 (6) 1.20 (8) other urinary Cigar .............0.77 (6) 0.94(10) treet cancers. Ci®arettes(day: 1-9 ..._..... ...0.91 (4) 1.10 (6) 10-1N ...........1.34(21) 1,03(37) 20-39 ...........1.68(16) 3.20(34) >_3J .............2.7G (6) 2.52 (5) All ...............1.4G(46) 2.15(82) Bladder cancer only. Hefers to nn for.ns of smoking. NS ...1.00 NS ...1.00 SM include er- ~10 ..0.66 !10 ... 1.52 smokers. !20 ..3.30 =20 ...2.81 NS include pipe >30 ..2.67 >30 ...6.41 and cigar All ... 2.46 All .... 2.89 emokers.

:3 cigarette smokers(6, 42, 112)., but the magnitude of this relation- ship is not as great as, that with squamous cell cancer in man. firrficctian.in, 2'zanxorigenictity. The importance off reducing total particulate.matterin cigarette ;moke is reflected in the dose-dependent results of'tMe Auerbach- Harnmond study. A major objective of experimental tobacco car- cinogenesis must be the reduction in the tumorigenicity of cigarette sa7okeand other tobacco products. In a recent article (820),. i1"ynder and Iloffxnann have reviewed the various methods applied to acliieve this goal. Among thesemethodsarethemodificatione of the tobacco itself„ the modification of the conditions, of tobacco pcrolysis, the use of additives, and the use of filters. The use of tilEers should produce a reduction of particulate matter as well as of gas phase components. Bross (.'P4)) studied 974 cases of lung cancer at Roswell Park. ]lemorial Institute and concluded' thatit smokers who switched to iiltler cigarettes showed.a decreased risk of developing lung cancer. Ilo+t'ever, even after switching„ heavy smokerswere still found tohave a mortality risk five times that of nonsmokers. S4ore recently, Wynder,. et al. (32k) reported on an interview audy- of :.5i1 patients with, histologi'call'y confirmedi lung cancer and S5'32 age and sex-matched, controls:. They found that subjects who had switchedd fromnonfilter to filter cigarettesteni or more years prior tiotheo study incurred a lower relhtivee risk of lung cancer at alllconsumption levels than that incurred byy those who continued to smoke7nonfQlter cigarettes~ . The authorssuggest.that this difference in relative risk may be due to the lower "tar" content in filter cigarette smok'e.. Prospectiv'e studies comicerning,the effeets of filter cigarette smokirng are presentIiy being conducted. Apart from variations in "tar" exposure due to filtration., itt appears that different patterns of smoking result inn the.inhalation of varied amounts of "tar." Graham, et al. (103) simulated dif- ferent inhalation patterns with the use of an analytic smoking ma- chine., He found that smoking a given number of puffs over a long period of time results in greater "tar" retrieval than smoking them over a short periodl. Also, he observed that taking most of the puffs at the end of the cigarette results in the highest retrieval while taking most at the beginning results in the smallest retrieval. Camplementing.these observationsiis the same author's case/con- trol study (10y?) of 183 men with lung cancer andl 161 men with diseases not related' to tobacco smoking. He found that the lung cancer patiients had significantlk_=greater high "tar"' yield cigarette smoking patterns than the controls, The risk of lung cancer was found to increase with the increase in mean number of puffs per 275

ICPIDE%I'pLOGICAL STUDIES (KIDNEY) A total,of 5,894 Americans died of cancer of the kidney during T96Z. A relationship between smoking and this type of cancer has been suggested by several epidemiological studies. The three major studies which separatelyexaQnine the relationship of'kidney cancer to smoking. (table 34),. namely those: of Hammond (118), )'hahni (139), and 4Vei'r and Dunn (306), have shown mortality ratios for all cigarette smokers t& range from 1.42 to 2:46. Retrospective studies by Bennington, et.al. (78, 19) have indicatedl a significant association between. all forms of smoking and renal adenoma, and adenocareinoma. EXPERIYIENTAL, STUDIES Numerous experiments have been undertaken by many inv.esti- gators to elucidate the rel'ationshiip of tobacco smoking to~bladder carcinogenesis. The two areas of major concern have centered upon the presence of a known bladdbr carcinogen, beta naphthylamine, in cigarette smoke and the presence of abnormal tryptopHan me+ talboiism in patients with bladdercancer: By virtue of data gathered concerning industriallexposure of workers, beta.naphthylamine has long been known as a, bladder carcinogen. Complementing such data was the work of Hhaeper, et al. (136), . whosubjected mongrel dogs to dailyy subcutaneous injec-tions and oral administration of commercial beta naphthylamine. Thirteen.of the 16'animaSs dpveloped.bladder papillomas and car- cinomas of the bladder. Saffiotiti, et all(.236) fed hamsters a.dieta containing.upto 1.0 percentbet'a naphthylamine and observed that 118 of'39 animals developed bladder tumors, almost all typical tran-sitional cell carcinomas. More recently, Conzelman, et al. (59), ad- ministered beta naphthylamine to 24 rhesus monkeys for more than 30 months. Transitional.eell carcinomas of the urinary blad- dbr were induced in 9 of the.aniQna9s, and a dose-response relation- ship was apparent. Pailer, et al. (207) andMill'er and Stedman (186), failed'to find this amine in cigarette smoke.. However„ more recently, Hoffmann, ett al. (127)) identified it in cigarette smoke. The autNrors,, noting theminutie quantity present in each cigarette (2.2 x 10"g), hesi- tated toattach a biologi'cal significancetio the finding. Of more recent interest have, t6een the.metabolites of tryptophan present in certain patientswithi bladder cancer.. A number of nor- mal and abnormab metlabolites of tryptophan have been found to be carcinogenicwhen testediby ihnplantation in the bladders of mice. These include 3~-}hydroxy-ky.nurenine (OHky)„3-hydroxyanthranilic

N ~ A iies-Mortality ratios TABLE 34.-Kidney and urinary bladder nanc_er--prospeotive at (Actual number uf deaths shown in parenthesey) SAt = Smokers. NS = Nnnsmokers. Author, yeeF, Number and Data Follow- Number couotry, type of eollection up years of Cigarette/dey Pipe,cigar reference popWa4on deathe Kidney Bladder Comments Hammond 187,783 white Questionnaire 3t/i - 287 NS .... 1.00(38) Pipe Data include patienta end meles in 9 and <10 ..i2.00(14) N& ...1.09(38) dving of proatatic Norn, Statea. interview. SM .249 10-20 .. 2.00(42) SM ...1.17(21) eaccinama. 1953, NS .. 28 >20 ... 3_.4__2(41) Cigar Data refer to u.S.n. NS ,..1.00(38) micrnseo_pi_e_ally (t80). SM ...1.06(19) proven cMrelnOmaB. Dolland Approx(metely Questionnaire 10 38 NS ...1.00 Ait SM by ]Iill- 41.000 male and fnll¢g- 5M ..A.41 amountin gfame 10G4. British up of death NS ...1.00 Gre6t physiciBns. certifiente. 1-14 ..0.59 Britain 16-24 ..0.65 (c4). >25 ...0.76 All .... 0.51 Best, Apprnnimately Questionnaire 10 11_4_ NS .... 1.00 Pipe Refers to 1966. 79.000 mal¢ and follow- <10 ... 1.38(29) NS ...1.00 genitaurinnry Canada (yl). Canadian veterans. uU of death certiRCete. 10-20 .. 1.44(57) >20 ... 1.43(16) SM ...0.56(10) Eigar cenrers as a group. A)i .... 1.40(10) NS ...1.00 SM ...1.16 (3) Hammond, 440,558ms1es Interviewsby 4 Bladder Cigarette a Cigarettee Mafe dntu onlv. 1906, 562,071 ACS 13X NS ............. .. 1.00(22) 1.00(23) Biadder(vcludee II.S.A. females voluntcers. SM .115 SM (age 45-64) . ..1.42(64) 2.00(59) other urinary (118). 35-84 sears of age in 25 NS .. 23 Kidneg SM (ege 65-79) _ ..1.57(28) 2.96(66) trectcancers. States: 104 SM . 82 NS .. 22 z4ess4eo

h] XPERIbi EN TAS1 5' TUiDY I)ontemNilll (76) hass recently reported the development of an eIluctivr and piracti'cable method by which small rodents (ham- sters, ratis. mi're) can beexposed to long-termi passive inhalation of cigarette smoke in a manner which circumvents the fatal effects of acute totiicit , v which rui'ned earlier attempts but allows for a dosage of smolke great enough to induce the development of chronic patho• logical changes. TheSyrian. Goldenn hamster wasfounds to be the most suiaalile species for such inhalation experiments for several reasons: its.resistanee to~pulmonaryinfeetions, its resistance.to the eftecVs of'nieoti'ne.as compared tlo.that.ofrats orcertain.strains of mice, and, especially,, itssusceptibilitly todeveloptracheobronehiel cancers after treatment with careinogens~ in contrast to its alrnostl total freedom from the spontaneous development of these tumors. IDt ntenv: ill demonstrated that the concentration of deposited ci cauettesmoke Nv as greatest in the hamster"slarynxaseompared to tkte otlherportionsof thee.xposed.respiratory tract (tabla2o).,, .uxD thed.the Tarcngeal epithelium wass the tissue which underwent iL, greatesG ,moke-induced histologieal changes. ]n. ~tudc ina,, the changes ini thelarynx;e the author differentiated r.~ e~exgev ofi epitlhelisl change, using.g as his reference the Atlas of "I'iin;or Pathologyoflthe Armed Forces Institute of P'athoTogy (5). TaLle 26; quoted by Donte ncill, describes the five types of change.. C1-:e% raragefroar ll.enigny su.chas epitheliall hyperpl'asia,.to pre- inaUign:uit, exemplified by.pseud~oepitheliomatousleukoplakia. "Clhe resnlta of the inhalation experiment are presented in figure II in ~chicli a doyage-relatied i'ncrease initheseverit,v of the epithelial h.:uu fe, is represented in graphi'c form. The author a~lsoreported, mml depictedlwithi photrnmlicrographs,the fin:dingof an earlyinva- sive,qtoantous cell carcinoma. This form of cancer isthe predomi- n:uit tYpe involving the human larynx. .CiUriiS4eYRY' AND CONCLUSIONS I. Epidemi:ological, experintental„ and pathologicall studies sup- port. the conclusion that cigarette smokingisa significant factor in the causartiom of cancer of tlhelarynx.. The risk of devel,oping larwtgeal cai~cer among cigarette smokers ass well as pipe and/or cigav smokers is.sign'sficantly- higher than amongnonsmokers.,The mat,anitnde of the risk for pipe.and cigar smokers is about the same w'dor av that for cigarette smokers,, or possibly slightly ]bwer. '3.. Experimental exposure to the passive inhalation of cigaretaesmoke h.rs been observed to produce premalignant and malignant changes in the larynx of hamsters. y

eontr.a:t to the sharp increase that took place in lung cancer rates~ in those years is probably due to several of the following factors. FSr~tL, pipe and cigar smoking are both significantly reldted to can- cer of'theoralcav.ity, and the'e i'ncrease in cigarette smoking among men, noted between 1920 and 1955, hasbeen„ to a large degree, accompanied by corresponding reductions in the use of pipesands ci' ars. S'ecomrd, aside firom the variou'schanges which the Interna- tional ClassiGcatian of Diseases (IiCD), ha& undergone during that period. the diseases discussed above arereeordedlin ICTI CodesI. I()-I.-1H which; includb somee neoplhsms not found to be related to the use of tobaccoL The various sites of cancer themselves do not roncributeeqpallye to the overall rate and are subject to widelydif-ferenfcure rates, so that their contributions tothe.total incidlenceritee isdi$'erent firomi their contributi:onn to the overal] mortalityrutefrnm.oral cancer: Although, more than 20;0Q6)'cancers of the'. On'ul cx~itx were estimated as newly diagnosed in 1967, the totaS. cnW!,E1 r of individuals recorded as dying from oral cancer duringtr;uyear%cas.onl}r6,718 (284').. Oral caucerr occ'urspredominantly in peopleof the middle and Jler fi~roups. llorethan 9Qpercent of'all oral cancers occur in per<ons ovcr age 4.5, , with.the average age at time of diagnosis aJpproXimating6'0. Although the major.ityof oral cancers occur in croc, thev.e isrecent evitlbncee that the ratio~ of malesatPeeted to iomalc" nffected isdeereasing (259'). I1IPIDESZI0L0GSCAL $`TCDIES' The u>eofe tobaceain various forms has been associated with the d,-veli,pn:ent of cancer of the ora,ll cavity and pharynx. The'.studies in this ,rrea of concern are truly international, many havi'ng been. carried outt in Asian :..dions as,well ass in the West.. The major pro~pecCive epidemiologiieaLl studies' have found in- erea,<ed rates of thesecancers'for cigarette smokers'aswell as for pipe andl cipnrsmokers (see table 27). Pipe smoking,. perse;r hash mv . been recogni¢edl as aa cause of.lipeancer (291). The methodoI- ut,°>' and re,,ults of the numerous, retrospective studies are sum-marized in tabie., t128-and. A28a.. These studies almost uniformlyy shotvsignificzint re'latianshipsbetlweenithe vaiiiousforms of tobacco u.<e ;md o" be orall cavityandy pharynx. Stu`i:(:-:i.~,.n r°'r}nshave.examinedthe.prevadenceor'rnci-dencco- ~,fp: entaiirttann change,, such as.orat leukopdakia, as.well asthat of cauce,r of the oral eavity.. In, many of thesestudiles„forms oftolSaeco use not prevalent in Western countries have been investi- gated, including reverse smoking(:in which the lighted end of thecivarette is kept ini the mouth.close tothepalate)o andthechewing, 285 a _{ :yr

T_AUee 36. Pancraatie cancer mortality ratios-prospective studies (Actual number of deaths shown in Ranentheees)' 511=5mokera NS=Nonsmokces. Author, - year, Number and Data country, typenf collection -~ re€ere ce Hest, pppnlntion Appro\imatT Qnestionnnirc 1966, 78,06 male and mnow-up Canada Canedian of death (=1). vetersns. certificate. Harimmnnd 440,558 males ~-- Intervevs by 1966 F6g,0y1€emales ACS U.S.A. 35-P(yeats voluntcer.s. (11H). ofagein25 States. Kahn US.mnle Questionnaire (Dorv) veterans, andfollpw-up 1966 2,255,674 ofdenth U.S.A. per.son renrs. certifirate. (1991. ~-~ Hiraynma, 265,118 m T- Trained PHS 1967, and femsle uree intrr- Japan adults 40 view and (125). yems of age follow-un of audnlderd den[hcertiEea[e. Weirand 68,153 mnlcs Questiotmnire ilunn, lo verious and folloe,-up 1970, occupntions of death U.S.A. in C.nlifornia. ce_rtificate. (.°0f). Follow-up M mher years - n€deaths Cigerettes Pipes,cigars 6-9M ., 35 Cu+rent (i.p¢eettesonLL_) pinee - N5 ..... 1.00 - NS .1.00 ~ <10 .... 1.40 (5) 611 ..2.60 (6) 10-20 ... 1.04 (16) Cipare >20 .... 2.37 (7) NS ..1.00 SM ..2.63 (1) Comments 262 NS ..... 1.00 (29) Maledataon :_.... SM ...z3a SM (uge NS ... 29 d5-f4) 2.59(/68) 54f (nge (5-70) 2.17 (95) 8tfi 344 NS .... 1.00 188} pipee t Aefers to cur_re_nt emokers fSM ...256 1-0 .... 0.89 (8) NS ..1.DD(86) of all types. NS ... 88 1020 ... 1.93 (66) SSl_ ..0.74 (®) 21-89 ... 2.18 (43) CiYare >35 .... 1.59 (7) NS ..1.00(98) All ..... 1.84(12fi) SM ..1.53(E7) Hoth NS ..1.00(88) SM ..0.93(13) SM ... 14 NS . .. 1.00 ~)n<O.D1) SM ..... t5-56 (14) f SM ... 71 NS ..... 1.00 -- SM includes ex-smekers. 2l0 .... 2.94 NS includes Pipe and cigar i20 ... 2.45 smokers. >30 . .. . 1.44 - All ..... 2.43 ' Unt_ess otherwise sGe_cified, dispnrities between the total number o[ deaths and the sum of the individnal smokin¢ categories are due to the ex- rlusion of either occasinnsl, misccllnneaus, mixed, n mokera. 10 19L3JM4O

,of or "1Tass;"which are mixturesof tobacco with either betell nut or lime ash,and, other ingredients (2J:1,. 255, 256),. Snuff dipping• a:habit in which snuff is placed in the gum and retained there for Irolonged periods, has also been associated with the dee•Ioptment of oral cancer (193,. 210), as has the ehevaing.of tuh:,eCtr (A'.i,.i'9dy,L-t1,29b'). 'fiw ri.~k of deve[oping a second primary mouth or throat cancer;, rrCtrr the recognition of the fi'rst primary cancer„ has been fou'nd'. t;I, h•Ivreater in continuing smokers than in those who quit smok- ;ne.:C11loC the patients studied by Moore (190) wereasymptomatic i-i :it Ih:ct thaee yearsfollowing the treatment of the first cancer. t tf' Uic 117 patients with adequate smoking histories, only 4 of 43 i ir pcrcent) who, qNitt smoking developedl a new primary cancer. t in tlSeother hand, 27 of 74 (36 percent) whocontinued to smoke dva, ll,pedia second primary cancer. 3 er, a study by C'astigl6ano (53) of patients treated for c,d e:uicer, did not show a greater risk of a second primary among .•Int:nniir.;1 smokers. In.this study,. 5 of'26'. (I9:percent) of those ,'.:!, nt- \cho, (lid nutt quit smoking developed a second primary ,;or.r, r a, cnmpared to 9 of 51 (18 percent). of.those who did quit. 1il c rute or quitting smoki'ng in the two studies is markedly dfif- ~nrut n:Ji6 percent in tihe Moore study andl62 percent i'm theCasti- tudY). From the data presented in the two papers, it is not d• ru evaluate the other significant ways in which the pop- i:atiwnntnEi,N have differed. (L,o9studied 408 males, with histologically confirmed cell cancer of the mouth or pharynx:This author dealt „G b. tl:.e qilestion of recurrent tumors in a somewhat different ~ii:mtner. The patients were observed forthe development of a sec- nei ~,r third primat;ucaneer at an. anatomically discrete siteof !ho nuouthand pharynxwithin.a median period.of three.years after I heiirs.t cancer.. He found that; a; secondd or third cancer (termed a coexi~ti'ng, ettncer)developed in 28 of the 408 cases. Among these _8 eases ~cith :;3 caexisting, neopLasms„ 21.7 percent weree heavy .smokers. but among.g their matched'': controls; theree were no heavy smukera. Coexisting cancers were mostcommonl~,t found.on the soft pulate. an anatomical site:thatis in direct contact with themaim- srreame off t'obac¢oo smoke. 3lorerecentPy, j°i"ynoter, et al. ('315)) studied 6731 male and 23 fenr.depatients with multiple primary caneers ofthef moutt and phar>nx. Theyobservedy that heavy smoking prior to the devePop- ment of'the oral aancerwas associated with a: greater likelihood (if decelbping a second primary. Also, continued smoking after the tinst primary was found to have a significant association with the oacurrenceof a second primary. 287 .:1 ~

acid WHA), 3!-hydroxy-2'amino-acetophenone (alll orthoamino- phenols), the 8-methyl ether of xanthurenic aciill (C'HXa), xant'hu- :enic xcidl (Xa), L.kynurenine (Ky), quinaldic acid, and 3-meth- nxcantlhrannlic acid (3CHiCA) (2,..36, 37, 39, 47, 48). OHKy and OHA are frequently present.in human urine, as is kynurenic acid ( Izi-A.)... Certain i'nvestigators have coneentratledltheir attention on the presence of abnormal tryptophan metabolites and: increased amount5of'normal.tlryptophammetabolitesin the urine of patients «itii bladder eancer ascompared with selectedleontrols (1„40, 46, ;. 1;a, '1-f, ?4Js 329). These authors have observed the increased cxcretim of Ky,.1KyX, OHKy, anthranil'ic acid, OH61,, andlacetylky- nurenine insuch patients. Yoshida, et al. (329),.in a recent study runcerningthe.relhtionshapbetween tryptophan metabolism and !.eterotopic recurrences of human urinary bladder tumors, reported L.:t those patients with recurrences showed abnormal metlabollte ticretion more often than those without recurrences. The relationship of smoking, to these biochemical findimgs is nnc<enth- uncertain.. Kerr,. et al. (11,3), in 30 . experirnentlson 3 <Mokers and 3 nonsmokerswhos were given large dosesoftrypto- pn.uis found that srnoking increased the urinary excretion of C)HKy r,d C1ILA and decreased that of N'methy9nieatinamidle (an end :m,•duct of tr«ptophan metaboli'smi)I. Kerr concluded that smoking nz"rfieres with the normal metaboIism of tryptophan. Recently, I:!rlonrr., et al. (45) studied 115 adultlsunder smoking and abstinence c,mditions.and fmund that exceptfor the basall excretiion of aeetylky- rvmceuine, tryptoplian metabolite excretion di'dl not change with >>r.uking or cessation. The authors also compared 13 nonsmokers ;,nit LZ regularcigarette smokers under basal and trypt'ophan- I,,adcd co:aditions. No differences were observed in the excretion of t:1u measured tryptophan metabolites. However„du~e:to its instabil- it'n-, OHA Nvas not measured. The authors concludedl that the rela- tionskhip of smokingtourinary+bladder cancer was probablyinotvia itss e ft•ect onn theky-.nureninee pathway of tryptophann metabolism. Another experitnental approach to the relationship of smoking and urinary bladder cancer isreflectedl in the work of Schiegel',, et al, (244, :...:i),. The auUhorss observed an. elevated eoncentration: of certain.ortiho-aminophenols in the urinee of.blad'd'er cancer patients and cig2rette smokers„ when compared with nonsmokers (244). More recently (2¢.5):, the same group compared.the chemilumines- cence of the nrinew: of smokers, nonsmokers, andd bladder tumor patienrts. They noted that nonsmokers showedl the lbwest level of luminescence (which they relate to: the presence of aromatic hydio- carbons~) and the bladder tumor patients the highest level. The norma9' cigarette srnokers" levell was found to be intermediate. 197

TABLE A7.-Grouyinpofpulmonarycarcinom:as Gteup L: A. Epidervmoid carcinoma. B: Small cell anaplast7c csccinomn /1'nat-ce11P cavvmomxl, Grovp IL: A.. Adenncarcinoma. B..BFOrtchio]o-okeol4n cell.carcinnma. C. Carcinuid tvmnr. D. DSucousgland tumur. Eatra. (not Inchmda7 in I and Ip:, A. LarBe ccll undiRerenNated ca clnoma. BI Combined epidermoid and adenocarcUwma. Unsuitable fou diagnosis. SaancE:. Kreyberg, G, (1ss). 334

A6 present, no definite conclusions can be draNan concerning, the inturreLationshipsof bladder cancer, atinormalltryptophan metab- :Jfl;m.,.and toliacco smoking, Further study is requii•edd in this and the.o.ther.areas of'bladder cancer pathophysiology,. $U:MMABY AND CONCLUSIONS. I. Elpidemiological studies have demonstrated an associatiorr of igarette : moking withcancerof the urinary bladder among men. 7ihe as~oci'ation oftobaceousage and'eancer of the kidney is less ~:uur-cut.. Clinical and pathological studGeshave suggested that tobacco uuoking may be related to alterations in the metabolism of trypto- u, a~nd may in this way=contribute to thedevelopment of urinary tP:;Ci eallcer. CANCER OF THE PANCREAS ~e eral prospective epidemiol'ogic studies have suggested a rela- *iun'hip between cigarette smoking and cancer of the pancreas: (c ,ble;fi'). A retrospectivestudv ofl46a,cases of pancreatiecancerJ'~ Ishii, et al. (137) has shown a dose-related increased risk of' nuacreatic cancer i'n association with smoking„ Analysis of dietary lsta revealed that the relative risk for pancreatic cancer from :moking was considerably greater than from dietary factors. No experimental studiesreiatimg to this question have beenn reparted. SUMMARY ANDCONCLUSIONS. Epidemfrological studieshave suggestedd an association between cigarette smokingand cancer' of tlie pancreasi. The'e significance of the relationship,is notcl'ear at this time. REFERENCES (1) AnEi.[-x, T:,.GsELL, O; T: Relatii•e risk of'pulmonary cancer in cigar.and pipee smokers.. Caneer. 20 (8) :1288-1296, August 1967. ('_'1 AI.1t'ASo, A., PAPA, S., TANCREDI, F., 1$LICIOi lYl. A., QUA.IL.IARIELLOi. E. Tryptophan-nicotinic acid metabolismm in patients with tumours of the bladder amdd kidney. Rritish, Journaf of Cancer 18; 386-389, 1964.. (3) .Yrvraoxv, H. M„ THaMps, G. M. B[adder.tumours.andsmoking..Interna-tional Journall of Cancer 5.('l) : 266-272, Marc13. 15„ 1970... (:i) AI<xIN', A.,,, WAGNER, D. H. Primarycarainoma of the lung. A diagnostic studq of one hundned and thirty-five casesiin.4 years. Jburnai of.the American.YIedicaU Association 1D6(8):587-891, February 22, 1936., 299. ~ . . . - ., ,. _ ..e.. ~+~. ~.'..

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TAlten A3.-Outline of methods used in retrospective studies of smoking in re6ation to lung cancer Anthor, year, Sex of Number of personu and method of selection countiy, rere Cpntryls Collectian of data Muller 1939, pt 86 lun cnncer decedents 66 healthy men of the same age Casen: Questionnaire sent to relati.vcs of da GermnnY -- reased. ---- (196). . (iontrols: NOt Btated. Schairerand M 0;1 csnrer decedcnts adopsied 270 men aaed 53 and 54 Cases: Questionnaire sent to next af _kin. SchAniger, (average age 53 9). f_,antrois: Qucstionnaire sent to 709. 1943, Germany (u43). _Potter and 5f 43 malee patients faler 40 years of 1,847 paticnt.s of same group with diagnoaes Cases and controls interviewed in clinica. ~Tully. age. uther than cancer. 1945. U.S.A. (212). Wassink_, hl 134 male clinic patients with 100 nurmal men of same age granps as caaea. Cases: Interviewed in clinic. 1948. ]uvg cancer. - Controls: Not stated. Nether- --l.naa (904). Sebrek et al., M 82 male lung cancer cases among 522 miscc llnneoue tumors other than lung, Smoking habits recorded during routine ho9- 1D50, 5,008 pa_tients recorded, 1941- larvnx. pharynx, ov lip, pital interview. U.S.A. 48. (Y46). Mips and M 444 respiratory cancer decedents. 430 sample of residents matched by age in Csees: Relatives queried by mvil question- ._ Poricq Culumbus, Ohio, _From census tractv atrati- naire ne_ pezeoval visit. 1960, lied by degree of e r Pollutian. Controls: 13avee-tmhnuse interviews. U.S.A. (186). JVV3JM[.Q

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BmSrRI r P. L., CASE; R. A. ML Carcinoma of the lung in wor&menn in the bichlomates-producingindush'ry ini Great Britain. British, Journall of Indu rual Medicine 13: 260-264, .1956i. (1_i) BLACK, H.,.ACxERMAev, L.. V.,The. importance ofepidbrmoid carcinoma in situ inrthe.hietogenesis.of carcinoma.of the lung. Annals of Surgery 136(1) n 4'4-55',. July 1952. i BLACKLOCK, J.. W. S. The production of lung tumourss in ratss by 3:4 henzpyrene, methy[choIanthreneand the condensate from cigarette smoke. British Journal.of Cancer 11(2)~: 181-1911, 1957. 1,'.5) Btnexcocx,. J, W. S: An experimental study of the patholbgieal effects of cigarette condensate in the lungs with speciall reference to.earcino- genesis. British. Journal of Cancer 15(4).:, 745'-762;. December 1961. i J(i) BLUmiE[N>. H. Zur kausa[en Pathogenese des Larynxkarzinoms unter BerucksichtigpngdesTabakrauchens, (Causal pathogenesis of laryngeall carcinoma with respect totohaceo smoking.). Archiv fur I'dygicne undl Bakturialogje VluncHen 129: 349-404, 1955. Bors., F. G. The.nature of.tumor-pmmoting agents in tobacco products. Cancer Research 28 (I1) ;2363-2368, November1968.. i1>I BocK~.,.F. G., MODRR, G.. E. Carcinogenic activity ofcigarette-smoke cor.densatc. I. Effect of trauma and remote X irradiation.,Journal.of tlieNational Cancer Instlitute 22(2) :.4011111, February1959., iP,nrx, F. G.,.__%'LOOBE,. G. E.,.CLARx;, P. C..Carcinogenic activity ofcigar- et:e smokecondensate=. III. Biolbgical activity of refined tar from seceral types of cigarettes. Journal of the National. Cancer Institute :14 (:1) : 481-498; April 1965.. ~-111 BDax, F. G., Mooae, G. E,,. CRoDOH, S. K.'Bumor-producing, activity of extnacts;of unburned tobacco. Scienee1lq5(3684)~: 831-833„Augustl2'1, 1964. 1) Baax, F. G.,.]1ooRE, G...E.,. DOWD, J. E., CLAR[c,..P. C. Carcinogenic.activ- itly of eigarettee smoke condbnsate.. Biological activity of'refined tar from certain Hrands.of'cigarettes, Journal of the American Medical .ass.reiatlion 1'81(8):668-673,.August.25, 1962:. f;!1. BoREN, H., G:. Pulmonary cell kinetics after exposuse to cigarette smoke. IN: Hanna, M. G., JR., Aettesheim, P., Gilbert, J. R. (Editors)..Inhala- ation Carcinogenesis. Proceedings off a Biology Division,. Oak Ridge National Laboratory. Conference,, Gat1i nburg, Tennessee, October 8-11, 11969. U.S. Atomic Energy Commission. Symposium Series 18i April 1070- ppi 229-241. BOREN4IREURD, E..,.ICR[yl, M., $ANDER6, F. I{.,,S4ERNBERG, S. S., BENDICH, A. Malignant.conversion of'f cellss in vitro by carcinogens andd viruses. Proceedings of theNattional Academy of Sciences of the U'nitedl States of .anlerlca 56: 672-679, 1966. (J"). BoRistTK, Y. P.. Raklegkikh u krys, vyzvannyy intratrakheal'ny.m vvedeniyem prodoktav kureniya. (Cancor of the lung iu.ratsind'uced by intratracHeal intubation, of tobaccosmokeproducts.). V6prosy Onklogi i 15 (6) . : 49-53„June1969., (J5)~ BovcHARD; Jl, IrIAY,. R. M. L'effet des gpudrons de tabac sur les greffes sours.capsulaires de poumon.chez la souris:. (Theeffec4'of.tobaceo tars on sub-capsular implants of the.lunge in mice.) Arehives~ d'Anatomie Microscopique . et de .3for.phologie . Experimentale 49 (3) : 307-332, 1960. 301 '-> 4

piiatory. tract of mice;, witluand w'itliout.expasureto cigarette smoke:. Rii•istadi Biologia, 59: 445-763'y.19661 (185) LEUCHTENBEREER, C-., LEUCHTENBERGER, R:. Cytologic and cytochemical effects on primary mouse lcidneytissue and'd lung organ cultures after exposure to whole, frceshh smoke and its gas phase from unfiltered, char- coal-filtered,, and cigar tobacco.cigarettes.Cancer Research, 29(4) r. 862-872; April 1969. (166) LEUCHTENBERGER, C.., LEUCHTENBERGER,. R.,. DOOLIN, Pl. F'.. A conrelatedl histologiual,, cytological, and cytachemical study of the tracheobron- chial tree.andllungs ofmice.expasedf to cigarette smoke. 1. Bronchitis: withh atypicall epitFieliall changess in mice exposed to cigarette smoke. Cancer 2(3).: 490-506;. bfa;+^June. 1958. (167) LEU(DHTENEERGERy C., LEUCHTENBERGER„ R.,. ZEBRUNI W.,, SHeiFFEH, P. A correlated histological, cytological, and cytoehemicall study of the tracheobronc}iial tree and lungs of mice exposedd to cigarette smoke. II. Varying responses ofmajor bronchi: to cigarette smoke, absence of bronehogenie.carcinoma.aftm•.prolonged exposure, and disappearance of bronchial lesions after cessation ofexposure. Cancer 13(4): 721- 732;,Jully.-August 1960. (168) LEUCH91ENnERGER, R., LEUCHTENBIIRGER, C., ZEBRUN, W., SHAFFER, P. A correlatedd histolagical,, cytological, and cytochemical study of the tracheobronchial tree and lungs of mice exposed to cigarette smoke. III. Uhal.tered incidence of grossly visible adenomatous lung tumors in female CF,, mice.afterprolonged exposure too cigaa'ettee smoke. Can- cer 13(5)'.: 956-958;.September-Getober 19ft (1&9)LEVIN, M. L.,GbLDSTEIN, H., GEBHARDT„IP. R, Cancer and totiacco.smok- ing. A.preiimihary report. Journal ob'tlie American Medical fissocia- tion 143(4).: 336-338, May 27, 1950. (170). Lmx1NT, F. Der Tabakrauch alsUrsachedes.Lungenkrebses. Spezieller Tcil IV. Atiolbgie und &iophylaxe des Lungenkrebses. (Tobacco smoke as causee of lungeancer. Special Section IV.IN:. Etiology and Prophylaxis of. Lung Cancer.) Dresden, Theodor Steinkopffy 1953. pp. 66-141. (171)LHaENFSV.n,A.'N'., LESnN„b1. L., bfooRE{,G. E. The association of.smok- ing with cancerof the urinaryy bladder in'humans. A.M.A. Archives;of Internal 3Sedicine 98; : 129-135, 1956. (172)' LITTLE, J. Bl, RnnFORD,.E..P., JR: Potonium-2110 inn bronchial epithelium of cigarett'e smokers.. Science 156(3762).: 606-607, February 3, 1967: (173) . LITTLE,. J. Bl,. RADSORD;, E.. P.,.JR-, 11tCCOkiBs, . H. L-, HUNT, V. R.. Ptilo- nium-210: in: lungs: and soft tissuesofs cigarette. smo&ers: Radiation R'esearch 22': 209; 1964. (174). LTTTLE, J, B., RADFORO, E. P:,JR., biaComns; H. L., HUNT,.V. R.. DistYibu- tian of Polonium-210: in.pulmonargtissu'es of cigarette smokers.. NewEngland Journal of hS~edicine .273 (25:) :.. 1343-1351,. December 16;,19fi5+. (175.). Locxn'ooD, K. Onn the etiology of bladder tumors in Kobenliavn.Fi•edpriksberg. An inquiry af.369. patients and 369 controls. Acta. Pathologica~ et IDlticrobiolqgica. Scandinavica.51(51ipp1ementum445)~: 1961. 166 pp. (176): LonesARD,. H. L.,, SNEGrREFF, L. S. An epidemiological study of lung cancen. Cancer 12(2).: 406:-413,. 9larch-April'.1959, (177) . LORENZ; E., STEWART, H: L., DANIEL, J. H,,.NELSON,.C. V. The.effects off breathing tobacco smokee on strain: A mice. Cancer Research 3.:. 123,. 1943. 3110 A

. TABLE A$.-(IaAtline of tnetlxorts used in retroapectzve studies of smoking inn reGutio 0 lung cancer (cont. Author, - - - - -yensJSexo€ Number of persons and method of eelection . ammtry, cases Collection of data reCFence Cases Controls Wicken, M-F 954 patients with primery, lung 954 age and _sex-matchrd controls from same Interviews with relatlve_e._ 1966, cancer. locale and deeeased from nonrespiratory ~ Northern diseases. Ireland (aen). Gelfand at al.. M 32 Patients with bronchugen_ic J2 age and sex-matehed patients Hoepitalization interviews. 1968, cancer. - Rhudesia (sa). Hlmsugi, M-F 185 Patients with lung cancer 491 persons sex-matched from similar alr- Cases: Haspitsl interviews. 1968, pollution regicne_. Controly: Interviews by trained public health Jap%n ---- aurses. - - Brad.shaw and M 45 Znlu Patients with lung can- $JI Zu_i_u_ Patients without lung caneer. Interviewed by trained African social worker. Sehnnlend, cer. 1989, South Africa (Netaq (41). Ormoae_tal., M-F 118 patients with Iung cancer. 5.089 controt persons without data on health Cases; Data derived from ease histories and 1965, history. interviews with relativee. Hungery Conrols: Intervtewa with a randum aample (xp{ . }. of train psssenqers. Wynder, etal., M-F 240 Patients with Kreyberg Type 480 aqe and sex-metehed patients Huspitalization in.terview. 1070 i luvg saneer. U.S.A. (as4).

TABLE A3. Qattkiyte of raethods used in retrospective studies of smoking in relation to lung cancer (cont.) Anthor, ycar, Sex of Number of pcrsnns and method of srlection country, cases __ Collection nf data reference --- Case. Controls -- --- ~ ~ ~ Levin et al.. M 236 cancer hospital Patients with 481 untienbs in same hospital with no.nma- Cases and Controls: Routine clinical history 1950, diagnosed lung eencec. lignvnt divgnosea, taken Lefnre diagnosis. U.S.A. (36B). Wynder and M-F 605 hospital and private lung 9NU patients of several hospitals with diag- Nearly all data by p_ersonal interview; a few Graham, cancer patienh_ t many y m__t_ss noses ath r[hnn lung rnnccr, rases by question e: a few £rom inti- 1950, - mate acquaintanres. Snme interviews with U.S.A. knowledge or presumption of diagnosis. nme with none. 595 diagnosed by tissve - e:amination, nme by sputum, snd anc by pleural fluid examinatkon. Meconnell M-F 100 lung c¢ncev patients, un- 200 inpadents of same hosnitals, matched by Personal inteeviews by the authors of both at e1.,1952, selected, in 3 hospitals in Li.v- ege and eex, without rancer. eases anJ controls. England, eruonl ere¢. (IR0). Doiland Hill, M-F 1,465 patients with lung eancer 1,465 Patients in same hospitalx, matched by Personal interviews of cases and controls by in hospitals of several ck_ i_es. -- eex and age greuD: aome with cnncer of almnners. 1952, other sites, some without cancer. Creat Britain (73). Saduwaky M 477 Patients with lung cancer 615 Patients in same hospitals with illnesses Personal questioning by trained interviewers. M al., in hosnitals in 4 staten. other than cancer. 1953. U.S.A. (Y9E).

TABLE A4.-Groaa7l ckaracterisGics in retrospectivc studies onn lung eancer and nd tobacco use SM=Smokers. NS-Nnnsmukexs. p' Males Femxles quthor, reaq - Cases - Controls Relstine Cases Contrnls Relative Cpmmen t s reference umber Pm.cent - s non- Per ent heayyy, mukers' umLer Percent non--~ smokers Pex ent heavy smokers' risk ratio SM:NS= umber Percent smokers Yernent henvv- smokers' umber Percent non- smokers Percent heavy smokers} _ _ risk - retio SM:N6r. Miillcr, $6 3.5 65.1_ 96 16.3 26.0 15.4 (') (+) (c) (q (+) (c) 1939 (i9s). Schsirerand Schtiniger, 93 4.2 31.2 270 15.9 9.3 c6.7 (') (1) (') (') (c) P) ... 16 female not 1943 (242). u ealvzed. Potter and 43 7.0 302 2,804 26.0 23.0 s4.1 (') (') (') (9 -(e) ... Tally. 1945 (y12). assink, 184 4.8 54.8 100 19.2 10.2 4.7 (+) (') (') (O (') Percenteges 1948 (304). estimates] trom chart. Schrek et al., 82 14.6 18.3 522 28.9 9.2 1.8 (O (°) C) (1) (') (') 1960 (P!C). Milieend Porter. 444 72 ... 430 30.6 „. 6.7 (') (•) (') (') (c) (c) 1950 (1BS). Levin et al., 2 16.3 481 21.7 ... 1.5 (!) P) (!) (4) (') (() ,.. Quantity 1050 (111). smnk~l not considcred. Wvndarand Graham, 605 1.3 51.2 780 14.6 10.1 13.0 40 57.5 26.0 552 79.6 1.2 2.9 tl 1950 (SIg).

LUNDIN, F. E., JR.,,LLOYDi.J. W., SMITH,.E. M., ARCHERr V.,E., HOLADAY,I). A. &Ibrtality of.uraniumf miners inrelation to radiation exposure,, hard-raekk miningg and: cigarette smoking-1950 through. September' 1967. Health. Physics 16:(5)~:, 571-578,.May1969. o I L tyCle, K.. M., Mccs+ltR, F. A.,, CAIN, J. R. Pulmonary, tumorss in mice exposedito asbestos.dust. A.M.A. Archives'.of Industrial Health 15: 207-214, March 1957.. ,; ~1+.) ]ACOSrEUti, R.B.,. GORDON, K. C...T., Joxes„T: Occupational.and per- smlal factors in the aetiology of carcinoma of the lung. Lancet 2: 651-656, October 4,.1952~. 1,+a 1 3facRE, P. N., BAR2PE9', J...M. Carcinogenic nitrosa~compounds. Advances in Cancer Research 10: 163-246, 1967. .+2) MaLTOVI, C!, CeaRE'efl, D., CANEPARI,. C., GHETTI, G., Incidenza della metaplasia squamosa dell'epitelio respirat'nrio inn rapporto all fumu di sigaretta. Studio citologicoo su 1000, indivitluii di sessomaschile ap- parentemente. sani. (Incidence of.squamous metaplasia of.therespii•a- tory epithelium imrelatGon.to cigarette smoking> Cytological stud)•on 1000 apparently healthy male individualsl)~ Cancro. 21 ('4') : 349-35B, 1968: , 7 av; ) SSARrINez, L Fuctorsassociated with cancer of the esophagus„ mouth, and phargnxx inPuerto Rico: Journal of the Nationa7! Cancer PnstiEute 4'2 (6) : 1069-1094i, June.1969:. ~bd'v:) 3IICrER, L„ SMITH, ISC El, BERLINER, S. W.. Tests for effect.of.asbesdos on Henzo(la)pyrenecarcinogenesis. imthe respiratory tract Annals of the New York Aeademy of' Sciences 132(Article.1) :: 489-500;. Decem- ber 31, 1965.. , b85) MILLER, R. L., STEDx1AN;. R'. L. Essential absence of beta-naphthylamine in cigarette smoke condensate. Tobacco 165I(8).: 32, August 25, 1867. (11F6) M'ius„C.,A.., PORTER, M. M. Tobacco smoking habits.and cancer of the mouth and respiratory.system,.Cancer Research 10: 539-542, 1950. (18'7) 11ILLS, C. A., PusTeR„M. M. Tobacco smoking, motor exhaust fumes, and general air pollution in relation to lung cancer incidence. Cancer Re- search 17:. 9811-990„1957. (1'8b) MtuN'cESArvo, R,,. SA'ePlorrl, U.. C'arcinogenic response off the hamster respiiatory tract to single.subcutaneous administrations of diethyl- nitrosaminc at birth. Journal.of the National C'ancerInstutute44(2).: 413-4i17;. Feblvary. 1970!. (189) M17NTESAxO;.R., SAFStoTT{ U., SHIISIx, P. The role of topical and sys- temic factors in. experimental respiratory careinogenesis. IN:Hanna, M. G., Jr., Nettesheim, P.,, Gilberti, J.. R. (Editors). Inhalation Chr- einogenesis. Proceedingsofs a Biology Division,, Oak Ridge National Laboratory Conference; Gatlinburg, Tennessee, October 8-11,. 1969. U.S.. Atomic Ehergg Commission Symposium Series 18.,. April 1970, pp. 353-371. (1.90)y. MooRE„ C.. Mult,iple mouth-throat oancer.. American Journall of Surgery 1110.(4) : 534-536, October 1965. (191). MooRC„C., CIIRISTOPHERSON, W. ML The effect of'cigarette-smoke eon- densate omhamster tissues. Exteriorized oral pouchh and skin.. A.M.A. .lrchivesof Sureerv84f41 - 425! 4A1- Anril 1962.. (192) . MooaE,. C.,. MILLER, A. J: Effect of cigarette tar on. the.hamster pouch. A.M.A. Archi,es ofSurgery'76(5.): 786-793. May 1958. (193). Mooac, G..E:, B[ssexceu„L. L,.,,PROeHL,. E. C.. Intmaorall cancerr and the use of cHe}vingtobacca.Journal of.theAmerican Geriatrics Society:l: 497-506, 1953: 3111

TABt.rs A3.-Outline of vnethods used in'refrosPective stadies of smoking in relatiou to lung cance'c (co W N N Author, year, C9untry, Sex of ca@es YJumber of persons and method of selection reference Controls Conectien of data Wynder and M 63 physiciens reported in AMA 133 physiciens ot same gruup dying of can- Msil ¢ueatiunm.ire to estatea of decedentn. Cornfie_l_d, Journal as dying of cancer of ecr of certain other sfte.rv. 1p53. the ]ung. U.9.A. Rovlumles, M-F- 812 lung cancer patients diag- 300 msle outpatients of e me hospital ovcr Cases and controls pueationed pbout smoking 1968, nosed at one hospital. 40 yeare of ngc. habits when taking case hiatorlee. 061 di- Finland agnoxen confirmed histologically; 494 d_lag- U51)' noeee confirmed by clinical, X-vay, and operative data. f.ickint, 1063 M-F 246 lung cancer patients in a 2,002 sample of Dersons without cnncc - ]iv- - Pecsonal interviews by etat[ membcs of eo-. , ('i¢rlllany (1z0). number u[ hospitals nnd clinics. ing in the same area a d of the sam sex 0.nd nge range 8a Cases. nper tl g hospitals and clmies. Breslow M-F 518 lung c_nneee patients in 11 518 patients admitted to same hospitals about Css an denn_ to_1_s uuestioned by trained Ct xl., California haepitalu. the same time, for conditione other than intcrviewera, each matched pnir by the 1964, . ceneer or shrst disease, matched forr rece, snme nerson. U.S.A. eex, nml p¢e group. (4E). Watson and M-F 301 patients at Memorial Hospi- 468 patients of same clinic during same The 769 ennsecutive patients of case nnd Cante, tal wi_th_ lung cnncer. period with diegnoses othet than lu_ng c_o_ntcol genups were nuestioned by the 1954, cancer. same trained interviewer. Control gr oup U.S.A. includes patients with ors] and csophageel (an5). _ . cancer . and bronchitis. - Gaell, M 136 men with diagnosis of bcon 135 a milar hospital petients with dlagnoses Personal interviews, all by the same person. 1954, vhrnl carcinoma. other than lung canrer, and of the eeme Switrerland age. (107). SOVS94E0

the ourcinogenicc effectt of tobacco smoke.). ZeiYSchrift fiir. Krebsfor- >cnu.ng 65; ; 465-470, 1963.. ~•JI licticau. N.. Lung carcinomaa in Ieeland. Lancet 2(6624.): 245-247, Auau:=t 12, 1950. i..:.i IUCxEikv, L. J., HERROC.n;.K. 14L.,Failuret'o produce tumorsin the ham- stercheek pouch by.exposure to ingredients.of betel-quid; histopathow loglc changes in: thepouch and other organs byexposumxe to known carcii:ogens. Jburnal of the National Cancer Institute 29:Q6)~c 1047- 1 e6 7, Pecember 1962. [IUN'fL1b1', G..J„ RAR80N, A. Sy. STEWART, H. IL., FR'ANK, A. S., YOUNG, I. 1.., JR... Rates, interview, and pathology study of cancer of the uri- narc bladder m New Orleans, Louisiana. Journal of the National fancerInstitute 41(i3) : 682-709, . September1968. •m UUTTacHOUOxURt; R..,,Ror, H.,.SeN GUPTA, B..K. Cancer of~ the larynx :u;d hy.popliarylnx. A cltnicopathological study with special reference ioaetiology. Jburnal.of the Indian.Medical Association 32(9).:.352- 3G2, May1,,.1Uo9- .~Cl I:nRSzrs~ B. Cancer of thedip. A clinical studyof 778cases with particu- ]ar regard.tio predisposing factorsand.radum therapy. Acta Rladio:- iogica (Shnplemen648):1-232,I943. -• 1:i5eNRt+.R,c„H., CAMPBELL, P. C., FLn:1NERr,J6 T. Chncer in Connecticut. l:ncidf,ncccharacteristics 1935:-1962: Hartford, Connecticut State De- parhuentof'Health, 1196h 97pp. 11 1:rMESxmtsT„ H., RE¢xzeny G.. Aromatische. Kohlenwasserstoffe imTatoaln:aucN. (,Aromatiehydrocarbons in: tobacco.smoke:) Beitrage zur. iabakf'orscHung.2(5):: 1'89-204,J4ay 1964. ~ ~ ISrzar, R.. P. Effect of alcohol and cigarette smoke as promoting agentshi. hamstor. pouch earcihogenesis.. Journal of' D'ental. Research. 48(6j . Part 2 ) : 1200-120:i,. November-December 1969. ,.+Y): FRRTEINy ,S.,S.., ANOREA., J.,,J'AFFEE, H., JOSHI,. S., FALK„H., MANTEL, N.. Cqrcinogenicity of thee herbicide maieicc hydr¢zid'e:. N atm•e 215(5108) ':. 1388-L390„ September 23, , 1967. ~._') Esse;Nnexc, J. M. Cigarette smoke and the incidence of' primaryneor 1llasm.of the.lung in.the albino mouse. Science.116::561-`J62; November 21. L952. ~."3). PALK, H. L., IfoTi¢v, P.,.MEHLER, A..Polycyclic hy-drocarbonsas carcin- ogens:fn man. Archives of Environmental. Health 8(5) .: 721-730, May 1964. ~?S) FExia, 1:. S.,. BARATTA,. E. J.. Polbnium-210: in. tobacco, cigarette smokeaa)d selected humam organs. Public Health Report's 8'1(2).: 121-127,.. February 1966. (95), FERRi, LI S., BARATTA, E. J. Polonium-210.in tobacco products and.hu!man tissucs., Radiological Health Data. and Reports 7(9) : 485«488y Septenbeu1966.. (.9ti) FLETCHER, C. 1L„HoaR;.D. Smoking and health. WHO Chronicle 24(8).:345-370,,.1ugpstl 1970. (r7) FRiEOr:cL, G. H., BURNEY, S. W., BELL, J.. Rl, SoTo,. E. Pathology as re- lated too tryptophan metabolite excretiony occupationall history, andl smoking habits inn patients with bladder cancer.. Journal of the: Na.tionaLCancer Institute 43':(1) r.303-306, JulyI969., (3s): GEL.FaNO, nL„ GRAHwnt; A. J. P:,. Lrcamm[Atm, S. Cairiimma of' bronchus: and the smokinghahrt in Rhodesian.Africans, Briti'sh MediealJournal 3{I5616):: 468-469, August 24, 1968.. 305

(67)DEU:A PbRTA„ G.,.KoLB, L., SxuBlx', P. Induction of timacheobronchiallA 1(5396).:1460-146.7, June 6j 1964. (76) DaNTENWrct, 4v., Experimentall investi[a.ations on theeffeet of cigarette smoke inhalatiomonn small laboratory animals. IN: Hanna, ML G.,,Jk., het&esheim, P., Giibert,.J. R. (iEditors). Inhalation Carcinogenesis. Proceedings of a Biology Division, Oak RidgeVational. Laboratory Conference, G'atlinburg„ Tennessee, October 8-11, 1969.. U.O.. Atomic Energy Commission. Symposium. Series 18',. April 1970. pp. 389-412. (77) DQNTENWIIi, «!., wIEBRCRF.i. B. Tracheal and pulmonary alterations following.the.inhalation.of cigarette smoke.by the golden hamster. IN: Severi, L. (Editor).. Lung Tumors in Animals~ Perugia, Itally., Divi- sion of Cancer Research, University of Perugia., June 1966. pp. 519- 526. (78). DRUCtcaLY; H. Experimental investigations on the possiblee carcinogenic effects of tobacco, smoking.. Acta. Medica Scandinavica 170 (Supple- ment369).:24-42, 1961.. (78) DRI1CxREY;.H., LANn3CHPTZ, t;.,.PREUSS1fANN„R. Oe5ophaglrs-carcinome nacH. Inhalation: von Methyl-butyl-nitl:osamin (MBhA) an Ratten. (Carcinomas of the oesophagus, induced.byinhalation of inethyl-buty+l- nitrosamine (yIBN:1) in rats.) Zeitschrift fur Krebsforschung 71(2),: 1445-139, July 1968. (80), D$UCKREY, H., PREU9aMANT', R., BLI1M,. G., IvANKOI'IC, S., AFKIIA!Yf„J. Erzeugungvom Karzinamen: der Spelser8hre durchh unsymmetrische Nitnosamine. (Esophageal carcinomas induced by asymmetricc nitro- samines.) Naturwissenschaften 50(3) :.100-101, 1963., (81). DRocxREr, Ht, PRECSSmANN, R., IvAxxovaC, S., S'cxM,AHC,. D. Organo- trope eareinogene lb'irkungen: bei 65 verschiedenen 5-nitraso-\'crbin- dugen an BID-Rattam (Organotropic carcinogyniceffects of 65 difPerent. SV'.nitroso compounds of R1l-rats). Zeitscliriftfur Krebsforschung 69(2).:103-201, March 22, 1967. (8$)I1RCCKREy, H., StHILDBACH, A. Quantitative Untersuchungen zur Bedeutung des. Benzpyrens }lir die carcinogene14%irkung. von. Taba- kraueH.. (Quantitative studies on the significance of benzopyrene for vations of Britishh dbetors:. (Concluded)'. BS-itish. Medical Journal. 1399-1410, May 30„1964. (75) DOLL, R.,. HILL, A. B. Mortality imrelation toamoking;Ten years' obser- vationsoflBritislidoct'ors.(Part1) British.Medical:Journalll(5395):. 66:: 183-195y 1965. (69) Dot.E,. R.. Cancer of.the lung and nose in nickel workers. British Journal of Industrial Medicine 15(4): 217-223, October 1958. (70) DocE„R. Mortalityy fiom.lung cancer among nonsmokers. British Journal of Cancer 7 :. 303-312,.1953; (71): DocL,.R..Mortality from.lung cancer irz asbestos workers. British Jour-nal of Industrial Medicine 12 (1')~: 81'-86, January 1955. (72) DOLI:,. R.. Occupational lung cancer: A review. British. Journal of Indus- trial. Medicine 16x 181-190..1959. (7.?) DOLL, R.,. HI[,[:,,A. BL. A studg of the aetiology of carcinoma of.the lung: British~ wledical Journal 2:: 1271-1286, December 13„ 1952: (74) DOEC,R.,HIiu,A.B:.Mortalityin.relationto.smoking: Ten years'obser- mate cells in.vitmo. Journal of Cellialarand Comparative Physiology 597, June 1958. . (68). DIAMOND, L. The effect of carcinogenic:hydkocarbons on mdent't and'd pri} carclnomas in the: Syrian golden hamster. Cancer Research 18: 592- 304

.-~. . _ . , . :. . :~ , .... ~... - : ....:.w4+trt lanl'"!~`+g!!.xYr~R~'9 /';MRarM1:b'N1.1 ... Z'ARLE 7A4.-Group 4t42 /aCtQrt8t lEs 5n T€aPNSp&Gt2Uf5 Att/_l(iCY un LIOil~ G¢ACET anl~ {0(iFGGO_ Q_(Se (Oont.) SM - Sm okura NS - Namsmoker v. Males - - Pcmnles - - Author, Cases . -_ . Cun(ruls : - . . Cmes Controls - year. ._ Rclutlve . - Relntive Qpmments referenre Pe ent Per ent ~ Prr ent Percent rfsk Percent Percrnx Peneenc Perceet risk Nmn- - ~ tieavy - heney - rntio Nu- hrnly non- henvy ratlo hec moA crs mokers• Number em.ukcrs smokcrs' dM:NB' ber moker. smnketsE Mumher, smokera mnkern' SM:NS? Randig, 415 1.2 34.2 361 6.8 17.9 ^5.1 33 51.5 3.0 131 70.3 0 2.2 1954 (218). WYnderetal., (9 (") (V (•) (O (•) 105 56.2 16.2 1,304 66.0 8.4 1.6 1954 la]FL - - Seui et at, 166 ... ... 2,124 - ... ... ,,. - ... ... ... ... ... @uantities ... IDsl (^_50). smoked stated as ane.zages only. Dif[erences - e st tistiaal_Iv gignifcant. Millsand 484 F.4 26.0 1,588 27.6 5.8 4.2 94 83.0 4.3 1,722 73.3 0.6 0.6 Percent"heuvy" Porter, - mokers under- 1957 stated. Only (187). 60~;E eurvcr resDOnse amang fe_m_ale cuscs. _Stochr, 2.101 1.9 28.2 6,960 8.7 22.3 4.9 255 57.6 17.2 3,402 68.6 10.7 1.6 1954 (269). Sehwaltzand 602 1.0 58.2 1,204 9.5 36.2 10.4 (•) (') (9 (') (4) (9 ... Denai.x. 1959 (347)- Haenszeland (4) (") (1) (") (l) (Q 168 51.9 14.6 339 60.6 - 8.2 2.5 SMmkin, - -- ~ ~ w 1058 (i~J). - -. __ _-. - - '

Part.A.. Wa=_hington, U.S. Department of Health;. F.ducation,, andWel:- fare, Publi¢Health Service Publication, 1967.. (288) U.S. PUBLIC HEALTH SERYICE.. NATIONAL CENTER' FOR HEALTH STATIS, TICS.: Vital. Statistiesof.the United States-1966. VoI. II-'.OIortality, Part.A., Washington, U.S. Department of Health',. P:ducation,, ar[dWel:- fare, Public Heallh. Service Publication, 1968. (289) U.S. PUBLIC. PIEALTH. SBRNICE.. NATIONAL GENTER' FOR HE.V.TIl STATIS- TICe...Vita1 Statisticsof:tlie United. States-1967:. Val. II-Mortalitg, Part.A..W.ashington, U.S. Department ofllIealth;.Education, and Wel. fare,. Publie. Health.Service Publication,. 1969. (290), II.S'., PUBLIC. HEALTH SERYdCE, NATIUriAL. t)ENTER,FOR HEALTH STATIS TICS. Vital StatisticsRates in. the. United States. 1940-1960. Wash-ington, U.S. D'epartment of Health, EtlucatSon„ and Welfare„ PublioHealtki: Service Publication No.. 1677., 1968. 881 pp. (291) U.S. PURLIC'HEALTIV SERVICE. Smoking and Health. Report of the Ad':-visoryCommittee.to the Surgeon Generalof'the Public.Health Service:. Washington', U.S. Department of Health, Education, and Welfarc„ Public Health Service. Publication No. 1103, 1964, 387'pp., (292). VAr.KO;. P. Koureni a vyskytt zhoubnych' novotvaru hrtanu. ( Sinoking and occuerencee of malignant tumors of the larynx.) Ceskoslovenska. Otolaryngo[ogie.1: 102-105, 1952.. (2.98)~ VANDUURENy B...L.. Tobacco carcinogenesis. Cancer Research 28(11):: 2357-2I362',. November 1968. (29p). VAN Douecm, Bl L.,. SIVAE, A'.,. LATrcSBrH, L., GoLUSCHavDT, B. M-,. SEGAL, A. Ilnitiatorss and promoters inn tobaccocarcinogenesis. IN: Wynder, ID. L.,. Hoffinann, D. (Editors). Toward a. Less' Harmful Cigarette. Bethesday. U.S. Public Health Service, National. Cancer In- stfitute. Monograph I+Io. 28,.June.1968. pp.. 173-180.(295)'. VAN, DUUREN, BI L.,. SIVAK, A.,. GOLDSCHnnOT, B. M.,, KATZ' C., MELCHIONNE, S..Initiatingactivity'of aromatic hydrocarbons in tw.7e stage carcinogenesis: Journal of the. Nationall Cancer Institute 44'(5): 1167-D173„ May. 1970:. (1:96) VAN DUUREx„B..L., SIvAA;,A.,,SEGAL,.A., ORRls, L.., LANCSETH, I4. The: tumoe-promoting, agents'of tobacco leaf'f and tobacco: smoke condensate. Journal of the National Cancer Institute$7 (4): 519-526;.Oetoben 19641. (29Z)~ VINCENT, R. G., MARCx,ETTA, F..The. relationship of the use of tobacco and alcoholl tb cancer of the oral cavity, phaaynx'or larynx. American Journad: of' Surgery 106 (3):: 501-505. Septemher1963. (298) VOGLEIt;. W. R., LLOYD„ J. W., M[LMORE, B., K. A retrospective study of etflological factors in cancer of the mouth., pharynx, and larynx'. Can- cer 15{2) : 2x6-2b8„ March-April 1962., (299) WAGONER, J. K.,.ARCHER, V.. E.,,CARROLL, B. E., HURADAY, D. A., hAW- RRNCE, P. A. Cancer mortality'patterns among U.S. uranium miners and millers;.1950througS[.1962..Journal of the National Cancer.Insti- tutie 32(4).: 787-801, April 1964. (1300), WA60NFSR:, J. K., ARCHF]R„ V. E., LUNDIN, F. E., .IR:, HOLADAY, D. A.,, LLOYD, J. W. Rhdiation as ttiecause ofImlg cancer among uranium miners. New Ehgland Journall of Medicine 273 (4) : 181-188, July 22,, 1965. (S0F): WAGONER, J.. K., MILLER;. R., W.,. LUNDEN, F. E.,:JR., ERAUMSNI; J. F., JR., HAIa,. M. E.. Unusuail cancer mortality among, a groupp of underggroundi metal miners. New, Englandl Jburnal of Medicine: 269(6).:.. 284-289;. August8„1963.. ~ 378 W ~ Q7 ~ ~ d

TABLE A13. Experintents eoueerning the effects of the skin painting or subcutancoas injection of cigarette smoke condensate or its constituents upon animals Author, A. Methnd, -veaz:Animal R. Fro uency and/ ntry, and duretioq Results reference etrain C. Material Wynder CAF[ mice A. Paintingshavedskin, Percent animals witM et al., B. 3/week for 2 years. Treatment: I Payitlomaa+ 1953, C_. Whol cigerettesmoke "4'ar" alane ... ........... ....... 69.0(81) Il.S.A. condensate in acetone. "Tar" and croton oil ................... .... 42.0(31) (?1T). Crotnn oilonce/geek. Acetone alone .............................. (80) Acetone and eraton oil ..................... (14) Cancer 44.0(81) 9_.7(31) (30) (14) Passcy 5 diRerent A. Painting unshaven No malignarLL tumore noted i either aroup. etal., skin. Papillom.a noted nn nne animal (in whnle "tar" group) which later regressed. 1965, arnins B. 2/wcek 17- 9 England (fQ?). anths. (209). C. Whale'Ysr" or neutralfraction. Crr, at al., Mice of 2 A, Paintingskin. Num6er animata with: 1955, strsins. B. 1 or 2/week fur Treatment: Papillomas England 18 months. nrn:Pn'ene I/week followed 4/30 at 18 .montha (seuarate grpup received only ly (FR5). C. 20 percenteigarette "tar" in aretone. by "Y®r" 2/week. "Tnr" alone ............... benzpyrene and showed no tumore). 0/60 at 18 manthe. 0.3 percent benznrrene. Camments 5 Number in paren- thcsia reyreeente total in that exPerimentalgrnup. Skin-6aintiny experimenta prior to 1953 are fully detailed in teb- ular torm in this article. ozV;sz,eo

I 9 tobaccos. Journal of. the National Cancer. Institute.3l(6) : 1445'-1459,. December 1963. (182)'. HoRIE, A,,. KoHCav;, S., KURY Tsuwe, M. Carcinogenes is im tha. esophagus. Il.,..Esperimentalproduction of esophageal cancer by.admihistrationy of ethanolicsol.ution of oarcinogens.. Gann 56(5).:'. 429-441, O.ctober 1'965. (1I33)I HvErr;Rj W. C. Experimental studies iiI metal oancerigenesis. VI. Tissue. reactions in rats and rabbits after parentlerall introduction of suspem simis of' arsenic, beryllium, or. ashestoss in lanolin. Journal of the Nationall Cancer. Instiitute:15(t): 118-1.29', August 1954. - (13-4) HoErER;. W. C.. Experimentall studies in metal'l oancorigenesis. IX. PuI- monarylesions in guinea pigaand rats exposed to prolonged.inhala- tiand of powdercrl metallic nickel. A..3f.A'.. Archives of Pathology 65: 600-607y June 1958. (1'.@5)HDErER, W. C.,. PAYNR,. W,. W. Experimental studies in metall carcino-genesis.. Chromium, nickel, iron, arsenic. Archivess of Environmental Health.5(5) : 445-462, Nove,mber 1962. (1i8'G) HVEPeR,. W. C., WIr.Er, F. H., WorFE,. H. U., RAnTA,. K. E., LEMING, M., F., BLOOD, F:.R-Experimental production ofbladder tumorsin dogs; by adminustrationn of beta-naphtlhvlamine.. Journall of Industrial Hy- giene andlToxicol,ogy20,(1):. 46-84, January 1938. (1.Y7) ISifII, K.,. NAKA3fURri, K., QZAICI„HL, YAMADA, NL, TAKnUCHI,.T. SlliZO- gan.no ekigaku ni okeru mondaiten. (Some aspects of the epidemiology of'cancerof the panereas.). Nippon Rinsko 26'(8) : 1839-1842, August 1968. (1J8~) JoalcsoN}.I)-E.,YlicyAR.d.D„RaronoII;,J.W.Nutrosaminesin~tobacco 1* smoke. IN: Wynder, E., L., HoffJnann,. D.. (Editors). Toward a Less Harmfull Cigaret'te: Bethesda, 34d., LSS. Department of. Health, Edu- eation, and Welfare, Public Health Service,.\'ational Cancer Institlute b4onograph 28, June 1968. pp. L81-189.. (139) KAHx, H. A. The Dorn studynf smoking and moitalityamong U.S. vet- erans: Report.on 8',z years of observation..IN: Haenszel, W. (Editon). Epidemio7ogi6al Approaches to the Study of. Cancer and Other Chronic Discases.. Bethesda, Md., U.S, Public Health Service, National Cancer Institute Monograph No. 19; January 1966: pp..1-120'. (140). KieLCr,R, A- Z. Cirrhosis of the liver,, alcoholism and heavy smokiiig asso- ciated'd with cancerr of the mouth andd pharynx. Cancer 20(6).: 1015- 1022, June 1967i. (1w1)KEIr,F:[t„A..K,. Ceilbl'artypes, survival, race, nativity, occcupations, habits and a5sociated' diseases in the patlhogenc-si'ss of lip cancers:, American Journal of Epidemiology91(5) : 486-499, il'Lay 19701. (1!.2), Ksil,EV; T. F. Polonium-210 content of mainstreamm cigarette smoke. S6ience 14'9~(3683) t 537-538„July30, 1'96u. (14s). KERe, W. K.,,BARxrn, bi., LEVERS, P:.E., Woo;,S. K-C., )LSexczrK,.S. The effeet.of cigarette smoking on. bladklerc,arcinogRns in man.. Canadian 1'VTedi ca3 Associationm Journal 93 (1) : 1-5,. July, 3; 1965'.. (1,44): KmA, H.,,OncoTo;,T.,.SAxaaromu;.K., biomeose,.8. Fukuokakemhokubu.ni okeru boko shuyo noo ekigaku too tokei.. (Statistics and epidemlolog~ of urdnaryr bladl3entumors inn northern Fukuoka, Japan.) Hifu to fPinyo 30 (5).: 883-889, Oatober. 1968. (145) KIraeARDA, IVf., 11'krmovtc, D-„Paxoa; D., Dauero; D. Contaminationn with polonium-2110, uranium and radium-2266 due to smoking. Health. Phy- sics 12:18(18, December 1966. . 3308 ~. N

TAISLE A12.-Autopsy studies concerning the presence of radioactivity in the lungs of smokers (eant.) NS-Nonsmokers. SM =Smokers. Author, yeur, Number couvtry, reference bf cases ltesulte Ferriand Mcan Po"° ievutq in vurioue ti,..uep (pn/0 wet ti®.ue) Beratta, Luny Liver Xidneg 1966, NS ..............30 0.031 0.103 0.080 U.S.A. (96). SM ..............19 0.066 0.125 0.0'!0 Rejewsky and Mean Pon° leve)e in uarious tissues (pc(g) Stahlhofen, LungPnrenchgma Rro.whiaitree Branchiatbifurcation 1066, NS ............... t 0.0025 0.0020 0.0012 Germany (E17). SM ..............13 0.0078 0.0077 0.0047 Little and Meun Po?'° fevela in vurioua cyitheliul Nnsuee (YCIg wet tieeue) Radford, SM ..............¢6 nranchiel wn]1 and aubmucasa ................................. 0.00d 1967, Bronchial epithelium: U.S.A. (t79). Bine ............. 2 Trachcu .................................................... 0.120 ~ Ex-eigsrette ...... I Lob r bronchi ... ......... ......... ............ 0.190 Never ............ 8 Segmentel bifurcation ....................................... 4.500 Comments {Dete act given. Smokers were considered those using more than 1 _Diek a day. The authors nated that their 8guree were cnn- siderebly smaller then those of Little et a]. (f78. 174) and also disagreed witb their data on bifurcation. ~ t"` 6LfS9~6E0

(225) RoE;,F. J-.C. Role of ;1,4-lienzopyrmoe imcarcinogenesisby tobacco smoke condensate. Nature 1941(4833) : 1089~110911, June 16, 1962. :. (226) RaTH:,,D., FeeoxjcxaoN; D. T., OPPENHeIM, A., LoNnaN, M. Bioassayofy the effects of smoking on 1)NA contentt of human respiratoryepi-thelium.. Cancer 21(6) : 1132-1136, J'une. 1968. (227) R/JTH, D:, OPPENRELM,. A., FHRnEi1CK5oN, D'. T. DNA-dependentt dlye bindingUy, oral epithelfum.Its relation: to.smoking habits..Archices of Environmental.Hcalth L7(1): 59-61,.July 1968.. ' (22$) RRYALCOLLEGFD OF PHYSICIANS. Air pollbtion and Health. Summary and Report on Aii~ Pollution.and Its EBPect.on Health. ByrUhe.Cnmmittee of tha Roya1. Collhgee of Physicians of Londonom Smoking and. Atmos- pheriu Pollution. Pitmam Modicall and Scientific Publishing Co:, Ltd., London,I970.80 pP+(229) RozENeIE.DS, J. G. C'an•cincnna of the larynx and hypopharynx in South Australia 1952-1966. Medical Journall of Australia.2(6): 244-249, August 5., 1967'. (230): RUNRCxLIIS, V. C. Natural rad.ioacGivity in tobacco and tobacco smoke. Nature 19I(4786) r 322-825„July. 22,.1961'. (231)'. SAccontnNNa, G. Radiationn exposure of uranium miners. U:S. Congress. Radiation Standards for Uranium Mining. Hearing;; before the Sub- committeee on Research, Development, and Radiation of the Joint Committee O'm Atomic Energy, Congress of' theUni'ted: States. 91st Congress, 1st Session, March17, and, 18, 1969. pp. 30LL--315. (232) SAnowsxr, D.- A.,. GiLLIAM~ . A. G., CORNFIELD, J. The statistical associa- tion: between smoking and carcinoma of'f the lung.. Journalof the Na- tionall Canoer Pnstitute 13: : 1237-1258,.1953. (23.4) : SAFFIOTTI, U'. Ekperimental respiratbry tract'.careinogenesis. Progress im Experimental.Tumor Research' 11 : 302-333, 1969. (23y) SAFP1oTN, U.`Experimental respiratory tract carcinogenesis and its relation toinhalation exposures.IiN: Hanna, M. G.,,Jr.,.Nettesheim, P., G'iLbert;.J. Rl (Editors). Inhalation. Carcinogenesis: Proceedings of a BiologyDivision~ Oak Ridge National Laboratory Conf2r•enoe', Gatlinburg, Tennessee, October &-ll, 1969. U.S. Atomic Energy Com- mission SS'mposium.Series.18;. April.1970. pp. 27-54. (235) . ShTFroTTI, 17., CEFIB, F.,.&oLS, L..Pf. A.method for the experimental induetion~ of bronchogenicec carcinoma. C'snoer Research 28'(1).: 104L 124, January 1968. ('236), SAFFIOTTI, I){;t)RFIS„F., 14TONTEiSANO, R.,..~`lELLAKUMAR,A. R. Ind1lctionn of blad'der'canmer in Nanlsters fedd aromatic amines. CHapter 10: IN: DEICHMANN, W. B.,.IIAMRE, K. L. (Editors). Bladder Cancer: Proceed- ings of.the.5th Inter-American.Conference on Toxicology and Occupa- tional Medicine. Coral Gables, University of Miami, School.of. Medi- cine, 1967'.pp. 129-135. (237) SAFe[oxrrr, U., CeFIS, F., SEIUSne, P. HistopathoIogyandlhistbgenesis of' lung cancerr induced in liaenster: byy carcinogens carried byrdust par- ticlbs.. In:. Severi, L.. (Editor). Lung Thmors im Animals: Perugia,. Division of' Cancer Research; Unieersitynf. Perugia,. June. 1966.. pp~537-546. (238) . SALLEY, J. J. Expwrimentab carainogwiesik in the cheek pouch of the Syrian hamster. Journal of Dental Research. 33 (2) : 253-262,. April: 1954. (s239). SALLEr,.J. J., Smoking andoral'd caneer. Journali of'. Dental Research 42'(Supplement to. No. 1)).: 328-339; 1963. 314

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W Y p 'PABLP ,A9.-Group characteristics in retrospective studies on lung cancer and tohacco use (son t.) SM e Smokers. N9 - Nnnsmeke ra. _ _ _ _ Males Femeles Author, - Cnses Gontrols Oases Controls Year, . - Belativo -_ Relative Gnmments reference Percent Percent - Percent Pernent ri5k- 1'rr eut Percent Percent Percent risk Num- .- hcavy nan= heavy ratio n'- hensy non- -heavy ratio bee mok rs sm6kers3 Number rndkers smokers' S6fiN9'Number smak : smoke_rsl Number smokers ~ smoketa* SSS:NS~ Lombardand SOD 1.6 .., 4,E88 1L0 . 7.9 (1) (f) (1) (t) (y (•) Authors' SnegireR, ralculations foe 19G9 (198). - - heavy smoking hased an lifetime number of Parks of ciqarettes. Pernu, - 1,477 6.9_ 34b 919 37.2 2 0.8 9.4 129 95.3 26A 1,U60 81.6 ~ 0.? 1.0 Quantities 1960 (rtt). _ given only in grams ner day. Haennzel 2.191 3.4 41.9 (`) - 16.2 12.0 5.2 (`) (•) (`) (`) (`) (') - ... Ponulation e[ aL. - - samplc of 1962 (++r). 31,flFusedas base. Not a case- - conrrol study. Lancaster, 238 2.5 86.1 476 20.1 71.2 9.8 (1) (q (!) (`) (9 (`) .., 1962 (1§8). Haenazel and (•) (`7 (+) f`) (9 (5J ... 749 60.9 ~ 11.5 (!) 67.3 2.5 1.8 PoOUlatian Taeubeq -- eaml'If ef tssa (115). aa.a3s used as base. Not a cnse-cnntrol study. ..+ . ,. 'r . . .. . .:. .. . .. .. .... ,.. S 46S94CU

4'ARL6 M. ©1ttEcno of lIlethpds used in letrospecttpo studies of smoking in relation to lung cancer (cont.) AutLoq ~year,- - Scx nf u,try, ra.ea F~e~, Number of ncraans and melhud uE .elentl,m Caee. Cnntrnla Cmnectinn of data Haenc xelund F' 158 lung c ncer patients evail- 339 patients i same hospital and service at Personal interviews by resident, medic_a_1 so- im_m. ahl fur ntervieww in 29 hos- same tIm next oldcr and next younger cial worker, or cl n c ec_r_e_tary. - 1968. Dpitals. than each case. U.S.A. (usl. LomLprdunJ M 60) m-n dying of lung cancer, 4,236 ca_ntrols in 7 groups including enlun- Pemu 1 interviewss by trained workers. SnegireR, microscopically confirmed. teees, hosVitsl end elinic patients, random 1959, populatiun s mple, and housrrto-hou9e ®ur- U.S.A. vey semples~ (1YS). Pernu, M-R 1,606 respiratory cancer patients 1.77.1 caneer-fr'ee persons recruited by Parish Cases: From ease hietories or meiled ques- 1960, in 4 ho.spitals and from cuncer Sisters of 2 institutes in all parta of the tinnnnires. Finland rrgistry. untrx. Gontrnls: guestionnair¢s dietrileuted by Par- (E1}), ish Sistecc. Haenszel M 2,191 sample of 10 percent of 31,516 random sample from Current Popu- Cases: 1fy mail from certifying Physicians et nl., white male lung cancer deaths laliun Survey, and family informants. 1962, in the U.S.A. in 1968. Conlr.ols: Persunal interview by census gnu- U.S.A. mernturs. (ltEl. Lan aster, 1962, Australia (i58). 238 hospital patlenta with lung 476 in 2 groups, 1 with other ee rr, 1 with Pereonal interviews o_f both oth cancer. ¢ome other disee.e, metched byea and tv-olsin hospitals. age. ases and con- Haenszeland F 749 sample of 10 percent of 34,339 random sample from Current Popula- Cases: By mail from certifying physicians aeu eq white emalelungcancerdeatha tion Snrvey used to estimate poDUlation and family infor_manta. 1964, in the U.S.A. in 1958 and base. Controls: Personal interview by census enu- U.S.A. 1959. merators. (115). OT6S9GE0

(146). KIItvU, S., KtinATSUNE,.M. Polycyclic aromatic hydrocarbons intheciga.- re6'te tarproduced byhuman smoking. Gann 57: 317-322„August.1966: (a47) Krv[mTS'os, K. P. Thepathologiceffects ofsmoking tobacco on.thetra- chea and bronchial mucosaL . American Journad: ofClinical. P2thology 33('4): 310-314y Apri11960: (148). KoexeN,. W., HocxeEttG, K. Untersuchugen~iiber den~Trypthophan-Stoff- wechscl beim Rlasen-Carcinom. (Studies about the tryptophan metah-olism in. the carcinoma of bladder.): Zeitschrift flir Krebsforschung 73 (B3) :. 251-D64,. January 29, 1970. (149)~ Kor[ri, P., FuK, H. L..Atmospheric factors.in pathogenesis of Pung.can- cer:.Advances in Cancer Research 7: 477-514.,,1963. {1b0) Koivx, P., FAitc„ H. L.. Polluted urban air and relatedenviironmentalfactorsin the.pathogenesis.of pulmonary.cancer. Diseases of the Chest 45,(3) : 28&-2q6, March 19644 Ils1); KocLUnaes, ]4. Smokingandpuhnonary carcihomn . Acta Radiolbgica. .39: 256-260;.1958.. r S.5U )KREflnovER, S.. J.. The effect of tabacco on. epithelial tissues of mice. Journal of the American Dental' Association 4'5(6)~: 528-540;.Novem- ber 1952. KaErae,xGi.L. Histolbgicaf. Lung Cancer.Types. A Morphological and Bio- logical' Cmroelhtiom Acta Pathologica et. Microbiologica Scandinavica (5lrpplementum 157).:'1962. 92.pp. ,,d 5;1 KaevnLxc,.L. AMiologyof Lung Cancer..A blorphological.PLpidemiologi- calland ExperimnntaL Analysis. Oslo,.liniversitetsforlaget, 1909. 99ppifir,1Ji KUHN, H., Tobacco: alkalbids and. theirr pyrolysisprodlictsin the smoke.. I.l"h Von Euler, U.S.. (Editor)s.Tobaeco A'Ikaloidsand Relatled Com-pounds. New.York,. NCacmillan, 1965.,pp..37-51. i!:: ~ KUnASSUxE, bl:, Koiaoxr, S.,,HOa[e, A. Carcinogeresis in the esophagus. I. Penetration of benzo(a)pyrene and other hydbocarbons'into:the esaphageal mucosa.,Gann 56g2) : 177-187„1965., ~,~-7; ) KitedaNTsa,.M~. The~J..Rurns~ AmBerson. Lecture. The causes.of lung.can- cei. American Review of R'espiratoryDiseases 98(4);: 573-590, Octo- ber 1968. i ! JS) LANCASTER, H: 0. Cancerr statistics in Australim . Part II. Respiratory s}-stem. 3Sedicai Jousnali of Aus¢i alia 1: 1'006-1011,.J'une 30, 1962. ~ f::0 LAss[rr, S., KUSCi[NEa,.M., D2um°,.R. T. Studies in pulmonaryy earcino- genesis IN : Hamia, 31. Ck., Jr.., t`''ettesheim; P., Gilbert, J..R. (Editors). Inhalatimr Caacinogenesis:, Proceedings of a Biology Division, Oak Ridge National Laboratory Conference, Gatlinburg;. Tennessee, Qeto- ber 8-11„1968. U.S.,At.omicEnergy Commission.Symposium Series.18, April 1970: pp. 321-35P. (ls°) IlAS.7QTZKa„ I. The effect of a,hydrocarhon-enriched fraction from ciga- irttee smoke an: mouse tracheas, grown ian iitro. British Journal of Cancer 22 (1) :105-109;. March 1968. (161) LACNyTZx[„Il The effect of a h}drocarbon-enriched fraotiomof cigarette ,moke condensate on human.fetal lung.gwwnin c;itro,,Cancer Research E8(3).:516-51'3,.9'Ikech 196&. i nc,) LEUraaznxx„ S. Cancers;, tabac, vin: et' alcool. (Cancers, tobacco, wine andlaScohoL)Cuncours Medical 1:,11'oP, 1109-1111, 1113-1114, 1955, (1+%--) Lec, A. \f., FRaUMava, J. F., Ju. Arsenie.and!respiratory cancer in man: An occupational study. Journal of the NationaC Cancer Institute 42 (6):: 1045-1052, June 1969. (1'44). hcltc[s1'uNnoRGER; C.,,hEUae7+EfliecersEk,.R: The roleof!influenzavirusin the development of malignant transformation in r;titro: and intlie res- 309 ~ ~ ~ Q7_ Q.R j

(194) MORGAN, J: G. Some observationson the incidence of respiratory eancer in nickel'workers: British Journal of7nduet'rial.Medicine.15:'.224-234, 1'9581 (195) :4IUHLnaoK„ O, Carcinogene Werking van Sigarettenrook bij, Muizen. (Carcinogenic action of cigarette smoke in mice). Nederlands Tij;l'sahrift voor Geneeskunde 99(31).: 2276-2278, July 30, 1955. (196) MULLER, F. H. Tabakmissbraueh and Lungencarcinom.. (Tohaceoo misuse and lung carcinoma). Zeitschrift fur Krebsforschung 49(1),:: 57-85, 1939.. (197) 1WiuNpZy N.,. CoRREA,. P., Racx, F. G. Comparative carcinogenic effect of t>vo.ty.pes of tobacco. Cancer 21(3)~.: 376-389, bI'arck 1968. (198). NASIEOL,M..The.EpitheliallPictureintheBronchiaib7ucosainChronic Ihflammatoryy and Neoplastic.Lung Disease.and'its ltelatfion to Smok- ing:.A comparati«ehistologjc and sputum-cytolbgic study. Stockholm, CytologyLaboratory, Department of Patholbgy at Sa6batsherg Hos- pital:,,Karolinska Institutet„ 11968. 72 pp. (;199) NELSoN,. N.. Ilnhalation carcinagenesis im man: Enriionmental and occu- pational ha¢ards. IN: Hanna, M. G., Jr., Nettesheim„P., Gilbert, J. R. (Editors)s Inhalation Carcinogenesis.. Proceedings of a Biology Divi- sion„ Oak Ridge. National. Laboratory Conference, Gatlinburg, Tennessee, October 8-111, 1969., U. S. Atomic Energy Commission Sy-mposium, Seaies 18, Apri1.1970! pp.,3-121 (2oa). NeTTESHEIns, P., HAwNA~ M. G., JE:,, DoxERe,Y, D: G:,. NESUELn,. R. F., HELLMAN, A. Effects of'ohronie exposure to.artificiallsmog..and chrom, ium oxidb dust.on the incidence oflung tumors in mice. IN: 1Hanna., M. G.,.Jr., Nettesheim, P.., Gillierty J.I;:.. (Editors). Inhalation Carcin- agenesis.. Proceedings ofaBiotogy Division, Oak Ridge National Laboratory Conference, Gatlinburg, Tennessee, October:8'-11, 19439. U.S. Atomic Energy.Commission Symposium Series No..18,.Apri1.197p! pp. 305-320. (20P). NEURArH:, G:.Zur Frage des Vorkommens von: N-Nitroso-Vcrbindungen im: Tabakrauch.. (Occurrencee of n-NCtrosoo compoundsin tobacco smoke.) Experienti¢ 231(I5): 400-404, 1967. (20Z) NEURATH, GL StiokstofBverbindtrngen des Tabak~rauches. (;Nitrogeun com- pounds in. tobacco smoke~.). Arzneimittel-Forschung 19~7) : 1093-1106, July 1969.. (203). OeHSNER, A., DE BAKEx, M. Primary.pullnnnary nlalignancy:.Treatment bytoial.pneumanectlomy,: Analysis.of 79collected cases and.presenta-tion of:7 personal cases. Sung¢ry,.Gyncaology, andl Obstetrics 681: 435:- 451,1939.. (204), ORnros„J., KAaAaSQxYay. G.,.BICi¢zx'ay. F., Shoxri, F. Lung cancerin the Hungarian plain. Neoplasma.16'(6) : 667-675,1969. (205). ORR,j.,vi'., Wp00HDI19E,.D..L., HAhIERy D.., MARCHAi\'T, J., HQN'ELL„J. .S.. Cigarette tbbacco,tars. Bti;tisH. Empire. Cancer. Campaign Annual Re- port 33: 238-239,.1955. (206)OTTO, H. Experimentelle. Untersuehungen an HaUsen mit passiver. Zigarettenrauchbcatmung_ (Experimental i'nvestigatimrs on mice through passive.inhalation.of'cigarette.smoke.) Erankfurtler Z'eitsclrr riff. fur P'athologj,e 73.: 1'0i2.3„ 1963: (207) PA'ILER,. ~:'L, HPBSCH, W. J1,.KUHLY, HL Iint!erslletrnng det' allphatlschen and aronratlisclicn prhuiiren und sekundaren Amine des Zigaretlten- rauehes mit.Hilfe derGaschromatograpliie und Massenspektrometric.. (Studyof the aliphatic and aromatic primarg=and secondary aminesofcigarettes smoke dyy gas chromamgraalhc and ntassspectrometry.). 312

~ TASLe. A4.-Crou_p characteristics in retrospective stvadies on lung cancer - and tobacco use (cont.) ~ = c SM-Sm ukers, NS-Nu nsmokers. Mnles ' Femalee Authoq Cnses Cantrols Cascs Controls - ycaq . -- - --. Ee3 tive - Relnti.ve Gommenta reterence Per ent Pernent r Perocnt Ps eent - l.sk perrent Percent Perrent Percent risk --- he -y- nl- hr by - tin - heavy +mrv heavy ratio Numhll nukrrs mukcrs` Number -- smukers sm_ okersr SM:NS= Numhc_rc m_ i~kers s smokers' Numher _ eu h kers hkers e smokersv gM:NS'. McUpnnell 98 5.4 38.6 186 6.5 23.2 1.2 ~- - 7 59.1 ... 14 78.6 ... 2.8 ct e1., - - 19$2(1g0). Doll and Hill, 1.357 0.5 26.1 1,357 4.5 43.4 9.4 10@ 27.0 11.1 108 64.6 0.9 2.1 Pereen[age 1952 (>s). . 'heavy" smnker underststed- Salowsky 477 3.9 ._ 615 13.'L .,, 8.9 (!) I'J N) (') (q (4) ,., ({rndient -- etnI.. - rrth amuu nt 3953 (z,e3). _ sm_ oked. Wynderand 6'd 4.1 - 67.6 183 20.6 29.3 '8.1 (tj (~) (+) (+) (+) (+) .-, CurnOeld, -- lus:f (314). ICUOlumies 812 0.6 68.9 300 18.0 25.0 ---- 36.0 ,.. ... ... (+) (+) (4) .., 1953 (151). Lickint 224 1.8 35.8 1,000 ~ 16.0 4.8 110.4 22 64.0 4.5 1,002 90.4 0.1 6E 1953 (12n), Flreeiow et el., 993 3.7 74.1 61A 10.A 42.7 3.2 ... ,,. ,,, 1964 (-0T). Watson nnd 265 1.9 71.7 287 9.7 61.6 1616 36 58.3 2.8 181 82.0 1.1 3.3 Conte, --- " 1954 (906). Gsell, 135 0.7 G8.1 135 16.0 14.0 s26.8 (q (+) (f) (q (+) (q ,,, ~ - 1954 (mz). eJ Y CtVss4eo

I TABLE A4. Group characteristics in re6rospective studie.s on Lung cancer and toLacco vse (cont.) SM = Sm nkers. NS - Nonsmoke rs. Mal® Females. Author, Ceasx Contxols Cases Controls year, Relative . Relative Comment; referenee Percent Percent Percent Fe cent -risk Pere.nt Percent Percent Percent risk Num- non- heavy - Le vy fe{t6 m heuvynon- heavy ratio her smokers amoker r Number m k rs mnk rs S4S:N5' N mber emok smukerO Number emakers smokets $M:NS' Wsken, 803 4.0 90.0 809 14.0 22.0 3.9 1$1 58.0 20.0 151 80.0 17.0 2.9 Heavy. smnkets- 1968 (308). . ¢reater than 23 s day. Gclfandetal., 32 6.3 ... 32 63.0 ... '26.3 (O (') (') 1968 (98). - Hitosugi, 124 6.6 67.8 1,839 13.2 66.0 2.6 61 69.1 6.6 2,362 80.5 2.9 2.8 Air.P Ilutioa 1966 (125). found tu have no e&ent pn lung cancer rates of non- smokers. Heavy mokcrs-great- er then 15 a day. Bradshaw and 45 0.0 ... 341 81.7 ... .., (O ... Sehoulend, 1960 (41). Ormos et el , 94 7.6 68.5 1.811 42.9 98.9 9.8 24 96.8 0.0 1.278 813~ 0.7 - 0.2 H eavv smokers- 1969(t04). _ ------- grcetcrthan 15 a day. Wynder et al., 210 1.4 67.5 420 21.0 40.9 s20.8 9_0 16.7 44.0 132 67.6 28,3 6.78 Heavy 1970 (584). - smoken- greater than 20 a day. +Far this ta ble, hea rv smokers are defined as those smoking 20 or more 'Based upun fewer than 5 case nonsmokers. ~ eigarettea P dcy, ilnlesa otherwlee etated. s lloee s n 9t apply. -- - -- y "Comvut.d according to method of Cornfield, 7. (61) . _ __ _ _ 9TV59LC0 t,.

(256): SHANTA„ V.,. KRISxNAn1URTIaI, S. Further sttrdies in etiology off car- cinomasofs theupper alimentary t1•act:. Acta; Unio. Ihiternationa]iscontra.Canerum 20: 586-594,I984. (257) SH.vERnIaN, S.., JR., GAnA'NTEy ML Oral. Cancer. University of California, San. Francisco Medical Center,. January 1970. 56 pp. (258) SPAIN, D! M.,, BRADESs, V. A., TARTER, $.,, NIATERO,. A. Metaplasia of bronchial epithelium.. Effect of age, sex, and smoking. Journal of'theAmerican Medical. A'ssociatiom 21l ($).: 1331-1334,. February 23„1970. (259). STASZEWSKI, J. Paleniea rak wargi,, jamy ust~nej, migdalkow i krtani: ('Tbbaeuo smoking andlitsrelation to cancer ofthe.mouth, tonsiLsand larynx.) Nowotnvory 10(2).: 121-132; 1960. (260): SeASZeW9xI,.J.. Palenie tytoniu~a rdk przelyku i zoladka orazchoroba wrzodbwa. (Smoking andd its relation to carcinoma.of the upper digest tibe tract (esophagus and stomach) and to peptic ulcer.) Polski T~godnik Lekarski 143 (1Fi):. 287r292;. Mag 4,. 1960. (261) STASZEwexI„J: Smoking andlcanoer of theurinaryHladder immales in Poland..BritSsh Journal of Cancer 20,(1) : a2-35, March 1966. (262). STEDMANS,R..L..The chemical composition of tobacco and tobacco smoke:.. Chemical Revieats'68IQ2) :. 158-207, April 1968., (26d)STa¢KS,. P. Cancer incidencein North Wales and Liverpool region in relationtlo habits andlenvirolnnenL British Empire.Caneer Campaign Annual Report 35. (Supplement to Part 2) : 66-95, 11957,. (Z84)STOCxe, P. Recent epidemiological studies of'f lung cancer mortality, cigarette smoking,and!air pollution,.with.discussion.of a newhypot'he-sis of causation. Britksh Journall of Cancer20.(14) : 595-623„ Necembe r 1966. (265)STocKS, P., CAnInRELL,. J. til. Lung cancer death rates among non- smokers and pipe and.cigarette smokers;.British 3Sedical Journal 2:, 923-929;.Octaber 15, 1955. (266) SIIGiURa„K.. Experimental productionn of carcinoma inimice with eigar-ette smoke tar. Ganm47'(2).t 243-244,.June 1956. (267) .CIUNDERMAN, F.. W., DONNELLY, A.. J. Studies of nickel carcinogenesis's metastasi¢ingpulmonary tumors in.rats'.induced by the inhalation,ofnickel carban}d. AmenicanJournal of Pathology 46(6): 1027-1041„ June.1965. (268) SCNDFIRbfAN, F.. W'.,, DONNEt:LY, A.. J., WEST, B., KINCAID, J. F. Nickel poisoning: 1'X.. Careinogenesis in rats exposed to nickel carbonyd. A.IhI.A..Archives'of Industrial Hea1tH.20(1):.3f-41„July 1959. (269) SUNDERMAN, F. WL, KINCAID, J. F., DONNEI:LY,.A. J\, WEST, B. Nickel poisoning. IV. Chr.onic.exposure of rats to.nickel earbonyl.,Areport after one year of observation. A,14I.A. Archivcs of IhtdustrialHealth16I(6) : 480-485, December 1057: (270) SUNDaRa:AN, F.. W., SUNDERMAN, P:W., JR.,Nickel poisoning. XI. Impli- catibn of nickel as a pulmonary carcinogen in tobacco smoke. Ameriuan. Journal.of Clinical Pathology 36.(3): 203-209i.15Sarch 1961. (271) SVosooa„ V. Ann analysis of some possihle'epidemiological faotorsin- volved imcarcinoma of the larynx. Neoplasma.15 ('6): 677-684, 1968.. (272) TAKANO, K., O80GOsHI, K., KAMITfURA, N., KANDA, K., KANE, K., KAM[YAMA, R'., SARA:VPOTO) K., Si1T0, H., SHIRAIk, Y.,,SF.I, ?,f., TANABE, T.,, HORINO,. M., b1rNAMI, Y., MOTOJIy. H.,, MORLTA, R., QRIHATA,. H., HIRAVAMA, T.,Shakudogan no ekigaku, toku ni atsui inshokubutsu, inshu, kitsuennarabi ni eiyo ketsuboni tsuite. (Epiddmiology of oan- cerr of the esophagus, withh particular reference tao thee effectt off hot 31'6'

3ABLE A3.-Q>etlitir,e of ntethodg tlsed in retrospcctive studies of srnvkinp in relation to hing cancer (con. 1 Author, -yeaq Sex of Number of peraons and method of seh•etion country, cases Coliectian of data refere-ce - Cases Controls - Randi¢. M__-F 448 lung cence patients in a 512 natiwts with other diagnnsce, matched Con[rl_ we.e intervienei at about the same 1054, nber of West Berlin hoapo- for ag . time as the casey, each c se-control pa_ir Germany tals. by the same phYSirian. - (218). Wynder et ai., 1966, U.S.A. (srr). Segi et al., M-F 1957, dasmn 1250). Mills and Porter, IJ57. U.S.A. (18>). 105 patients with long cancer in 1,301 natients at Memorial Center with tu- Cae Perxnnai interview or questionnaire several_ New Ynrk Qity hospi- mms of sites other than resnh'atory, or n ded w_ elose relativc.v or frieuda. tals. upner alinrentary. Controls: Personal interview. 207 patients with_ lung cancer in 5.fi:IG patients free of cancer o 420 local Cns nd controls b y neraonal interview 33 hospitals sa all parts of health cen[ers, selected to approximate inR lon¢ nves[innneire on uccupntionel the country. the »ex and age distributinne of cases. and medical history and living habits- 578 residents of deMed areas 3,310 pap i tion sample nnproximatelr pro- Cm s; From death certiflcntes, hospital xec- dying of respiratory caneer. pmaiunai to caaes as tegasds nreas of resi- nrde, and e]ose relatives or friends. denee, end 10 years mmore in the area. Cnntral.: Persunel home visits or telephone calls, usually interviewing housewife. 6tocka, M-F 2,366 patients aufferinR from ox 9,362 nneelceted patienta of the aame area Cnses: Histories taken at the hasyftal_ from 1957, dying with lung cancer within admitted for cu ~ nditions other th_en cancer. relativea by health .'sitom. England certain areae. -Conerels: Personal interview in hospital. /essl. - -- - Sc_hwertzend M 602 patienta with hronchopul- 1,204 patients i8 Rmnpe) in semc hosnitals Personal interviews in the hospital: css_en Denoiz, monary cancer in hospitals. with nther e _ with nonm.align_nnt ill- and controls at about the eame time by 1957• ness, end ¢cc_i_d_ent caees, matched by age the same interviewer. France grou4. (247).

Fachliche Mitteilungen der Oesterneichischen.Tabakregie No. 7: 109- 1118, Aprili 1967. i_'0s): PhPAS[coEAOU, G. N., KonxowcxA, P., Carcinoma-in.situa of'the righfilowert bronchus: A case report. Cancer 4(1):. 141-146, January 1951., 1209) :'. PassnY; R. D., Rbs, E. M. F., VImDneroxs F.C., BERGEL, F:, Et(ERErn„ J. L., LEwIS,. G. E., MARrIx,. S. B., Boynawn, E.,. Siats; P:. Cigarette smoking,and'.cancer:.British EmpireCancer Campaign'Annual Report. 92: 60-62,.1954: ('10). PEACOCIC;, R,. E., JIC:, GREErrsERG,.B. G., BRaWr.EY,.B'. 1£.. The effect ofsrmfF and tobacco an the production of oral cascinama:.2ln experimen.tal, and epidemiological study,.. Annals of Surgery151.(4) : 542-550, April 1960. ('11), PEamo,.di. An epidemialogical study on cancer of the digestive organs and respiratory system:. A study based on. 7,078 cases. Annales :4ledicinae Internae Fenniae 4'9(Supplement.33) :: 1960. 117 pp. (:,'13) POTTER, E. A,,,TCLLr, :4I. R:The statistical: approachto the cancer prob- ]sm im Massachusetts. American Journal of Public Hea1tHh and the Nation`s. Health 36:', 48.5-490, Mny 1945. (z1r1): PaoTZEi_, M., GIARmNa,,A. C., AceaNO,.E. H. The effect of liver i'mbal:- ance on thedevelopment of'oral tumors in:miue following the.applica: tlpn ofbenzpyrene or tobaccoo tar. Oral Surgery, Oral. Medicine andl Oral Pathology 18(5).:' 622-635;. November 1964. (_'.1, i: QoaaEIARIet.ca;. E„ TANcRF:m, F.,, FenEtE,.L., SAcCOHe, C..Ttyptophamnicotinic' aci'd ntetaholism: in patie,nta with tumours ofthef bladder: Changes in t'aie excretory products after treatment with nicotinamide and vitamin B, . British Journal of Cancet 19:367-372, 19611, 5)RAocoRO, E. P., JR:,.HVT1T, V. R. Polonium-210:A volatileradio-elemente inn cigaeettes. Shience 143:(360f1) : 247~249, January 17, 1964. (.11.8), RAnFaRn, F- P., HC52, V. R:, LITTLE, J. B~ Carcinogenicity of tobacco.imoke constituents. Seience16o(3890) : 312, July 118, 1969. 1 117i ItajEwsxz, B., STaHLr[oaE:c, W:. Polonium-2100 activity in.the lungs of ciganettee smokers. Ntttlure 209:(u03o4: 1.312-1313, March 26, 1966. i118) Rattn(G, li. Ilnter:uchungon zua- Atiologie des Bronehialkarzinoms., (Invrstigations on tlhe etiolog~~ of broncliiall carcinoma.) O'ffentifche: Gesundelicitsdien=_t 16(0): 305-343{.llecembar1954. ~2iD) REOnr, D_ GI, dncv>_I, V. C..Experimentlal production ofcancen'witHhnteI nut, tobacco mrzl slaked16me mixtlure. Journall of the Indiani JledScal. Asaociati'on 4'9:(7)~: 31r318, Octobcr 11, 1967. .l. f@EINGOin, 1. lI'.. QITOM;oN, R. E., KoxStiAUSx, B. E..Bronchogenic car- cinoma: A study of 60 necropsies. American Journal of' Cliniual Path- ology 20; 019-520,.19oO. r=1.) IBGnoN. R. H. l:tfect of tobacco condensate on re<piratorytract:of whitePekin ducks_ A.J11,. Arcbives of Pathology 69(1) : 55«63I. January 1960. !..'.c'2): l:one(ss, NC. '1':. Bronchial epithelh;umn in smoking and nonsmoking eol-lege, stttdents;, Journal of the Amenican College Health. Association 1] (4) : 26„266,. a2,rill 1966. 12ocI':(n-, 15. E., SPEeR, F. IL The.ill.effects of cigarette smoking in dogs. lntori~ational Suu'berc_'.46(6).: 520-53UI 1)eaember 1966. I RbCFF.Y„ E. E.,, SPRER, F I)., THOSiPSO\, S', A,,. AHN, 1{.,J., HIRosEj, T. E'xperintcsriall st'url}• on effect of' cigarettesmokr_ condensate on bron- chial nmco~a.. Journall of the American Medical Association 182 (11) :. 109a-1N7n8, December 15, 1962. 313'

TABLE A13.-TxPerintents concerning the effects of the skin painting or subputaneous injection of cigarette smoke condensate or its constituents gc)lon aninuais (cont.) Author, Animal A. Method, yenr, and B:- Frrerlueucy end/ country, atrNin or duration. reference - -- C. Mateiinl Druckrex. Rats A. Snhcutnncoue 1061, injection. GermanY B. 1/weck for 60 weeks. (ra). C. Smokecondensatein tnicnnrylin and alcohol. Bocketal., I_CR6wiss A. Pain.tingshavedskin._ 1962, mlce B. 10/week (or I year. U.S.A. C. Cigarette"tac". ISI1. ~~ Roe, Albinn mice A. Painting shaved skin. 1962, B. 3,'week tor 84 wrrks. U.S.A. C. \Yholesmoke"txr" (225). withaddedB(a)P enacetone. ResulLr Commente Group; Sacnamar }ControlgrouD. 1 C ....... ..........~...........,... 1/5 j ExVerimentalgraun. . i E .................. .............. . . 15/75 I 'FrcatmenL' 6arvivinp at 19 iaecke Perue.nt Porrent Shirt Skin cmmor nroDiasia Standard cigarette . ... 2i/N0 25.0 64.0 Standard ciBNrette .....,.,. ... 21-~:Sn SA 57.0 Standard cigarttte .......,. -.. 16/'f0 36.0 44.0 Standnrd cigarette ......... ... 13/39 23.0 62.0 Filter cigarette ............ ... 30/30 'i.n 2?.0 Fllter cigarette ............ ... 30/30 3.0 23.0 Acetone only .............. ... 66!66 COntrol ................... ... 65/65 Treatment: Srvrui.nora Percent akinturnore Author concluded "T.," and U.025 mg. B (a) P..... 26 12.0 thatci6a[ette n'£nr"nndO.Ofimg.BfalY ...... 15 "TSr"'and0.25mg.B(a1P ...... 15 °'Par"and125mg.B(a)P 14 27.0 smoke contains 13.0 cocar.cinogens. 64.0 B(a) P125m6. ~...... ..... ~~... IJ Druckrcy and Rats A. Subcutaneous Trratmmnt (RP nig,/eeeck): Snrronme Srhildbach, iniectiun. 30 .................................. 2G/20 1063, B. 1/week Sur 700 daye. 10 .................................. ~~~~~~ 14i40 Cr.manY C. Benzpyrene in R . ............................. ..... 8/50 (At). trieanrrlin. - (solvent) .................... 2/76

TARt.E Ai4. F.syer(tuents coruerolLnrt the effect of cigarette xu/uke or its constitnents ortn tiaslea and organ cultures (cont.) u a w Anthnr, yiear, d ntry. irrence T issuc or urgsn mdt.re alaterialfdeliverv Revulls Crocker, Vnr orzan AnNice[ionot S~usmous meteplasiu: (re4uent plcommybic cells: dediRerentistion of eP+thelium -- 1970, cultures: R!n)Pinsernm. (inhibited by Vitamin A) U_.S.__A_.(6P). a. Wholesnck- IinR hnmster b. trnrheas. Whulebron- chialtubes frnm late fetnidogs und monkexs. azKs14eo

., _ -_,.. ;:-49 e ;•.: m m N Author. year. cnuntry, reference Little et el., --1964,--il.5.el. (173). Hill, 1966, U.S.A. U%5). Little et nl., 1965, U.S.A. (1t(). fiABLE A12,-,Autopsy sttudres concerning the proso_n_ne nf rudiurnetivity in tlr.e lungs of smokers Number of cases NS ................ 6 SM .............. 12 NS ............... 6 SM .............. 4 NS ............... .. ... 8 SM ..............26 NS = Nunrmukerx. SM = Smokers. Results Com ents Pa! a/e4eLe Peilbrunchiu: - lymyhnodee 0.011 0.D11 in LnriayX Li9aite9 (PC/y t4sBne) Lung (nvernpa) 0.001-2 0.008 BroncAia! eLit/peNuln negligible 0.028-1.26 Vertebral bodies, renal cortex, apleen, and urinary bladder_ sho_we_d_ no diRerencee. Mem, Pa' d BraneLial[ree Alveolan -~- 3.1-~ 3.6 7.3 9.9 ls in_ v_ ve fiasnus (yclkg tissne) Totalianu Liver 3.21i.8 8.6 20.0 Kidney 15.0 20.6 The authors found no excessive concentratiens at bronchial bifurca- tions. PoPr levols in variua<a eroithediaE traaue reginua of 4ung (nc/g)t Site: - Mai t m bronchus . .._ ..............._.., ...,.,.,, <0.2-1.9 Leber bronchua ................................. <0.2- 1.0 Baeel seamental Lrunehus ............................... <0.2- 2.6 Upner segmental bifureution ........................... <0.6- 7.8 Lawer, seemental bifureation ........................... <0.5-18.9 The authors noted c siderabin internersonal variation but did find a trend relationship be- tween ineree_sed d_ai_ly consumptton and i - creased Pn=ro levels in lung parenehyma. No such relatienship was noted fur age of indi- vidual at death or for total uack-ycars. tSmukere only. gi6S94C0

TABLE A13.-Experiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon antinw.ls (cont.) 0 Author, Animal rear,and- couritry, etraih ,eerence Wynder et el., 1957,. U.S.A. ($Yx). A. Method, II. Frrquency and! - duration, C. Material Resutes Ccmmente Swi_ssmic A. B. Paintinxskin. Varied for 12 TccaLment: ' Namtrcx Perccnt paPi!lamaa Percent earcinn»tae mentha. 6/week ...................... 50 12.0 8.0 C. Wholecunden_sate 3/week ........~ ............. 50 3810 16.0 in ;cetune. ?/w.eek ...................... 40 10.0 3.0 1/week ...................... 40 6.0 Wynder and C__AFr or Wright. Swiss 1957, miee. ~ U.S.A. (J2d). Paris I miee Number 3o 40 30 30 Whole "tar" ................. 30 A. Painting shaved skin. B. 3/week for lifespan. O.. Who)e ~~tar'ar. nrfQtine free "tar" derival from pipe and cigarette tobacco. Nicotine free "tar" ,..,,...,,. Cigarette "tar' .............. PiPe " ~~ tar'. .................. (3ellhorn, 1958, U.SA. (95). Bock and Moore, 1959, U.S.A. (f8). 11 A. Painting shaved skin. B. Varied for 1-2 years. C. "T_ar" in acetane, benrPYrene, croton oil. Treatment CAFI: ~ Whole "ter" ................. Nicotine free "ta_r" ,..,.,,... Cigarette "tar" .............. Piee ".tar" ................... Treatmcnt Swiss: Percent Percent Swiss mice noted paviUama. carc_inomar tobemoresue- 53.0~27.0ceptible. 73.0 25.0 Majority of carcino-_ 30,0 30.0 sens noted to be 60.0 20.0 in neutrelfraction of condensate.53.0 10.0 43.0 20-0 63.0 33.0 63.0 60.0 Trcatment: PaPBlomae Cnrcinomae Benzyyrene (twice only) ............ 20/529 5/628 Croton oil (S/6 week) ............... 4/26 0/26 "Tar" (5/6 week) .................. 3/559 2/559 Acetone (G/6 week) ................ 0/30 0/30 "Tar" and eroton nil (6/6 week) .... 10/175 0/176 Swies female A, B. Painting skin. 5/week far litespan. Group: Number (ivinp at 8 months Pereent Skin tumors at 64 weeks . . . mice C. Wholecondensate Peinted ....................... 49 13.0 . .. irradiation. Painted andlrrad(ated......... 65 44.0 Irradiated ..................... 36 ...

TaBnQ A13. Ezperiment& concerning the effects of the shixtn painting er su6rutanoous ia}7ectionaf cigarette smoke condensate or its constitutnlts upon anitBals (cont.) Author, A. Methrzd - - - xeaq Animal D. Fne9uevcY end/ 1 eountry, sndurduaHon. ' ltesulja Comments reference strain C- Meterial Munoz et al., Swiss ICIt/ A. Painting shaved sk_in. 1968, 4a mice B. VarieJ. V-fi.A. C. "Tar"from dark and(Columbian) and Colombia light ([1.S.A.) (1a>). tnbacco9. Dark tobacca "Ear" At riek Tvmare Ca+cinomae_ Thc authors noted 4.0 nercent ..... ............ 81 60 17 8.0 nercent ................... 41 46 1 6 LiChttcBacca tar: _ _ _ 4.0 Percent ........ .......... . 95 26 6 8.0 Percent ................... 98 54 20 Aceto6e ................... 81 U 0 a shortenedlutent neriod fn_r d_ark tobacco. Devies end Albino A. Painting shaved skin. Day, mice D. Varied regimen. 1969, C. Cigerette snAGreat slgsr candensate. B_ritain (65). Percent of e_arcinoma_Leuring animnln at 118 vmnke The authors concluded TreuNncnt: (netna( number of animaG iu yarenthe.ne) that the lack of 89t1 mg. 150 ntU. 75.9. $7.5 mg. . 3tanderd cigarette ........ 20.1i291 13.2(19) 0.7 (1) ., Cigar ..................... .. 27.1(39) 11.1(1@) 2.1(3) Cigan tnbacco cigarette . . 13.9(10) - .. .. diRyrence in re- .-_ aul[a Ram the firet and_third groupe under treatment ~ - suggestathatthe Inc esed tnmri_ genfcity of cigar tobacco is due to phrsiesl proceseing factors.

S.[snrRUD, KI..Squsunousmetaplasia otithe respiratory tract epithelium: .kmautnp;y studyof'214 cases:2.,Rclation.to tobacco smoking, occupa. tiun, and residence. Acta.Pathologicaet.Microbioingica Scandinavica -1:11 1) : 47-61, 1958, I-' LI 1~I L. D.,, RAD, K.. C. y7., KatANaLxnR,. V. R,. Smaking, andl ehew,ing<~ftoLacco in relhtimi to cancer of tHe.upper alimentary tract. Britisliylcdical JournaL.1: 11111-11114, May7, 1955. S<I[_~a¢IxE,.E., ScHaBrroRR, IC..Lungenkrebsund.Tabakverbraueh. (Lungg raurrr and smoking.) Zeitschrift fur Krebsfot'schung 54?'.261,-269;.. I!),IM. .~IuLnGt:r..J. LS, Ptrxn&; G:,. BA:vows[cr, L Urine composition in.the ctiolo;y of bladder tumor f6rmation: Journall o£ Urology 97 ('3) :479-48.1..3larah 1967. _ I: n ScHU-EGrL, J. U., Pirx[rr, G..E., NisHtMURA,.R., DUHe, G: A. Studies in tha.etiology and prevention of bladder carcinoma. Journal of.Urol6gy. 1011(3),:,317-324'.,,SIarch1969. 1 ScH[EGSL,.J. U., PtFx[NS G. E,, SHHLTZ, G~. N. The aetiology of bladder tumours. Rritish.Journal ofVi:oiogy41(6).: 718-723, December 1969. R., RAl(ER;. L. A., RALLARD,. G. P., IUOLGOFF, .5".. Tobaccoo smnking,g a, :m etiologjc factor in diRease:.I'. Cancer.. Cancer Research 10: 49-58;1950. '4lnucaRTZ,.II.,,IDENb[x„F.-F. L'enquette.francaise suxl'etiologiedu can-rrr hroncho-pulmonaire. RoI'e du tabac. (French investigation on: the. ~.tiulogyof bronehopu.IMonary cancer:. Role oftobacco.). Semainee des; 1-Iolrilauz. de Paris'.33. (62/7) : 3630=3643, October 30, 1957. ~_ 1<I ~n[nVaaTz, D.. 11ENO[x„ P.-F., A.vcUean„ G.. Reeherche des locaSisaLions ~Icu uaneorr assaciees aux facteurs tabac et alcool chez l'homme. (Re-,taoch on the localizations of.cancer associates with~ tobacco ~and alco- liolic factors.in.man.) Bulletin d'e1:4ssocia6ion Francaise.pour 1'Etude dc Canceu 4'4:', 33C. 3611, 1957: _ 1 ScIM ~.aRTZ;.D.,,FLAMZNT,.R:, LEULOUCFI;.J.,,DENOex, F.-F. Restilts,of aFrenclt~ surveyy on: the role of tobacco, particul'arly,inhalation, in dSf- fnrAnt rancer.sites: Journal of the N'ational C'ancer.Institute.26 (5) : 1o83-L1fi8', 3Iay 1961. Searl )T., FlrtxusHlhPA, I., FoJISA1CH, S., KURtHARA).Ml, SAITO, S., As.4NO„ K.,, KAN[oi, M.. An epidemiological studv on~ cancer in Japan. Therepmrt of'the. Committeee for Epidemiological studyy on Cancer, Spon- 3m~ed by the Ministry of Welfare and Public Health. G`nmn 48 (Sup- plement);: .1'piri111957. 63 pp. I_'.71 J SLLIKOFF;.I. ,7.. BADRR, R. A.,. BADER;. M., E., CHURc, J{„HAMMOND, IC.C. .Ashestosisand.neoplasia:._9merican Journal of Medicine 42(4): 487- 496, ApriL1967: (_.%' ) SeLUxarF, 1. J.,. H_aarnrOnn,. E.. C., CkURc,.J. Asbestos exposure, smoking, and neoplasia. Journal of the?:merican Medical Association 204(2) : 106-112, Aprili8,1968.. 1 -'~%) SERSO1TtIIN;,W'.J.,.HUR'LER, P. Nitrosaminesas environmentaLcarcino- gens. IC.. Evirlencefbr the presence of nitiosamines in tobacco smoke oondensate: CancerItesearch26(4, Part 1):; 57a-579;,April 1966. (.1J4) SRRCONTtrn„ W: .J., SMIT, JL H.. EvSdencefor the occurrence of N-nitros- amines in tobacco. Nature 214(5984) :, I69-1170,. April 8, 1967. 1;15) SHAxTn, V.,. K~RrsHNUy'MuxTicr„ S. Further studies in aetiology of car- cinomas of the. upperr alimentaryy tract. British Journal of' Cancer I7 ( 1):: 8-23, March 1963. 315 [3

(302) Waa[„ P. N.,. KEHAR, U., LAH>'Ri;. B. Factors inflhencing oral andd oro- phanyngeal.cancers in India. BritishcJournal of Cancer19.(4): 642- 660, December196S. (J0J), WAINGROW', S, M.,,PBoRN,..D:, I1cARn, F:.F. Dosage patterns of cigarette smoking in .3merican adults. American Journall of. Public Health.and theNatiun's. Health 58(1),:54-70, January 1968. t8n4) WASSIrrK„ W., F. Ontstaansvoorwaarden voor longkanker. (Conditionss forche.originr ofIhng eancer.). Nederlands Tljdschriftvoor Genees- kunde 92 (46) : 3732-3747„ November13, 19181 (13u.;) WAxsoN, W. L., CaNreE,. A. J.. Smokingg and.lung caneer. Cancer 7(2) r. 24.5-249, March 1954. (1arra) iS'Ern, J.. M., DtxN, J.. EI, JR. S'moking and mortality: A prospeotive. study-. Cancer 25:(1): 105-112, January 1970. I:.lug) WEr5NURGER, J:. H., WF.I6BUR0FiR,. E.. K. Tests for chemical carcinogens. IN: Busch,. H. (Editor).. Methods im Cancer Research. New lork,. Academic Press, 1967, pp. 307-398. i.7,,•I WICRES,.A.,J..EnvironmentaLandPersonalFactarsin.LungCancerand. Bronchitis Mbrtalitty im Northern Irelandi,.1960-62'. London„ Tobacco Research Council, Researcln Paper No. 9, 1966. 84 pp. i J'0 l CVD.rtAMF, M. J. Extensive carcinoma-in-situ inn the Uronehiall mucosaassociated with two.invasive bronehog¢nic carcinomas. Reportt of case. Cancer 5(',4) :: 740-747,July 1952. r._7Pr1 WrNne;R, E. L.,. BRaae, I.. J. A study of etiological factorsin cancer of :i]eeso0liagus. Cancer14(I2)~: 389-413, Maoch-ApriC 1961. Idad,) WSSnra, E. L.,,BROS3, I. J., CbRNFIEID, J., Q"DOrvNEiB,. W, E. Lung.can- cerg in ~~omem A study of environmental factor.s. New England Jour- nal of libdicine 255(24): 1'111-1121,.DecemberL3, 1956. ~f_ i S\:I susR„E..L., Bxosa, I. J., DAy, E. A study of environmental factors in. 1':)ncrr of the larynx, Cancer 9(L)::86.110, January-February 1956. yI"YsneR„E. L., Bxocs, I. J. FELDMAN, R. 31. A study,of the etiologieal factors in cancer of:the.mouth. Cancer 10(6): 1300-1323„November-~osatnhrt' 1957 . WrsoUR„E. I;,, CoaNFIErD, J:. Cancer of the lung in physicians. New clneland Jiournal.of Medcinc.248(S1).::441-44'4',. March 12, 1953. WvsoeR„ E. L., Don0, IT., BLacli, D. A., GANn,. R., C., R'SOORE, 0. , S. I•:pirlcrniulugicinrestigadlion of multiple primary cancer of the upper alimnntary and respiratory tracts. Cancer 24(4):: 730-7391. October 1969. (.116) «'rsUDlt, E. L,,,GRAxAM4 E. A. Tobacco smoking as a.possible etiologic factor iix bronchiogenic carcinoma. A study of six hundred and eighty- fourproved cases. Journal of the American Medical As-sociati;on 143 /-1) :. 339~:3:56',. blag27;1950,. 13t2) WrNot:¢. E..L.,.GRAaaM, E. A.,.CRONINGER, A. B..Experimental.produc- tiun of carcinoma with.cigarette tar: CancerResearch.13: 855-864, 1DJ7I (J':J91 WYNDER. E. L:,,GRAIIAh]{ E. A,,,CRONINBER, A. B..Experimental.produc- tiun of carcinoma with cigarette tar. II. Testl with different mouse -tcain=. Cancer Resrareh 15::445-448, 1955. (3J0) IVTNDFx, 7j. L., IIIOFFMA'NN, D. Tobacco and Tobacco:Smoke: Studies in Esperimental. Carcihtngenesis! New York;, Academic Press, 1967, 730 pp. (J2o) 1F'v.Noea, E.. L., HoIrrMAwN„ ll1, h7k,perimental tobacco carcinogenesis. Science 162 (3856),:: 862-87d„November 22, . 1968. 319 ta'.)'

9M,S94E0 TARbs A19: F.x7lerlmenEs concerning tfle effect o Author, yea t y, refrrence Tiasne nr nrRnn-CUl[urc Matcrinl/dqlivery, gn tssae and organ cultures Results Pouchsrd Mousclung. Tobaccurmukecon_densate Increased t ber of mitotic abnormalities in the treated cultures; particularly in and May, Derfusiou fur 24 hours thefir;t 6um10 daya after grafting. 1960, sndsubsequent France Is57, grafting under renal cepsule uf mir.e. Awa et al., Human fetal lung. Direct exnnsure to 1961, smoke from: JePwn (16). a. Wholrefaareller- h. Tobacco alane. c. Paper alone. Thayerand Kllmammalian . Keneler, tumorcellrr 1964, U.S.A. (275). Herwaldand SWRmiceend Sachs, golden hamster 1966. embryea. Israel (np), Paper smoke induced the muyt seecre chen:-es, consisting of cytaplasmic vee.t- .... olizatipn and npelear Nyhmeris. A1so noted wr s desrease in the mitotie index and a ne e in abnormal divisions, more so with naper.emoke than wit_h_ the othertwo 5 Cigarettesmoke ndensateapplicxe tion: flltsred_end unfiltered cigare(tea. Significant growth inhibition was shown in unfiltered smoke. Cytotazie compo- nents were noted in both the gas and particulate nhnses. Direct application of Henao(a)nyrene c sed increased cell transformatlon as manifested by: beew(a)nyren_e a. Hereditary random erowth pattern. [R(a)PI. b, c. Progressive grnwth aa tumors after.subeutaneuus injeetion Into adults. Ability to grnw rontinuuusly in culture. Crocker at al.. Suckling rat Application of Treated cultures eealed cellNar metaplasia, basal cell hyperplasie, increaeed 1965, trachrain R(a)Pinncetone. mitotic rate, and ierea v srd It'-thymidine inso.ryoretfnn pmnnrtional to the eon- U.S.A. (CS). nrgan culture. ntra[inn of material L. ial and duration of application. Diamond, Var s o Application of Inhibition of cell growth. 196, tinu "uscell R(a) P in either U.S.A. (68). etreins dimethylsulfuxide Imammlian). (I]M50) or pnrathn. Ite smoke uz its constituents on

r } y tzVss4eo TABLE A13.-F•xperiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon aninutEs (sont.) Author, Animsl A. MethoA, year,end B. Rrenueucy and/ udTry, atrain or duratian, reference C. Material wYnder at aJ., 1955, U.S.A. (318). Mice of 4 A. Painting shaved ekin. se_carate U. 3lueekfur80daysk strains.- C. Whole condensate ,o aecinne. Hamerand Outbred A. Paintinsunshsved Woodhouse, nlbino skin. 1966, strain B. Vaded for 18 months. U.S.A. mu.e. C. Whole"taryacetone, (nffl. benapyrene [B(a)P7, croton oil. Sugiure, $ockland A. Painting unahaved 1956, Swiss U.S.A. albina (266). mice(60). Graham Albino New at al.. Zealand 1957, rebbits. U.SA. (I01). Guerinand Mice Cuzin. ( Pasteur 1967, strain.) U.S.A. (109). Reaults Strain PaPi((omaa C5RBL ....... .................... 10/89 &wisa ................................. 22/86 a Comments Carcinomas No tumors noted with 2/89 nceiunc alone. 12/86 Stresses differencea in y sceptibility of stram. Tqcatm,ot PapiUOmaa ••Ter" 2/week ....................... 1/50 •"Car" am_1 rratnn uii 1/week. ........ 2/30 B( n) P 3 times then "Yar" 2/week 4/30 B(a) F 3 timey ....................... 0/30 Pnp(Aomas Carcinemaa B. C. skin. 3/week for 2 yeare. Whule"tad'. 16/44 12/44 A. Painting eheved skin. TreatmmiE: B. 3/week for f yeera. Cundensate .......................... C. WholeconJcnsate. Condenate and cmton uil 1/wenk. Croton uit and aretnne 1/week. Aeetune 1/week ..................... (only 44/60 lived from 365-596 days). PapiRomae Cureinnmaa The authors ce.v(e.w 41/41 5/41 previoue experimcnte 10/10 2/10_ with rabbits in 0/3 0/3 taCularform. 0/7 0/7 A. Paintingaeckskin. B. 2/week for >1 year. Oripina1 r..mber Survinnrs iC. 112 ...................... 51 Pap+tlomae 0/51 Sarcomaz 0F§1 t Control8roup- F ExPeeimentalgroup. C. Whole condensate. IE.672 ......... .......... 220 10/220 5/220

foad and drink, drinking, smoking, and nutt-itional.dbficiencies.) Nip-pon.RSnsho 26(8):.1823-1828, August1968'. (2Y7) TaRJAN, R., KEdrENr, T: Multigeneration studies on DDT'ih mice. Food and Cosmetic Toxioolbgy 7:. 215-222,.1969.. (274) TERRACOL, J., CALVET, Jl, MAR@cES, P., CoLI:, J.. Le tabac et Ies cancer du larynx. (Tobacco and cancer of' the larynx.) Vie Medicale. 4'8:. 1149-11G0., August 1967., (225) THamI:R, P. S.,.KENSLER;.C. J.. Cigarette smoke: Charcoal filters reducecomponents that inhibit growth of cultured humam oells;, Scienee1I46 (:3644 ): 642-644,. Octobe r 30, . 1964. (87H) THORARINKSOK,. H.,, H,ILLCRI6ISSON,. J,,, BJARNASON, 0., PETERSENy. G. Carcinoma of the lungin Iceland. I)i'seases'of the Chest 52(6) : 754- 759i December 1967. (277) TlwrON, ID~ L.,.CROCRER,T. T. Duration of bronchial squamous meta- plasia produced in dog¢by cigaretle.smoBecondensate. Journal of the Nationall Cancer Institute 3&.(3) :.487-495,. September 1964. (2?s) TYLFCOTE;.F. F:..Caneer. of the lung. ILancet 2: 256-257, July 30, 1927.. (27ey ti.nHxER, W., STORES, C-. Rronchogeniec careinoma-in-situ. Report of'f a. case with positive biopsy', cytolbgical examination,., and lobectomy. Cancer 5.(2),: 369-374,.March 1952. (280) U'.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELBARE. Report ofl the Secretary's Commissionn on Pesticides and TheirReiationship. to EnvirmmlentaS HealtN. Washington, U.S. Depantment of Health, Edu- cation, and Welfare, December 1969. 677 pp. (981) [J15. PbBLIC HEALTH. SERVICE. NATIONAL (:EN-TERI FORHEALTH'. STATIS- TICS! Changess in cigarette smoking habits between. 1955 and 1966. Waahingt'on, U..SI Departnlentt of Health, Education, and Welfare. Vital and Health Statistics Series 10„Number 59', Public Health Serr i ce. Publication. No. 1000;. A p ril 1970. 383 p[I.. (38'2) U.S. PCBLICI HRALTH SIIRPICE. NaTIONAL CENTER. FOR' HEALTH STATIS- TICS. BTortalitly;fi•om diseases assaciat'ed with smoking: United States, 1950-6-1, Washingtlon, U.S'. Department of Health, Education, and Welfare, Vitall and; Hualth. Skatistics'Series 20,. No. 4, Public. Health Service Puhlication No. 1000, Octlobcr. 1966. 45 pp. (:.A7) U.S. PIIBLIC HEALTH SERFHCE.. NATIONAL CENTER FORHEALTH STATIS- TICa.. VitaL.Statistics of the United States-1961. Vol. IT-Murtality, Part A. Washington, S7.S. Uepantmentrnf Health,.Education, and Wel- fare„Public HnaltH. Service Publication,.1964. (284) U.S. P1IBLIC HEALTH5'F.RVICE. NATIONAL CENTF.R~ FORHEALTH. STATIB- TICS. VitaiStatlistics of'the Unitad States: 1962. Vol. 11-Mortality, Part A. Washington, U.Si Departmentof IHealth,Education, and Wel- fare,.Public Healtlh. Service Publication, 1964. (285) U.S. PUBLIC HEALTHi SERVICE. NATIONAL CENTER FOR HEALTHi STATIB- TICS. Vital Statist'ics of the United States-1963. Vbl. II-3{ortality, Part A. VSlashulgton, li.S, Department of IHealth,.lidhcation, and Wel- fare, Public Health. Sels.ice PubLicatian, 1965. (288) U.S. PitI3LIC HCALTIB SERVICE. NATIONf4C. CENTERi FOR. IIEALTHSTATIS- IICS, Vital Statist'ics of the United States-1964. V'ol. II-Mortality, Part A. Washington, U:SL I lepartment of Health, EdVxcation, and Wc1- fare; Publi'c Health Sem'ice Pubticationy 1966. (28.7) [1..5. PUnLIC. HF]ALTH. SERVICE.. V ATIONuIL CENTERFOR'. HEALTH. STATIS- TICa: Vital Statistics of.the United States-1965. Vol. D1-Mortality, 317

TABLE A13: Experiments concerning the effects of the skin painting or subcutameo2[s injection of cigarette smoke condensate or its constituents upon, nniuutls (ewtt.) l Authur, A. Method. ycur, - Anfmal H.Ccequency und/ try, and or duration. PEmerence strsin C. Material .. Besuib Comments Homhurger et ul., CAFt mir.e A. B. Painting eheved skin. 2-@/week for 2 year.r. F.oudnna_aEe: ~ Com,tete avtoystca Pereeryt Ppyptomae I'UrcenE Carcinomae -- ~~ 1998, U.S.A. C. Various tobacco candensutcv in Pipe tubaccu Cigar tabacca ......... ................ 77 84 as.u 27.5 1s.o 16.0 (I51), acetone. Cigarette tobacco ............. 82 27.0 15.0 Denzpyrenr .................. 54 10.0 20.0 Acetone nn_Ir ...••~••......... 02 ... ... Bock et al., 1965, U.S.A. Swiss ICR A. mice B. C. Painting clipped ekin. 10/week for 11 weeks. Varinussmoke Bercentconcentrwtion oftar (tyDecigarette)r PnrnnLt F/!*ninin9 tAen~nka Perccnt rauer Pezcent rnncer aud payIIlomo (29). condensntesin 9.2 (stsndnrJ) ............... 96.0 20.0 6'1-0 _ . leetnne. A.s (standard) .............:. 93.0 27.0 67.0 7.9 (flnglishstandard) .....,.. 90.0 24.0 58.0 N.9 (kinB) .......... ~~. . ~. ~. . 100.0 28.0 69.0 4.0 (filter) ................... 95.0 9.0 26.0 4.4 trlter) ................... 100.0 10.0 41.0 2.5 (filter) ...................9P.0 4.0 16.0 Acetone control .............. ... . . ............... 94.9 .... ... ... Untreated control ...... ...... . 100.0 ... ... Y a Van Duuren Swiea ICR/ A. Painting ehaved skin. et nl., Ha miae B. Initiating agent once- 196G, Pmmnter 3/.eeek fgr ll 4.A. 12-14 months. (296). C. DMBAt, tobaeco trartv cign- rette "tar". Cnmulutivennm6a_zalmiuewit6 t7,12-dimethyl- Initiator Promntcr PaVillnmas Carcinomaa bena(s)anthracene. DMBA ...ti;thrr tobacco leet extraet .............. 4/20 0/20 O........ Fkher tobsccoleaf extraet .............. 0/20 0/20 DMNA ,,.Chnloroformtobaccolcufcxtract ......., 1/20 0/20 O........ Chaloroform t b cco Irafext:net ....,.. 0[20 0/20 DMBA ...Cigarette "tar" ....................... 11/20 4/20 O ........Cigar'ette ••tar:' . ....................... 0/20 0/20 U _..,.... Acetone .............................. 0/20 0/20

-T-ABI.e A15. Ex7tltrznteqats cotiserning tke effect, of the instillation or implantation of cigarette smoke or its constituents into the tracJeookr-0netiial tree of animals Author, A. Method year, Animsl B. Freauener and/ untry, eild-- ordnratinn Ae.uhs refrrence sGain C. Materiul Bincklnc__k, CR white 1957. rats. (!reat Britain tg4) A. inirction into Innc parenchyma by thm~acqtnmy. B. Once. CL a,4-henzpyrenp olivenil, with dead Tb bzcilli nx in cholesterol, riRarettc "tar". qella P-orta Syrian solden A. Direct tracheal rr al. - ha~.+:.eers, in l9lnatinn. ]958, H. Weeklyulxtu U.S.A. 45 weeks. (6>). C. 1 Um,eent 5,12-dime- . thylberrs.(n) nnthr®- cene (l)MDAI, ¢Rare-ttr ^tnr" cm"entrnte, 1,4-hunapyrene: n. 8 mR. in ulive oil b. ,1 ma. in nlivr oil wlth dead Tb bncilli c. 5.75 me. in e.hnlesterol nellet Cigarette Ynr": ' a. In nlive nil L. In olivr. nil with dead Th bacilli Numbpr witA tv.wrs/numbez ezpoeed 5/6 sarcmm.. 2/4 sarcoma, 4/8 eauemous cell carcinoma. 1 /P .m~umone cell careinnma, 0/ln. 1/R anrcoma, 1/A enuamoue ceB eattinnma. Controlz: a. O.lfi cc. nlive oil b. 0.1x cc. alive oil with dead Tb bacilli r. Ohnlrstm.ol pelless 0/d- 0/4. 0/4. nterinb INeeks n.DMHAG0~c./wcek ,.,... 4& Srzrvivore at 2l/ viceks/origuml num6er cxpoeed 10/20 NumBer of ha.maters wiUh truchco6ronchiat . careinomne at dcath 9 h. "Tnr" 200 µg./week 32 11/21 c. DMISA 50 tyR./werk ... ,.. 12 9/20 d. then "bu"200, pr./.erek . .:t0 DMIiA 100 pR.Lweek ... lA ?/20 4 e. DMHA 100 aR./wmk ~ and 'Snr" 500 l 20 9/20 µR./w2Ck ..............1 Higdon, 1.960. ILS.A. WhitaPekin ducke. Cantrds: 99 A. Intratracheal inieNinn. B. Daily for 721 days. No nennlastie changes noted in either the exncrimental nr tvmtrol grauna. - -- 4=a11. Expnrimental C. Tabacen emidenvate Rrouh: 52 tn liauid netrulatum. 3l!Sn-. ..~.

TABLE A24.-Number and percent distribution, by highest number of cell rows in the basal layer of the trlte vocal cord, of men classified by smoking category Current cigarette emokere A'ever xmoked Ex-clgaretce Gigarlpipe Les than 1 1-2 Dacks 2 or9 eore rcgulariy emukere smokcrs pack e day a day pack .day Num- 6er Per- emv Num ber Per- cent _Num- 6er Per- cent Nam- her Pgr- eent Numv- ber Per. cent Nx+n- ber Perv cent f' Totel ...................... .. SN 100.0 116 100.0 94 100.0 125 1000 329 /00.0 190 100.0 Le.c than 5 cell rnws ........... ... 30 34.1 7 6.0 4 4.8 3 2.4 1 0.8 0 ... 10 5 .......... ....... 5 cellroms ............ ... 29 33.0 27 23.3 20 21.9 27 21.6 38 11.6 20 . 12 . 6 cellrews ...........- ... E 9.1 15 12.9 15 6.0 25 20.0 51 16.4 24 .6 i cell rows ....................... ... 6 6.8 12 10.3 18 19.1 12 9.6 88 11.6 19 CO.U 6cellrows ........................ ..... 8 9.1 1 , 12.1 9 9.6 1_8 10.4 4 11 30 26 9.1 7 9 23 14 12.1 4 7 9 cellrows 1 1.1 7 6.0 7 7.4 6 . . . 10urmarecellrows ...... ...~.... .. ~ 6 6.8 84 29.4 21 22.3 89 31.2 146 44.1 9U 47.4 Saurce: Auerbarh, 0. et al. f91. \ Number of cell raws CV6S94LC0

TABLE A34, h'xporineents concerning the effect of cigarette smoke or its constituents on tissue and organ cultures (cont.) Author. Tissue or urRan Culture Material/delivery Result. lfurenf ruund et al., Hamster lun4 Applicationof a. Increased appearnnse of n smell chromosomes and telecenlria chromosomes. 1966, tissue. D(a)Yincither b Increa.sed ability to ¢eoa in hemster cheek p ouch and there become epindle- U.S.A_ (s'8). DM50ordimethyl- eell snrcomaa. _ - - fmmamide. ' Ou macd, Chicken embrya 1966, muscular Frnn e (1yni, ezplants. Lasnitzki, Miceneonotal 1UGN, $nrland U60i.. trnches. L_ uso itskt', Ifumen fetallung InLA, in organ culture. Englend Uct). Chon et e_I.,_ Mnuse lunx Itlb9, budembryonic U.S.A. (54). cuitures. Lguchtenberger -- \lnuseltmg nntl and kidney Leuchtenberger, ti.a.ue and 19G9, nvgan cultures. swRzerland (165). Application of Incressed mitotic xetivity and incre_ased incidence of annmalous mituse®. tpbaccu extract. Applicxtinnofahy. a. Inc eased hnsel cell hy.perplasia and pleomorphism of newly formed celie, drocarhon-enriched b. Inereased epithelial mitosis. fractinnofwhule -~ smnkc condensnte. Application of a hy- a. Ccllular enlargement and prumotion n( growth of new bronehi. drnrarban-enriched b. Increased mitoaes, bronchlel epithelial hyp_erplusla, snd spusmous_ metaplasl traction of whole e. Inhibition n€_ atromol BrewtL. -- - ~smk¢ candensnte. Application of a. Cellular disorganizetinn. II(a) P in llMSO. b. Cellular pyknosis; nu<lear shnpe and size irregulariWea. c. Increased epit_helial mitotic rate and decreased mene1 nehymel mitntlc rate in those cultures expnsed to if(a)Y veraus those expmM to pyrene or DMSO. Exposure to fresh smok¢: a. IInfiltered. a. Decreased RNA production, pyknosis, and death of cells. b. Activated b. Similar resu$e, hut rhwlges were of minimal severitr. ---eharcoalfilter. ----~---c. Cigarette or c. Similur edects as group a., but less severe. cigartntrscco.

TARLe A15, E;cpe2•intents concerning the effect of the instillation or implantation of cipurettu sntake oe' its eonstitttents into the b'ackenhronc&iat t2'ee of ani?nalta (cont.) Author. year, Animal_ country, and referencc sGilfn Sa/Rotti et el., Sxrian g0lden fDGG, hnmstms. U.S.A. (C9^). SstHotti et a_ 1_., _Sy.rian golden 1969, hnmsters. U.S.A. (P95). Boriavuk, Wistsr rats. 1969, xnr m (9.) A. Method _B. FrEYUeney nntl( or durption C. Materin] A. lntratracheal ulnti0n. R Weekly for 15 weeks. ©.I3(a) L(3mg.) ~atLaehed to fine hematite dnst. A. 48ire mesh nellet mplEntation into Dwnehus. B. Lifetime. C. B(a)1°, methrlchnls_n- thvene (MOA). A. Intratracheal ulntion. B. Weekly fqr 15 eks. C. a(a)Pattac_h_e_d to e fine hemetite dust. A. lntratracheal ivtubeLion. B. Munthly uu to 10 months. C. Cigerelte "ter". Numb rautnpsied: Male .....,.....' -.. 23 Female ....... . ..... 17 Resultn Pereent tnmor- Y r_fcrof bc:ingof tl io 1n i g eu.vianraat ~ala ]s_v'ecka a~15 100.0 I1 100.0 Numhe- of e ~ore/nripinal f mplant: n ptmb er in Oraup Wirr mesh only ..... ...... ~ .............. 34/36._.. MCA ..................................... BRL91 B(a)1' ................................... X9/91 Total Tota! num8er nu mbcr of reapfratory of dtmore lraccnnncePa 24 18 17 1s Inoeulate: Cnntrul .................................. 176 Number of au.imnla Irith hnlo caacr.r 43 57 NamAer of rynnzst/os u~k& rcnpirntory vnet tuntora it(a)Pinhematite ........................ 55 35 Hematitc onlr .. ..... . _ .. .. .. ........ .. .. 41 - Nnmber funf/ Du+nt.ion of niC f r+amdcAimr Inoculate: (+nmi0~n) Controls .................................. 11/20 12 Unfractianated 'Ynr" ..................... 24/200 10 Renicotinized "tar" ..... .................. 9/45 9 (I/9 met@plusia) Neulral "tar" trectian ................... 14/100 k(2/14 carrinnma_s, ---~ ~~ -1/14panillnrYedenome). ' Thiss graup also r ived one inlection of urethane intraneritoneallr.

/.a4 Y S94E0 TABLE A21-Olttli7te of reitrospect7ve shtrl_iea of 6ottncc Authnr, yeu. ntI y. referetfee Sax Numbvr Gsaes Method of selection Nnmhre Schrck ct ai.. M. 73 Referrnls from V.A. hospitals in 'entire 522 1950...__ _ . ~ midwesP to V A Can C t r, Hines, U.S.A. (G40). Illinssi., danng 19i12 44 1 lcnts with larynx-phnrynx tumore clinically or his- Winglually diagnoeed: ~ Pc+ccvte Nonsmokers ................ 13.7 Cigarettes ...... ........... 79.5 Cigars ....................~.~. 3.7 Fi.pes ....................... 6.8 Vslka, M-F 226 Clinic patients with cancer of the 7arynx: 109 "___ .._.. . _ 1952. Czechoslovekia Yerrrnt (292). Nonsmokers ._ ............. 75 ~~ Cigarettes .................. 83.2 Cigarv ...................... 4.4 Pipes ....................... 10.6 Sadowskyetal„ _M_._ 298 White male admissions to hospitals in 1959, New Yo k G ts, 4lissonri, New Orleans, U.S.A. (x9x). Chicago: patlente with dia_g_no_sed Inryn- gea) tumnrs, 1938-43: ~ ~ . . ..-- .... I'err.cnt Nunsmnkers ................ 4.0 ClRarettes only .............. 60.1 Cigars only .............. ... 2.2 Pipeonly ................... 4.8 Snme comhinetion .... , ...... 28.9 615 se and cancer of tlce larynx Controls Method of selection Ycu . set of referrals, patients with tumory other than Ilp, lung. lar- ynx-phnr'ynx: Psrcent Nonsmokers ........ ...... .. 23,9 Cigarettes .................. 69.2 Cigare ..................... 10.0 Pipes ...................... 11.5 Clinic patients of same age group with other dingnnses: Percent Nonsmokers ................ 22.2 From s set of edmisaipns, patientss th Illnesses other than cancer. Percent Nnnsmokers ................ 13.2 (',igarettes unly ............. 53.3 Cigars only ................. 3.4 Pipe only ................... 7.0 Some comhinatinn ........ . . 23.1 Colleetion of data Random eample of 6,003 admirslons: qnestinm nnires trom Hings re- ferrals fur 1942-44: . urdsincluded smoking history. Medical history and uues- tionnaire in alinic. Sample of 2,605 out of 2847 interv{ews (in- cluding smoking hie- tucy) by trained lay interviewers.

TARLb: A16.-Expcrilaents concerning the effect of the inhalation of cigarette s7nok•e nr its eonsl;t,l;'rls opae the respiratory tract of animals (cont.) (Figures in Vs*"r!1+"' represent total number survivm's in apccific group) Author, yeaq country, reference Animal end etrain A. R. C. Type of exposure puration Material Reeults Cummeuts ~. Leuchtenberger Female CFl mice: A. Chsmber. . Number with ~ et. al., C. 243. cigerxttes eeucrc hronchitie; 1960, E. 360. per dsy for I Expoau+a peribronchitis; V.S.A. (167). month to 2 yeera. Number Num6cr of (en44h atypjra! epithe- C. Cigarette amnke. oftn ciaarettca (wmntha) liatproli)erntion 151 ...... 25-1,626 1-23 30 150 0 0 2 36 .. 100- 200 1- 3 7 35 ...... 250- 500 6- 8 7 34 ...... 600-1,600 9-20 8 51 100- 400 3- 6 4 63 ...... 100- 400 8- 6 17 Leuchtenberger Femele CFl mice: A. Chamber. Number Fereent of mice Presence reeence of tumors et nl., C. 166. B. '_.-A cigarettes of mice 6zposure with pdmonnry shawed an age- 1960, E. 231. per day for eznmined (dnyx) ade>wmataustumors relationship U.S.A. (168). 17-600 days. 81 . ....... .......... . 0 56 independentof ki C. Cigarette smoke. 39 ... . . . . .. .... ... ..... ...... 17- 99 41 ng exposure. smo 35 ....... . . .... ... 100-199 37 51 .......... . ...... ,. 200-600 66 Otto,196J, Albino mice. A. Chamber. Germany C. 60. B. Approximately (3os). E. 199. 12 cigarettea perr day for varying intervuls. C. Cigarette smoke. Num6er Exnoeure Numberwith of m Nane. lunu tumore ezamined _ Varying 0 pulmonary ademm.6s. C. 60 up to 24 21 pulmonary adenomas. E. 189 munths. 2 epithelial carcinomas.

TABLE Alh.-Expcrin{enis concerning the effect of the instillation or implantation of ctgalctte smoke or its cmtytetufuts into tleee trackeohrouclt?td tree of aui)nady (corit.) _- Antnov. A. med,ml -. .- yea Am mal k Prequ.,cv nnd/ ... tite`v. - and - oedurutmn ¢r.ults -- referemte strain C. Matminl H_lecklock, Cli whitr rats. A. Im_ vulutinn ut 1961, tlmrurntomv. (hent li. Onceundsnurifued llritain at I w(-ck 6> a... ([s). C1.C:1_bnrettetohacco smukr condensate /ieerold and 9yriun golden A. Dunhum, hnmstnre" 1962. li U.S.A. If"-). C. Aackeyetal., Doge. A. 1962, U.gi.A. B. I.Y414 C. Tipton snd Mongreldugs. A. Crnckeq Conerolxroupand 1964. experimcnta_1 B. U.S.A. gruup-t9. C. lntretruchesl uculation. 0.5 cc./week for_ 5/6 montns: Benro(alurreoe Twem,so or olive uil. Bronchinlinoculation or stimVlatian. 3-5 times/week for uv to 5 resra. Cigarette smoke condensatc _B_eonchiwl inocnlation. Deilyfor$davs. Cixarettesmoke (R)9). condenate. Nvmber of rafP Pcrccn[witR aubynavtttunnep Guntruls ....... ...................... _..... 275 1.5 (1 cnrrinnma, 3 sarcomes). Cigaru -ondenxute ........... ........... 72 11.1 (6 carcinomas, 2 sarcomas). Euuerin alone ........... .................... 44 2.3 (1 sarcorne). NunlAer of .Numbtr ,oRk NumLer of trachen- _M_ntm I: 6a_mstcrs Oemora br . ).yjtumors B() inT.reenGo ... 6 3 5(8 pat,llnmas, 2 cerctnOmm). 6(e) Pin'AVeen601 6 3 9(d pspillamas. 5 carcinomas). TweepGO .......... 6 0 - _._..._. . B(u) P in olive oil .. 6 u Olive oil .... ....... 6 0 racc_dure: Number of dope Groasive caco(auma Cnr , ma- c sity Pre- .une chaanne Sq,mmous mclaplnaia mitltatupieat rhaayes /nftam- ?1u6ion Controls .. _ ~ Sl 6 24 Manipulation oe bronehus .... 25 _ - 7 25 Smnkecundensete 130 1 3 25 99 128 Rapid in_ductiun ef squampus mptapla.ia in conden.ato-ezposed snimals. No tabular data is presented. OMISWIE0

TABLE A23: Nutuber and percent distr-ibeltiPrt by relative frequency of atypical nt{clei among true vocal cord cells, of men odaxsified by .smokireg category (100 percent atypical cells defined ns arcinoma) Per ent atypicel nuclei Current cigarette emokers Nerer emoked Ex-cigarette Ciaertnioe Lee: than 1 1-2 paaks -~ 2 or moee regularly amokerx smokers pack a day e day paaks a day .Yum- bar Prr- rant _N_v.m- 6e- Per- oent Num- ber Per- cent Nmm- 6er Ycr nent _NUm- ber Per• cent Num- ber Per- cent Total ....................- .. 88 100.0 116 100.0 94 100.0 125 100.0 320 100.0 190 100.0 None .............................. cc 75.0 86 ]4,1 1 1.1 1 .B .. 0_.. - 0 Less than 50 ....................... p 9.1 14 12.1 4 4,3 25 20 0 4 1 2 0 - 50-59 .............................. 10 11.4 13 11.2 50 63.0 fi4 . 43.2 87 . 26.4 28 - 16.9 6o-c9 ...... .......... ~............. 4 4.5 1 .9 23 24.5 21 16.8 1J6 35.3 75 39.4 V0-70 .............................. 0 - 2 1 7 9 9.6 9 7.2 44 1&.4 99 20.0 80=80 ........... ............. 0 - 0 - 2 2.1 2 1.6 19 5.9 11 5.8 90-99 .............................. 0 - 0 - 1 1.1 0 -- 6 1.5 0 - _tno:_ ~ Carcinome in eitu .............. 0 - 0 - 3 3 2 19 10 4 52 ' 1 ]nvveive carcinOmn ............ 0 -- 0 -- 1 . 1.1 n . - 2 16.9 .6 36 2 18.4 1.1 , I 9ouree: Auerhaeh, 0. et e1. {e). Z6VS94C0

TABLE A221-9u-n[rnnry of'reseeLts of'retro.speetive stnd:iesof tobacco etse and eo.ncer'of th.elarynra(Figu.rese i-parentheses represent. ratios:based on less than 5 case noasmokers.) Ihvestlgatorrefcrence Relatfve:risk rstio t all amoWes tb:nonsmokers~ SebreN ef.al.. UiSA. (2E8) . ..... ....... ......... ..................... 2.0 Valko;.Czechuslav'akia (2M1:) .............................................. 3.6 SadowskyetalLU.S.A.(2SY) .__ ............ ..._......_........ ..... 3.7 Blii.mlein, Germany/26)......................................,.,.,,,,,,- 25.5 Wvndexet all. U.S:A. (9t2) : ............................................... 23.6 WYnderetal.,India.(1lP) .............................................. 311 Safiwarteetel.,,Franae (248) ............................ __.......... .. 4.6 Wvmderetal., Sweden (942)~ ....... __ ........................... ........ 610 Wxndex~et al.. Cube (325). .... .........................._................ (18.9) (mrsledonly) . Dutta-Choudhurietal.,India (x6) : ...................................... Stazeweki, Poland (z5v) . .............................................. ... Svnboda,.Czecho,]a.vaMia (2Yl) :...................... .._.............. .., 4.3 (N0L0) (jnalnnnlyJ. 8.3 tLomputedlaccording tmmethod of Gmnfield,.J. (e1). 359;

TAnI e A16.-ExperptuctaEs cnnt'ea&ir.p flte effeet of tloe tiztkalatxol>, of aigaretto stlLrzke ortts cnnsfitttcuts rlporz thn r,spr/afmcy hmct of reuialtu]n (c-ovlt.) r 9e~s9~eo Aulhur, (Figures in nu enthe,es rvp*ezent totnl nvmhn.r sw~ci.ocs i spreific group) Animal and stain A. Type of exposure B. puPatinn C. Matedar Reenlts WYndcretxl., MaleCi4116P A. Cha_mber. 1106S. . B. Up to 316 II.S.A. (Ytl). 2~md F, eignrette. mora than 40. C. Cigarette smoks. nidngen dioxtde, vnl t,leauds_.. and aldehydes fnund in viga- rctte smoke, winee influeneu snvs. Laskin et al., Rats: A. C,hnmher. 10?0, C. 45. B. t hotu~ per day U.S.A. (15Y). N. 3. for up to 600 days. C. uenzo(a)uyrene nso1, SOa atmnsphrre (3.fi p-n-.n.). Hammond licnale dotrs. See text et .1., 3970, U.S.A. 1119). senr. htty, reference Commenla Cuqrlusluns:l }Regults not Previdfd No s,lnamuus cell respiratory c r noted. This is attributed in tabular fmm. to the limitation of inhsJation time (CO and nicotine acute elfects) nnd lo Ihe anlWcmienlly and phyeiologically intricate sal pn.ange defense system. }zlnogar t rigarette smoke, NU2, o volat,le acide a_nd nlde- hrdee leads to e r nctive hyperplasia and metuplasln, both of which wele noted tr: 4e r rsib_le. Sw n inllue ir e.nosure Produced hyperplustic and metafd.I _n elTeeia which could not be enhanced by aubse t qusnt ..., _ e to cignrette smoke. [sxpos,ne Number Atnmsyhne ronlrols _ _3 Atmnxnhere plus benzo(n)- _ Suuamoue cr.ld mr0/ 3 aa py^eneezVosure ........ 21 2/21 SC; controls .............. 3 0.1 3 SC2 plus benzo(a)- pyrene expnsure ........ 21 5/21

1

TABLE A21.-0uGdine of 9:etresPee6iue.stvdies of toGacco use and eancer of tke larynx (cont.j R OW9G€0 Author, year, Cases Controls country, Collection of data reference Sex Number Method of selection Number Method of eelectinn _Stasrewski. M. 19G0, F. Poland (259). 207 Patients admitted to chronie _dfsense hos- 13 pital during 1959 and 1959 uwith hieto- Imtkally confitmed squumnus-cell car- e n of the Isrynx: Fc_rcen_t Nonmokere ................ 0.5 Cigarettes only ......... . ..... 87.9 Fipea and/nc cip.nra ........ 1.9 '9ieavY smkeri' ........... 88.4 lnhalers .................... 96.1 Female emokerg ............. 30.8 Rozeabilda, 1967, Auntrell r (229). Terraeol et al., 196PFrance (274). 6_voboda, M. 1968. F. Csechoelorskia (9'1t). 191 Patients admitted to 3 major hospitals 21 with cancer of larynx and hypophxrynx: Pereent Nonsmokers ................. B Smokers ..................... 92 Heavy smokers .............. 30 961 Private acrvica and dinic patients of ENT hnspitN: Pcrcent Nonsmokera ................ 12.1 Smokers .................... 87.9 205 Patients admitted tn e regional hospital 10 over e period of 6 rears all confirmed hlstaloR lly. Percent Nonsm k r.. g.9g Cigarettes ... 96.63 Pipes . ... . 2.44 912 Patients admitted dpring 1987 and 1968 Author interviewed pa- 1,9t3 to chronie di.seeee center [ur e_nccr- tients suspycted of IunR ous and naneancerous conditions pre- cancer for smoking vumahly not related to tobacco con- history and background. sumptimr: Pcrcenf Nonsmokers ................ 1'/.8 Qigarettes only ............. 60.6 Pipes and/n cigars . . .. 11.1 . "Henvy smokerx" -........... 49A ]nbalern .................... 66.8 Female umokers .... ....... 8.4 No ontrolv. No ennb•nls. Patient interviems. 820 Male controls Casesr patient interviewe. Controls: not stated. Pe[Lent N m mokers ...... 22.0 C g .ttes ( pprox matett) 71.0 Pipes (apB xrmately) - 7.0

TAD[.e €116.-ExPerinae'nts conatn-ntng the effect of the inhalation of c.igaxette smoke or its cnrastitttonts myort the respiratnry tract of animals (covlt.) (Figvres in. parenthe9es reuresent total n mhcr s specific group) Author, yeaz, Animal A. Type of exyosu_ r_e_ Country, and D. Duration --~ referertce strain C. Material Itesulte Comments Itockey and M_ang_reld_og__s: A. Trachealfenestra- SDeeq C. 11, tiun (lo). 1966, E. 19. Nustrll inheln- U.S.A. (zss). tion (v).I1. Trxcheelfeneatra- tiun-2R4 treat- nt dars. Nnmtrilinhalation- 180 treatment dars. C. aignrotte amoke. Auerbach - Deagle dogs: A. Trachvustnm et al., G. 10 (2 with D. Up to 12- --- 1967, trachepstnma), cigarettes per U.S.A. (10). E. IB. day for up ~ to 421 dnys. C. Cigurettesmoke. Harris and C54DL mice: A. Chamber, Negroni, C. 200. It. Fmnke-12 eign-_ 1069, S. 1,437. rettes per 20 Englend_ mice for 12 (121).. minutes every other day for lifetime. C. Cigarette smoke, infiuenza virus sol. Lenz- pyrene aeroeol. 3nnmm.us tCarcinome in situ ) Ngnerptasia mctapta- noted in 5 separate with - sia witk Pre- Carci- sites in thfs laRam- atypicnl atryUieai canceraua enimal. mutionn jcuturaa fcaturee clmayee in eipu Controls (I/) . 9 1 1 0 0 Tracheal tenrstra- tiun (10) 10 6 6 1 tf Nu.tril i - - - hnlntinn(0) . 6 0 0 0 0 Suntvnls,experimen~ Nu histoluqic change in bronehisl eyithelium: a. 1 animal died at 24 days and no histologic chang_e noted. D. 5 tmimals sacrificed at 421 days and nuclearr atypism noled in ellL c. 2 e m_ als died at 229 and 278 aays. and nunlaar styptam was noted but of lesser eeverily than in those sacrificed at 421 dnys. Treafmnnt ,yumbcr Contrnls ................... 200 influenzx aernsol elou_ e 682 Denzpyreneaerosol. (4 exposmcs) ......200 Smoking .................. 200 ]nflucnza and benrpyrene_ . 200 Infiuenraandsmoking ..... 165 Num6cr of Thia strain of mice Iunp ca_ rc_inomae_ ie nutad for ite 0 lack nfapnntaneoua 1R 1 g t or formation. A I. _ nnsed to 2 o.ignretlc smoke A(all edeno- shoaed no hyper- carcinoman) plastic ep+thelial 8 changensnch as 3 those noted by Lcuchtenberger.

CHAPTER 5 Pregnancy

~ N P TABLE A21.-Oldiine of retros, ect iue s tudies o f tobacco etso and cancer of the larynx (emrt.) Authar, year, Cases referen e Sex Number Method of selection snusm- Wynder et al.. M. 60 Pntirnta at Radipmhemmet with 1954. -cell c r of larynx, #rsm 1952 _Swe_d_e_n (9_2k_). thrnogh 195$e ~ Pescent Nonsmokers ................ 6 Cigarettes .... ............. 4'/ Cigars..... ................. 17 Plues ...................... 15 Mixed ...................... 17 Controls Numbcr Method of selection Collection of data 271 PatienLs from same s r . and time, By trained lay inter- with c ce.r nther than squamous-cell ie.rery fn hospital. of luqnx: ~Pe_rc _ ent Nunsmukers ................ 24 ,.... Cigarettes ............. 3G Cigars ...................... 9 Fipes ...................... 16 %Ixed ...................... 13 VPynder etal., A/. 142 Clinic Vatient4 1n linyann during 1956-.5y, 220 Same saurce and time; apparently pa- Inlervicw of patie_nts 1056, ~ ~ F, IIY with histologicnlil' d~agn~s.d evider- 214 ticntx with uther than leeynx, in ehnic. Cuba (5¢5). mald eencer of larynx. lung. or yral ... ity, melched for age: Percent Peresnt Mnl e Female Matc Fcmalc Nunsmokars ......... 1 13 Nnnsmokers ........ 16 66 Cigarallex ........... 62 72 Ciqarettes .......... 45 27 Cigare ............... 20 G Cigars ............. 22 6 Pives ................ I .. Pipea ............... 1 .. Mixed ............... 16 9 Mixed .............. 16 .. Dutta-Choudhuri M-F 592 Patients in Calcutta e r husvital dur- 288 Not specified Tobacco hietoriea ub- et el., 1959-- India (86). ing 1950-54, with laryngeel tumur ding- nused and confirmed by biousy or emgar: Percant Percent tained during 1951-54, apparently by inter- viewer. ~ -~- -Nunusers ................... 14.1 Nonusere .................. 41.7 Cigarettes or bidi ........... 91.8 Cigarettes or bidi ........... 52.1 Chew ....................... 8.1 Ch2w ...................... 3.8 IIoth ....................... 6.0 Both ....................... 2.4

TAeLE A1C.-F.°spe/qnents cotecerning Qkr of/'aqt of the inhalation of cigarette snlnk_c_ oe' xt.a cnnstit¢ents upon tfae y%spiratory tract of a,nimaLc (Ftanres in psrentheses represent tutal numher su..~uutx tn epecific group) a a Author, year, cuuntiy, referince Animal and strain A. Typeufexpoaure 33: Duration C. Material Results Comments Lorena et al., 1943, Strain_ A_mice: tC. 97. A. B. Chpmbcr. Up to 693 hours. E. No ineceas in tumnr formation . over that noted in contmle.This strain of mice does beve a hereditary U.S.A_ (177). $E. 97. C. Cignrette smuke. tendency to tumnr formation. Essenberg, Strain A mice_ : A. Chmnber. FercenA of Lrny pum.ors 1952, C. 32. B. 12hoursncrdsy C. W.4(ta) - U.S.A.(9E). E. 16. C. forlYear. Cigaiettesmeke. F..01.2(?3) Milhlbnek, Hybrid (020x A. Cbemhee. Psrrentuitha7vnolnrrnrciimmns 1955, DBA) mice: B. 2 hours per day for C. 31.0 Netherlands C. @2. up to 681 days. E. 99_.0 E. 29. C- Cigarette smoke. 1'auchtenbersex CNtalbinamice; A. Chamber. 2vofehcezycyomtenlmieesemaved.et al., C. nnd E. 275. B. To e eigarettes 1;5 ba.al eell hyp_erplssla. 19158. nev dny.frem 14 etyuica7 bnsal ccll hyperplnsin. U.S.A. (166). I1 ?01 days. 7 d'splneia.-- C. Cluarettestnuke, smumeus cell metaplxsie. Cuertn, IC and Wieter A. Chamber. A+rrnfnyr oJ rnb mith pn/mmiary tamore 1059, strain rats. B. 45_ minutes C. 24 percent of 39 survivors. Frence (10x). C. 40. per day from E. 5.1 perecnt of 68 sm'virnrs. E. 100. 2-6 months. C. Cigarettesmoke. tC. Gmtcnl. IE. Experimental. Na epidermoid csncer noted: Papillavey adenocoreinoma_ wa_s most common. Perecntage dilTerence signifleantat 0=0.01 leeel. No other ty ue of lung tumors were found zeVss4Co

TABLE A28. Otetline of rrtrosprclier s•tulFirs n/ lubaceu vrnr urtd rrutrr.r oJ the urttf raritu (uwtt.) IHata nGmined frotn Itntient intcrrYew tv!d other e cyl Author, year, untr Cuses Controls cu g. reference Sex Number Methnd nf selecAinn Number Method of selection Ledermann, M. 240 Pntients with cancer of oral eavit_v and 62 Fatients with enncer of _ski n, hmre, and 19551 phnr5nx: musele: Ph (1G2) n P t P t v rc . crecn_ ercen Nonsmokers ................. 4.6 Nonsmokers .......... ...... 17.2 >20 cigarettes per day ....... 23.4 >20 cigarettes pee day ...... 18.6 Wyoderetel.. M. 543 Patients with cancer of oral cavity: 207 Patients with cancer of other sites and 1957, F. 116 232 beni¢n disevses: - -~ --- --- U.S.A. (J18). Percent Pecccnt Male Fcmafc Male. Rc+natc Nansm.kers ......... 3 47 Nonsmnkers .......... 10 Ciears ............... 20 - Cigxr® ............... 13 Pipes ................ 11 - Pipes ................ 6 Mixed . ............... 8 Mixed ................ 6 Chew . ............. 17 Chew ..... ........... 3 Cigarettes ........... 57 53 Cigarettes ............ 63 >35 cigarettes >35 eiqc:ettes per day ............ 29 per day ............ 17 >16 cigaretteg >16 cigarette9 per day ............ - 34 perday ............ .. 11 6chwart zetal., M. 332 Hospital patients witb cencer of oral cev- 608 Hospital patient. with nan-cancer ill- _ . .194Y, France (248). ity and pharynx :. .. ... . . . .. . ness and accident cases ege: mutched by Perrcnt Percnnt Nnn.smokern ................ 16.4 Nnnsmukers ................ 21.4 Cigarettes only .............. 6_2.G Cigarettes only ............. 58.2 Pipes only .................. 3.8 Pipes only .................. 3.0 m P W Comments Differences between cases and controls for both high and low alcohol in- take v e ihsignificant when smoking is con- trnlled. 9I r.-iJL(aO

TaRi,e A16`E-xRerintants concernang the effect of the inhalation of cigarette saaake or its constituents apo72, the re5pirtttory tract of anittaatg (nont.) (Figures in parentheses ceprescnt total numhpr survivnrs in specifie group) Author. yeat; country, reference Animal A- Type of exposure and R. Durationstrain C. Material D_untenwilland (;oldenhamsters. A- Chamber. Wiebeeke, C. - R. Up to 4 cigarettes 1966, - E_._ 320 per day for up p Gennany to 2 years. fbY). C. CtR rette.smoke. Leuchtenberger and Leuchten. Fcrger 1966. Switeerland (164). A. B. C. Chamber. tlato1,000houm. Cigarette smoke, exposure toin- fiuenze virus (PRe). Hurnher o1 animatq ` dead at 540 dn_y 40 .......... 40 .............. 80 .............. 143 .............. Results Comments Daity MET des - desyuama- nvernPc HiatoEagic tive metsplasie. ezposrme findinpsin MET hraneh = bron- (ciparettee) ... . dead anfmafe_ ehial papillary I e/ 40 MET des metaplsela. 2 8/ 40 MET des PAP trach -=treche a l 1-2 44/ B0 MET des (3 MET _ _ papillometa ar branch, 2 PAP tracb) intense trachenl 1-4 67/143 MET des (13 MET metaplasla, Marked epuamou. cetL.aetpp6nsi_o (percant) Cnvtrnls (!np); Male ...... . - Female . - Smnke exposed (s?) ; Male ....... - bronch, x PAP irach) Ma_rked traneOreesian Marked o/ iunD d_yeplasia Pnrcnchyma (pcrcent) (vereent) Female Virne expneM (69): - Ma) . ....... Femnle Smoke and 11.0 21.0 • v¢us . expased (ca): Male ...._. 9.0 43.0 Fcmale . .. _ . 29.0 64.0 3.0 18.0 5.0 118.0 f38.0 1Epitheliel tissues of these snimals showed an increased frequeney of cellular atypism. The authors coneluded that PRB influenxa virus may act as a eofactor In malig- nanttvensformaHan. A

TA&CE A28-Outlane of retrospective studies of tubnrco ust+ and cancer of tko oral cavity (Data nbtginsd from natlent interview nnd other ®uu.vesi I u P V4bS9LE0 Author, ycur, Cases ntay' reference Sex Number Methodofeelection Rorder i93U. U.S.A.(4!). Ebenius. 1943, Sweden (Lf). Levin _al._, 1950, U.S.A.(t69). 526 Series of clinic patientx with epithelloma 11 of the lip: Percent Tobacco usere ............... 80.5 Smukera ...._ .............. 76.1 Cigerettes .................. 0.9 Chewers .................... 24.0 Pi.pes ....................... 59.0 Cigars ...................... 38.5 43B Clinic patients with cancer of the lip: 35 Par rnt Mate Fe_raate Tobncco users ........ 79.7 - Tobacco usere (aI1ViVes) ......... - 6'I.6 Pipes ................ 61.8 -_ Chew er use snurt 47.4 - Cigars and cigerett® .. 12.9 - 148 Cancer institute nntients with cancerr of ~ the lip: Peresnt Smokers .................... 84.6 Ciaarettes .................. 45.8 Pipes ....................... 48.1 Cigars ...................... 26.5 Controls Number Method of selection 500 Seriee of elinic patients without epithe_- liomn of the lip: Percent Tobacco ueere .............. 78.6 Smnkers _ ...................... 76.2 Ciearettes .................. 44.4 Chewere .................... 13.4 Pines ...................... 28.6 Cigars .............. ....... 44.0 s0U Notdcfined. PerccnF Male Femaie Tnbscco uaers ........ 68.7 - Tobacco users ........ - tl-2 Pipes ................ 22.9 - Chew or use snuR ..... 60.7 - Ei4>reandefgerette. .. 12.6 - 51 Cencer Institute Uatients with non-esn- cer dis.easea of same site: - --- ----- Pe.cent Smnkers ................... 74.0 C.igarettes .................. 43.0 Pipes ...................... 30.7 ClHars ..................... 34.9 Comments t Estimate of preval_e_nc_e_ of use.

Author, o'eac, c -untry. trfecence Yoshida et al., 1968. Japan (ssn). Tqgtp A35a.-54ezmmaaxj of results Qf retrosPecttive studies of smoking and cancer of the bladder (coPtt.) Percent cigarettes HelatTve rlsk rntia: Yercent nunsmukr.rs Per ent Aeavy emokers rcent amoked All smokers to nonsmokers Kidu et al., -- 1968, Jnnan (144). Dunham et sl., 1`J68. U.S.A. (85). Anthanxand Thomas, 1970, EnRland (J). -~---- ----~ -~ --~ - Sex 51, fases 8.0 Cnntrlos 22.7 4'a%rs 43.4 Cond'ols &3.0 C'uses - Cnntrala - - Ali sm k.re 3.4 P. G2.1 ec < hI. 11.8 ll.0 22.0 20.0 F. 16.0 21.0 - - - 1.4 3L 8.6 14.5 - - 49.4 45d F. 62.2 01.5 -- - 32.0 28.2 F. 6.,9 6.3 - - 36.5 29.1 1.0 Hea.y Fieerette Commente emokeis emakers

TABLE A28a.-$umnuw'U of v'esttlt...• uf retro.shectivp a6ttJies of s~n dcivy hr( (yfpc nnrl o, 'stt sn,lcrr uf dL~P«ei6/v1 flitre (cotat.) Author ~~ CiEar tt -~-~ Pi"' I p.-r. 1 C sni 1 b¢,.rn Retel nut ~- reference pigarette and agars Flidi., only other fo ms nnly chewmq cheaing bfiseelln neou. VyynderL•esl .~ Oralana. .............. ............. ...... .... ...... l)~nlflnd ............ ............... L4es1 phar%nz, Vhar nx. Malg S-1 klnle (}), Femnle (}) Female ({) Wy'ndcretal. Yharxnx (-FL _ ............. ..... ............... ........... ..... ,.Poncue. .............. ..--..-.........Plpeaandci¢ere (?"dS1 uther sites I-L . qingiva, mbined-_ pharyna (+). tonqne (+). F'eacock et¢I. .............................. .......... .................... ... Oral (+)r.................... .SnuK,rai b ....... _ .... _ ........ ................. ........................... ....................... ...... ..I'ipes and claars ombined-lip, nralcavitr (t). Staszewaki (-5v).., Lip. oral a t+) V agler et al vinrent and Marehette . (297) ......................................................................... ............. . ............... Aliforms com- . ...... ...... .. .. bine~l (+). Fcmnle 1}) Snu6-lin and huecalcavityin both cases. ................. ..................................................................................................Al lfurms Shanta and ............. Krishnnm_ nrthi Ixss combined- oral (}), pFmrynX (}~.. .................................... ...................... ....... ........... Lip. Allsmnkine types bnccal -pharynx (}), mVen9a 1+).. pnattnnyne tf) All £orms wm- bined-lip, ornl cavity, pharynlt 1}). Mssra€o

C©ntents Page Introdnctioni ....................................... 389 Effect on birthweight ................................ 389 Effect on outcome of pregnancy ......................... 390 Experimental studies ................................ 407 Summary .......................................... 415 References ......................................... 415 LIST OF TABLES 1. Summarv ofinet'hodsusedinstudyofsmokingandhuman pregnanc.% ~..................................................... 391 2. Maternal smoking and infant weight ................ 397 3. Maternal smoking andiprematurity .................. .....400 4. Comparison of abortion, stillbirth, and neonatal death in, smok.ingg andd non.smokingg mothers. . .................. ...4Y15 5. Human experimental datai on smoking;and.pregnancy .. 408 6. Animal experimental data on, theeffeet of smoking and nicotineon pregnancy ........:............................_. 41'.1 387

TASLt: A28; Putlins of retn'ospnctiale sdudies of fubncco ttse and r;aneer- of the oral cavity (cont.) (Data obtained from patient interview and other so es) Author, yen country, referenee Jex Number Mills aud L'orter. M. 124 1950, 'U.S.A. (}xr), Maoce et PI., 1953, U.S.A. (+9.4t. Cases Controls Methud of selection Number Method of selection _De_n_ths from cancer of oral cavity in Cm-. 18; Smm~lr af nnpulation of Coh,mbus, QLiq, nati andDetrolt, 1940-45 and 1942, in proportion of color, sex, and 46 re5pentively: aue ns in cases: Pcrreent Percent Cigarettes only .............. 35.5 Cigare-ttex nnly .,•.•..•..... 32.4 Pi1les,ei8ers.orPipes,ciRars,or_ combinations .............. 64.8 cumbinntinns ............. 29.7 Patients o er 50 years old since 1961 wfth cence, of oral cavity: Pcrcent Chewers ................ @8.U Pipes ....................... 42.0 Cigars and cigarettes ........ 38'.4 Sndowsky et al.. M_ 1,136 Itospitnl patients with lip, orel, md pha -* 19@3, Htgeal csneer- 1938-43', lI.S.A. (238). - Percnnt Cigxrettex nnly .............. 42.1 Cigncs pnls ................. 40 Pines onlr .................. 17.8 Mixed ...................... 28.2 Sanghvi etal., M. 657 Hospital natientx with c n_f oral cavi- 1955. F. 31 ty 4nd phnrynx_: India 1241). Po.ccnt Mnie FcmatB Smnke snd chew ..... 38.8 3.7 Smoke only .......... 46.7 6.2 Chew only ........... 11.7 64.2 Neither .............. 2.7 25.9 38 Patients of s e age groups with bo- nign ral lesions or benlgn BI1rNlfal onditi ns: -- Perc ent Chewers .................... 31.6 Pipes .............. .............. 47.4 Cigars and cigarettes ........ 52.6 Patients with illness other than cnncer: P-erennt (,'ignrettes only ............. 63.3 Cianrs only ................. 3,4 Pines u_n_ly .................. 7,0 Mixed ...................... 23.1 288 Hospital patients with diseaees other Cumments Smoking is of bidis ymong 112 than cancer: both caeee and controls. Pr... nt Mnte Fema[e Smnke and vhew ...... 24.0 - Smoke nnly .......... 50.0 6.3 Chew only ............ 8.7 23.2 Neither .............. 17.3 70,5 SV6S9LG0

Y'ABLE A21.-Ontlifte of retrosycetive,shtdins o( LoDacco ttse avtd cancer of tiae Iaryns: (cont.) Author, yeei refere~c, e Sox Nwnher RlGmlein, M. 241 1965, ---~Germeny (86). Ca.ses Contruls Method uf seleution Nnmh¢r '.slethod of selection Clinic patients with caneer of Inrynx: 200 Patients with no IarYngcel diae®ee: Peewnt Percent Nonsmokera ................ 0.8' Nonsmokeru ..........,,.... 1_8.0 Heavr smokers . . ............ 99.3 Heavy smokers ............. 4.3 Inhalvrs .................... 95.0 Inhalers .................... 17.0 Wynderetal., M. 209 White male inpatienta Mcm rial Caucer 1956, Hsaaruh Center during 1@G2 to 1954, U.S.A. (312). with henig_n or maliennnt epidermoid tmmors of leovnx: Percent Nnnsmokers ................ 0.6 Cigarrttes .................. 86.0 Ciear9 ...................... 7.6 Pipn ....................... 5.0 Cigarsfpipes ................ 1.0 Wynderetal., M. 132 Laryngeal e ncer patients at Tata Mem- 1956, 0r/al Hospital, 1952-54: India (e/SL ---- --~- Pcrcent Nonsmokers ................ 13.6 Ridis ....................... 78.8 Cigarettes .................. 5.3 Hnokah ...................... 1.5 Chilum ..................... 0.8 Schwartzetel., M. 121 Patients hospitalizM from 1954 throngh I95^, 1966 with Inryngeal cancer, in Paris France (248). and other larxe cities: Pcrcmrt Smnkers .................... 06 Inhalers .................... 58 Roll their own ciqarettes .... 44 209 Patients with other than epidermoid caucer, individually matched contvola in same institutions: Pcr ent e Nnnsmnkers ................ 10.5 Cig:u~rtes .................. 73.7 Ciuars ..................... 10.1 Pivcs ...................... 3.8 Cigarcrpipes ................ 1.9 132 Controls individually matched as for U S.A data abote: Pcreent Monamekerx ................ 30.3 Hidis ....................... 62.1 Ciaarettea ..:............... 4.s Hnnkah .................... 0.8 Chilam ..................... 2.3 242 Same time and sources; patienta hospita]- ¢ed far non-cenceroua conditions or traumo: Pcrccnt Smokere (P<o.05) .......... 84 Inhnlera (p<0.05) .......... 47 Rol] their own cigarcttee .... 31 Collection of data naonal history taken in clinic. Patients and pgntrohM a.ver 40 vearp of age. Trained lay interviewers. Interciews for entoking end mMi.cal hiatorice. Cases and controls lndi- vidually matched within nstitutions; each mem- ber of a set auestioned by the sae e trained lay_ interviewer. eMs4eo

x a TAB[.F; _A_28-Qut(irte of retrospective stvtrti_es of tobacco use ttnd cancer of the oral cavity (cont.) (Data abtained from patient interview and other sauree_c) Authar, renq country Cases Controls , reference Ser Number. Method of eclectiun Numbe r (9ommente Method of sclection Shanta and N. 552 Patients with oral and pharyngeal cancer 300 Conteolnresidingin Krishnamurthi, F. 200 (nnsure of conOrmntion): 18U sme area -atched 1964. Percent fnrage,eca,an d India (YSB). B_urea( Axterfo r _Paeteniur _ class: Meles: No tobacco habit .... Lip - osa m 2A tonYUc 7.2 tmmuc 2.0 Pharynz Mntes 5.3 ~ 391 Smrrkera ..._..... .. 50.0 45.7 66.6 75.0 72.8 62.7 Numbcrufcases .... (12) (293) (69) (48) (130) (300) Females: No tobacco habit .... 14.3 11.0 33.3 - Femnlee 40.0 88.8 Smukers .. -_ 4.7 5.5 - 8.8 ~- Numhecafauses .... (7) (t62) (18) (4) (25) (100) Wahiet al., M. 589 Patients with ornl and pharyngaa] car ' 19fG F. 232 cinomu India (S0Y). Peryent Nonsmokers ................. 9.62 Smokerv .................... 17.05 Chewe_rs (Betel nut) ......... 35.44 Bolh ........................ 34.88 Hirnynma. M. 360 Patients with oral n_n_d pharyngeal card- . 277 Patients with other (vnspeeifled) dis- 1966 F 176 nome: 163 Centraland . pc*cent eases: Peresnt South East Mafe Fcrnale Male Female Asia (Ind). Nonusers ... _ ....... 1.6 2.5 17.0 33.0 Smoken . ............. 17.1 2.6 23.8 1.2 Smokers, tBN and tobaecqchewera . 46.7 6A 24.9 1.8 689 Patients matched for age, sex, rxligion, 232 and social class.-~ Pernmit 66.6 21.2 6.9 6.4 Found only a suggestive association between elcahoi-drinkine and oral cancer in non- chewere only, f BN-Betel nut.

TABLE A2&.-Outline of retrnspec.tive studies of Fnhrtcco tr$c and cancer of the, oral cavity (caaat.) (Data obtained from yntient interview and other s,.mrces) Author, year, Cases Controls c... Try, - - - Comments reteenee Sex tiumber Methodofselecttnn Number Methodo6selection .- Wynderetal., W. 278 HnspLLal cl,nv. patients with cancer of _20 Prtie t in snme chnics with non.mslig- 1957, F. 31 orol cavitY and nherynx: 211 nnnt emaditions, matched by sex and Cuba (agS). o$e. Percent Peruent Male Female nfale Female Nonemoker; ......... 4 24 Nunsmokere .......... 16 86 Cigarettee Ciearettsc -- predominantlr ..... 45 62 predominantly ....,. 45 27 Cipars prednminantly . 33 PL CiK^re uredominently . 22 8 Wynder et el., M. 116 Msle patiente ith cancer of oral cav(ty 115 Malc p t nts in same hospital with ean- Alcohol detn significant ]95?• nnd pheryn, cer of sites r,ther than aral, phsrynx, only far_ hypopharynx. Sw¢den (S:P). lary ., lung, esophagus, breeab - Percent Pdreeree Cigarette5 .................. 36.5 Cigarettes ................., 26 Cigers ...................... 13.0 Cieara ..................... 9 Pipex ...................... 12.2 Pipes ...................... 16 Mixed ...................... 15.7 Mixed ...................... ]3 Peacock et al., M. 25 Hospital patients w$h ural cancer: 74 Patients in eeme hospital without orel 1060. F. 20 72 cancer snd 117 male and 100 female U.S.A. (2t0). nuLpatienta, randomly selected. Percent 32.8 nercent of first group, and 4_3.3 per- Chewed orusedanuR aver30 cent ef nrcond group chewed or used years (all patients) ........ 65.6 anuR uver 20 years. Staszewaki, M. 383 Male patients with ornl cancer: 1960, - - - Peraent Poland (P591. Nnnemokere ................ 6.7 "Neevy" emoking index ...... 72.8 Cigarettes only .............. 72.3 Pipeennd/orcicare .......... 12.6 912 Male patients with other cencerove and non-cencernue canditinne: --- Percent Nonsmnkere ................ I2.3 "Heevy' smoking index . . . 49.0 Cigarettes only ............. 60.5 Pipes and/or clgap ..,,..,,, 11.1

' 0 V-7 CSVS94E0 TABLE A28a.-Sufntn¢n7j of results of retrospective_ stulie_ s of smoking by type and oral cancer of detailed sftes (dont.) A thor ~- - Cigarettes Pincs Pipes and Cigars Tobacco Hetclnut f re _ Cigarettes andcigwrs thdts only otherf m nnly chewing chewing Miscellaneous ~ Wxhi et a3. Anterior (.90P) tongnea_nd buernl murose, Males (+) ... ............ .......... . .................Anterior Allformscom-- ........l tnngue n_nd_ btned-a31 bvicenl sites (}). y mucosa, ~~ Males (+) _ Hiravama (124).. ................... ................. .......Alleites 1-)................. Allsites (-)... All sites 7 ................. Allformecom- bined-base of tongue (}), orcpharynx (+). - Smoking only combined buccsl mueusn (+). Keller ((dP)....... All sites (+) ..... .............. .......... Allsites (--)..... .......... ,.Allsites (-).............................. .,,.A11tvPessmoking combined, heavy -floor of mouth and tongue (}). Martinez (l89)..... Orslcavitv. .................................... ~ ~ Phervnx (+) .......... .......... ............... ~.................... ... Alltypea of smoking, heavy, combined-aral cavity (+). pharynx (}). Keller (141) ....... Lip (-) ................................. . ......... .. . .. ... Lip 1+) .... Lip L-) ........ . . .. .. . , ........... . All typcs of ~ ~~ - - ~mokingcom- binedJip (+). ' Only in individuule of low economic status and over 60 years old. Symbob: I+) -ainnificantseanciation. 1-) = i.tion-absent or not significant. f' 1= assoei.tinn of doubtful s3gnifleance.

TABLE A28.-Outlz Author, year, country, eeTeeence Sex Number - Keller. 1961, U.S.A. (140). 408 Martinez, M. 1969, F. 38 Puerto Rico (28Y). of r-etrosyective studies of luLru-co use and co.tecsr of the oresl cavity (cont.) (Uatu obtai-d frou, paiient inte,voew and other suurces) Cases Method uf selectiun Petients with squamops cell careianma of 408 oral cavity and ompharynx cenfirmed his.tologically. Three New York City VA Hospitals 1D53-63: Percent Nonusera ................... 5.1 Cigarettes .................. 68.6 Pipe onlY .................... 4.0 Ciasr only ........ ......... 6.9 Controls Commenta Nethud of selection Nest male patirnt admi_ttedto _ss_m_e _ho__s-_ Excessive alcohol c_on_ Bttal within 5 xear age range. sumption noted for s involving floor, esopharyni, and Percent tonpue. 14.2 Findings indicate the 56.4(pE0.0001) assnciatiun of heavv 2.9 drinking with cancer 6.1 Independent of the amount of tobacco ueed. Pntients with epider uid carcinoma of 345 115 male and 38 female hospital o clinic Cass s. found to consume oral cavity and pharyx : 114 patients without cancer; 330 male and more alcoholic beveo- -- 76 female reeidents of eeme region, axe than cnntrols. age end aex metched. Percent Percent Nonsmokers ................ 13.7 10.2 Heavy tobacco users ......... 24.8 12.2(p<0.0001) Keller, M. 301 Patients with nrimary basal or euuamoua 1970, cell car of lip: U.S.A. (141). Percent 304 Patients from aame hospital matched for age and race. Percent Nonsmokers ................ 7.$ 16.6(p<0.001) (Ygarettes only .............. 60.2 52.8 Pipe only ................... 6.0 3.4 Pipe, other .................. 6.3 0.4(p<0.01) IL u P V t Q%S94c0 :_.,:

: I M TABLE A31, Su7lama7y of methods used in retrospectvie studies of tohacco use and cancer of the esophagus Author, -- - vear. Csses Controls ntw. Cefetenfe Sex Number Method of selection Number Method of selection - Collection of data Sadowsky e[ el., M. 104 White patients admitted during 1938-43 to 615 Whlte patients with illnesses other than Obtained by 4 specially 1953, selected h ptals in New York City, ee admitted to ssme group of hoa- treinedleyinterviewere. U.S.A. (gaf). Missqur N w Orlean_, and Chicago. p tel during same perlod. 242 recorde out of s tatal of 2,847 excluded be- came uf incumplete or Vuestiensble smoking histories. Sanghvi e_t sl., N. 73 Consecutive clinic admiseione to Tate me, 288 1955, morinl Hospital, Hombsy, India (E41). 107 Gonsecutive clinic admiesione of Datlents Hy means of "detailed th t caeer questionsry." No other Ce tiveadmissions of patients with details given. cancers other than intraor.l ur eao- phogus. Wynderetal., M. 39 Patients admitted to Radiumhemmet, 115 Patients admitted to same hospital with 1957, F. 35 Stockholm, during 1952-55. 156 cancer of skin, head and neek region Sweden (JYx). other than squemous eell cancer, leu- kemia, colon, _e_nd_ ot_he_r eitea. No matching. Stessewski, M. 24 Paicnts admitted to Oncological Snatitute 912 Other aatients eent to Inetitute with No details given on _- 1960, during 1957-59. symptome pmbebly not etio]ogically _ method _ of data collar Poland (Mp), ronnected either with smoking or with tion. No .ge adjust- diseases of esophegus, vdomach or du- ment or matching. Av- odenum_ . crage age of e6ncer patfent.r, 60.5: contrnhl, 63.

TABLE A28.-Qufiline of Tsfroagcet[nc sdtrHe6 of tobacco rlar uvd rattrev: of tlio oral (w'it7f (coott.) fnata..btan:ed irn.n nuuent intmview m:d ulher a,nr'es) Author, vear, COUntry, referenee Sex Number Cases selectim~ Method of Vogler et al., \t. 189 Clinic patients with cancer uf lip and oral 1962. F. 92 cav.ity: U.S.A. (s98). -- Peroent Ma}e Femak 4hewera ..._......... t32.9 - 6xceeaivechewers .... 22.9 - 6nuff diDPen ........ - 72.0 Excessiveanuff dipper+ ............ - 41.8 Tobaeco uncm ... , .... 90.0 90.0 Contrale Nun:ber Methodo€selection 521 Patients of same clinic with other c- 1,064 r nan-maliKnant condition®: Percent Mafn Femade Snuff dippera ......... ... t6.1 Tubacco users ........ 66.0 66.0 Comments t Due to varying tabular treatment of data, Der- centages of tobacco users are not all based on the same number of csnen. Vincentand 66 Successive patients with lesions of bu<cat 100 Succe.5xive patients attending geatrofn- Male patients used con- Marchetta, 16 csvity and nropharynx: 5a t: tmal clinic, age-matched: stdersbly more dcahol 1968. Pe>eent than malc mntrolg. U.S.A.(Y4Z). Oral Oro- Mwlee: Cuvity pharyns Pcrccut Data refers to all forms of amoking expre5sed Nonsmokers ......... 3.0 - 27 0 a. cigareLLe epuiealente. <20 cigarettes - , CiRarette epuivalents: per_ day ............ 18.3 16.1 24.0 I clgar = 5 cigarettes >20 ci¢arettes per dey ............ 79.7 84.9 49.0 1 Pine = 2 cigarettes J BN=t3etel nut. Females: Nonsmokem . ........ 66.6 28.6 92.0 <20 cigarettes perday ............ - 8.0 >20 cigarettes per dsy ............ 44.6 71.4 10.0 WS9fY440

V V TABCE A32.-Atypacal nuclei in basal cells of elrithellusb of osoPl/aglls of ulale>, by suloknlg habit.c and age Atypical nuclei A. Allmen: ---Numbecmen ..... ............... Tatel~sectionst~...~..~............... Noptypicel nuclei ................. Sume but <60 percent atypical ..... 60 percent or more etypiesl ........ B. Men under age 50: Number men ...................... Totaisectiene ..................... No a5ypicalnuclei ................. Some-but <60 percent atynical ..... 60 yertent or more atypical ......... C. Men e¢ed 60-69: Numbermen...................... Totalsections ..................... Noetypicalnuclel ......... ....... . gomc bnt <60 percent atypical ...... 60percentnrmoreatypical ........ D. Men aged 70 or older; Number men ....................... Tots!sectiena ..................... No atypical nuclei ................. Some but <60 percent atypical ..... 60 percent or more atypical ......... Neversmoked reeularly Current Ciqnrettcs. Ex-ciae:ettes eiue, cigur Other ---'- Num- bc+ Per- ent Num- her Pur- ocut Num- bsr Pc.- ecnt Num- 4er Pcr- cent Num- ber Per- eent Ul - 979 161 - 89 - 62 -_ 787 100.0 6,762 100.0 ],586 100.0 766 100.0 622 100.0 783 93.1 167 2.5 770 48.5 53 6.9 195 37.4 52 6.6 5.389 79.8 765 49.3 666 09.8 3SR 60.5 2 0.3 1,196 17.7 51 3.2 25 3.3 10 1.9 26 - 236 - 29 9 - 7 223 1 00.0 2.069 100.0 259 100.0 ' 1011.0 _63 _30_0.0 190 _ 85.2 71 3.4 21.7 1 1.3 4 7.5 33 14.8 1,863 90.0 19 76.6 74 96.1 46 86.8 - 135 6.6 2.7 2 2.6 3 6.7 44 - 445 - 109 - 38 -- 31 - 379 100.0 3_,853 100.0 053 100.0 310 100.0 256 100.0 393 98.4 83 23 461 48.4 37 11.9 74 28.9 4 1.1 2,915 75 6 452 47.4 261 84.2 178 69.6 2 0.5 855 22.2 40 4.2 12 3.9 4 1.6 21 - 9N - 44 - 42 - 24 - 186 100.0 840 100.0 356 100.0 379 100.0 213 100-0 170 91.9 13 1.5 263 67.4 15 4.0 117 64.9 16 8.1 621 74.0 118 91.5 358 93.1 03 43.7 - - 206 24.5 4 1.1 11 2.9 3 1.4 ' Sections with s ncuithellum present. Source: Auerbach,0. ct al. (15).

~ a > TABLE A29-ExperiTllenta6 studies corecerning oral carcino_genesis (cont.) Author, y. Method. y.ear;- Animal R: Fre4aencysnd/ untry, - and or duration. reference strain C.Metcrial. Desolte Originat Percent at i$ mpnt_k_a with uum6er PaP+dlomae Cancer . Alcohol end CCA treated .............. 40 74 46 Alcoholt r ted ........ ............ 40 84 SO CCl4 treated ......................... 40 90 40 Nntnxin ............................. 40 15 Protael et sl., Swiss Webster mice A. Swabbing of labial 1964. with yume having mucasa. U.S.A. liver damage in- B. Up to 13 months. (Yt_s). ducedeitherby C. 13(a) Pin acetone. CCl4 or ethyl alcohol. Reddy end Anguli, 1966, India (4l9). Elsay, 190. U.S.A. (DO). S.wiss femele A. mice. 11. C. Syuian Golden A. . hamsters. R. C. Intrnvaginal n.tillatinn. D_ailyfor924-&80 duys. 'Tan" miature af areca n.rts, lime, and ehcwing tobacr.o. Applicetion to cheek poueh. Daily foc 200 depx. Serrssult.. Origtnal num6er Suruivora g0 40.... Leeione 9_/40 ralaed paplllomatons malignant growths 4/40 possible carcinoma. in situ. Treetment: Oriyinal numEer Mortality rate Number onimab Pereent with tumors Percent w(th cancer DMRA Alcohol Smoke 29 41.0 17 100.0 50.0 DMAA Alcohol 29 66.0 10 60.0 40.0 DMBA ....... Smoke 29 42.0 14 100.0 70.0 DMDA ....... ...... 29 48.0 16 100.0 38.0 Alcohol Smoke 29 42.0 14 - ._ ....... Smoke 29 42.0 14 - - I LS6S94C0

TABLe A2&a.-Sumqrp4yy of results of retrospective studies of smoking by tg~re and oral cancer of detailed sites - -----~ .. . .. nuth r Cigarettee Pipea Pipesand eigars Tohncco Belelnut -rcf 9fgyrette_s nd rigurs Bidia nnly other forme anly cAe6iing rhewing MiacelLneous Broders (43)...... Lin f-)... ......................... .LiP (+)......... ............Lip (-) ....... Lip (-I-)..................... Eheniue (87). .... .................L_iV 1-)..........,,....Lip (-H,~..... ., .......,,........... ..... Lip (-)..,... .....,,....,,., L rin et al. (1fiB).. Lin (-1.. ...... ............. Lip (+)........... ..... . Lfp (')............ ._. .._..,......... .,. Mills and Orel (") ......... .................................................................... .... .......... ................ PiRes and eigars Porter (leF) ombined-nral f#). Munre et el. f+38) ................_.... Lip. ..,,...,,,Lip. mouth mnuth (-) .................. ~........ Lip. ................ SnvH-IiD. mnuth (+) moulh (+). Sadowskg Lin.tonaue, ........................Lip,tongue, .,,.....,.,.TUnaue, ._.._....,...... .,...,.,.,..... etnl. (-3i) othm•.oral, ntheroral ({) other phn.rnx.(-)..... orel(') ..... . Sangh.i et sl. ([4l) ~ ............... ......... ........Oul (-f~),........................ ..................... . Orel (}).,... .......... ,.... If amukere and chewerz-base of tongue ~~hypoOharynx I.ederm®n (M^.)...Arel ........ Wxnder.ete1, Floor of ....... ............... Eeehsite ,,,..,,.,,,,Eerhsite(})..Gingive, ..,...,.,......, (313) muuth except lip (q..,,. Male (e) toneue (})..,, Feme.le f+l-... - ---- Schwarlv etal . ................. Pharynx (-F)........ ...Oral (-)................... 17 . ............... ....,.,.,....,,.,,,.........., (248)

TABLE A29l h'xperilnental studies concerning oral careinogenesis (cont.) Author, year, c0untrr, re[erenee Animel and- strain A. Methud. B. Yrequency and/ or durution. C. Material. Reeults B¢mstcrs A. Applinnt nn to eheek pouch, B. See eanlts. Treatmcnt: Cigarettes S per week ......... OripinuE Nr.mhur 40 Survivora 6_6 Duration 64 Lesions - G. Sce,ssults. DMRA once .................. 13 6 129 2 hyperplasia Croton oil 3 per week ......... 10 10 90 - DMBA once and cigarettes L per week ................. 3U 28 81 12 hvperplasia DMBA once then craton oil 5 oer week ................. 9 7 1 d dyykqretoels 1 c¢rcinoma 7 hyperplaaie 6 dyskerstosia 3 csrainoma Bock et al., 1964, ICR Swiss mtce. A. Paintingmoune sk'n Num6er Eumure/ uumber mfcc U.S.A. (SO). B. C. See results 36 weeks. Vsriaus extracta of unburnedtobacco OMDA. Treatment: DMBA once then: Acetone benzene extract ........................... To6acco equivalenE (cigarettea/dai(y) 2.5 mith Enmora (amaRpapiGamee) 16/7 Ooncentrated Ba(OH)zextraet .................... 0.6 1818 Diluted Ba(OH)2 extract .......................... 0.5 6/2 DMBA unly ...:............ ........ .............. - - Acetune benzene extract ........................... 2.5 - ConeentractedBa(OH)2extract .-_.._._.,.-...... 0.5 Diluted Be(OH)a cxtreet .......................... 0.5 None ............................................ - 9S6S94g0

TABLE A35a.-Summtaty of results of YetzoaProtivr sflll7tas ef' sntokiap mnl rmicnr uf FAr 6lnddu" w m Authoq Percent nunsmokers ycsr, ntr>y, rcrkence Sex Cnsen Controls Lilienfeld et al., M. 15.0 29.0 1056, F. 87.0 89.0 U.S.A. (171). Schwartz et el., M. 11.0 20.0 1961, Franeg (249). Lockwood, M. 1961. F. Denmark (175). Wrndcr et al., M. 1063, F. U.S.A. (8E6). Cobb and_ Ansell, 1965, U.S.A. (67). Steszewski, 1964. Pulnnd IP611. Ier.cvtcianreRas Rrlntireriekratl- lereenthcavyemokers m"kM Allsmokerstonunsmokers P garctto Cnmoents Cas Conteols Ca=cs Cwtrols smnk All ers Heuvy mnker -smnkces 61.0 44.0 2.3 ... 2.7 Cigarette and otber. ... ... 1.4 ... ... - 83.0 70.0 2 ... 2.2 Cigerette only. 0.0 13.4 30.0 ]_5.0 30A 15.0 1.6 8.0 3.0 56.0 66.0 4.0 4.0 ... ... 1.5 1.2 ... 7.0 18.0 47.0 22.0 85-0 63.0 2.9 5.2 3.3 Phases A and B corn- 61.0 86.0 6.0 ... ... ,.. 3.9 ... ... hined. 4.6 25.8 79.4 43.3 ... ... 7.3 10.3 6.4 16.0 85.7 65.7 87.1 12.2 2.7 8.1 2.9 Cigsrettes only. Deeley snd Cohen, M. 2.4 1966, Englqnd (66). 99VS94E0

TABLE A25. Sumrnaxy of mothods ased in e•adrespacfim.c xUufn y u/ tru/t,kiu<) tuwf c.ult:rloi 16c lndde:r Author, year, Cflses Controls reference Ses Number hlethodofselection Numbe, etbud of election i Lilienfeld at al., M. 1956, U.S.A. U%t/_ P. :i2t 116 Admissinns to Roswell Park Memorinl ]n.stitute. 1945-55 mer 45 years of age. . . .. .. ". Same ass mnlcs ............................. 137 109 317 No disense patienta. Drnign bladder conditions. No disease patients. Schwertx et al., 214 Admissions to hospitals in Paris and s few 214 Hmdthr individuals admitted to same hospital 1961, largc Dcovincial cities since 1954. because of work or traffic aceident, matched Frsnce (¢/9 6 by 5 year age gruap. Lnckwond. 282 All bladder fumors reported to Dsnish Cv n _282 _ A. Frnm I tion rnlls atvhed with cases ae- 1961, A'! licgisler during 104'L-56 and Ilving at time 87 eacding to s, nAe. marital atatus, neruPa- s Denmark (f 1 of inte_rview in Copenhegen and Fsederieks_ tiun, and tm iaence. hurg. (Ine.ludes bladder papillomas). B. Another eantrol group obtained fram sam- ple nf Dnnish 3lnrhiditv Surrey (1952. H153, and 1954) ccompared with resV?Ct to smok- Illg hlYtnrles. Wynder, 200 Firstphase: 200 1963, 50 Admission to several hospitals New 50 Adm to same hospitals (exduded cancer r U.S.A. (6Y6. York Gity during January 1SI57-Decem- espirator.y syspem, uppr alimentarr tract, uf ber 1960. . ardial infarction) matched by sex and ~c Second phuse: age 100 Admission to same hespitals duriog 1961. .. . . ... . . 100 Same as shur.e. 20 20 Cobb and Ansel], 13C I'atients admitted to VA Hospital in Seattle 542 120 patients with caneer of sigmoid colon, 222 1965, U.S.A. (57). 1951-61. pelicn}s with non-neoplastic pulmonary dis- 69VS94E©

TAnre. A33.-AfJPinrtl nuctei irt basal cells of epitbelq7t7A of +snplea,qu.c aF raales, Irll auialrtrif of .enruF'ing and age Current riqarette smoker& Neyeramu_ke_d_ regularly i il h l t i l <.1 nnck 1-2 paske >2 packs ¢i - Ce s w t_ _ a nue yp ca Nuvnhcr .-- Pcrcent Numhf ~ -_ r P_ rrrrl Nnrnbor Pcrrcret A_'ynlber Percesrt A. A_ Ilaqas. ..... _. ... .. 91 - 179 4I'3 187 Totaleeetious` ................... V89 100.0 1,.5_44_ 100_0 3,G20 10U,0 1.599 100.0 No atypical nuclei .... ..... ....... 733 93.1 89 5!.i 00 1.1 39 2.5 Somebut<611percentatypica] ..... 52 6.6 1,341 86.8 2,957 81.5 1,001 69.1 60 nereeut or mnre atypic_a_ I........ 2_ 0.3 114_ 7.4 633 17.4 44p 28.4 Q. Men vnder nqe 50: Number men ............... .................... 26 ... 0 - 132 - 55 - Tntalsectinnar ................... 223 100.0 432 100 0 0 1,169 100.0 459 100.0 No ntypfcxl nuclei ..... .......... . 100 852 48 11.1 21 I R 2 0.4 S,nmcbut<60gm~centatyP&al ...,. 35 14.8 3S2 N82 1,0XFl Bi.z p82 83.6 60 percentorennre atypical ........ ... ... 3 0.7 59 5.0 73 16.0 C. M uu yged 50 g0: - -Number men .......... ......... 44 ... 92 - 240 - 113 Tntalee_utlonar ................... 349 1_00.0 789 100.0 2,110 100.0 948 10u.0 No ntrnioal nneloi ................. 373 98.4 30 3.8 18 6.0 35 3.9 Somc Lut `60 nercgnt ntypicn] ..... 4 1.1 694 87.9 1.607 i5.0 614 64.8 60pesrcntormweeatrni_esl ..,..... 2 0.5 6, 8.3 491 23.2 299 31.5 D. Meu agoi 70 ur nlder: NumUer men ..................... 21 ... 3tl - 41 - 19 _- TntnlsecllunsI ................... 18G 100.0 822 100.0 {114 100.0 114 100 0 No atrpiexl nuclei ................ 170 91.9 ll 3.4 - 2 ].1 6omcbut, 60pereentatyPicei ..... 16 8.1 266 82.3 261 25D 95 54.7 60 nercentwmore atypical ........ ... ... 46 14.2 g3 24.1 77 44.2 i Sectinns with somc rpithelium present. - ~ Snmre: AuerLach, 0. et al. NS).

TABLE AB1a.-Su>nrr7ary of resuLts of xetrospcct'rce xtudias of tobacco use and cancer of the esophagus Autlwr, ueur. ruVntry, referenee Sadowsky et sl, 1953, U.S.A. (¢s2). Saangxhi et a],------- 1955, India (241). Wrndcr et al., I95i, Sweden (f2R1. Stes:rwaki 1960, Poland (350). Schwsrta et al., 1961, Franee (P4a), Wyndrr and Bross, 1961. U.S.A.and India lpto). T+kena et at, IOG9, J6nan (272). Bradshew and Schonlend, 1969, Suuth A}Aca (41). Mnrtive, 1966. Puerto Rico UaJ). Ameciann males Ameriean females Indian malm Indian females Relative riak raEu. Pe~cent nnnsmakera Ca.es fi]nntrt~Ie £ereene hearv amnkern Peraevt inhalerp mm~ng emakera All amokefe to nonamukers - Cnses 6mtruis Gaacs Cvntrn~s All amokcn Heevy m kcrs - -__ _--= an - 0 13.0 24. (ebont)85.0 (about)92.0 - IF.0 95.8 69.0 89.6 90.0 3.6 3.0 17.0 Tntnl n+noan! emnked 39A 3&0 6 6 dnifu lviynreltrei 16.8 ]6,U 6.0 15.0 48.0 330 -- - 3.4 4.4 41.0 48.0 27.0 1_6.0 - -- 5.1 3.2 13.0 28.0 __ - - _ 2.6 - 7810 94.0 4.5 _ Sv.O 23.0 15.3 3L7 31.6 6.9 - - Ss 1T,3 AveraO< D.mScrn) - 4+d,u smokcd ].5.3 . ..... 16.1 -- -- ~ -

TAe[.e A29.-_E-.ptriratmtuf s/vdics cul¢ccntiuq oral cu.rcinoprytasix Acthoq reac Animal ntry, and rufeFCncr. sti'Sn A. M,vhnd. 11. h'R`.nur_ncvand/ rduratiitn C.~MUterial.-- X-h:aer, 1952, II.S.A. (153). "B Swus and C57 mice. A. 1'nlntiny of lovwer lip mueocutaneoue rcglon. Il. 10 times in 76 days. C. Cigarettesmnkeentrute°._ N :aos1 c rus.[ 1' ngeT i:tr/:ls SIr _'I `rimFntnl nmmplp. SrJl", 36 Syrian A. Pu:ut glcheek Nuo:hrrnJ y.mryq myt/t 1959, hamster5. puurh_ Treatment~ m:ru rvara Arulpr: tnrrtvre U.S.A. U. :t per week for 16 AceLnne eolvent ... ........ ... .. 4 1 (JY6). Wcrhs. Benvenesnlcent ......-.... ..... 4 - - C. llenx (a) nyrene in nretnne nr bcnzunc. Hol,ti and Ermnla, 1456, 60 Alhlnn mice (40enntrnb). A. Painting of lips andnr,lcpvity. 13. 140 times in 12 No orul or labial chunges seen Finlnnd mnnths. (130). C. Tnbacco"tar`. Moore and Miller, 195N. U.S.A. (fBd). 80 Syrian A. Mutcrlulsnaked onto Golden hemstersa vad and +eeured in cherk puuch. R. Wads replaced F times in 2 yesrs. C. Smoke randenxate Banz (a) nn,ene. Nvmb 'fr'Ptmryt Orig(t:n( nn mbar 5'ua or Jng l yrnr Number tmnora Inftpmmation nad bnnn[ rcil hpnn+nEunia Cmttrnls ........... ............. 30 23 4 timnke rmrdensate .. ............. 911 56 32 Ben f iq naTem . .... ...... .. ..... 20 16 9 Strain IC and train W rat. A. Chamber fnhalnc9on f tnhn . n.make. r Onyirml n ndr n r 9ur /vore Aimcnf , t ra 6. Lail)' (".) . rmicnL 40 39 0/30 C. Up to St.~ mantTs. Famrimunlal ....... 190 68 5/62 (3/5 definite bRllhcI Vama) J Y7KJi.(4o

INTRODUCTION In,recent years, there has been increased' research on envirom mentall factors which nta:y adverselgaffecty the unborn child. The potential effect of maternal! smoking on the fetus has been of par- ticular interest because of the large number of pregnant women who smoke and because smoking is an environmental influence which could be controlled., Based on 11970 surveys ofl' smoking habits in representative samples of the U'.S., population, it is estimated that one-third of American women in the child-bearing age group of 15' to 44 years are cigarette smokers. What propor- tion of these give up smoking or cut down substantially on their smoking..during.pregnancy is.not known. EFFECT ON BIRTHWEIGHT Ep'sdemiolbgical and experimental st'udies have supported.the view that maternal smokingg during pregnancy exerts.a.retardinginflUenae on fetall growth: (tables2, 6)., Analysis of.over 100,000, births sliowsthat tliec infants of mothers who smokee duringg preg- nancy have a mean birthweight of 6.1 ounces less than the infants born to nonsmoking mothers (table 2).. Several studies have docu- mented that this effect i's independent of other factors known to exert a negative influence on infant hirthrtvei'ght, such as elevated maternal blood pressure and small maternal.size (1,.38, 39). The reduction: in, infant birthweightt is great2r among heavy smoking motliersthan:light smoking mothers (12,21, 23, 30, 41„50;,58).,,and has been found inpregnanci:es t'erminating in each trimester (1,`?,. 16, 23, 40, 51, 54). In a study of more than 48',000' women, Under- wood„ et a].. (S1) demonstrated that infants born to women who smoked during paat of their pregnancy were significantly smaller than infants born tononsmokers;o and that infantsborn to,womenn who smoked!t'hroughout their pregnancy were significantly smaller than the infants born; to women who smoked during parf of their pregnancy. Russell, et al1. (39) havee presented evidencethat al- though infants bornn to smakingg motherss weighed lesss than tltoseof nonsmoking mothers, they grew more rapidly during the first six months of li2e- At one year of age, children born to smoking mothers weighed nearly the same as those born to~ nonsmoking mothers. They concluded that smoking exerts,a retarding influence 389

' TnB1.H 1.,SurrtmarnJ of aztet(lods'used in stlldy of sonoking and he4.vnan pregnancy (cont.) Author, year, - Retrospective Number country, --oe~of referenCC praypectiY6 persons McDonald and P. 177 L6erref w. f.anfnrd, ians, U.S.A. (,y6). Patersun et al., R. 7,740 1965, U.S.A. (t4). Data eollcction Case eelection Comments Cooperative study i vnlving 17 hnp White, nomnrried p_rimigravidaa re- e.ing ohstetric c . r a g- yar perfod.-_. .. . . Incmdes only those maltiparas whoxe k pitala in 13 statb. using U.S. . Air prior infanta weiKhed i2,500 Force ubstetricnl code. zrnms (Caucasians). All preg- nen[Ie5 with any ompllcatlon were Ehclutled. Cea9rean aectl4na and hlduced delivery wcre e - claded. .- Regular attendees at prenatal elinic. Robinson. P. 1,614 Interview. 3986, Burma (a>). Underwood etal., R. 4,440 1965, U.S.A. (so). 46.8 percent of .w.omen smuked cheronts. Inferview by obstetrles] resident. f'uerpera] xomen from Roper Hus- Women frnm RaVer Haspital Data wns obtained on 16,159 prea- pital and Medical College Hospi- .. were of above a rage eco- nancies frothe. 4,440 women. tal. Onlr inixnls weighing >1,000 m c st t. s. Women from grems wcre included. Medical Colllege Hospital in- eluded Neqro and white patients. Downing and _R. 6,659 Review of clinir .. nrds from 1952 _Six-yosr total of nbstelrical patienta Chanmsn, to 195k. at rlinic. 1966. U.S.A. (7). 94VS9C4E0

Author, A. Method. yevr,- Animal It, Freauenar end/ couvtry, and or duration. reference strain C. Material. Peacnok et nl., 124 Syrian A. . Pecking of ehgek 1960. Go_Ide_n hamsters. pouch. U.S.A. B. 1 year. (210). C. SnuR, Tobacco, Bland material. Dunham and Syrian Culden A. _P_aekingof cheek Herro)d' hamters. pouah.1068, B. Narmal lifespan or U.S.A. 5'30 months. (d4). _ C. Hetel Ouid ingredients 7-12 dimethzlhenz(a)- anthracene (DMIfA), Methyleholantlvene (MCA) in bgeswaa pellets. T-ABP,e A29. Fxperiv7)ental sta6dties xanrsr-ntin n I ca'rcinoge,ne&i& (cont.) Aesults o tnmars noted in any of the 42 animals surviving over I year. OriyixaL Trentment m. ber nu setelnnig ................... ae6 - DhiliAandMCA ............. 71 i9ypcrpEaeia Madipnnnt and(orin- poacA Snr ara flan motion ta+~.mrs 99ry overl~year ~19 - 5fi/]3 ovm6-30 mnnths - 23/6fi Moore and AlLinu hnmstcr A. Painting ornl muco_sn. Christo- exteriorized A. A per week [nrfi83 Treatment: phersnn, ural annch. days. Cnntrolo ....................................... 1962, C. Cigarettecmake Smuke<onden.ate , . .................... ......... U.S.A. onden.nte. (tsa). DMRA in 0b1{ DMHA_ .......... ............................... petralntnm. 8nlley. CAP3 strain 1963, mlce. U.S.A. (St9). A. Ultravioletlight expoame tn and painting of lips. B. 3 per week for 98 eks. C. D( e) P in acetone Cigarette emoke U V light. Treatment: Ultraviolet light and 6 cigarette smoke .................... 40 9(a)P and UV light .................. 40 [IV light ............................ 40 ?(a)Y .............................. 40 dn imn[s +aith tes ons (time) 0/IH (at 392 days). 0, 20 (at 337 days) (10 showed hypcr- keratosis). 14/21 m c-roscopic c ers (at 90 days) ( Inva$1\'e 9au4mn119 C9neer originating in the skin at the edge of the p9uch). Dnzutiun Tumors eoka 94 - 48 94 45 9%S94cU

°PAB1.ID A3].--5ummmry of inethods lrr4ed in retxospeetive etudies of tohtticco use and caneca' of tho esophagas (cont.) Authar, ----- _ - ---~_ .- - "year, Csaea Controls 6S6S94£0 reference Sez Number - Metbodefvclection Number Methodofpelection Schwartz et el., M. 362 Admieplnne to hospjtals in Paxis and s 362 iiea{tb> indSViduels admitted to same hns- 1D61, few 3arge provincial cities since 1954. yftal because of work or traffic neei- Frunce (349). dents-matebed by 5 year a4e group snd time of admiss(an. nd W'ynder and Bross, 1961, U.S.A. (9t0). 57 Wynderand 67 Sross, 27 1.9G1. India (dl0). Tekano et al.. '. 1(7 I963, Japnn (3TB). 33 Ganeer patients se_en in Mem_arial tfewt- tnl, New York City, and Kinggbridge and Prooklyn VA Hospitsls-during 1950.6Y (86% white). Seme hospitals end asme time pesiod ea_ male uatients (86% white). 150 Pstients aeen in same hospitals during same time period with other tumars. 64 j.-malignant tvmnr: 36^,i-beign con- ditions. Matched by age with cancer pntienta. 3; Same es with regsrd te male eontrols. 43?c had malignant and 67% benign_ numora. Colleetion of dAtn Interviewed by team of apecinlly trained inter- wers who interviewcd the largeat pruportion_ pussible of aLL caneer_ patients. Cases and mstehed controls inter- viewed by ®ame persnn. Dafw collected by trained inte[Yiewers. Admitted to 1'nte Memo.dsl Hospital Bom- 134 Patients with other forme of cancer ex- Interviewed by one per- ba5. cept for oral cavity nnd lungs: as well son. sa varlous benign diseasee. 16% of male and 4% of female eaneer ceses ' histnlo¢lealh• oonfirmed. Patients with esopha¢eal caneee. 167 Patients with canecreu.+ and non-can- Interviews at varioua 33 ~eraus diseases af nnndigestive urgans. huspitela. Caees and cnntrols lYe-matc.hed.

TABLE 1.-s^ummaay of methods used in study of smoking and hunaan. pregnancy (cont.) 6OCt6S94tc0 Author, yeaz, Retrnspecti.ve Number ntry, of Data eollection referrnce_ Ruospectiue nereons Mulcahyetal., 1', ton InterviewLr¢hvsieixn. 39i0, Irelantl (29). . 'W4J'y+'"v Csse xeteetion 100 mothers nf tcrm infants who e free from all significant medi- cal and obst~2rical complications. AII were bi4ween 20 and 30 Years of age and x re Para III nr less. AIl_ had normal dcliverieg. Half .. smnkers of 10 or morc ciqn- reLLe.s per day. 1 Comments {.

on fetal'.growth and that after delivery this is largely compensated forby a: period of morerapid growth. As dbcument'ed in more than 1!"i prospective and retrospective studies, smoking mothers have significantly more' infants who are premature, as deffi'nedby weight albne (<2,500) grams, than do non- smokingmothers (table3):. Buncher (4); studied the mean dura'- tion of pregnancy in smokers and nonsmokers in a survey which included 49,897 live births, He found that women smoking 20 cigarettes a dayhad a mean length ofgestation which was approxi'- mately one day shorter than that.of nonsmoking women. He.calcu- lhted that this shortening of gestation is enough to account for only 10 percent of the known~ rediuction in birthweight.that is associated with. maternal smokins, EFFECT ON OUTCObZE OF PREGNANCY Some controversy has' surrounded, the question of. whether ma- ternal smoking during pregnancy is associated with an increased risk of spontaneous abortion,,stiilbirth, and neonatalldeath. Table 4 summarizes the studies which have dealt with this question. Some of the studies did not demonstrate such an increased risk (T„ 50, 51), while others did (12,.23,.:33,. 58). Many of these reports (7, 23, 33,. 34,. 41, . 49;, .58). were based on retrospectivee stludiesandi'nclud'ed women delivering their infants in hospitals and infiantswhose' names appeared on listings of newborn children (table 1). As Russell, et.al. (39)' have pointed out, such studies may be sub- j'ectto selective bias sinee they tend to underrepresent women who, have aborted. These retrospective studies.adso did not systemat- ically control for maternal social class, parity, and maternall age,, all of which are related to.the outcome of'pregnancy and'. also are, related to smoking inn some populations. In a prospectivestudy of' morethan.2',000pregnant.women„Russell,e et.al. (;t9)) have:demon- strated a:significantly higher percentage of unsuccessful pregnan- cies (that is, abortion,.stillbi!rth, or neonatal death) among women who smoked duringg their pregnancy than among those who did not. Ilie interpreted his findings to mean that 20 percent of ". .. un successful pregnancies in wom.en who smoke regularly wouldi have' heen'successfull if themother'hadlnot been a regular smoker" (38)~. The Second Report of the 1958 Britishi Perinatali Mortality Sur- vey published in 1969'is one of the largest prospective studies to deal with thi's ques8ioni (5). , It.iincluded 98 percent of the total bi,rths registered dhring one week in March 1958 throughout England, Scotland, and Wales. In this studyr, a large amount of obstetric and sociobiologic information was obtained on 17,000 singlpton births.. This study reported that "the mortality in babies of smokers was significantly higher than in those of nonsmokers." The increase in 340

TABLE 1.-Summary of OnCUaods used in &Ctldy of smoking and f4tbnuan p'Regnancy (cont.) S46q94EO Author, ~ - rear, ketrospective Nomber ntr" or - of Datacullectiun Ceseselectiun Commmte ieferenee proapective peraone - -~ - Yerushalmy, F. 982 Formquestionnalre. Pregnaneies terminxting in abortion 1962, t were excluded. U.5.A. (53). Murdoch, R. 500 Peteonalinterview by author. 1963, U.S.A. (yo). 0'Lene, R. 1.031 1963, U.S.A. (1a). Zabriekie. R. 2,000 IJ63. US.A. (68_). Yeashalmy. R fi,A00 1964, iI.S.A. (5b). MacMqhon et al., H. 12,192 Standard U.S. Nnvnl Obstctrical Code Sheet wuu used with supplementrl qucstiona. A_dditinnal infprmatiun was oblained from prenatal hls- tm'r. History was obtained during the postpertum period from _2.000 eon- aecutive births nveu a 6-month period. 1965, U.S.A. (84). Mail questionnaire. All mothers deliverin_g at Nebraska Methudist Hospital frnm Se_ptem- Ler 1962 to January 19fi3. i Uyt Coucesian womea who had "Smokers" defined as those inqle pre gnancies delivered vs smuking reg ularly each day. _ ginnlly u Yet a 6-month period. _ _ Twin deliveries were umieted. All w were members of Kaiser 5.381 whites 1_.4_1_9 _Neg_roea. Foundation Health Plan. Only - pregnanciey lerminsting in aingle, livx births included. All races et cept whiteaand Negroes were ex- eluded. Mnthem of single, whitc, legitimate Rirthweight based on birth live births. Mothers wee restdents eert_i_Rca_te. of Musseehusetts end delivered in May or June of 1963.

TABLE 3. Maternal smoking and prematurity (cant.) (Figures in parentheses are the abaolute number of premature births) Author, referenfe Duration of Weight geata£on Perecnt of premature infants Mean duration of pregnaney Nonsmokere Smokers Nonamokers Smakem P_ e_teraon <37 weeks CiparetACa perr day etal., 1_.3_ (58) 1-10 1.4 (16) (contd.) 11-20 2.3 (38) (34). >20 2.4 (11) Comments Robinson <2,500 g. 16.5 (152) 31.0 (181) (9>). Underwood t l <2.500 g. G LtipareHee perday Percentagee and absolute num- f ature bi re ths b e ., e (5U). ruuu: 1 4.5 (108) <10 4.2 prem a er o r based on 16,168 pregnancies 10-20 5.9 reeorded in 4,440 women. <20 7.2 Graup 1. Smokere vs. non- li 7.6 (42) <10 12.6 mokera p<0.026. 10-20 12.3 Croup IL, III. Smokem ve. >20 15.9 nonsmokers P<0.001. III 9.9 (770) <10 14.1 - 10-20 14.8 >20 10.2 Downing No data No.data 2.2 (66) 3.3 (88) and Chauman (>). Reinke and <2_.500g_ 10.6 (163) 16.7 (210) 37.7 weeks 37.67 weeka p<0.001 Henderson <35weeks 20.3 (113) 22.8 (368) p]0.06 (SC). S9P-.94EU

TABLE 3: Materna! smoktirtg and preznata4.ryGy (Figures in narentheses nre the absolute number o£ nremature births) Premature by Author, ref rence - rati D of - Percent of premature infants e - u on _ Weight gpstatiori Nonsmokers Sm,~k4re Yervshalmy ' 4'• lbs. 5.9 (36) H.1 (80) (54). Murdneh <2.5U0 g. (8) 13.6 (35) (xul. (l'£.anc . <2.500 a. •i.1 (29) 11.8 (55) (Y9) Zabriskie <2,500g. 3.83 (40( 9.93 (95) (Wd). Mean duration of pregnancy C Nonsmokers Smokers omments Cigarette8 perdaY: Prvtma(urtfy <10 ........ 6.54 (260) 10-20 .....- 9.11 (305) 20-30 ... .-.14$0 (264) >i0.... ....m.5a (3N) YerushnlmY <51bs.8uz, {Yhite ........ ....... .~.5 (112) 6.4 (198)/n60.01) Infants of smoking mothers (54). Neura ............... 4.9 (46) 13 4 (64) weighed less than infants of nonsmuking mothers in ¢aeh gestationnl age. <39 weeke White . ..............t5.9 (188) 0.5 (140) t DiRerence between r.mokers and .. . Negro . ...............13.4 (125) 16.7 (R0) nonsmokers not significnnt. McDonald <2,50pg. 6'4gnxottueperday end 4.6 (4) <!0 4.8 (2) f.xnford >10 8.3 (4) (16). Petcrson <6,500 g. Ciparattea Der dav Overall incidence of prematurity etal., 2.5 (111) - 1-10 3A (35) smokcrs vs. nonsmokers (3). 11-20 4.6 (80) gnificant at p<0.001. s~ a >20 3.4 (16) _ _ - a t

TASLE 8. Materna2 amoking and prem¢turitnj (cont.) (FiRUres in psrenthe_ses arq the absolute number of premnture births) Premature by Author, f fl i f Perccnt nt premuture infmLLa Menn dnratia of pregneney C t re erence Weight urat on o uesta6on Nunsmokers 9mo kers Nunsmokers Smokers om en e Underwood <?,500g_. Ci._aareSma ver dna prematurity by birth weight roee et sl., 5.4 (1,414) t-10 '!.5 (571) directly to a aignificant degree (6t). ]_1-30 9.4 (1,368) (P<0.01) witheach smoking - - <36 weeka 5.9(1,442) >30 1-10 11.2 6.9 (146) (525) c.atesory. Data suggested that smoking in 11-30 7.5 (1.089) any trimyeter decreaaed btrth >30 7.5 (118) weight. Buncher IIirthe t Smokes 20 cigarettes per day. (6).. Male 39.65 weeks t 39.36 weeks Femalc 29.69 weeks t 39.51 weeke Butlerand <2,600g. 5.4 (602) 9.3 (4:13) Aihermen A significant (p<0.01) difference Ter was found between percent of and Guld muthere who smoked mdthose who had premature (47). deliveries end the control grnup.

TABLE 1.-SatrnntaTu of nbet)tods used in study of smoking and lapamtnn pregnancy Author, year, ntry, reference Retrospective Number nr of - Data colieetion Vrnspeetive pe[sana Simpaon, It. 7,499 1957. U.S.A. (44). Lowr, H__. 2,042 1959, England (9d). Case seleetion Comments QuesHonnaire was filled mtt 48 hours - after delivery for all patients at Sa_n Rernaodino Countr Hospital Multiple blrths cxch:de_d. The connty hosPita3 population was diRerent, with 50.6 per- r ont of the birtha being for AYCars, Same form ueed fnr. Mexioan". 2 yearx at St. Bernnrdines Hns- pital and Loma Linda Hosnital. Que6tionnairc was fl4d nut for every Non-Euroeeans and women with Soripl wrorkera Perfarmed wumsn deRVeting at one of e_ tw n htrths were excluded, interviews. Birmingham hospitals nver a 5- month period. Frazier et al., 1961, P. 2_.73_6_ (a) Intarvicw. Ih) Prenatdl clinic history. All Neero .omen n seen at Baltimore Nnternity ]nterviewing Service in Nonvmukers include occenional amukurs. U.S.A. (12). (r) Rirthnndstillbirthcertificate... 1959 who w scheduled for de- livery at Baltimore City Hnayital and who received prenatal care i chnic of Baltimore City Health Department. Herriot et al., it. 2,745 1962. Scotland (16). S_e_veland R. 1,416 Rcth, 1962, U.S.A.({t?. Questionnaire filled o_ut for Aber- deen city residenta whn were de- livered in Aberdeen City Hospital over a 1-sear period. 1,600 conaecutive patienta admltted I.mluded werc private and ward pa- Wom were considered to Newark Beth Lreel Hospital tients. Negro and white paUents, mekera even if they emnked were interviewed. primiNravidas, and multiparaa; onJy 1 cigarette perr daY- [:eaarenn sections, elective induc- - tinns, nnd multiple pregnanriey cluded. v4V594,£©

`!_ 1 TABLE 2.-Maternal gmofcing and infant weight (Numbers in parentheses indicate absolute number af infante i respective gruuRa) infant weight Author. reference Non moker Lowe (3J) Male ......... 'L431bs. Female ...... 'f331hs Total ........ 7.33tbs. E1Q C+L ver (607) 5.16 (639) 6.44 (1,146) 6.98 4Tetpga day (1fiY) (163) (350) F_vsziec 3,080g. (1,T1T) et a].. (lE). i(erriot Nadetn ............... (1,47 etal., ~~ -- (ls). Savelsnd White ......., $,374 g. (9N2) Roth Negrn ........ 3,173g. (364) Effect Rect on infant weight was independent of maternal age, parity, or complica- tiuns of pregnancy. Nonamokers include occssionel amokers. Effect on infant weight wss independ- ent of maternal age, parity, height, or sncial eloss. Giyarettce ycr dny InJant weiphy W hite smakers: 1-10 3,210 e. (161) 11 20 ............. 8.198g. (184) >20 ...........~~ 9p10 B• (83) Negrosmokers: 1-10 ............. 3.0429. (169) 11-20 ............. 3,012 s. (64) >20 ............. 2,968 g. (14) Murdoch 91bs.S.5oz. (242) 6 Ibs. 16 oz. (256) 8.5 oz. CiDarettee ~ (90). pe_rr day Infant weinhE lliHerencein mean weight pf infant of smoker Commente Smnker vgrsus nansmaker >iP sigare6f€a pc_r day 7.05 (165) 6.67 (147) 6.87 (312) 170, 2,024 g. (1.019) (6 nz.) ) Nodata (1,272) 160g. (6.6oy.) 3,141 , (428) 2339. (8.2oz.) 3,031g. (240) 1429. G 1-10 .......... 7 lbs. 2 oz. 11-20 . . .......... 6 lbs. 11 oz. >20 . . . .. .. .. .. . 6 lbs. 30 oz. >40 ............ 6 Ibs. 8 oz. . ............ . .. ... 0'Lan (ta)~ 2,97A g. (666) 2,938g. (465) 40g. ( 1.4oz.)

TABLE 2. Maternal aluaking and iufqz}t weight (avn6.) (Numbers in parentheses indicate absolute number of infants i respective groups) Author, refer ]teinke and Henderson (SB). Nonnamaker _ - 3,136g. (1,@42) Kize* (i9). Data not available Underwood et al., Smoker Data not available 238ig. (1,614) -- Cionrcttc. ~- - pc+ dnv (51). 3,395g. (24,866) 1-10 ........... 3,286 g- (7,609) 11-30 ........... 3,196 g. (14,450) >30 .........,. 3,182 g. (1.670) Mulcahy and 113.2 oz. CiC.'ettee pe:r dng K 1- 4 111 4 nnggp (Y8). . ........... oz. 6- 9........... 102.3 oa. 10.-14 ...... ..... 102.0 oz.. 1619 ........... 102.9 on. >20 ....... ,... 102.4 nz. RuearTF-- BP et el., <140G 09 117.2 :L .7 oz. (9E47 107.2 =t 1.0 ov. (d96) (89). 140/ 90 114.2 i 1.2 oz. (240) 108.9 ~ 2.4 uz. (117) >150/100 99.9 i 2.6 aa. (l38) 90,8 2 5.8 az. (86) Butler and Albermen (s). 3,376 g. (11,146) 3,205 g. (6,666) m _MuleahY at el., 8.82kg. (60) 8.43 kg. ( 50) V a (P9). Difference in mean weight of infant of smoker -- Commente .cr.rua nonemoker --'- 14Eg. (6.2ax.)(pG0.00) 97 g. (3.4 oz. ) Total number of patients-2,095. 109 e, (3.tl oz.) 199 g. (7.0 uz.) 213 9. (9.Soz.) The efteet of maternal smoking on fetal 10.0 az. weight was independent of mateenel 5.3 oz. parity, age, height, educational level, 86 oz. attitude to preenmcy or work during pregnsncr. [ather•e eacial class, ean- so.3's social elaee, and eex of the c_hild_ or premature delivery. 170 g. (6 oz.) Reduction of mean birthweight of babiea born to smokera w independent of unduly hi_¢h pmpurtfon of babiee bpm ureterm, and matema] faetore Includ- ing social class and maternal height. SJt6 F. (14 o.z. ) z"Ssc4eo

, a $ TABLE 3. MndernaC slYtoking and prematurity (cont.) (Figures in Varentheses et'e the absolute numberr of premature births) Author. Premature by Percent of Premature infants Nonsmnkern Smokers Mean duration of pregnancy Nm.amnkera Smokere Commente Number and Percent of p_ remature infants: Nunsmakers . . . 6.39 (328) Cigarettes per dayt 1=5 .... .. 7.06 (47) 6-10 ...... 11.18 (g9) 11-15 ......11.30 (31) 16-20 ......13.6 (57) 21-30 ...... 25.0 (13) >30 ........83.3 (9) reYerence Duration of weight g£bCGtion Simpson <2,R00 a. Name of hnepital: 444). County .......... 7.77 (1441 11.4R (96) I.umaLindn ..... 6.16 (86) 1213 (49) St_Nernaraines. .. 521 (98) 10.50 (119) Lowe <260 days 6.4 (5P) 10.6 (58) 279.9 ds_ys 258.5.days At each week of gestation, the fs.f), - mean birthweight was lower in babies of smokers. Rrnaier <2,500g. 11.2 (175) 18.6 (179) 339 weeks 38.4 weeks Infants of smokers weighed less_ et sl.. than infants of nonemaktt__s (1E1~ for wide rangE of preg- nancy duration. Herriot No.deta Nodata Socialdavs: - 2.745 patients in the study. et al., I sod 11 ......... 4.0 4.8 At each week of geetation, the (16). III .............. 3.5 6.8 mean birthweight wss lower IV and V..... ... 6.3 12.6 in babies of smokem. 36 weeks White ............... 2.6 (10) 4.9 (21) White .39.8 39.4 Roth Negro ...............18.5 (50) 11.3 (27) NeqrO .38.8 38.8 . (4e) t<2,500 g. White ............... 1 8 (7) 3.S (16) t Prematpre by weight but ma- Nexro ............... 3.6 (13) 8.3 (20) ture by date (>37 .weeks).

TABLE 1.-Sutnnary of rnetlmds used in study of smoking and human pregnancy (co Author, year. Retrospective country, or re€erence prusyective Number of persons _Rasenholt at al., ~ 6. ?,OY3 1066 U.S.A. (x&). Reinkeand Heuderson R. 3.156 1960, U.S.A (SC). Kir 2.095 1967, Vmczuela (19). Underwood et gl., P. 48,505 1067, U.S.A. (st). DuRus and MecGilll.rey, 196tl. Scutland, (8). Mulcahy a.nd Knngqs, 19fiN, Irelend fE8). 1 ) Data nellection Case acleetiun Cumments Epidemiplyaie euestionneire. Mvch Study puyulntion was identified by 95.A p¢reent of mothers were data collected-over telephone. Ad- rhe listing of newborn infants in white. ditiunxl data obtained from birtb a Scattlr newspaperr during May, rerti6cates. June, and .iuly of 1964. Twins were exNudcd. Registration data of prenatal clivic Negro w who delivered _sin_ gle_, live inf nts from 1962-64. Patientn r eiving care at ' concep- r,nn yalo ia9" in f!arncsy. Code sheets submitted from 44 warld- Women with singlc pregnancies de- wide val nstallatinns. Code liveredof infnnts weighins m sheets w cre completed hv the at- than 600 grxms between auly 1e tendinR ahysieian uuon the mo- 1963, and June 30, 1966. ther's admission to the labor room. Antenlalclinic reeords. All "booked" married city primi- The number of cigarettes gravidae attending the ntenatal smaked was not c0nsidercd. rlinirs during 1960, 1964, and 1965. Hasnitalrecordrevicw. Mothers admitted to the Coombc Huspttai from April 1953 to_ Oc- ' tober 1964. Lz4VS9L4C0

TABLE 1. Sum'. Author, year. Retrospect ive Number country, or vCffEEOGe prnspectiv uf e persnns Russell at sl., 1'. l,1 l0 1968. _ _ FEngland (J9). Tokuhate, ]t. 2,016 1968. UU.S.A. (48). Runcher, 49,897 1969, U.S.A. (4). 8utlersnd P. 17,000 Albermm, 1969, Great Britain (5). Terris and R. 197 Gold, 1969, U.S.A. (4f).. y of methods used in study of smoking and human pregnancy (cont.) t:s9e selection Cemments Data callecte d by Senior research Wamen attending the two main ma- Included some threatencd abor- m'dwives over s 4 to 6-yeer termty units in Sheffield, who tions and some with "bad" period. "comprised reaennsbly repre. obstetrical histories, eentative samplcS' Multiple preg. nancies were . omitted. Personal interview or mail question- nsiue of surviving family members. Data obtained from IS.S. Nevy ub- st tneal study from 1963 to 1966. Smoking data obtained by physician at the time of mutherb adm_iss_io_n_ to labor raom. - Women selected from Memphis end Control group taken frum same Shelby County death registry who registry. They died of causea died of cancer of genitalia or other than cancer and mera breast s e 1950 and who had matehed for r e, age at been marrVed. death, end year of death. Women with single pregnancies de- Includes c reported by livered of infants weighing mnre Undcrwood et al. (4r/ in than 500 grams between July 1, 1967. 1953, and June 30, 1965. The D tis_h Perinetal Mortality S.ur- 9N percent of the tnt 1 births reR- Another 7,000 perinatal deaths vey of 1958 when a Iar¢e a unt istered during I week in Mernh were aurveyed by identical of obstetric and sociqbialogic in- 1958 throughout England. Sent- methuds over a 3-month formation was obtained fnom birth attendants, records, and at Inter- view with the mnthers. land, andWales. period. _Public Health Nnrse tntervlewed each mother on first or second pnst- pertum day. Premature 14egro ward births (<2,5U0 grams)with no known cause of prematurity. Controls mxtched by e ex, birth order wore of infant. age, andmnritsl status nf the mother. OMVS3440

precelampsiay smoking appears to increase the risk to the fetus be- cause of low birthweight and increased perinatal mortality (8). In a case-control study of sudden, unexpected death in,infancy, Steele, et aI. (w6)~ observed that the percentage of. smokers among mothers of cases of sudden, unexpectledldeath, 61.2',percent; was significantly greater than, the percentage among mothers of con- trol$, 39.5 percent. The possible teratogenic effectl of maternal smoking hasnot been. adequately evaluated. Although it does not appear to be a major factor, there have been too few studies to determine whether ma- ternal smokingisa.significant teratogenic risk: (5, 23.,,28, 50). Cbncern has been expressedi about the possible Iong-term effects on the children of women.who smoke during pregnancy. Butler (6.) recently reported the results of a follow-up at age seven of the babies studied inithe B7itishPerinatal study ofi1958. He foundthat the children of the mothers who were "heavy" smokers during pregnancy showed significantly decreased height, retardation of reading ability, and lower ratings on "social adjustment"'than the childremof nonsmoking motliers: Tihedifferences were independent of such factors as social.class, age of mother, and parity. EXPER'IM,ENTAI6~ STUDIES' In the past decade; research on the effect of smoking on pregnancy has increased. Summaries of human and animal experimental', data i.n this area of studyy are found in tables 5 and 6, Elevatedi carbon monoxide levels have been found in maternal and fetal blood in women who smoke. Carbon monoxide is an i'nhi6itor of carbonic, anhydrase and as might be expected the activity of this enzyme is. decreased in the cord blbod of infants whose mothers smoke. The significance of elevated fetal carbon monoxide is not.clear; how- ever,, in an extensi:vemonographe on this.subject,. Longo, (22) has coneluded that ".,. . the decreased availability of' oxygen resulting fromm elevated. (fetal)) earboxyhemog]obin levels, is probably in- jurious to fetal tissues."' Other changes noted in the infants of smoking, mothers have included a mild metabolic acidosis and a higher mean hematocrit (56)_Twuo studies, (9; 52) have shown that placentas of'women who smoke have a significantly greater ability tohydMox3datebenzo[a]pyrene than the placentas.from nonsmok- ers. Such.findingsh suggestthe possibility of fetal.exposure to:o car- cinogens; however, the significance oftfiese findings is presently- speculative. Early animal studies (10, 42) showed that rats andi rabbits exd posed to: nicotine or cigarette smoke have smaller offspring and more wnsuccessful' pregnancies than control animals. Recent radio- .07

TAeLe 4.-Cmroparison of abortion, stillbirth, and neonatal death in smoking and nonsmoking mothers NS = Nonsmnkers $M = Smnkrrs Numbers Rates/1 IWU taml Lvohe Author, Total births Abortions Stillbirths Neonatsl deaths Ahortions Stipbirths Neonatal Comments deaths reference NS SM NS SM NS~-SM NS 551 NS SM NS SM NS---SM Lowe (s5). 1,1.55 668 t47 123-0 t30.U t Iveludes first-dny deaths. . . Fraaier 1.717 1,019 tll tI6 40 28 t6.4 t15.5 23.3 27.6 t°Fetaldeath". etal.. (12). Sseel and White 383 428 2 5 ~~ 6 8 --~ ~ 6.2 7.0 10.4 - 4.7 Roth Nearo ' (41). 364 240 8 6 6 3 22.0 16.7 13.7 12.5 O'Lgne 1,027 887 91 112 88.6 126.3 (33). Zshriskie P,650 2,769 250 343 4P.7 ]25.7 _- (58). Yerushalmy (54). White 3.318 2,163 40 30 12.4 13.9 Necrn ll39 480 22 11 23.4 22.9 Peterson 4,455 3.285 0.6 1.2 4.0 0.9 et al., 49VJJM4©

1 TABLE 4-Comparison of abortion, stillbixth, and neonatal death irt smoking and nonsmoking mothers (aont,) N&-Nonsmekets SM=Smokera Numbere Ratea/1,000 total births Author, Total births Abortions Stillbirtha Neanatal deettis 4\bortipns Stillbirths Nennntal deaths Comments refere.ce NS RM NS Sbf NS SM NS SM NS SM NS SM NS SM Dowutng 3,029 2,630 126 107 =32 /29 41.6 40.7 }1 0.6 j11.0 } Stillbirth plus sad Chayman f2/. _ neumtel death. Underwood 24.89G Y8.629 - 8.4 8.7 }11.8 12.1 j } Excludes perinatel N aJ'• _ _ deaths in Premeture (51) _ infantn (p>0.05). Russell 76P: tlncludesaboamo' n etel., <140/90984d9G i24 }32 (=27 (((j66 , etillbirth and (9v), =140/00 340 117 j16 t8 j 41 ~ 68 , neonetaldeath, >140/90 138 36 i20 }ll I1145 314 j Bload pressure. Tukutsta White Data baeed on use_of (49). 2.555 743 1246 }112 j96 }151 clgarettes only. No_nwhita -} Includes stillbirths 1?86 350 }l4d }6d j141 }183 and miscerringee. Butler 11,145 4.660 215 129 146 FO 19.3 27.6 13.1 17.2 and Alberman (5). v" 6R6S9LE0

W m TnRLE 2.-Materna( gmoking and infant weight (cont.) (Numbers in parentheses indiute absolute number of infants in respective grouDs.) Author, erence Zabriskie (se). Infant weight Smoker veisusnonsmoker 3.320 2. (1.043) Mscblehon Male ........ 1Z4.0oz.~ (3,053) etel., Pemele ...... 119.9oz. (2,906) (eA. McDOnsld ana Lnnford (26). Nunsmoker 111.68oz. (87) unaerwo.od et al., (s0). Group: 1 . _.... II ....... III ....... 3,522, (2,406) 8.3049. (667) 3,126 e. (7.775) 8,091 g. 1 (957) 229 a. (B.1 oz.) 116,3 oz. (2.173) 7.7 oz. 111.9 oz. (3,011) 8.0 oz. L:ght emover Heuvy emoTres No sign(1lcsntdiHerencebe. 110.83oz.(42) 109.38oz.(q8) Ditferenee in mean weight of infant of smoker tween mean hirthwelghts. Ci9arett¢a - - - - per day For>20 cf0orettee Yer day <10 ........... 8,349 g. 368 c. U2.5 o_a. )( V<0.001) 10-20 ........... 3.2399. }(1,720) >20 ........... 3.169 g. <l0 ........... 3.171 e. 212 g. (7.5 oz. ) ( p<0.001) 10-20 ........... 3.146 g. }(660) >20 ........... 8.092 g. - <10 ........... 2.9389, 115 g. (4.1 oz.) (p<0.001) 10-20 ._........ 2,966g.f(3,o40) - >20 ........... 8.011 g. . . Commente CiDa.eften Ptr daa Infane um(yhE <IO ............. 6,205 g. (260) 10-20 ............. 3.0909. (395) 20-30 ............. 2,970 g. (264) >30 ............. 3,190 e. (36) Cignrettes Infantwcight perAay louncca)-- ~ ~ Male Female <f0 . 121.2 (668) 116.6 (595) 10-20 . 115.2(1,262) 112.2(1,259) 20-40 . 114.6(1,_166) ,083) 108.9(1 >40 . 1111.2 (66) _ 111.7 (49) Patients were divided into 5 grouFS: I.... Pcivste patients of above sv. ensge economic statua. II.... White patients of averege ecommaic etatu.. IIL..,Negroepatients of law eco• - mi atatua. t Total for all~emokers In each group. RavenSolt Male ......... 7.801b. (171) 7.211bs. }(167) .5$Iba. (9.4nz.) 1 Smoked >7b00 cigarettes durini preg- et a., Femsle ...... 7.50 lb.. (150) 7.051bs. }(ISl) .46 ]ba. (7.2 oz.) nnncy. (J5). T8VS9tLEO

TAaLF 5.-Human experFmentat data on smoking and pregnancy (cont.) Authoq - - - - veat, eountry, nesiyn of atudy $eeulte Comments referenca -- Nebert et el., Aryl hydrocarbon hydruxylase activity was de- Siznificantly hikher (n<0.001) levelp of_ aryl bydro- 1969, termined in the otacentas obta:ned from 97 esrbon hvdruxylase were found in women with U.S.A. (31). w.emen at the time of childbirth; 46 uf the a history o_f ciKarettr emoking. - womgn nmoked between 20 rd 49 cigarettrs per dgy durina preg_nsney snd 51 wumen were non- smokcre. Welch et al., genzpyrene hydroxylsse and.minoaso dye: Erzymee were found in the plecantsa feom all 17 1969. N-demethylase activity was measured 1. 17 hy- smokers. Ma deteetable actiuity was obseeved in U.S.A. (5t). mnn plecentar obtained after childbirth Irom the placentas of nonsmokers, smokm•s and in 17 human piscetns nbtsined Lram nansmokera. --~--

Contents Page Summary ............................................... 423' References ............................................ 429 LIST OF Z'ABLES'. 1'., Smoking and peptic ulcer disease mortality ........... 424 2. Summary of results.of retrospective and cross sectional studies of peptic ulcer and smoking .................. .. . 425 3., Methods used in retrospective and cross sectionalstudies of peptic ulcer and smoking ........................ 427 421 ~4 - `-

I

mortality rate was found for both stillbirthsand neonatal deaths, andi was somewhat' greater' for stillbirths but not significantly so (see Ehtler, table 4'). The aut'horsstate that "'...the differences between mortality rates in babies of smokers and nonsmokers prac- tically disappear when they are.compared within groups of similar birthweight's .... It therefore seems reasonable to conclude that the increased mort'alityrfound in, babies of mothers who smoke is ac> eounted for by the overall excessoflow birthweight babies in this group.,. ." with theiirattend'ant high. risks. In 1964, Yerushalmy (54) reported on a group of'6,80o women whose pregnancies terminated in single, livebirths, excludi'ng.still- births and aUortions, The study was prospective and was controlled for maternal age and parity.. He noted that neonatal mortality in infants born to smoking mothers and weighing less than 2,500 grams was significantly less than that of small infants born to nonsmoking mothers, He referred to these small infants of smoking mothers as being "apparentlyy healthier" than those infants weigh, ing less than 2,50 0 grams who were born to nonsmoking mothers. As this reportl showed, when compared, to infant's weighfing.more than 2,500 grams; a small (<2,500 grams) infant faces a greatly increasedi risk of' neonatal' mortality, whether' it is born to a smok ing mother or to~a nonsmoking mother (54). The neonatal death rate for the small infants of smoking mothers was less than that for small. infants of nonsmoking mothers, but neither group can. be considered' "healthy," having sharply elevated death rates. The overall neonatall mortality for babies born to white smoking mothers was 12 percent higher than that for babies born to non- smoking mothers. This is not significantl!sr greater than the neo- natal' mortality of' infants born to nonsmoking mothers. On the other hand.it is'.also not significantly differentfrom the:3I percent excess mortality reporteed!by Butler, et:al. (5), which is statistica3ly significant.. Interpretation of the neonatal mortality among the imflants' wei'ghingg lpssthan 2',500grams in the Yerushalmy study is dif- ficu'It. By considering only live births, the series may have included ahigher proportion of infantswhose smaller birthweight was pri- marily due to a modest grow.th retarding influence of maternal smoking and not to other more serious congenital defects and' intra- uterine inf3uences. Butler, et al. (5) have shown that smoking mothers have significantly more stillbirths than nonsmoking' mothers; and Russell, et.alL. (33)have foundd thi.s.to be true for both stillbirths and abortions,. For reasons which aren't elear; smoking mothers have been found to have a reducedi incidence of preeclamptic toxemia as com- pared to nonsmoking mothers ('S.T ). However, given the presence of i.w

PEPTIC.ULGER It has been estimated that 10 to 12' percent of all people will suf1- fer fz•om peptic ulcer disease at some time in their lives (17). In the U.S'.A.in 1967, there were 5,323 deaths from,gastric ulcer and 4,502' deaths from duodenal ulcer (22). Several studies have docu- mented.an association between smoking and. peptic ulcer disease,, which. is stronger for gastric ulcer than for dtiodenaP ulcer: Prospective studies indicate that male,cigarette smokers have increased peptic ulcer mortality ratios (see table 1)~. AIthough.a trend toward increased mortality from gastric ulcer is seen in cigar and/or pipe smokers, the data do not allow significant conclusions to be drawn.. Similarly, no firm conclusions can be drawn about female smokers, Retrospective studies have consistently shown smaller numbers, of nonsmokers in the peptic ulcer groupss than in matched control populations (tables 2' andi 3)~. Cigarette smoking has been shown to reduce the efficacy of antacid therapy in documented pepticdisease (3) and to slow peptic ulcer healing (7). One stu,dy indicated that smokers who had undergone surgical treatment for their peptic disease had more major complicatlions,, incllading recurrence of' peptic disease,, than nonsmokers, (14)'.. Numerous studies iln both animals and man have been performedi to investigate the effect of smoking or the administration of nico- tine on the gastrnintestinal tract. Studies of'gastric secretion and! motility in normal controls and in patients withpeptic ulcer dis- ease as well as in experimental andmals have produced conflicting results (4s.16;18, 19,.2b)~_. SUMMARY Cigarette smokiu g males have an increased prevalence of peptic uleer disease and a greater peptie ulcer mortality ratio,. These rela- tionshipsares stronger for gastricc ulcer than, for duodenal ulcer. Smoking appears to.reduce.the effect'iveness.of standard peptic u[cer treatment and to slow the rate of ulcer healing.

4 V a 47 A ,. TABLE 5.-Hutnan experimental data on smoking and pregnancy (cont.) Author, yeaq ntry, Design of study referenee Results Comments Msntell, Cord bloods from 50 smokers and 59 nonsmokers _A_ decrease i rarbnnic anhydrase activity in the Carbon monoxide ie 1064, were analrxed for carbonic xnhydraseactivitye nrd hlmds of infants whose mothers smoked was an inhfbitor of r NewZeeland noted. carbanic anhydrsse. (25). Scopcette, CO ~oncc entratinns were m._easnred in the venous CO levels were higher in smnkerS than in van- 1968, blood of 46 pregnant women, including smokers smokers. CO neentrnt were apn 'mately Italy 1481. A.nd nnnsmokers. Funicnlar venous blood was the .nme in m aternal Aad funicular venous blood. AnfllyZefl at the tlmP of delivery. Yo_unoszaietal., 32 a with m mal prcgnancies were atudied (a) Nean. CO saturationn of IIb in the venous blood 1966, of whom 16 smoked >20 einarettes a day. Both of the cigarette smoking muthers at the time of Canada (56). groups of w n had normal deliveriee and delivery was 8.3 per'cent and in the nonsmoking healthy infants. Biochemical changes in the firSt mothers 1.2 percent. The corresponding mean um- .-- 4tl hours of life were studied in the infunts. 61 1.en bi nd levels were 7.3 percent and 9 percent. (b) The blood Plh, pCO2, and bicarbonate and lac- tate valueg in both groups of infants were within normal limits. (c) The infants of smoking mothers showed a higher meau hematoceit and mild metabolic acid- _ osis. E_ngel et al., 3] expcriments w re perfermed on placental blood Hnman placental blood has a lower relative afFnity 1969, amnles ohtsinrd from 15 pregnanries to deter- far CO than adnlt blood. It .v v caleulated that the U.S.A. (9). mme relative plBnity of buman fetal Hb for CO affinity constant of fetal Hh was approximatelv and Oz. - 20 percent Irss than that of Hb A. ,.

CHAPTER'.7 Tobacco Amblyopia

03765513

TASr.E 6~.Anitmal experintental data on the effect of svnoRing and nicotine on Pr2grianey Author, yenr, .ntry, An.imal Design of study reference Essenbergetal., Albinu_ rat. ~ 39! "yupng" from pregnant rats exposed to 1940. Lobeccu smoke and 113 young from pres- U.S.A. (10). nent rats which received parenteral nlco- tine were studied. Sshoene_c_k_, R__abbit. Smokc from one ci¢arette wss blown into 1941, the nnstril of healthy does by means of e U.S.A. (df). ' cutheter eech day. The duos were "emnked" daily throughout pregauney and laetapion. 1V0 yovng from 28 littrrs of 7"smoked" dnes were studied. The oRSpring were not subjeeted to smoking at any time. Nishimuraand Mouse. 230 pregnant mir.e were injected, par®ter- _.. Nakei, nlly, with nicntine. Animsls were sacrificed 1958, at term and mid-pregnancy toinveatigate Japan (!f). the state of the pregnancy and the develop- ment of the offspring. Gntling. Chick embryo. 1064, U.S.A.(SJ). Results The ynung of treeted mothers were under` Comments 113 "young" eerv.ed as weight: the Young frem nicotine injected cuntrnls. mothera were mnre underweight than those from smoked mothera. Increaeed fetal wast- age and neonatsl deaths were observed in treated animals as campa[ed to controls. (a) Offspring from " moked" female rabbits Litters from the pre-e wer smaller at birth than controls (17 vious generation per ent). 9eryoJ p0 control9. (6) The etillbirth rate waa 10 times as great in the " moked" group. (u) The mortality rate w s greater tn the effanring of the "smoked" does. Nicotine had e lethel eReet upon mice em- 225 full-term fetuses bryns and also had w teretngenic effect a removed from 29 n their skeletal avatems. untreated mice were used aa contrals. Chicken embryos were treated with doaes of Nicotine induced cephalic hemstoma forms- nicottne varyfng from 12 pg. to 1,000 µg, tion and central n_ e_rvous system depression. The effects of phenothiazines, eorticoste- rnids, and cetecholamines were_ alsu studied.

TABLr. C.-Anivnal ezperimentpl data on the effeat of sntg6ing and n Author, yeer, conntrg Animal reteicnee aeckerand Rat. King. 35GG, TIS.A. (€). King and Aat. BECker, 1P66. UK-A. (YI). Masier and Armstrong. 3969, U.3.A. (El). otine on p_rcgnanay (ao>at,) Ilenign of ¢tudy Results 100 Primiparn prcgnAnt rati reeeive_d a qine gle heavy wbcntenmua Inientian of nicn. tinr on the 21at das nf p>egnanry. 9ne day prior to rxpected term delivery. Fetsl wastaze, weight of newbnrns, neonatal deaths, and uregnnnt animals' respqnses were noted. (a) Mortality wes grester smong pregnant rats then amnna nontwls. (5) Pregnant ralx showed rnore marked hy- nerventilatian en_ d less body temperature depresslon than controls. (c)-Dehvery wes deiaYed 2 to 4 days. (d) The young weighed leas than nurmsl and rviveA "poorlr'duriuq the first es hours of life Pregnant end nanpregnant rsts were i_n t)shurne-ffiendelrataLD50: +ne.7k0. jected subcutanenuslv with henvr doses of Pregnantadults ................ 27A n 2 peroent solution of pure dentine for Nqnpregnancfemeles .......... 93.6 the purpose_ of determining the E.RSO for Neonates ........ ............... 14.55 females of this strxin (OShurneNnndep. The 3.DaG for neonates of this strsin wsa Pregnant rata tended to die signifieantwlwter alsn determined within 6 to 2/ houn_ of than nonpregnant rats, hut their tnferance normal hirth. ~ for nicntine w.es less. Alternate prrgnant rwts receiptd aral nieo- (a) On higher nicntine intake, there wee t(ne in the dosage o_f either .U5 mg.lg. or lowerin¢ nf food intake, .10 mg./g- of food. On the 2Uth dsy, the 16) There we:. nu change in fetal weight or rsts were killed end the _fe_tuses were_ re- length on either eoncznlraffimn mo_ved. - (e) There ap_peared to he no eAect un the number of live and `ebcorbing" fetuees. Commente 100 nonpregnant rats eerved ae controls.

isotope studies in mice (µ8) have indicated that nicotine and its metabolites accumulate in, the placenta and are passed into the fetus. Many of the experimental studies were designed!tlo determine the pathophysiology of the effect,of makernaD smoking on the fetus'. The experihnental'conditions in the several studies varied greatly as did the results.,No unified concept of the effect of maternal smoking on fetal growth or on the outcome of pregnancy can be derived from the presently available research. SUMMARY Maternal smoking during pregnancy exerts a retard[ng, influence on fetal growth as manifested by decreased infant birthweight and an.increased incidence of prematurity, defined by weight alone: There is strong evidenee to support, the view that smoking mothers have a significantly greater number of unsuecessful pregnancies due to stillbirth and neonatal death as compared to nonsmoking. mothers.. There is'insufficient evidence to support a comparable statementt for abortions., The recently published Second Report of the 1958 B!ritishPerinatal Mortality S1lrvey, a carefully designed. and contirolled prospective study involving large numbers of pa- tients, adde further support to these conclbsions. REFERENCES (1). AeeRivATxrc, J. R:, GksaNERG;, B. G.,, WEtts;. 13.. B., FRAz1EE, T. M.. Smaking,ar, an independent variab[e.in a multiple regression. analysiss upon birthh weight andd gestation. American Journal of Public Blealth~ and the Nation's. Health 96 ( 4).: . 626-6331. April 1966.. (2): Bacxen,. RL F., KixG, J. E. Studies on.nicotine.absorption: during preg:- nancy; II. The effects of:acute.heavy doses ann mother and neonates. American JbnrnaS of Obstetricsand.Gynecology 95(3) : 515! 522', June. 15, , 1966. (3) . BeexeR; R. F., LITTLE, C. R. D!, KiNG, J. E. Experimental studies on nicotine absorption imn rats during pregnancy. LII. Effect ofsulY- cutaneous injection oflsmall chronic dbses uponn mother, fetus; andd neonate. American Journal of. Obstetrics and Gynecology 100(7): 957-968, April 1„1968. ('4)BvNcxER, C. R..Cigarotte smoking,and.duratlion of pregnancy:.American Journal.of Obstetrics and Gynecology 103'.(7),:: 942-946„April 1, 1969. (5). BUTLER, I+II R.,, ALEERrr[AN„ E. D. (Editors). The effects of smoking in pregnancy. Chapt'er5'. IN:. Pcrinatal Problems. F.dinburgh~, E; & S':. Livingstone, Ltd..,.1969: pp. 72-84. (6), BUTLER, NL R: A national long,term study ofperioatal hazards.. Prer sented at the Sixth P,?orld Congresss of Gynaecology and Obstetrics, New York,. Aprill12-18', 1970, 11 pp, . (7) DoWNUNG, G.. C:, CHAPMAN, VV. E. Smoking.andipregnancy.. Astatistica(A study of 5,659 patients. California Medicine 104I (3)I : 187, March. 1966.

Contents Page Summary and conclusions ............................ .436 References .................... ......,........ 436 ' 433

B` . TABLE G. Animal experimentaE,data on the effect of smoking and nicotine on pregnancy (cont.) Author, year, muntry, Animal refrrenbe -----~ Becker et al., Rat. 1965, U.S.A. (a). Tj'alve et al., 1968, 8weden (d81. Fahvo and Rabbit. Sieber, 1969, U.S.A. (ll). Design of study Resulte Comments Controlled populatio.ns af nregnant rats were (a) With the lower dosage of nicotine, the Control rats were in-_ injected twice daily with doses of nicotine hirthweights, survival, end develnpm_ental jected with saline. varyiog from .5 mg./kg. to 5 mg./kg. Ef- status did net difier from eontrols. fects on pregnant rats end newLurnn were (b) With th_he higher_ dnssge,pregnant rets studied. cunsumed less food andgained less weight than control muthers. Delivery dates were prolunge¢ 2 to 4 days or more. Young underweight and fetal in appesranee. There were no abortions and nn prematuve young. The nassage of "C-nicntine snd Its metaho- (a) Nicotine icotine and its metabolites accumulated lites from the mother into the fetuses was in theplncenta and passed into the fetus. studied. (b) The metabulitex m'escnt in the fctus (1-methyl-'4C)-caReine and G-('H)-nicotine we e given to 6-day pregna_nt rabbits. The do e[ r nicotine was 50 µk./kg., intra- s. producinR Plasma levels similar to th o attained in man by cigarette smok- ing 1-06-.09 µ&/ml.). originated from the mother. (c) The- psssage of nicotine into the fetus wes the same during the last four daye of Vregnaney_ (a) One hnur after ('H)-nicotine treatment, a high leyel of radioactivity compared wi_th that in mRternal plasma was found in uterine secretlon (ratin=10.8). (b) Unchanged radioactive n tine nd snme uf its metabolkes were present in the pre- mplantation biastocyst (blastocvst/plasma ratio ,r. 3). Rndioactivity in nteriue ee<retion was not found in nonpregnant cUn- trols. 96659~~0 t

TABLE S.--Summary of results of retrospective and cross sectional studies of peHtic u[cer and smoking Author, --yesr. Pereentnanemoker country, reterence Geses Controle Barnett, Tntel .......... 18.0 25.0 1927. Restric ... .. 16.0 U.S.A. Duodenal ~ ..... 20.0 (£). Trowell, Duodenal_ ...... 8.0 17.0 1934, Eneland (21). Edwards et al., Percent of peptic u7cer by onoking categorV 1969, Never smoked .................. 6.0 England Formerly nmoked .............. ....... . 6.7 . .. (s). Cigarettes: 1=9 per day .............. 9.+1 10-19 per day .............. 9.8 >20 per day ............... 12.0 Pipe ...................... 6.6 Pipe and cigarettes ........ 8.5 Amount of tobecco used Cesey Controls Aveesge number: Cigerettes .. 12.0 per dey..........11.1 yee day Pipe ....... 1.6 euncee peu week.. 2.15 ounce® per week Allibone and 38.0 54.0 Flint, 1956, England (1). Dollet e.l., Gegtric: Gastric: PerCent amnking >25 eigurettee pe, day - 1958, Mnles ..... 1.3 4.7 Males ...... 10.6 us - England Femalea ... 51.1 6619 Femel® .... 1.1 1.1 (7). Duodenal: Duadensl: Meles ..... 2.1 6.8 Meles ...... ]0.2 12.7 Females ... 58.7 62.0 Femeles .... 1.9 1.9 90SS94£0

03765515

niuting or a 0 m nnmoryear, country, reference Snntag end Wallace, 1935• II.J.A. (45). Hsddon et aL, 1961, L.S.A. (14). TAace 5.-Human expxrinlental data on annok?n.g and gregnancy Design of study Results Fetal heart rate before anA after smoking was Average fetal heart rate before smoking was 144.0. studied 81 times in 5 patients. . The a erage fetal heart rate for the eighth to the twelfth minute after starting to smoke wae 149.0. Carbon manoxide leve]s were measured 50 mokers and nnnsmoken + a prenntal cl_inic. Twenty-six pah'ed msternaland umLilical vein blood specimenn were obtuined at parturition and tested fmCO levels. (n) Carbon monoxide levels were significantly (1K0.01) higher in smokery than in ... smeke,s. (b) Carbon monoxlde_ r4 centretions in paired cord end matcrnal blood specimens were approxlmately eq+ml. r) 0, carrying capacity cord and msternal blood was_ reduced in smo_k_ers comn_ared to non-_ smokers. - Comments Heron, 1962, 68 pregnent smoking women were studied during (a) CO levels maternal nnd fetal blood w¢re A control group who NewZealand labm to determme th cHeat wh h smoking -highcr i net nts whn smoked had never smoked (ls). mi¢ht have on th. grading" of the infant at (G) Hespi t infants of mntherp who smoked was compared with . Kumarand Zourlas, 1J68, U.9.A. (20). horth. CO levels w e mcasured in buth mother (ook lunxer to be established and neripheral cy- the surveY group- snql fetuc, anosis was mnre common. The in vh~re eaecta of cigarette ameking nn uterine ectivitv were studied ini9 Pregnant -gravidas nem~ term and not in labor. The Lt vd+o cae.et nf niCOtine on human pregn&nt 9nd nonpreg- nant myometr'ial etrips nas studied. Youngend Blood CO levels were studied in 19 full-term par- Pugh turient womeu, 16 of whom had normsl deliv- 1963, eries. Six of these smoked 10 to 20 cigarettes a England (65). day. MaMrnel blood was enalysed 15 to 90 minutes prior to delivery. Fgtal blood wes taken from the nlacentalend of the umbilical vein. (a) In more than half (10/1S), a definite Increment in uterine activity waa . noticed dnring cigarot2e soking. --~ ~ --(6)m No oxytacic effect of nieotine on myoumetrial 'triUS w85 nnLW. CO content of umbilical .v n blood at normal deliv- ' .52 and .36 volumes percent i infants afmothers who smaked and mothers who did not smoke, as compared with .33 and .28 volumes percent,respectirely, in the maternal venous blood. e ti~A~FS~' N-6 Blood CO levels were also studied tn non- smoking ma]e labet mtory workera in London and in mal.a in Antarctica. . LsVS94Eo

i01111110 a a TABLE 6. AnimnC cxporimental.tl¢ta on tlcg effect of snnakivaD and n4cotine on pregnancy (cont.) Author, year. cauntiy. Animel reference Welch et al., Rnt. 1969. UU.S.A. (5E). Ynunoszai Rstr et al., 1969. Cenede (av). Cnnads (51). Sheep. KlrschGeum et al., 1970, U.S.A. (t9). Design of study Rats which were pregnant for 18 days were given 40 mg./kg- of 3,d-henznvrene; 1,2- henzmdhracene;1,P,5,6-dibenxanthracene; chrysene; 3,4-benzofiuorene; enthracene; pyrene: fluoranthgne: perylenc; phen- anthrene orally, and BP-hrdroxylase - tivib in the _Ulacents wea meesured n24 hours later. Pvegnant rnte were exnused to smoke from regular tobacco c3garettes, non-nicotine cig- arettes made with lettuce 3enves, and non- cotine cigarettes (lettuce leaves) to which 15 mg. of nicotine w added. The rate were forced to inhale cigarette emuke by plerin¢ their cages In e smnking chember. CO levels were maintained between 2 and 8 percent by exnnsing the animals tu smoke 5 times a dey at 2-hour intervals. Other groups of rats were fed restricted diets, receiving from 55 to NO perce_nt ut the food consumed br-eontrol rats. Intravenoup injection of fresh solutions oG nicotine, and eimulated smaking of ciga- rettes, were carried uut upnn pregnant ewes. Cerdiovaseuler functions, Including gsseoue exchange and blood flow of both the ewes and their fetuses were atudied far ecute effects. Resulte Comments All compounds tested stimulated: Placenta frnm control RP-hydruxl9e actixity in the plaeenta. rats Gossessed very l,2-benznn[hraeenc wes the must active In- low BP-hydroxylaae ducer of l3P=Axdroxvlase. -- aetivits. . (e) Fetuses of ell smoked rats w e growth retarded compnred to conrol nimals, those esposed to tobacco smoke (cigarette) being mn_st severelr affected. (5) The amount of food consumed by rate expesed to cignrette smoke was reduced. (r) There was e qig_nificant direct relation between fetal body weight and the average amount of food enten during pregnency. (d) Fetal weight wasreduced in pvppartion to the decrease in muternal fuod intnke in the two groups of rate expasedto the let- tuee leef ciqarette nmuke.In rets exVOsed to tnbaccn cigarettes, fetal weight waa re- ducnl more than expected from the de- cresse in maternal food intake. No significunt chsnges were observed as e re..ult of either nicotine administration or mnke inhelnxion. Control rate were handled in the eame way except that they were not ex- poeed to cigarette smoke. Eath experiment tn- cluded a ontml yeriod during which attainment of a eteady etate was ehe aim. G6tIS9Geo

TAB[.E 3: Summary of results of retrospective and cross sectional studies of peptic ulcer and smolting (cont.) OQSSM(aQ Amount of tobneco used referenee Ceses Eontrnls Cases Controls Authar, year, Percentnunsmoker - country, Knsnnen ~•Pept;c.• ...... 10.0 40.0 CfRarette9p2rday= .... . . and <10 ........ 10.0 7.0 Fursstr5m, 10-20 ...... 19.0 19.0 1966, 20 ......... 42.0 26.0 Finlan_d_ >20 ....... 19.0 10.0 I/sl. - --- Gilliesand Gestrie ........ 18.0 44.0 Mcnn.numbercigurettesperday: Skyring, Dimdenal ...... 62.0 71.0 Gastric .... 23.3 17.1 1968, - - Duadenal .. 23.2 23,0 Australia [)u_rntian of.smuking (years) : (9). Gastric .... 30.2 28.0 Duodenul .. 24.2 28.2 Gillies and Gastric ........ 19A 55.6 Skyring, Dundenel .. 36.6 1969. Anstress U03. Mnnson, Duodenal ...... 32.1 46.7 iD]0, Gastric ....... . 1A.2 U.S.A. Not Specified .. 432 (?6). Pcrcentamoking >20 ciRarette9 per day Age: Ga.trie Duodenul - 80......... 38.8 2].3 80.1 30 ......... 45.9 43.0 47.1 45 ......... 60.2 49.6 46.9 60 ......... 54.1 40.4 44.0

(16)~~ PAcxARO;. R. SI Smoking and the~~e alimentary tract: A~ review. Gut 1:: 171-174, 1960., (19): PALMER, W. L. Pepticc ulcer. Chapter32.. IN: Paulsoni M. (Editor). Gastroenterologic Medicine. Philadelphia, Lea &. Febiger, 1969, pp. 710-757. (18)ScHNEWRF;, J. Gl, IYa;, A.. C. TheeffecE of tobacco smoking on: the alimentarytract.. An~experimentaC~ studyg of man and animals. Journal. of the: American Medical Association 112(10): 898-904, March 11. 1989.. (1'9)'~. STEIGMANN, F.,,nOLEHIpE, R. H., KAMI!NSKI:, L. Effects of~tobacco smok~.- ing on' gastric acidity and motility of hospital controls and patients with peptic'.ulcer.. American Journal of Gastroenterology 22:: 399-409,, 1954. ('2O) . THamesoN, J'.,H. EffecLS of nicotine and tobacoosmnke onigast!ric secre- tion in. rats with gastricc fistulas. American Journal of Digestive Diseases 15(3): 209-217;. March 1970. (E1), TRDwELL,. 0.A. The relation of tubacca'smokingo to the incidence of chronic duadenallulcer: Lancet.1: 808-809; April 14, 1934. (`l2) U.S. PURLIC HEALTH SERVICE. NATIONAL CENTER FOR HRALTII: STATIS'- TICS. Vital.Statistics of the UnitedStates-1I967, Vol. H-Mortality^„ Part A. Washingtonl U.S. Department ofHealth,. Education~and! Wel- fare, Public Hea]tih Service.Publication, 1969.. (t3)~ WEIR, J. M.,. DUNN, J.. E.,.JR. SMoking and mortality: A prospective stNdy: Cancer 25 (1) :: 105-112',. January 11970. 430

TAnLE 2. Methods nsed inn retrospective and cross sectional studies of peptic ulcer and sntoking (cont.) Anthor, -- --- year, country. $ex h'umbe_r_ Method of selection referenG . ...... . . .. Raeanen and Fometrbm, M 48 Gastric. Gl Duoden.L 1966, Finland (l9). es an M and F 100 Gastric. Skyring, 60 Duodenal. 1968, 1868, Australla (8). Successive male dmt a with pep- tic ulcer treated at medical olinio or outpstient d_e_p__a_rt_m_e_nt of Uni- e[aity Hospital. Only pPtiente under 65 vean of age or those who had been working were_ m eluded. Patients with peptic ulcer-were ee- _ __ 1ected from hospital admisaione in 1967. Gillies and MnndF 10Gactrie. Skyring, 48 Duodenal. 1969, 18 Uncertain Australia luretion. (10). Monson, M and F 62 Gastric. 1970, 4452 Duodenal. U.S.A. (15). 139 Nat apeeifled. 1,405 workers from a broadcaeting -mpe_ny, a manufacturing c - pany, and s bvs company were interyt4wed for a history of pep- tic ulcer. 643 physicians from Mesenchueetta who responded sfNrmatively to e questionnaire sent to them in 1967 aaking how many had had s pep- tic ucer. Cnntrola __. _ Gommenta Number MethodoLSelection -100 Successive men treated at medical A spectal questionnaire clinic who bad no gastroivteatinal wep used for the symptoms o e;gnx af CHD. intcr.iew. 150 Matched by age and aex from the Diagnosis well established same ward at the same time and v.ith X-ray, gastros- with abeenee of aign.p or symp- eppy, nr surgery. tums or past history of upper yastro nteatinel disease. IQO Two control groups: All informetion obtained 1. 100 peptic ulcer patients pre- vuely reported by authors. 1,$2@ 2. 1.329 workers without ulcer. 625 Qontrala .we.re physicians without ulcer disease who were metehed to ulcer patients by year of birth. by queetion card. All uleers were proved by X-ray or surgery. Diagnosis established by X-ray or eurgery e_xcept for 46 "clinical" casea.

}) I SOSS9LEQ Author, yeer, Number and couutry, -Cyp2 Uf-reference population Dnlland 41,000ms1e Hill, Hritish 1964, phvsiciens. Great Britain (516) . TABLE 1,-Smoking and peptic uEcer disease meortaEtity (Nombers in parentheses represent actual nnmher of deaths) SM=Smokers NS--Nansmokers G=Gastrir D-Duadenal Mortality r atios Data collection Actual deaths Cigarettes/diy Dipe Cigar Comments SM NS Gastric Duodenal Gastric Uundenal Gasthic~Duodenal Queetionnairc 64 tFeptic Ripe/cipnr lTotalnumberof - and follow-nn NS ~ 1.00 4.00 deaths were tao of death AII cigarette 7.00 smxll to pllow certificnte. 1-14 ge, per day 2.33 senarsle examin- 15-24 10.33 ations. B25 7.33 Hammond, 440,568 Interviews.by G-B3 ...... 11 NS _. . 1.00 111) 1.00 (22) 1966. malcs35- ACS volunteers D-93 ......22 SM( ge45-64) 2.95 (k,l)2.Bfi (J3) U.6.A. 84 years o€ 4M ( ge 65-R9 ) 4.06} 1.50~ (11). agein25 States. Kahn, U.S. mele Questionneire G-78 ...... 12 NS ............. 1.00(1&) 1.00(26) 1.00(12) 1.00(2G) 1.00(12) 1,00(25) 1966, veterans and follow-up D-119 .....26 SM 2.84 (4) 1.59 (5) 2.90 (7) 1.58 (8) U.S.A. 2,?65,674 of death Alleigerette .... 41,1309) 2.98(57) (12). person yeare. certificate. 1-9 ........... 3.95 (6) 2.30 (6) 10-20 .......... 2.77(13) 2.74(26) 91-30 .......... 5.45(15) 5.98(22) >39 ...........11.67 (6) 2.89 (3) Weirand 68,153males Queationnaire Dunm in various end follow-up 1970, necupationa of death U.S.A. in California. certificste. IE31. --- ,,,,,,,,,,,,, ... 1-00 Nodeethsfrom 44 NS All cigarette ,.. 0.53 seetric plces oc- ~10 ............ 1.00 0.40 curredin nonr =20 ............ 1.67 0.69 amokers and risk 730 ............ 2.38 0.82 ofthosesmoking Y10/dev was set at 1.00. NS in- ciuded pipe, ciqar, and ex smokers.

(27) VVoxES, F.,.PtCAnD; C. IY..The rolbe of vitamin B,_ in human natrition. Clinical Nut.rition3l(5)r 383-390;.September-Cctober 1955. (28) WYNDER, E. L., HOFFMANN, Dl Certain constituents of.tobacco products. Chapter 8. K.. Vaporr phase off tobacco smoke. IN: Wynder,. E. L., Hoffmamn, I):.. (I:ditors).. Tobaccoo and Tobacco Smoke. Studies in F7x- perimental Carcinogenesis: New York, Academia. Press, 1967. pp. 4511P53: 43e'

(8) DUSaus, G; M:,. SIacGlnLlvaaY;, I, The incidence of pre-ecfamptic toxaemia:a issmokers and nonsnlokers. Lancet 11(7550) : 994-995, Mlay 111, 1968'. (9) ENGEL,. R.. R., RonxES, F: L., 0'Nvnc,. J. D.., CacLlsoN, H. A... Relatireaffihity ofhuman: fetal'.hemoglobin for carbon monoxide an& oxygen. Blood 33I(1): 37-45, January 1969. (10) EsSeNSEeG,.J..BT., ScxWivD,.J. V., PATrtAe, A. R...The effects of nicotine and' cigarette smoke onn pregnant female albino rats and their off- springs.. Journal of. Laboratory and. Clinical Medioine25: 708-717, 1940.. (11) FAeao; S.,,81Eeea; S. M. Caffeine and nicotine.penetrate thepre-i'mplhn- tation blastocyst. Nature 223(5204) : 410 1'I1, July.26, 1969. , (12) FaszlFm, T.. M., DAVIS, G:. H., GOCneTE1Ny H., GaLDnERC; L. D. Cigarette smokingand'g prematurity : A prospective study. AmericanJournal.. of Obstetrics and Gynecology 81(5): 988-996, May 1961. (13) GATLIrvG,R'..R.Effeetofnicot'ineon.chickembryo:ArchivesofPathology 78(6) : 652-657, Deaember 1964, (14). HnnnoNS W.,,Jx:,.NESarrT, R. E-L., GAUaIA, R.. Smoking and pregnancy: Carbom monoxide in blood during gestation and at.term. Obstetrics andlGynecology18('9) ::262! 267, September 1961. (15) I3EUtovyH..J'.,The:effectsofsmokingduringpregnancy::Areviewwitha preview: New~ Zealand Medical Journal 61:545-548, November. 1962. (1B). HE&ecnTT, A-, BzLC.Fw[CZ„W. Z., HYT7oN, F. E.. Cigarette smokingirt pregnancy. Lanceti 1:: 771-773, April 14~ 1962. (12)KiNG, J.. E., BECKER, . P.. F.. Studies on nicotine absorption duringpreg- nancy., I. LU,,,: for pregnant and nonpregnant rate. American Journal of Obstletrihs andl Gy'necolbgy 95(4) : 508-514, June 15, 1966. . (18). Ktftscl6eAUM, T. H.,,DiLTS, P. V.., J6:, Bn[NKYtaN, C. R:, III: Some acute effect'sof smoking.in sheep and their fetuses. Obstetrics and Gynecol.- (25)M'ANTeoi, Cl. D. Stnoking, in pregnancy:: The role played by carbonic anhydrase:. New. Zealand Medical Journal. 63: 601-603, September November. 1963. smoking habits.. American. Journall of Epidemiology 82(3).: 247,-261„ (21,.). bLneMAHOrv~. B., Airesx, b9., S,weea;. E. J:. Infantl weight and parentaC' children. British.Mcdical. Journal.2:.673-676, 0ctbber.10,1959: (23) LowE, C: R:. Effect ofl mothers"smoking habits on birth.weight of thei'r Sciences 174(I).: 3143-341',. October 5, 1970. (22). LoNGO„L.. Dl Carbon monoxide in the pregpant.mother and fetus, and itss exchange across the placenta. Annals of the. New York Academy of. Noorvosok'. Lapja.32(2) : 163. 167„March.1969, (21) LASZi.o; V. A dohanyzas karos hatasai a gestatiose folyamatbkra., (The deleterious effects of'smoking on the sequences off gestation.) Magyar. 4113-417, October 1, 11963. contractility~ American Journal of Obstetrics and.Gynecology 87(3):' vivo effect of smoking and: invihro effect of nicoGne on.human uterine (2p)KcnfArz; D., ZouR[_AS, P. A. Stud[ess on human premature births.. II. In 595-643, 1967. newborn.). Revista de Obstetricia yGfnecol'ogia de Venezvela.27(4),.: (19) Ktzea;.S. Inffuencia dellhabito defumar sobre:el embarazo, parto yrecien nacido. (T:ffect of the smokinghabit on pregnancy, delivery, and the ogy 35(4) : 52 7-5:36,April 1970. 1964.. 416

(Z6), MeDoNAtD„R. 16.,,LArFORD; C. F. Effects of smoking on selected clinical obstetric factors. Obstetrics.and Gynecology 26(4) : 470-475, October 1965. (27): MoSIER, H..D:, JR.,.ARGfsxnoNG, M. X. Effect of maternal nicotineintake on. fetal weight.and length, in. rats. Pi•oceedingsof the. Society for Ekperimental Biology and Medicine R24(4)'.: 1135-1137,. Aprii 1967. (278). MULCAt1Y, R., KNAGCS,.J. F:Effect of age,.parity, and cigarette smoking onn outcome of' pregnancy: American Journall of Obstetrics andl Gyne- cology 101(6) :844-849„J!uly 15, 1968. (89)' MUiCAHY, RL,. MU8PH7,. JL, MARTIN, F. Placental changes and maternal weight in smoking and nonsmokingmothers:American Journali of Obr stetrias.and Gynecology 166(5):: 703-704, March.1, 1970.. (30) !llUaooc[[i, D. E. Birth weight andd smoking, Nebraska State Medical. Journal 48(~11):. 604i606,November 1963. (91) NEeERr, D.,W., WINatER, J., GECeo[N; H. V.,Aryl.hydrocarbon hydro- xylase activityy ih human placenta~ from cigau'ettesmoking andl non- smoking women..Caneer Research.29(QO):.1763-1769, October 1969: (132)I NIeHIhtGRA, H., Ni1HA'[y K.. Developmental anomalies in offspring of pregnant mice' treated withh nicotine.. Science 127 (3303) : 877-878,. April. 18, 1958'.. (83) 0'i1ANE, J. M.. Some fetal effects of maternal cigarette smoking. Qbstet- rics and Gynecology 22(2): 181'-184; August.1963'. (31,) PETERSON, W..F.,, tiloKESE;,K. Nl, KAUTRErnER„D. F. Smoking and pre- maturity. A.preliminaryI:eport based on study of 7;7410 Caucasians. Obstetricss and Gy.necology'26(6) : 775-779, December 1965. (85), RAVENII9LT, R'..T., LEVINSKI„y1. J., NEpLIST, D. J., TARENAGA,.M. Effeet9ofl smoking upon reproduction. American Journa9l of: Obstetrics and' Gynecology,96(2): 267-281, September 161 1966. (36): REINKE, W,. A.., HENUtxtsoN,M., Sinokingandi prematurity in: thepres- ence of other vaz-iables.. Archives of Environmental. Health 12(5)'.: 600-608; May 1966. (37) RoRI¢rsa[v;. P. 'Yshwn nshym. Bwa:mmywt vzmn hhrywn whshp'tw~'I h'm h'wbrr whylwd. (Smoking, by Burmese women during pregnancy andd itss inflhence on the mother, the fetus and the newborn.)' Harefuah 69.(2) :: 37-39, 1965. (38)RvssELE,.C. S. Another.hazard of smoking. NewScientisd41(631)::64L 65; January 9, 1969., (89). RUSSELL, C. S., TAYLOR, R., LAW, C. E. Smoking,in pregnancy,,maternal, blood pressure,, pregu.ancyoutlcome,y baby weightt and growth, and other relat'edlfactors. A prospective study. $ritish~Journal of Preven- tivee and Social Medicine 22 ( 3):: :119-126;, July 1968. (40)RUSSELL,.C. S., TAYLOR, R.,,MADDisor¢; R. N. Some effects.of smoking iiv pregnancy..Journal of Obstetrics andl Gynecology of the British Com: monwealth 73: 742-746, October1966. (41)'. SAVEL, L- E., RoTI[y E. Effects of smokingg in pregnancy.:. A continuing retrospeetivcstudy: Obstetricss and Gynecology'20(3):313-316., September 1962. (42) ScnoeNEaK, F: J'.. Cigarette.smoking in pregnancy. New York State Journal of Medicine. 4'11: 1945-11948„ October 1,. 1941. (4?). SCOrrETTA., V:. Sull contenuto di ossidodi carbonio ne1 sangue circolante digesta-nti: fiurnatrici.. (Carbon~ monoxid'econtentin the blood ciicu- ~ 417 Q'7 ~ ~ ~ ~. ~

Author, year, country, referenCe 3ex Number Earnett, M 66 Gastric. Patients admitted between 191& and 1927, 17R Duodenal 1926 Gnly cases with complete U.S.A. (9). amoking history selected. . Trowell, M 50 Duodenal Not stated 1924, England (21). TABLE 2. Methods wsed in retrospeetive and croas uectionat studies of pepGic vdeer und smoking Cuntrnls Method of selection Comments 500 Selected at randomm from the gen- 1. Retrospective review eral aJmissions-males. 20-60 Years records at PeterRenL of egc. Rrigham Hospital. 2. Ulcer diagnaais prob. ably well established. Selected at random from wards of 1. Interviewed by inves- a general ho.nkal, tigator. 2. Ulcer diagnosis cnn- firmed by X-ray and(or sn geU'. Allibone and M end F 107 Consecutive admissions to hospital Flint, of paments with gastric and du- 19§8, udenal hemorrhnge or perforation. England (1). Doll et al., 1958, England (7). M and F 327 Gastric. 338 Duodenal. ilicer patients in Doll and Hill Lung Cancer Study plus additional pa- tient_s in Central MiddleseX Hospi- tal. Edwards etal., M 1,937 Men aged 60 and over on 11 General 1959, prndioners' lists w xamin¢d England andintervieweJ by these precli- (B). tinners. Represents about 84 pec- ent of all such men on these lists. (9 percent non-response due to death end!nr untreced.) 107 Matched by age, sex, and time of Patients and controls in- adm ssion from acute general sur- terviewed by xeme gical emergrncy ndmissions. observer. 1,143 Bntients with non-ulcer diseases. 1_. Same interview¢rs and Each c e mtched with 2 cme- Questmnnmre in cases trol patients af same aex_, 5-year and controls. age group, aml Jametype of 2. Ulcer diagnosis prob- plece of residence.Male patients ably we_l_I established._ mutchrd by sociul slase. Of 143 considered to have a peplic ulcer, 68 were confirmed by X-ray. 90SS94E0

TOBACCo AMBLYOPIA Tobacco amblgopia (tobacco-alcohol amblyopia) is that syn- drome of visual failure occurring in association with the use of tobacco, with or without the concurrent use of alcohol, and with or without concurrent nutritional deficit's. The disease has a subacute onset; leading to a: loss of visuall acuity and color perception (12). It is characterized by centrocecall scotomas which' are bilateral but not necessarily symmetrical'and w hich have sloping diffuse edges and by the presence of nuclei of denser visuallloss within the large scotomas(22; 23)'. Shch.visual impairment is.not unique to tobaccoamblyopia4 as it is also seen in neurodegenerative disorders, such as Leber"s hereditary optic atrophy (7, 25). Clinical information on tobacco, amblyopia.has appeared in nu- merous articles throughout the past century..This information has' been reviewed by Silvet'~Ge, et aL , (';17)1 and~, more recently, by Dunphy (5).. Pure tobacco amblyopia ('TA), that is amblyopia unassociated with.excessive alcohol intake or the exposure to other toxins, is rarely seen in the United States today (12). Walsh, et all., (23), have observed t'hat when TA is found it is usually present iinn association withi nutritional or idiopathic vitamin, deficiencies.. Victor (22) recentlyobserved that the type of visual dpfect seen in tobacco amblyopial may be found in. clinical circumstances in which tobacco is cleamly not a causative factor. PLe questions whether TA is distinguishable from other ffiorms of amblyopia Th.e.prevalenceof.this disorderhas'.been variously estimated in the past at.from 0.5 to4.5pereent of all.eye clinic patients'. (20',.23)..hIowever, currently in the United States, it appears to be a rare condition. Silvette; et.al. (17) have observedi that the incidence of tobacco ambl~opia appears to have decreased substantially during the past decades. Other authors (3, 15) have also..commented on this trendl. Although'reference hasbeen made to the increased fre- quency of certain types of tobacco usage in patients with this dis- order, adequate population studies'.with propercont'rolshave yet to be performedL The association of thi's disorder with the use of tobacco is strengthened by the frequent clinticall observations of improvement fiollowing the cessation of smoking although improve- ment has been noted by some to occur without cessation. Research into the pathogenesis of tobacco amblyopia has cen~ 435 ~'~

!1

REFERENCES (1) ALL[BONE;. A., Eiirviy F..J.. Bronchitis, aspirin, smoking, and other fac- tors in the.aetiologyof.pept'iculcer. Lancet 2: 179-182, July 26, 1958. (2) BnR}ETr, C. W.'potlaccosmoking as a factor.in the production af'peptic ulcerr and gastriec neurosis,. Boston Medical and Shrgical. Journal 197(12) .: 45 7-459, September 22„ 1927. , (3) $@tTTERMAN'„ RL. t.' ,. EHRENFELB, I, The influencee of smoking upon the management of tHe peptic ulcer patient. Gastroenterology 12(4) i: 575- 585,.. Apri1.1949. (4) CoOrEa„ PL, KNIGHT, J. B'.., JR:, Effect of cigarette smoking onn gastric secretions of patients withh duodenal ulcer:New EnglandJounnal~ of Medicine 255. (1) : 17-21,, Julyr 5,.1956'. (5) Doit,.RL, H¢t.,,A. B. Mortality in relation tasmoking: 10.years'obser- vations of British doctors. Part Il British Medical Journal 1'.(5395).: 1399=1410, May 30; 1964. (6) IDou.,.R., Ht[L„A. B. Mortality in relation to~smoking:. 10'years' obser- vations of British. doct'ors. (concluded). British Medical Journal 1I(5396) :. 1460-14fi7,. June 6;. 1964. (7): DOLL, R., Joxes,. F. A., PvcoTre;. F. Effectt of smoking on tkeprodhctfion and maintenartce of gastric and dhodenal'l ulcers. Lancet 1: 657-662, March 29.,.1958.. (8) Eb}uARes, F.,. MCKEOwN, T., WHTTFtFV.D, A. G.. W.. Associat'ion between smaking, and disease in men over sixty. Lancet 1: 196-201, January 24, 1959. (9) Gra.LIES,. M., SxYRING, A.. Gastric ulcer,.duodenaC, ulcer and gastric car- cinoma:. A case-controll study of cerSain social and environmental fac- torss. Medicall Journal of Australia 2(25) :, 1132-1136, December 21, 1968.. (1o). GILLIES, bf.,A., SxYRCNG,.A. Gastric.and.duodenal ulcer.. Theassociation between aspirim ingestion, smokingandg family history of'ulcer. MedP.- cal Journal of Aust!ralia.2(6).: 280-285, August 9, 1969. (11). HAMntONO;E. C. Smoking in relation to the death~ratesof l.million men and women. IN: Haenszel, W. (Eflitor)~. Epidemiological Approaches to the Study of Cancerand Other Chronic Diseases. Bethesd'a., U.S. Public Health~ Service, National Cancer Institute Monograph.. No. 19, Jianuary 1966;, pp. 127-204. (12): KAHN.,. H. A. The Dorn studyy of smoking and mortality among, UlS. veterans: Report an 8'l years of observation. IN: Haenszel, lFq (Edi- tor). Epidemiological ApOroachestb the Study: of Cancer and. Other Chronic Diseases. Bethesdal U.S~ Public Health Service,. National Cancar Institute. Monognal>hNo. 19, January 1966. pp. 1-1251(13)KASANEN,A.,.FORSSxxoM,.J..Socialstr•essandlivinghabitsin.theetiology of' peptic ulcer. Annales Medicinae Internall Fenniae 55.(1) : 13-22, 1966. . (10 h1U2TY4 W. F., JR., RovasELox, L. M., DELANY, G~. J. Smoking and its relation too nutritional status of patients following, gastrectAmy; a five-year fbllow-up ~ surveyof 171 patients. Annals of Surgery 150 (1) ,: 76-84, July 1959. (15), MoxsoN, R.. R. Cigarette smoking and body form im peptic ulcer. Gastro- enterology 58 (3) : 337-344, March~ 1870.. 429

tered upon the interrelationships of cyanide. me'tabolism„ vitamiln B;z, and'.other vitamin deficiencies. Three reviews of this materiall have recently appeamed (i, 12, 22). Numerous studies reviewed in these articles suggest'that'tobacco arnblyopia may result from,the incomplete detoxification of the cyanide present in tobacco smoke. This failure of detoxification may stem firomor be intensified by inadequate dietary intake of necessary nutritional factors. This may be the reason.for the association of this.disorder with exces- sive alcohol intake and with its rel'atedl nutritional' deficits (2, 4, 6, 8', 9,1'0,11, 13,1Iy,16„1'8, 1'9,.21., 24,.26; 27y.28)~. SUMMARY AND'. CONCLUSIONS Tobacco amblyopia is presently a rare disorder in the United' States. The evidence suggests thatl this disorder is relaEed'to nutri; tional or idiopathic dpficienci'es in certain detoxification mee'han. isms; particularly in handling the cyanide component. of tobacco smoke: REFERENCES (1) OATADIAN MEDICAL ASSOCIATIONJOURriAL.. TO$accdamblyopla. (Edi- torial) Canadian Medical Association. Journal.102 (4) : 420, February 28, 1970.. (E) OIIISHOLMI„1. A., BRONTE-,$TEWART, J.,.FOULDS, W.,S.. Hydnoxocobalamin. versus c}ranocobala¢ni.n in the treatment of tobacco amblyopia:. Lancet' 2(7513):: 450-451„ August 26, 1967: (3) IDARRr;, P'. W.,, WILSON, J. Cyanide, smoking, and tobaccoo amblyopia., Observationss on the cyanidecontent of tobaccoo smoke. B4itish. Journal of O.phthalmology 5i (5).: 33fi-338{.May 1967. (4) llREYFUS,.P:.M.,Blood transketolase levels in.tobacco-alcohol amblyopia Arcliives:af Ophthalmology 74(5): 617-62D, November 11965'. (5) DLtNPHY, P7- B. Alcohol' andl tobacco amblyopiaz. A historicall survey. American Journal of Ophthalmolbgy 68(4).: 569-578, October 1969. (6) FOULDS, W. S., BRONTE-SuTEWART, J. bt,,, CHISHOLM, I. A. Serum thio- cyanate concentrations in tobacco.ambl~'opia. Natur.e.218(5141).: 586, May 11,. 1968.. (7). FouLDS, W. S.,. CANT, J.. S.,. CHI5t1ocN., I. A.,. BRONrrE-STEWART,. J., WIISoN„ J. Hydroxocobalamin~ in the treatment of Leber's hereditary optic.atrophy: Lancet 1!(7548).: 896-897, April 27, 1968. (8) FOULDSi, W. $.,. CIIIBHOLST„ 1. A., BRONTE-STBWART, J.,. WILSODA, T. M. Vitamin By, absorptionn inn tobacco amblyopia.. British. Journal of Ophthalmology 53!(6) : 393-397, June 1'969'. (9): FOULDS; W~.. S., CNHSHOLM, I. A., BRONTE-STEWART; J.,, WILSONJ. T. M. The optic neuropathy of pernicious.anemia: Archives: of Ophthalmol- ogy 8Z(4).:427=432', October 19691 (10). FREEMAN, A. G., HEATON, J.,bf. The.aetlolbgy of retrobulbarr neuritis in Addisoniam pernicious anaemia. Lancet 1(7183) : 908.-9111, April 29, 436

relationship of smoking toinfectiousres-piratory disea e in, 227-229retrospective . smoking study me thods forr lung neoplasms in, 323'-328 serum lipid differences, in smokers vs: nonsmokers in, 98; 100, , 1011 smoking relatibnsllip: to tlirombosis' in, 130, 131 smoking' and'd nieotine effects on animal. cardiovascular function ih., 1.07-112smoking2 and. nicotine effects' on humann blood llpids„123-126 smokingor nicotine effects om human catecholarrtine Ieve15', 1119 smokingg and nicotine effects on human. cardiovascular system„ 113-114, 11!6, 117-119 smoking,and nicotine effects on human peripheral vascular system, 133-134 surveys ofcigatette smoking in, 66 tracheobxonctual tree changes ihn smokers andd nonsmokers in, 259-263 Uranium miners see Occupations Urban environment contribution to lung cancer mortality, I1 relAtianship ofl lung neoplasms, smoking,, air pollution ~ro y 252-255. Urban. populationss lung.peoplasmsin, suspected etiology of increasedl276. Urinary bladder see BladdSr Uterus cigarettee smoking effeetson gravidic, 408 UhilityCompany employeess see Occupations Vascular system see.dto Blood evculation„eardiovascular system, cerebrovascular system, throm- boangutlsobliterans pcripheral,, smoking and nicotine effect on, 9, 72-73;.75, 1133-134 Venezuelamaternaf.smoking and infant weight.in, 450 metfiodss used in smoking study and humanipregnancy,445 Ventricular fibrillation death from, nicotinee effects.on„36 Ventilatorgfunction tests see Respiratorysystem Veterans sre Occupations Virus inR6enza.,, cigarette smokeeffeets on: re- sistance of mice withl 1733 ihfluenza, nitrogem oxide effects on squarell monkey resistanceto,.173 Vitamin deficiency relationship to . tobacco amblyopia Xenon. radioactive, regionall pulrttonaryfunetion using, 14'7 458 R U. 5. GOVERNMENT PRINTING OFFICE: I971 0-420-11I9

i (11). HEATOnI, J. M., McCoRealcK; A. J. A.,, FREEmIAN, A... G. Tobacco amblyo• pia: AA clinical' manifestation o31 vitamin«B1z, deficiency. Lanceti 2(204'1)~: 286-290, August 9,. 1958. (12). KNox, D., L. Neuro-optithalmology. Archives of Ophthalmology 88~(1):: 103-127;January 1970. (1J)LINDSTRAND; K.,, WILSON, J., MATrHEwS; D. M~ Chromatography and. microbiologicall assayy of£ vitamin B12 in smokers. British MedicaI. Jaurnal! 2 (5520): 988-990, October 22,.1966: (14): LINNELL, J. C., S$fITHI„A. D. ML, SMIIRiH, C: Lp. WILSON;.T., MLATTHEwS, D. M. Effects of smoktingon metabolism.andlexcretionof vitamin Bis.. British Medical. Journal 2(5599) : 215-216, Aprill 27, 1968:. (15) SpHEpeNS;. C.. C,Is tobacco amblyopia a deficiency disease- Transactions of'the.Ophthalmological Society of the United Kingdom 66: 309-331,. 1946. (16) .SQHIEVELBEIN„H., WERLE, E., SCIIiULZ„E, K„ BAUMEISTER, R. The influ- ence oftobacco: smoke and nicotine on thiocyanatee metabolism. Naunyn-Schmiedebergs Archiefur Pharmakologie und Experiinentelle Patholagie 262(3): 358-3651 February 5,.1969.. (14). SILVETTE, H.,.HaAS„H.. B., LAHSON, P. S. Tobaccoo amblyopia. The evolu- tion and natural history of a"t'obaccogenic" disease. American Journal. of.OpHthalmology50(1) : 71-100, January 1960. (18) SMITH, A.. D: M. Retrobulbar neurit'dsin~ Addisonian pernicious anae- mial, (Letter) L,aneetl 1(7184).:. 1001~-1002, May 6, 1961.. (19)' SMITH, A. D: M.,. DUCKETT, 5. Cyanide;, vitamine Br_, experimental demyelination and tobacco amhlyopia- British Journal of Ekperimen- tal.Pathology 4fi(6): 615-622, December.1965. (P0). TrtA@PAIR; H.,M. Toxic amblyopia,.includingretrobulHar neuritis. Ttans- actions of the Ophthalmological Saciety.of the United Kingdom. 50: 351-385, 1930: (21) VICTOR, 241.. Tobacco-alcohol amblyopia. A critique of current concepts of' thisdisorder; witihspecial reference to.therole.of nutritional.deficiency inn its causation. Archibes of Ophthalmology 70(3).:313-318; Septem- ber 1963. (22) VicTOR, M. Tobacco ambIyopia, cyanide poisoning and vitamin B,,, de-ficiency;. A critique of current concepts. Chapter 3'. IN: Smith, J- L. (Editor). Nerro-Ophtlilamology:. Symposiumm of the University of Miami and the Bascom: Palmer.Eye Institute. Hallandale, Florida, Huffman. Publishing Co., 1970:, pp. 33-48:. (Y8) WALSH, F.. B.,,HOYT;. W. F. (Editors), Neurotoxic substancesaffectiirtgthe.visual.andocular motor systems. Chapter 15: IN: Clinical Neuro- Ophthalmology, Volume: 3„ 3rd Edition. Baltumore,. The Williams & Wilkins.. Company.;1969:pp. 2613-2616. (24) WATSON-WILLL4btSJ E. J.,, BOTTONILEY;, A. C:, A.INLEYy.It.. G., PHILLISS,C.I. Absorptiun ofvitamimB,_ imtobacco, amblyopia, British Journal of Ophthalmology 53($).: 549-552, August 1969. (25) WILSaN, J. Leber's hereditary optic.atrophy:. A possible dbfectt of cya- nide metabolism. Clinical Sbience:29(3) : 505-515, December1965,. ($8) WILSaN, J'.., MATTxEws, D. M. Metabolic inter-relationshipss between cyanide, thiocyanate and vitamin B1c, inn smokers and nonsmokers. Clinical. Science 31(1).;.1-T,. January 1966..

Ind!ex. Abortions smoking effects.oni 13' Aborflons,spontaneous, comparison ofstillbfrth and neonatall death~ withI . inn smoking and nonsmok:mg mothers, 390, 405-006, Acidosis metabolic, smoking mother effects on. in• fant;.407Adenocarcinoma prevalence ibn male andd female smokers.s and nonsmokers,.250 relationshipof cigarette smoking (ot 246-249„296 Adenoma papillary, induction ibn mtsby exposuree to cigarette.taxs; 348'9 pulmonary; inductiom in mice by ciga- eette smoke inhalation',. 349~9 renal,, relationship of smokingto,.296 Adrenal gland catecholnmihe rel'easefrom, nicotine effectson;. 36 Advisory Committee on Smoking and Nlealth estabGshmenf andd conckssions of study by, 3 report' on cigarette smoke and condhn- sates effects on.oraln cavity of animals, 288 Age alypieal nuclei inn esophageall epithelium: arranged by smoking and, 379-380 current cigarette smokers by sexi'and, 66 effects.on CHD„27., 39 AHA see American HearTAssocution Air~ pollution as causeof.COPD, 152, 216-217 effect on COPE) development,.175i relationshipp of lung neoplasms, smokmgand place.of residence, 252-255 role in.etiology of lung',cancer, 11, 276'. Alcohol efTecft of consumption onn esophageall neoplasmsin smokers,.289'; 2933 effect.of' consumptionn on laryngeal' neo- plasmsamong tobacco users, 280 effect of consumptiom onn tobaceo: am-blyopia 435436 effect of heavy consumption and heavy smoking on oral neoptasms;. 288 ethanol, penetuability of dissolved benzo(a)pyrene in mice esophageadepithelium, 2933 relations'hipp of smokingg and,, in' human tuberculosis,.172Alcoholi5m patientss viitb,, smoking and ventilatory function in,.213 Amblyopia characterization .of', 4355 development from cyanidecomponente of tobaceo:smoke, 14'inoidence of, 435, American.Heart Association poolingg project omCHD, 23~.28, 30, 39Aminoaao dyes activity in placenta ofl smoking mothers; 410 Anginapectoris cause.of,21 incidence with cigarette smoking, 24, 3'7' in Danish twins„smokers vs, nonsmok- ers, 51 in twins, constitutional factors, 50-51 prospective studies of, CHD morbidity relation to~smoking 37, 39' Animals, seee alsoo specifrc.animals.e.g:, cats„dogs,, rabbits, etc., atherosclerotic lesion, development in,, smoking enhancement,.36. carcinoma induction in,, from arsenic, 257 cigarettesmokee effecft on. pulmonary physiology and; stmcture in, 162'2 developmenn of lesions from cigarettesmokee inhalation, 111 effectes of nicotine on uardiovascular, systemof157, 807-1122 esophageal neopl§sms's in, induction by nitrosamines, 292'' respiratory tractt of, neoplastic changes' following, cigarette smokeinhalation,. 238-239 skin of, carcmogenicity of tobaccoo tars, 238,267 tests of„witHsmoke carcinogens, 1.2'2 ventilatory function changee fnom smok- ing, 10'. Anti-trypsin, alphat COPD'predisposition from genetic ati- senceof, 150 d'~etermination using immunoelectro-phoresis, 151 relationship in puBnonary emphysema„ 10-1 I AnthraniBc acid, 3-hydroxy- uribaryexaetion.of, smoking effects on.,. 296 Aorta aneurysms of,. cigarettesmoking', effect on, 9, 67, 71, 75. atherosclerosis in, longg term smoking etYects,.52-56 Areca nut see.Betel.nut Aroma tic aompoundss carcinogenic properties ibn cigarette 439

urine oflpatlents with, 296-297relationship off cigarette smoking to,.299 u;}ary, cigarette smoking~ relationship, U.S. morta6ty in..1967, 294 Blood' see also specificc components of blood, e.g.,.cholesterol, lipids, plateletss carboxyhemogloBin formatiom in, from smoking, 60, 755 clotting, cigarette smoking effects on, 9, 36 Blood.ciiculation, comnary' altetation: followutgg cigarette smokee in- halation, 58 effectt of eariations~ in hemoglobinn and hematocrit, 66 Blood pressure diastolic, cigarette smoking~effects, 8', 23 diastolic,: in. smokers's with CHD,.21-22, 24,42 high, riskk factor inn arteriosclerosisoh- literans; 72 high, risk:in.mortahtydrom CVD, 67 hypertensive vs. non-hypercensive, mor- talityaatesofCHD'y in, 422 nicotine effects on, 36 relationshipof smokingg and.CHD,.43; 47 smokers vs. nonsmokers, 41, 42. 103-104 systolic, mortality from elevated, with CHID, 42 BP-ttydroxylase see under'Enzymes Btadycardiadevelopment in dogsPJven nicotiue, 57 British Berinatal Mortality 8urvey results.of',.390 Bronchitis, chronic'. ' cigarette smokingcause and effect rela- tionship, 3, 99 defmition,.139 mortality in,cigarette smokers, 179 mortality rates in 1967', 1399 smokers vs. nonsmokers, 195-205. Bronchogenic carcino ma see Carcinoma, bronchngenic. BroncHopneumonia development in dogs'following cigarette smoke inhalation, 2711 BroncNopulmonary disease, chronic ob- structive ,me also Asthma, bronchitis„emphysema, respiratory diseases air pollutionrelationsfiip in„ 1L52~, 216-217' characterization of, 1139'9 cigarette smoking effects on develop:- menty.4;9-11, 175 efTec.t't of smokingcessationg on develop• ment{. 10 genetic factors iir pathogenesiss of, 148', 150-152; 205 '. increased prevalence of heterozygotesint 151-152'2 mortality in pipe, cigar,, and cigarette smokers, 175 mortality rates from, 139-145 smoking effects on ventilatibn-perfusion measurements in, 1153'. Buerger's diseasesee ihromboang8tis obliterans Burmw methods usedd in smoking, study and human pregnancy, 393 Butylamine; N-methyGnitroso suspected.carcinogenic properties in ciga- rette smoke from, 265 Cadmium in cigarette smoke, relation toemphy- semao pathogenesis,.154 Calves see Cattle. Canada COPD'morbidity of smokers in,. 204 human experimental data on smoking and.pregnancy,409d ihfec'.tious iespiratoryy disease in{.relation- ship to smoking, 228 kidney and bladder neoplasmrimsmok- ers~in,294 mortadity mtes from COPD, 139-141,.145 mortality ra tiosfrom' COPD„ 143 mortality ratios in smokers and non- smokers. from pancreatic neoplasms, 298 thrombosiss in, smoking relationship, 132 veterans of, lung neoplasm mortality ratios insmokers and nonsmokers, 241 Carbazole, 9-methyl- possible importance in tobacco oarcino- genesis, 266 Carbon-14 ]abeled smoke partihulatedepositiom in ham ster. re spiratory tract, 281-282 Carbonic anhydrasee see Enzymes Carbon monoxide in cigarette smoke,, formationn of car- boxyhemoglobin, 8'-9 effects on cholesterol'-fedlrabbits, 65-66 effects onn humam physiology, 60:62 levclsin cigarette smoke, 599 levels in fetal blood of smokingmother¢, 407<10, Carboxyhemaglobih effects ot1 elevated, on fetal tissues, 407 formation in.blood of.smokers, 60', 75formation from. CO in. cigarettee smoke, 8-9. Carcinogenss action om oral'l cavity.,., effect of sahva, 288 fistingg of, in cigarette smoke„265-266'. in smoke„effect on oral cavity, 12 Carcinoid prevalence in male and female smokers and:.nonsmokers, 250. Carcinoma formation following animaf skin.painting withh smoke condensates, 337-342 induction in ratsexposeds to cigarette tars, 3489 undifferential, relationship to cigarette smoking, 248-249 Carcinoma, alxeolar' induction in mice.bycigarerte smoke.ln- halationl.349 441

Carcinom a,. anapl9sticc pre+nalencein, male and female:'smok:ers and.nonsmokers, 250 Carcinoma, broncbogenic development inn dogs following',cigarette'smeke.inhalation, 269,.272-273'. mortalityfrom;y relationships: to smok- ing, air'pollution and residence„253 mortality in smokers vs. nonsmokersas- bestos.workers, 257 Carcinoma,, epidetmoid'd mortality from;, relationship tosmoking,o air pollution: and residence, 2541 prevalence: in male and fcmale smokers and nonsmokers, 250 relationship of cigarette smoking to, _246-249. Caroinoma, epitheliall inductionn in rrdce by'cigarette'smoke:in-halation, 350. Carcinoma, oatt cell relationship of:cigarettesmokingf to, 247. Careinama;.squamous cell' development in mice drinking alcoholic', benzo(a)pyrene, 292 inn oral cavity,, relationship totobacco'o use, 366-367 Carcinoma,.tracheobronchial ¢mduction,in hamsters by. cigarette smokee in stillation,. 346-347. Cardiovascular dicease sSce.afso.Coronary dlseasee atherosclerotic, cigarette: smoking, rela•tionship,.4 Cardiovascular.system nicotinee and.cigarette smoke effects on, 56-58,.107-1.1'8 Catecholamines adrenal gland.release; effect of nicotine on, 36 effect on blood flow inn coronaryy arte- ries, 58 release bycigarette:smoking, 8release imanimals by nicotine.,:57, 1119 Cats cardiovascular. functionn ins smoking: and nicotihe effects on.,] 10; 11.11 ciliary function in, effect of cigarettee smokcon, 222224 lungs of, cigarette smoke.effeet onsur-factant activity, 225 Cattle ciliary function ih„ effect of cigarette smoke on, 221 CBE see Blood'd circulatlomcoronarp Central nervous system effeetsofcarbon monoxide imsmoke on,.. 60' Cerebrovascular disease definition of; 66 mortality from,., effects off cigarettee smoking on., 9 mortalityy rates from, smokersvs: non- smokers, 66-70 Cessationn of smoking effect on COPD developmentt in Britishh physicians, 11422 effect oaCOPD morbidity in smokers vs,. nonsmokers„146effect on development of COPD, 140. effcctt on mortahtyfrom. COPD fro 175 improvements in respiratory system 1481.1499 relation tbn incidence and mortality fhom CHD,32~ .46d8,106'. CHD see Coronary disease Chemiluminescence see Luminescence Chewing see Betel.nut andd tobacco. Chickens ciliaryy funct3onn in, effect off cigarette smoke on, 223' embryoss of, effect, of cigarette smoke on, 344 embryo of, nicotine effect6on CNS,.411 Chile. atherosclerosis autopsy studiesinl55atherosclerosisin, no smoking effect found„56 Cholesterol rabbits fed, earbon monoxide effects on, 65-66 serum, cigarette smoking relationship with, 8serum, control in coronanp, disease,. 21-22 serum, relationship of ngarettesmoking, to:levelsof, 41, 43' semm, relationship of elevated withh ciga- rette smoklhgg inn peripheralvaseular disease; 72 serum, ih: smokersvsS nonsmokers,. 41, 98-102 serum, im smokers with C11D,.23-24,.43:' synergistic relationship of carbon mon-oxide in coronary'atheromatesis, 63 Chromium respiratorgy tract carcinoma in . workerss exposed to,.256 C'hromiumcompounds lung neoplasm mortality ftom,.257-258 Chronic obstructive pulmonary disease see Bronchopulmonary disease, chronic obstructive Chrysene carcinogenic propertles' in. cigarette'e smoke.from;.265Chrysene; 1'-methyl-carcinogenic prnpertiesim cigarottee smoke:from, 265. Cigarette fdtersadvantages inn reductionn of particulates;. 269,275 reduction, of lung neoplasms from, 13Cigatette smoke alteratiann of coronary blood flow, 58 bconchog¢nic carcinoma induction in dogs inhaling„269~ 270' cadmiumm levels: in,. 154 carbon monoxide levelsin., 599 carcinogenicity of components toani:-mals, 1.2, 277. cause of'deatb in dogs from inhalation,.. 271 ci8ary movement inhibition, 267 effect onn tissue and.organd cultures, 267, 343-345 442

effecn of nickel on inductian.ofilung aryl hydroxylase, 256-257Sightary risks in,.l' 1 inhalationn by dogs, lung neoplasm devel- opment, 268-269, 272-274! inhalationn effects on animal' respiratory tract, 268-269~ 349-353 inhalation effects on hamster larynx., 281,284 listing of identified orsuspected.tumori- genic agents, 264F267 2-naphthylsmine.identified in, 265 neoplastic changes inn animals inluling, 235-239'tobacco amblyopia relationship . too cyan- ide metabolism in, 435-036 Cigaret.te.smoke condensatesoarcinogenic effect on aniinal oral cav- ities, 288 carcinogenic propertiess om animal', skin, 337-342' etTecte of instillationor implantation: in animal hacheobronohial tree, 34'6-3488 effects. on tissue and'd organ cultures,. 343-344 painting skion of animals with, 337-342Cigarette.smokers. arteriaL occlusions in, 73 atherosclerosis inianrtic.and.coronaryarc teries, 52-56 atypical nuclei inn malee esophageal epii thelium, 379-380'0 bladder.neaplasms.in, 293-295 cell rows and atypicalicellsin vooalicordss of, 280, 359-360 cessatibn effects on. COPD, morbidity, 146.,.197;.199';203-204 cessation lowers lung neoplasmm rate in, I1 cliangpsin.ventilaforyfunction and pu1-monary histology, t75Cf1Din. AFPApoolingprojeet; 28; 30, 39fflD.risk by, 23-25 comparative risk for lung neoplasms, 237 declinee in Britishphysicians,:48 development off altered ven tilatoryfunc-tion iu.young.,10development ofl esophageal neoplhsms,. 112, 293 development't of'.Iaryngeal neoplasms, 12 developmentt of oral neoplasms, 12' developmentt of secondlprimary ordl neo- plasms m.continuing, 287 effectt of filtersomemphysema develop- ment, 162 efiects,of inhalation on bronchial.reacli-vity,.164effect'l on cardiovascularr system, 56-58',. 1'07-1 li8 effectss onn utedneactivity in gravidice women,408. esophagealineoplasm mortality ratibs in, 290-291 etiological cause of'lungneoplasms, 23~9histology and smoking relationship of lung neoplasmsin.246.249infants buth weight„397-399: inhalation effects on humann pulmonary function,. 163, 1.66-1169 kidney.neaplasmsin,294-296 laryngcall neoplasm induction in, 354-357 Ibngg neopllasm mortalityy in„ 240, 243-244 mortality from cerebrovascular disease, 67-70' mortality rates alYected'.by sex, 3 mortality ratios from COPD„I42-144 mortality ratioss frompancreaticem neo: plasms in, 298 mortality ratios from pepticc ulcers in;. 424, pep tie ulcer in, smoke.effec tss onn antacid therapy, 423 percentagee of women of ohildbearingage, 389 pussible. processes' fon increased mortali ity ih,4-5. postoperatiuepulmonary complications in, 174, 230 pulmonary sudactant! activity in, 172, 225 relationship of asbestos in lung neoplasm, mortality, 257 relationship in coronaryand lower.limbr arteriosclerosis,.72 relationship of former to lung neoplasm. development, 276 relationship to infectious resphatory dis• ease,.172; 226-229 relationship to laryngeal.neoplasmdevel-opment in, 2811 relationship to lip or oral' cavity neo-plasms, 361Q70 relationshipp to lung neoplasms, 275relationship5 withh bladder neoplasms in men,299' re9ationshipwithdust on COPD develop-mentl 153 with peptic: ulcer, 427 risk inCI1D, 8 risk of COPDin„140 survey by age andl sex,.6 survey of U:S„ 6. Cigarettes developmentt off esophageall neoplasms, by, 12, 293 tar levels of', relationship too lung neor plasm. development, 276 Cigar smokersarypicall nuclei in ma1Ct esophageal epi-thelium, 379 bladders,neoplasms in,.293-294 cell rows and atypical cells in vocall cords of, 280, 359-360 COPDmorbidityin, 146,. 197-198,. 201-202,204-205'. effectss of sm.okee on bronchial reactivity;, 164 es29pOhageal neoplasm mortality ratios in, kidhey neoplksms in, 294-295 lack of risk inCVD, 67' 12ryngeal neoplasm induction in, 12„ 354-357 lung neoplasm incidence in mral 8witzer- landl 244 lung neoplasmm mordality in, 11, 240-243 mortality ratios from CO.PD~in, 142-143„ 145 443'

environmental and atmosphericc factors of;.252-255 groupings„246.334 group characteristics of tobacco use in smokers and nonsmokers, 24D, 244, 329-333 histology. and smokingg relationships, 246-249 mortality expected in. U.S'. in 1970, 237, 239 mortality fromm chromium compounds, 257-258 mortalityy inn cigarette smokers by dhra- 5om,.240,244 mortalityy in smelterworkersexposed' to arsenic,.257 mortality in smokerss and nonsmokers, 240-243 mortality, in smokers in. Norway and Finland,245:246 occupational exposuree effects om patho- genesis of, 12 prevalenceine males and females by tumor type, 246, 2500 reduotionn in numberr using filter-type cigarettes,. 2755 relationship of asbestos and smoking: to, 257' relationshipofl female smoking, 24'6, 251 relationship off smoking.g to, 237 retrospective study methods for smoking rela tionships ,. 240„323328 smoking caure: and effect.relationship„3 smoking habitt studyy of patients.with„3 types.implicatedin smoking,.237U.S: mortality rates for 1939'vs. 1967, 239 Mhcrophagess effeclt of. cigarette smoke of action on staphylacoccus, 165 Mammals see also specifioc mamrnals cellsof,s effeott of cigarette smoke tars on,343 Medical studentsseeOccupationsMethylben¢u(a)pyxenesre Senzo(n)pyrene, 1-mettiyl-9-Metlryl carbazole: we.Carbazole,9-methyl- Metliylchrysenes.seeChrysene, 1-methyl- Methyl-indole see Indole; 1-methyl+ M'e thyl-n-bu ¢yNI ttosamine fee' Bulylamine, n-methyl-nitroso- N -Metlrylnicotinamid0 . see' Pyridiniumm compounds, 3carba•moyl-f_-mettiyl- Mice, bladder neoplasmss in„ indhction bytryptophan tnetabolites, 296embryo,6 lethall effects ofnicotinrf on, 4111 esophageal epithelium of,, alcoholic benzo(a)pyrene penetrability of,,292'. esophageall epithelium of, oil desolved~ benzo(d)pyrene pcnetraflilityof,, 292' IUngss of, effects of eigarettesmoke on, 343s.344', lung neoplasm incidence in, from, . chrom- ium roxide dus0 exposure,.25'8 pulmonary carcinoma induction in, following asbestos dust inhalation, 257. pulmonary changes from chronic nitro- gen oxide umhalationl16h, 220 pulmonary changes in. cigarette smoke inhaling„159 pulmonary clearance in, cigarette smoke effects on, 170 resistance too pneumonia bacteria follow- ing cigarette inhalation, 173'3 respuatorytract of, cigarette smoke ih- halation effect on,. 268-269, 349-353 skin painting of, smoke condensates ef- fects on, 267, 337-342 Miscarriages see Abortion, sponlaneous. Mollusks eiliary,funetiom in, effect of cigarette smoke on, 223. Monkeys athexogenicc effects of carbon monoxide andd hypoxia, 64 ciliary functionn in, effectt of cigarette smoke on, 222. fetall bronchial tubesof, effects of ciga- rette smoke on, 345Ilhesus; development of bladder neo:- plasms from 2-nzphthylamine,.296 squurel, nitrogen oxide effects.on resis tance:to.pneumococcus, 173 Morbidily ratio CHD: in smokers.with predisposing fac- tors, 24 CHD: in smokers vs. nonsmakers., 21-22, 24, 30-35 CHD, relation too smokingy.32-35, 37,.39 CHD, retrospective studies, 40, 93-97in Danish. twins, amoking effects on, 49-51 development of COPD inn smokersvss nonsmokers, 145, 195-205 Mortality rates from bladder neoplasmsin U:S. fox 1967',293 fromm bronchopulmonary disease, 141-145 cerebrovascular disease, smokers vs. non- smokers, 66b'7„68-70 CHD, paired combinations of high risk characteristics:m, 25' CIilD,.retrospective studies,.40, 93-97 CHDin smokers vs.. nonsmokers, 24, 26-29 CHDin U:S„ 211 in Danish twins„smokingeffeats.on, 51 from esophageall neoplasms m U.S.. in 1967,289 fromkidney neoplasms in U.S. for 1967, 296 from lungg neoplasma for 1939 vs. 1967 in N-S., 239 from lungg neopl6sms expected in 1970, 237,239 fromm lung neoplasms in smelter workers exposed to arsenic;.257 fromm orall neoplasmsim 1967, 285 449 • ~.: .,.~....

myoeardiaPinfarctiomin„32, 38-39 relationship toinfectious~respiratory dis- ease, 227' relationship of laryngeal: neoplasmsde-velopment in, 281 relationship of neoplasmsof oral cavity with, 12',. 361j365~„367+371 mortality mtioss from pancreatic neo- plasms in., 298 mortalityy ratios frompeptiom ulcer in, 424 risk of CHD, 8 risk of CORD, 10 tiskk of lung neoplasm development, 276 CIliary activity see RespiratorysystemCirculation: see Blood.ciiculation. Ciixhoses see Liver Civil s'ervantss see Government employees under Occu- pations Coal minerssee OocupationsCongressional Ilegislati on: see Laws Connecticut CanoerRegistry. &gures.ons age-adjusted' larynx neoplasm ihcidence,277frg8r4es on: incidence of oral neoplasms, Consti tutiona118ypothesis relationshipp to CHD and smoking, 4849:, 105-106 COPD seeBtanchopulmnnary disease, drronicc obsttuutive ., CornsBk smoking, lack of arterial epinephrine levelincrease,57. Coronary blood'd flow' see Blood circulation, coronary Coronary disease sre also Angina pectorisages adj ueted~ratesin smokers,.23 artedosclerotic, mortality rates in U.S., 21 atherosclerosisin,s effects'.of'smoking on, 4,63' blood pressure of smokers vs. nonsmok- ers, 43, 47carbon7 dioxidp.effeots onoxygen uptakein„62 cigarette smoking relationship, 5 death ratios of paired combinations of high risk, 25 first, mortality ratesin.smokersvs,s non- smokers, 24~, 26-29incidence9 andmortafityl rates's in former smokers~ 46,4748 'infarc tionn in N YC pipe and cigar smok-ers;.32;.38-39 , infarctian relationship to physrcal.activ- ity„smokers vs. nonsmokers, 44 in smokers with predisposing:factors, 24 morbidity relationship of smoking, to, 32-35,:37.,39.,.93A7mortality' and morbidity, retiospective studies, 40, 93'-97 444 mortality fiom,, relationship toelectro- cardiographi c.findings, 42: mortalityy ih:obese vs..non-obese; 45 mortality rates in, hypertensives vs. non- hypertensives; 42 mortality rates in, smokers vs. non- smokers; 21-22 mortalityrates in, with increased.car6.on monoxide, 622 mortality rates of paired combinations of high risk, 25 . mortality ratess of cigarette smokers from~ . AW14 poolingproject, 28,.30„39 mortality rates of U.SI vaterans; 26,.38 myocardiall infarction in Danish twins, 51 nicotine effect onn coronary blood flow m,58' relation of trfglyceridesdq,65 relationship of blood presure and smok- ing, 45, 47relationship7 of heart rate and snoking; 45,47 relationshipof physical activity and smoking 411, 43, 44 relationship to constitutional makeup and smoking, 4849, 105-106 relationsltipto ECG abnormalities and smoking, 45; 47' relationship to obesity and. smoking, 4'3-05'risk factors. 23-24, 4041 smokersageeffects~s on development, 27„ 39 smoking.risk factor,.8 sudden mortalityin., smoking effects on,. 52 Coronary hearCdisease See Coronary disease Cows' see Cattle Cresol suspected carcinogenic agent of cigarettee smoke, 266 Cuba lary'ngeall neoplasmsinj relationship to tobacco use„356 relationship of tobacco use and neo-plasmsof oral cavity, 364 CVD seeCerebrovasvular disease Cyanides metabolism of, pathogenesis oftobacco'amblyopia rela tion ship ~ to, 435436 in tobacco.amblyopia etiology, 1'4 Czechoslovakia laryngeali neoplBsms in, relationshiptop tobaccouse',.354,357 serum lipid difference inn smokers. vs. nonsmokers in, 101 Death rates seeAfortality rales Denmark atherogenic effect of carbon monoxide andihypoxiai 64 bladder neoplasms in, methods and re- sults in retrospective stbdies of smok- ing and, 381„383 carbon monoxide effectsons human blood lipids in, 129

I carbon monoxide effects onn rabbit blood'lipids iny 129'9 serum fipid differencess in' smokerss vs. nonsmukers~ Iny 102 twins in,, angina pactbrisin smokers vs. nonsmokers, 51 Deoxyribanucleic acid content increase in smokers oral epi-thelialcells,.288 levels ian micee lungexpased to.cigaretteo smoke,.161 Diabetes effecti on CHDin smokers„24 risk'k in mortality from: CV D, 67 Diabetes me0itus, relationsliip with cigarette smoking in peripheral vascular disease, 72' Dibenz(a,h)acridtne carsinogenic properties in. cigarette smoke from„265i Dibenz(aj)acridihe carcinogenie' properties inn cigarette smoke.ftom„265-7H-Dibenm (c,R)carbazole' car~cinogenioc properties, in cigarette smokefiomi.265Dibenzo(a,u)p-vrene see Benzo(rst)pentaphene DietHylnitrosamine suspected carcinogenic properties in ciga- rettte smoke from„265'7,12-D'unethyl-benz(w)anthracene see Benz.(a)an t'hracene, 70 2di me thy, l- Dimeth ylniitosaminc. suspected.carcinogenic propertiesin.ciga-rette smokefrom,265. 2,3-Diphoxphoglycerate effects of carbon manoxidee on, 60{ 1. DNA see Deoxyribonucleicc acid. Dogs atherogenic effects of nicotine in, 120 bladder neoplasmss in, fed 2-naphthyl- amihe; 296 bradycardia and tachycardia in,.fo0ow- ing, nicatine injection, 57-58 bronuhogenioc carcinoma induction in,n from cipsrettc'e smoke inhalation, 269, 270 cigarettee smoke instillation or implanta- tion effectks on tracheobronchia.lreel of, 268, 347 death in, causes',from.cigarette smoke in-halation, 271 effect of cigarette smoke on.pulmonary clearance in;. 164, 170 fetall bronchiall mbes of,.effecli of ciga-rette smoke.on, 3455 lungs of, cigarettesmoke effects on' sur- faclant activity, 172, 225i lungg neoplasms following cigarettee smoke inhalationl 239, 277 lung neopbrxmss in,.types.and lobes where found, 269, 272-273 myoeardium of; nicotine effects om, 58' neoplasmi development in smoking,.perr centages of', 274 pulmonary histological changes in ciga- rette smokeinhabng, 158, 159-160 .-F respiratory tracti of, cigarette smoke in- halation effects on, 2685, 352, 353 smoke induced bronehoconstriction in, atropine.effects, 163 smoking and nicotihee effects on blood lipids in., 127-128 smoking and nicotine effects on cardib- vascularfunction in,.107-112 smoking and nicotine effectss on care- cholamine levels in, 119 Donkeys effect ofl cigarette smokee an pulmonary clearance'in„164, 171 Ducks cigarette smoke instillation or.implanta- tion effects on tracheobronchial tree of,.346' Duodenal ulcer see Peptic ulcer. Dusts COPD development fromt.153, 218 Egypt relation of'f human pulmonary histology andismoking, 163 Electrocardiograph findings on., CHD mortality relationship to, 42 reading abnormalities, relationship to smoking:andi CHD., 45, 47. Electrophoresis usee in determining scrum.levelofalphat- antitrypsin, 15.1 Emphysema alphat-antitrypsin absence type genetic faotors;.150 cigarettcsmoking effects on., 9 development ihn dogsfollowing, cigarette smoke inhalation,.271 development of„ rel9tionn of cadmiurmin smoke to, 154 grade: II or 111,, smokers vs- nonsmokers, 162 mechanism inalphat-anlitrypsinn absence type of, 151 mortahtyy fiom;, effectt of cigarette smok- ing on, 175 mortality, rates from„in 1967, 139 pulmonary, definition, 139Employment.. seeOccupations' England see United Kingdom Enzymes see also Papain activity oFl, effect ofismoking, 165 aryl.hydrocarhon hydronylase.activity in placentas at childbirth, 4'L0 aryl hydroxylasc, effect of nickel in ciga- rette smoke aninduction of, 257 benzu(a)pyrenee hydroxylase, activity'in placentas of smoking mothers, 410. carbonicc anhydrase; carbon monoxide inhibition im fetal cordd bloodd of smok- ing mothers, 407 carbonic anhydrose,.decrease in. activity in fetal cord bloodd im smoking mothersi.409Epidermoid carcihomw see Carcinoma, epidermoid'. 445

lungs of, cigarette smoke effeetson sue- factantactivity, 2255 respuatory changesin., exposed to ciga- rette.smoke,162 Hamsters benzo(a)pyrene inhalation by, effect.of asbestos dust on carcinoma induction, 257 bladder neoplasms in, fedi 2+naphthyl- amine, 296 cigarette smo ke. instillationn orr implanta- tion. effects on ttacheobroncltial tiee of;.268y 346-348 laryngeal malignanciess in, following smoke inbalation, 12'2 laryngeall neoplasms following cigarette smoke inhalation, 239 larynx of, effectt of cigarette smoke.in- halation on, 281., 284'4 lung, and.d emtlryos,, effectss of' cigarette smoke tarson;. 343-344 pulmonary. changes from chronic nitro- gen dioxide inhalation, 220 respiratoryy tract'lof, C-141aticledlparticu- lates depositionin, 281-282 respiratory tract of, cigarette smoke.in- halation effects on, 268, 351 Health Insurance:Plan~(NYC)'. myocardial.infarction.in pipe and cigar smokers.under,.32;.3'8- 93 Heartt see also Antiythmia, brachycardia, myo- cardium and tachycardial cardiac rhythmm of, effect of.nicotine.on, 36 fetal, increased rate by maternal smok- ing;4081 myocardiumof„nicotine eHects on oxy- gen demand, 388 myoca:dium of„cigarette smoking.effect on, 5, 8 rate,, relationship to smoking andICHD, 45;47 Heart disease &ee Cardiovascular diseases andlcoronary disease Heights decre.ased,, in children of smoking mothers;.407' Hematite dust respiratory tract neoplasmss in hamsters exposed.to, 348Hematocrit'. infant;, smoking mother effects on, 407, 409' variationsim, effect on caronaryblood flow,.66'. Hemoglobin see alsoCarboxyhemoglobiir afftnity for oxygen, CYJeffects on. 2,3di: phosphoglycerate control of, 60+61 variationsin, effect on coronary blood flow, 66 Hens see Chickens Heteracychc compounds carcinogenic properties in cigarette smoke,264,265Hexamethonium blbckagc of1 nicotine cardiac.stimulation by, 57 HIP of NYC see HealthInsuranceRlan (NYC): Hookahs' smokers of, laryngeal neoplasmm induc- tion.in, 355 Hungary' retrospective smaking:study of methods foriung.neoplasmsin:, 328 Hydrocarbons see Aromatic compounds heterocyclic compounds H'ydrogen cyanide in cigarettee smoke, effectss on body ozi- dative metabolism, 62 3-Hydroxyanthranilic acid see Anthranihe acid, 3-hydroxy- 3-Hydroxykynurenine excretion of, smokingeffcetson, 296. Hydroxyproline levell in mice lung exposed to cigarette smoke, 161 Hypertension. see Blood pressure Hypoxemiaa arterial, carbon dioxide effects on, 61, 75 Hypoxia aort.ic' atheromatosis development in rabbits exposed to, 64 postoperative, development in smokers, 174,230 postural, mechanism~ in asymptomatic smokers vs. nonsmokers, 1147 Iceland Iung neoplasms in, relationship to tobac- co smoking, 244 Indeno(1,2,3,-cd)pyrene carcinogenic properties in cigarette smoke from, 265Ihdia esophageal neoplasms.in, retrospective studies of tobacco use with,.378' laryngeal neoplasms un relationship to tobacco use, 355', 356 relationship of smoking too tuberculosis in, 227 relationship of tobacco use and neo- plasma of oral cavityy in, 362, 36& smoking andd nicotine ef'fects on.human cardiovascular system.,.117' smoking relationshipp to thrombosis in, 131 Indole„ 1-meth yl- possible inittlator'in tobacco carcinogene- sis, 265 Industrialworkersl se'e plant workers under.Occupations Industrialhazardsl effectt of dust on COPD development, 175, effects on COPID development in smak. ers,.153-1154, 218-219'Infant see also. Neonate sudden death. in;n relalion of smoking and nonsmoking mot:hers,.407InOuenaa.virus. effect't on dogs inhaling', cigarette smoke;. 351 4'47 C. fw' ~ ~ C!T N' Go

resistance ofmicefollowingf cigarette smoke inhalation, 173 Inhalation studiess see under Cigarette smokelieland: acute effectt of cigarette smokee on. Humanpulmonaryfunction, 168 CHDD monafityy and! . morbidity in smok-s ers and. nonsmokers in,.94 CHD mortality and morbidity in, 96. Iungneoplasmsin, retrospective smokingg study of methods in, 328ttaternal smoking and infant weight, 399 methods used in smoking study and human pregnancy> 394, 396 northern,, mortality rates from COPD„ 144 occupational exposuroandsmokingrela- tianshipsto COPD in:, 218 relationship of lung~, neoplasms to smok- ing,, air' pollution and residence in, 254 serumm lipid differences im smokers vs. nonsmokers iny.99smoking and nicotine effects omhuman peripheral.vascularl system,.133'smoking rel2tionship: to thrombosiss in, 130 Israel cigarette smoke effects an: animall em- bryosin,343's mortality ratcss from COP6) in, increase, 140: Italy human experimentall dataon: smoking and.pregnancy,409serumd hpid differences im smokers vs. nonsmokers in, 100, tracheobmnchiulltree changes iwsmokers andinonsmokersin,:263lapan bladder neoplasms in, methods andl re- sults in retrospectii+ee studies of smok- ing and,382,384 CHD mortalityand morbidity in, 96 cigarette smoke effectsons human fetal lung tissue .ln„343 esophageall neoplasms in retrospective studies off tobacco use in, 378 kidney and bladder neoplasms of smok - ers. in, 2955 lung.g neoplasms in, retrospective smoking studyf af methods m,.326, 328Inng,neoplasm mortality off smokers and nonsmokers in.,,243morfality ratiosftoms esophageali neo- plasms in, 291i mortality ratioss from pancreatic neo- plasms inn cigarette smokcrs.ln, 298 relationships.oflung neoplasms to: smok-ing,, aii pollution:, and residCnce in, 255! Kidney neoplasmmortality rates in. IU.S.for 1.967,.296 relationship of tobacco use, 13, 299 in smokers and nonsmtikers,. 238, 294295 Korea relatiom of humann pulmonary histology and smoking in,.255 448 tracheobronchial tree: changes in~ smokers and.nonsmokcrs of, 259: Lactoncs suspectedd carcinogenic agents in ciga- rettc smoke, 265 Laparotomy postoperative pulmonary complications following; lnn smokers vs,.nonsmokers, 174 Laryngeal neoplasms development in hamstersfollowing ciga- rette:smoke inhalation, 239 development in. smokers, 1.2', 281 mortality in smokers's vs.. nonsmokers, 237-238 mortalityratios'from,.277-279 relationship to, tobacco use and.develop- men tt of, 354-357 relative risk mtios from tobacco use, 277,.358U.S. mortahty in 1967',.277Larynx epithelial changes in, classification of, ''. 281,283 hamster, C-14 latle led particulate:deposi- tiom.in, 281-282 Ilaws PL 89:-92,requirements for.smoking haz- ards.literature review.,,7 PL 9t-222, requirementss for smoking hazards review,7 Lip ncaplasmsrelationship of tobacco use, 361, 362, 365,.367relationship7 to pipe smnking„289 Lipids bluodl effectt ofsmoking.on levels of, 65-66, 123-128 serum, differences in smokers vs. non, smokers, 4'1, 98~-102'llipoprateins infiltration in arterial walls;.carbon, mon. oxide effects on, 63~ in smokers vs. nonsmokers, 99-102Liber cirrhosis of, rates among cigarette smakers,.5. Longshoremen see Occupations. Luminescencee teehniqpes of, use inn determining aro- matic hydrocarbon in urine, 297. Lung diseases. See 8ronchopulmonaryy diseases', adeno- carcihoma,, carcinnma;, tuberculosis Lungs fibrosesin,; smokers vs- nonsmokers, 1611 hamstery C-14 labeled particulates depo- sition in, 2'81-282human, effects of cigarette smoke on tis-sue from, 343-345 Lung neoplasms, aupo0ution: role ihetiologyof, 1.11 cause and effect relationship of smoking,. 276 cigarettoe smoking risks, 111 developmentt in dogs following cigarettee smoke inHalation,.239' effect:of sex on development, l1

smoke from, 264„265 detectionn in urine using: chem0umi- noscence teehnique, 297 stimulationef placentall Bp-hydroxylase activity in pregnant ratsby, 414 Arrhythmia formation in nicotine stimulated dam- aged myocardium,.58 Arsenic l.ung, neoplasmmortahtym in smelter workers exposed to,. 2577 respuatorytracty carcinoma inn workers exposed'. to, 256, 257Aateries aneurysrw in aorrtic,, cigarette smoking ef- fectson,.9., 67, 71!, 75 atherosclerotio, increased'd bycigaretrtee smoking„8, 63' flow, of carotid, cigarette smoking effects on{ 67 hypoxemia, devclopmentt fromm cigarette smoking,. 9 occlusions of„ cigarette smoking effects on, 73 walls of, mechanism.of lipoprotcin infd- traGpn,.63walls'of nicotine.-induced necrosis, 63Arterioscletosis see also Thromboangutis obliterans in aorta and coronary arteries„cigarettc smoking effecta on, 45, 52-56'6 clgzrettte smoking,effects oni 8 developmentt byy increased carboxyhemo- globih formation, 9 development: of,, carbon monoxidee ef- fects on, 63 develbpment of,, effects of nicotine on, 38 lesion~ development in, smoking,enhance• ment, 30 peripheral„ cigarette smokingg effects on, 72-73 Arteriosclerotic heart disease ('pSHD) see Coronary disease Asbestos'workers see OceupationsASND see Coronary disease Asia aee a(so: specific countries of Asia Centrall andi Southeast,., relationship, of' tbbacco use and'neoplasms ofbral cav- ity, 366 Asthmw bronchial, cigarette smokingg effects on„ 110, 1175 Atherosclerosiss see.ArteriosclerosisAtropine effectson.bronchoconstrictibn in dogs, 163 Australia COMmorbidityinismokers in, 203laryngeal neoplasms in,, relationship too tobacco use, 357lung neeplasm in, retrospectivee studiess of, 327 peptic: ulcerin„ methods for retrospe.c- trveand'cross-sectione studies ofsmoking and, 426, 428 ' 440 Bacteria effect of cigarette smoke on action of macrophageson, 1655 pneumonia, mice resistance following cigarette inhalaSon,.173 Bank employeestee Occupations Benz(e)gcephcnanthrylene carcinogenic properties in cigarette smoke from, 264, 265 Benz(a)anthracene alcoholic solution of, penetrability of micee esoph ageall epithelium, 292'. Benz(a)anthracene,7,12:dimut'hyll carcinoma induetion: in, hamsters.follow- ing.instillation of, 346 skin painting with, papillbma and carci- noma induction in mice by, 341 Benzo(b)fluoranthene see Benz(e)acephenanthrylene B enzo(j)f]u oroan thene carcinogenic properrtiesih cigarette smoke from, 265 Benzo(c)phenanthrenee carc'inogenic properties'in cigarette smoke from, 265 BenzoUsr)pentaphene carcinogenic pmperuesin cigarette smoke from, 265 3,4-Benzopyrene see Benzo(a)pyrene Benzo(a)pyrene ability of smoking', mothers to hydroxyl- ate, 407 alcoholic solution of, penetration of mice esophageal epithetium,.292' carcinogenicity of;in relation.to asbestos in hamsters, 2577 carcinogenic properties ih cigarettee smoke from, 264, 2651 detoxification by lungarylg hydroxylase; 257 effects~ of instillation or implantation.inn animal. traclieobronchial tree, 346-347 effects on animal tissue and organ cut-mres in, 343-34'5 effectswith~ influenza viruson cigarette inhalation by mice,352 sarcoma induction in rats following ih-stillation of,.346' skin painting with„ papilloma induction in mice by.,,337-338 Benzo(a)pyrene,l-methyl- carcinogenie properties im cigarette: smokedrom,. 265. Bctel nut chewers of,.relationship with oral.cavityl neopla sms,.366, . 369-370 _14~ Birth weight ~.4 a Nrnn~.~ '-V Blacks maternal smokmgand infant weigh t, 397 maternal smoking and prematurity, 400401 Bladder neoplasms frequency in: smokers's vs. nonsmokers,. 238„293-295 methcrd's of retrospectivee studies of' smoking and, 293, 381-384 presencee of tryprophan' metabolites in'

Epinephrinelevelk in arteries, cigarettee smokingg ef- fects on, 57 Epitheliomas8p, relationshipof tobacco use with, 361 Epoxides suspectedd carcinogenic agents'.in ciga- rette.smoke, 265 fisophageal neoplasms fiequency in smokers's vs. nonsmokers, 12„238. induction in.artiarrals by nitrosamine, 292 methods and results of retrospective studies of tobacco use,.289,.375-378 mortality rates in U.S:. for 1967;.289 relationship to smoking; 293'. Esophagus basall cellss of epitholium of, atypical nucleii in male smokers 292, 379-380 Ethanol I see Alcohol'. Exrsmokers see Smokers (former). Factory workers seee plant workersunder.Occupations Fanty acids blood,, effectt of smoking on.levels of, 65. levclsinssmokers.vss nonsmokers, 102 rise inbloodn serumafter'smoking,.36 suspected carcinogenic agents off ciga- rette.smoke,.266Fems hearrt tieats'& in, increase in, smokingg mothers, 408 tissues of, cfiectsof elevated carboxy- bemogtbbimont.407 Fibrosis, in.lung; smokers vs, nonsmokers, 161 FibtiOation ventricular, deatMfrom, 36 Filters see.Cigarettetilters Finiknd blood pressure differences in smokers vs. nonsmokers in, 103 COPD morbidity in smokers of, 2(100 lung neoplasms in;, res'trospectivesmok- ing study ofinetAods.in, 325',.32'7' lung, neoplasm.mortalitym in, relationship too tobaccoo use, 245-246, peptic ulcer in., methods and results for' retrospective and cross section studies ofsmaking;and„426,428 serum lipid differences's in smokersvs: . nonsmokers of, 98, 99 smoking andd nicotine effects on humann tilood lipid's in, 124 Fluoranthene alcohobcc solutiom of, penetrability of' esophageal epilhelium, 292 Flax mill.workersseeOccupations Former smokers" see Smokers ((nrmer). Formosa acute efTecf of cigarette smokeon humann pu Imona ry function in,.169 France bladder neoplasmsm inl methods and re- 446 sults in retrospective studies of smok- ing and, 381-383 CHDmortality and morbidity in,94,97 COPD mortality of smokers in, 201 cigarette smoke effects on animal l6ng tissue.in,343 cigarette smokee effeets. on chicken em. bryos in, 344 cigarette smoke inhalation . effects on rat respiratoryttact;..349esophageafy neoplasmsin,.retrospectiUe studies ofYobacco use.with., 378 laryngeal neoplksms in, relationship to tobacco use,355,357. lung neopl4sms fn,, retrospective smoking study of methods in, 326 relationship of tobacco useand neo-plasms of'f oral cavity,.363 Framingham Heart Study morbidity ratios inCHD,24Fungicid'es cnncentmtionn in cigarette smoke, 265, 266 ~ Gastric ulcer see Peptic ulcer Genetics factorss of, cigarette smoking relation- ship, 5 factorss of, in COPD pathogenesis;. 148',. 150-1.52,205 twin-studies;, effects ofl smoking, 49-52,. 99 Germany. CHD morbidity and.mortality. in,95-96', 97 cigarette smoke inhalation.effects on ani-mal respiratory tract in„350laryngeal neoplasmsin;s relationship too tobaccouse„355lung,neoplasms in,.retrospective smoking, study oFl mcthodsin, 323, 325, 326 polonium-210 levels's in lungs :of smokers's in, 336 smokingg and nicotine effects an human. blbod.lipids; 125. Glossary of terms used..in smoking.and.ventilatory function, 215'Glucose metabolism and insulin response, altera- tian effects on myucardial response, 66 Glycogen Ievels.ins micelung.exposed to.cigarette smoke;,161 Government employees's see OccupariansGraphire respuatory tract carcinoma in workers exposed'd to, 256 Gaeat.Biitain.cee United Kingd'om Guanethidlne blockage.of rucotine.cardiac stimulation by, 57 Guinea pigs lung neoplasm development following chronic nickcl.carbonyll or dust'inhala- tion, 256 s...=_.,1:.. -. t i

suspected carcinogenic.propertiesin.cigac rettesmokeirom, 265 Pipe smokersatypicall nuclei in malee esaphageal epii thelium, 379 bladder neoplasms in, 293-294 cell rows and atypical cells in vocal cordss of, 280, 359-360 COPD morbidity in; 146, . 197-198, 201-205 development of cllronib.branchopuhnn-nary disease,.10. developmentt off esopAageal neoplasms„ 113,293 developmentt of lung cancer, 11 developmentt of oral neoplasms, 1.2~ e 29pOhageal neoplhsmmorta8ty ratios, kidneyneoplasms in, 294-2955 lack of risk.in CVD, 677 laryngeal n.eoplasms' induction, 12, 354-357 16ng neoplaran' incidence in Norway, 244 lung neoplasm incidence.in rural Switzer-land, 244 lung neoplasm mortality in, 324-327' mortaiityy rates fkom. COPD., 142-143,. 145 mortality ratios, from pancreatic neo- pl9sms, 298 mortality ratios from pepticc ulcer, 424 myocardial infarction in,.32', 38-39 peptic ulcer in,.427relationship toinfectiousrespiratorydis-ease„227 relationshiptn laryngeal neoplasm devel- opmenq281. relationshiprtolip neoplasms; 289relationship9 to oral cavity neoplasms, 361-364, 367risk.of CHD',:8'. risks on lung neoplasm development. 276 Placenta ability to hydroxylate benzo(a)pyrene in smoking mothers, 407' Platelets adhesiveness'.of increased, from:cigarettesmoking, 99 aggregation of, cigarette: smoking effects'on, 36 blood, effect of smoking;.66, 75 Poland bladder neoplasms. in,. methods andl re- sults in retrospective studies ofl smok-ing and', 382, 383'CHD mortality and I morbidity in, 96'6 esophageal neoplasms in., reVOspectivee studies of tobacco use.with, 378 laryngeall neoplasms in., relationship to to8accoo use, 357 relationship of tobacco use andd neo- plasms.of oral cavity in,.364serum Gpid differencess in smokers vs, nonsmokers in, 100, 1022 smoking,and nicotine effects on human blood levelsin, 124 smoking relationships tothrambosis in, 131 Pollution see Air pollution Polonium-2l0 suspected carcinogenic.agent in cgarettesmoke', 265'~267, 335'-336 Post office workers' see Occupations Postoperative pulmonarycomplications see Respiratory system. Potassmm40 ~ presentin tobacco leaf,.266 Pregnancy seenlso. Abortion (s'pontaneous)t, pla- oenta„stillbiith, neonate human,, methods usedd im smoking study of, 391-3966 maternal smoking during, effect on fetall growthh and weight, 389, 397-399maternal smoking:during„effeuts on fetal gowth, 13,415 nicotine effects ommyometrial strips in, 408 unsuccessfulj smoking effects on, 13 Prematurity maternal smoking and, 390,400401 Prisoners see Occupations Proteins' see Lipoproteins Protozoae ciliary function in,, effect of cigarette smokeon„165,224 Public Health Servicareview of medicall literature on smoking hazards, 7 1967 study of, starting, pointt for neww studies, 4 Public laws see Laws Puerto Rico esophageal neoplasms iny retrospeelivee studies of tobacco use withi.378 relationship of tabaccouseandneo• plasms~ of oral cavity in,.367 Pulmonarysystem see Respiratory system Pyrrofidine, nitroso-suspected carcinogenic properties in ciga, retlte smoke from, 265'~ Rabbits atherogenic effects of carbon monoxide:e and hypoxia,.64 atherogenic etlfectss of nicotine, 120-122~ blood lipids in, smoking and nicotine effects on 127 cardiovascular function, in, smoking, and nicotine effects, 108, 109 ciliary function in,, cigaretlesmoke ef-fect on„22P.-22T cholesterol fed, carbon monoxide effectsan, 65-66 offspringl of,.picotihe and smoke effeclson.birthweight, 407 ofEspring,, smoking. effects on' stillb'uthi and mortahty, 411 pregnanls lritium-labeled nicotine effectss in, 413 pulmonary changes.in cigarette smoking„ 159 pulmonary clearance in, cigarette smokee effect on, 164, 170, 171~ 453'

studies of.tobacco use with, 378' genetic studies oB twins in.,.smaking,ef- fects.on, 50, 9.9' laryngeal neoplasmss in,relationship, to tobacco use, 356 relationship of tobacco useandlip neo- plasms in, 361 relationship 6f1 tobacco use and neo- plasms of'f oral. cavity, 364 serum lipid differences inn smokers'vss nonsmokers of, 99 smoking andd nicotinee effdats on human cardiovascular system i.11.5'. smoking and nicotinee effects on human perupheral:vasculAr systeml 133'3 trackeobronchial treechangese in xmokers andl nonsmokers in, 263 SwitzerlandCHD: morbidity and mortality in, smokers vs, nonsmokers, 95eigarette smoke effectsonmice.lung and kidney tissue in:, 344 cigarette smoke inhalationn effects on. mice respvatory tractt 357. Ihng neoplasmm incidence in cigar and pipe smokers of rural, 244 retrospectiti7esmokingstudy of inethodsfor lung neoplasms ih.,.325' serum hpid differences. inn smokers vs. nonsmokersof~ 100 ilachycardiadevelopmenta in dogs inducod by nico-tine, 57 TAO see.Thromboangutis oBliterans Tars, tobacco carcinagenicity on animal skin, 238carcinngenic8 properties from cigarette: smoke, 11, 264,.265content in cigarettes, relationship 1o:lungo neoplasm development1.275:, 276 sarcoma inductionn in rats following in- stillation, 346 skin paintingw'ith.,,carcinoma inductionn fr~um;. 337-342 Telephonecompany, employeessee Occupations Tcratogenesis maternal'smoking implications in, 407 in: mice embryos, nicotine effectson., 4111 Tetraethylammonium chloride blockage of nicotine cardiacc s8mulation by.57 Tex.tile workers's seeOccupatlons Thromtloangiitis obliterans defmitian, 73'3 remissinnn of, cessation of smoking ef- fecLs; 74 Thrombosis smokingeffects on, 66, 130-1,32 Tissues culturesof;, cigarette smoke effects on cell growth and reproductiont. 267', 343-345 hypoxia of, carbon monoxide . effectsorq. 6t Tobacco see alsoall forms,.e_g- Cigarettes, etc. 456 chewing of,, relationship to Gpand qa] cavity neoplasms, 361-363, 36:i-366 leavesl.presence:of potassium4ffin, 266 iihbacco amblyopia see Amblyopia Tobacco tarssre Tars, tobacco Tongue hamster, C-14 IaBeledl particulatee depP_ i 2 ~ 282 sit on in,. 81- Toxemia preeclamptic, incidence in smoking and nonsmoking mothers,.404,.407' Trachea hamster, C-14 latleled'd parrticulatedepuo- e sition in, 281-282 Tliansportation employees .cee OccupationsTriglycerides ' CH64ncidhnce relationship to,65~ smokers vs, nonsmokers, 99400,.102 Trypsin see Anti-trypsin„alphat . 7f ryp tophan. metaboGsmm alterations by smoking,.297 alteration in. urinary uact.neoplasms by smoking,.13 carcin ogenicity in micebladd'ets, 296 relation of' excretionn in smokers andl nonsmokers, 297Tuberculosisrelationship. of smokers vs:.nansmokere to, 1172, 226-228 - Tumorigenia agents . see Carcinogens Twins angina pectaris development:in, smoking effects on.,,50-51. genetic studies off smoking effects on, 49-52. smoking effectss on mortality and mor- bi]ityin,51. Ulcers see. Peptic ulcers United Kingdom bladder neoplasmsin,.methods in retra• specti:ve. studies of smokingand, 382-384 blood pressure differences inn smokers vs:.. nonsmokers in,. 103, 104 British Perinatal Mortality Survey of„ 390„395,.404,415 cigarette smoke effects on human fetal lung.and mice trachear3441 cigarette smoke effects on human pubL monary function, 168', 1699 cigarette smoke effects on mice respira- tory tract, 352 cigarette smoke implantation effects an rat tracheabroncfiiaf~ tree ih; 34'6.34T comparison of abortions, stillbtrths,andl neonatal deaths in smoking andl non- smoking mothers; 406' COPD morbidity in.smokersin., 195'-197., 203,.204 effect ofcgarette smoke on animad.cifr ary function.in„221 human experimental dsta on. smaking and pregnancy,408 kidney and bladder neoplasms im

from.peptic ulcer in U.S. in 1967',.423. ihformer smokers„rel3tion to CIHID,46, 47-08 in Swedish twins, smokers vs. non•smokers, 51 . smokers vs: nonsmokers, 3 U.S. male veterans from CHD; 26, 38 Morrtality ratios CHD with high risk characteristihs, esti-mated, 25 from esophageal neoplasms„prospecfive and retrospectivestudies, 289-291 from I2ryngeal'neoplasm, 277.-279 from lung neoplasms inismokers ihNor- way and Finland,.246fvom lung neoplasms, in males byciga- rette smoking duration,24'0,. 244 from pancreatic neoplasms in. smokers and nonsmokers~ 298-299 from peptic ulcer in smokers.and non- smokers, 424' smokers vs. nonsmokers;, fromm lung . nec- plssms, 240-243'. Mouth neoplasms frequency in smokers and nonsmokers„ 238 ' smokinginduced,.12 M ucopolysrccharidesfunction' as surfactants in lung tissue,. 1172 Mussels ciliary function in, effeets of cigarettesmoke.on,221,222 Myocardlum effects of hydrogen cyanide in smoke on„62 oxygem consumption inn nicotine stimu, 19ted„59 oxygen requirements fbt, nicotine ef-. fects, 58. 2-Naphthylamine development of bladder carcinomas and papillomas ihn dogs, hamstersandmon-keys given, 296 - suspected bladder carcinogen in.totlacco smoke, 265 National Center for Health,Statistics survey of.US: smoking habits by, 5b6 survey, om rcl'ationshlp of smokingandg incidence of respiratorydisease „ 173'. National Clearinghousee forr Smoking.g and Health responsibiGties„7 1970survey of smoking, 6 National Cooperative.Pooling Project mortaGty statisticss fromm coronary dir ease,.21-22 National Library of Medicine . assistance in literature review om smok- tng„7 Naturalgasl respiratory tracTt earcinomaa in workers exposed to, 236. Negroes see Blacks. Neonate see alro Fetus, pregnancy„ prematurity birth weiglle, effect of maternal smoking on,.389;.397-399 dealh„comparison, of stillbirth.and abo:- uions. in smoking and nonsmokingg mothers, 395, 405-006'6 death, differences of birth weight and, in ~ smoking and nonsmoking mothers, 404 death, smoking metherss ef7ects on 415'5 rats, LDso nicotine determination, 412Neopiasms seealro: specific neoplasms„ adenocarci- noma„carcinoma,.lung neoplasms,.etc, adenomatous,, inditetionn in mice by ciga rette smokee inhalation, 350 bladder;, in smokers and nonsmokers;. 293-295'.,381-384bladder, metRods of retrospective studiesof smoking and, 293, 384-384 bladdery relationship of tobacco usage to„299' bl9dder,, relationshipp to cigarette smok-ing,13,.299: blad0er,. U.S. mor tality in 1967.,,293 development inn smokingg dogs,, percent- ages of;274 esophageal, frequency im smokers and nonsmokers; 112, 238 esophageal, methods andd results of retro-spectivestudies of tobacco useini 289, 375-378 esophageall mortality ratios, 289-2911 esophageal, mortafity rates for. US. in 1967,289 esophageal, relationship tosmoking„293 kidney, mortality rates in U.S, for 1967,. 296 kidney, relatienshipto tobacco use,.13„ 299 kidney, in smokers and nonsmokers, 238,294-295. laryngeal„12, 237-239, 281 1 laryngeal„ relationship of tobacco use and.development of, 354-357' Ikryngeal, relative risk ratios from tobac- co use, 277, 358 la ryngea I,. U.S.. mor lali ty in.1967, 277' Gp, relationshipto smoking,.289 ~ tip, relationshipto tobacco use, 361, 362,.365,36P mammalian, cigarette smoke effect on, 343 oral cavity, relationship of tobacco use, 285, 3611-367. orallcavity, relationship to.smoking, 289 pancreas„ relationship to smoking, 298-299' Netherlandscigamtte smokeinhalatione effects on mice.respiratory 4rac lin, 349 lungg neoplasans.in, retrospectivesmoking studyof methods for, 323serum~ lipid difference, inn smokerss vss nonsmokers of, 101. New York City myoeardialinfarctions in cigar and pipe smokers in, 32, 38-39New Zealand humam experimental data~ on smoking and pregnancy,408409 Nickel lcompoundssuspected carcinogenic agents in ciga- relte smoke, 26'5

smokers~ in, 2944 mal respiratory tracts, 34'9-350', 352, lung cancer mortality in: mal4s in Eng- 354 land and!WalEs, 240 maternal: smoking andd infant weight.in, COPD, morbidity inn smokers inl 195, 196„198-200i 201-2Q2, 205 397.,399' methods used m smokingg study and hurrtan.pregna ncy„391..394-395mortality, from cerebrovascular disease rela ted tosmokingin, 68 mortatlty mtcsfiom. COPD in.,,lack of increase,.140. mortahty ratios from esophageal neo- plasms iny.290. mortality. mtiosfiom laryngeal neo- plasms in, 278' mortality ratios fromm pepticulcen in smokers and nonsmokers in, 4244 occupational exzposuree and smoking rela- tionshipsto COPD in. 218-219 peptic ulCeri in, methods and msults of retrospective and cross section: studies of smoking and, 4254288 physicians in, decline in cigaredtesmok- ing.rates, 48 physicians in, rrwrtafrty from lung neo- plasms in smokers and' nonsmokers, 241 pulmonary functionn in, cigarettcsmoke effects on, 168 relatiooships of lung neoplasms".to'smok- ing;s air pollhtion,, and'residence in, 253-254 relationship of smoking mberculosisin, 226 retrospective smokimg studyrofmelhads for'lung neoplas'msin{ 324, 326 semm~ lip9d differences in smokcrs vss nonsmokers in.,.101. 102 ' smoking and nicotine effects omanimal cardiovascular function Inl 107smoking and nieotinee effects on human blood lipids in, 126 smoking and nicotine effects on:lluman cardiovascula r s'ystem' in, 115 smoking relationships.to thrombosis in, 131 L'nitedlgtatcs~ acut'c effect of cigarettee smoke on human pulmonaryy function in, 166-167,169'atherosclerosis autopsy studies in, 53- 55 bladder neoplasms in, methodsands res sul,ts in retrospective studies ofsmokt ing and,.381-384. blbodd pressure dI[fere.ncesn in'smokers vs. nonsmokers in, 103=P04 CHDmoztality and modlidityin smokers vs. nonsmokersim.30-35, 37., 93-94 comparison of abortions, still0irth and neonatal'.: death in smoking and non- smoking mo thers. 405406 eigarette smoke effccts~ on animal tissues in,.343-345' cigarette smoke effeats pullnonary sun factants and surface tension. 172, 225 cigarette smokaimplanlalion effeets on animaLs Iracheohronchwl.tree, 346-348 cigarette smoke.inhalation effccl6.on ani- effects of cigarette smoke.on animal cili- aryfunction in, 221-224 esophageal. neoplasms in, retrospective studies of tobacco use, 378 esophageal neoplasmm mortafity in,, in 1967,289' human ezperimentall data on smoking and pregnancy in, 408-010 human pulmonary function following cessationn of smoking: in, 149 kidney and bladder neoplasms. in smokers'.in., 293-295laryngeal neoplasm incidence in 1967, 277 laryngeal neoplasm int relationships tb tobacco use, 278-279', 354,355lung neoplasm mortality im smakcrs and nonsmokers in, 240-243 maternal smoking and infant weight, 397-399 1 methods used in smoking~ study and human pregnancy, 39'1-395 mortality fiom~aortic aneurysm related to smokingin„7I mortality fi~omm cerebrovascular disease related to smoking, 88-70mortality from lung neoplasms expected in 1970,237,23'9 mortality rates for bladder neoplasms in 1967,293', mortality rates for COPD, increase of 139-140 mortality rates for kidhey. neoplasms'.in 1967.,296mortality rates for lung neoplasms in 1939 vs. 1.967,.239 mortality ratios for OOPD„142-145 mortality ratios for~ esophageall neo- plasms in,.290'-294 mortality ratios.far laryngmal ncoplasms, 278.279 mortality ratios for pancreatic neoplasms in smokersandlnonsmokers in,.298 mortality raliosfor peptic uh:er in. smokers and nonsmakers in',.424! occupationalexposureandl smoking rela-tionshipsto COPD in, 218-219 oral neoplasm incidence in, estimated for 1'970,.2841 peptic ulcer mortality in.1967in y.423 peptic ulcer in, methods and.results for retrospective and cross seetlonstudicsof smaking.and'„425-426-028 polonium=l'l0 levels inn lungs of smokers in, 335-336populktions, of, COPIb development in, 10 relationship of humanpulmonaryhistol- ogyand srnuking.in, 1V55-157 relationship of tobacco,usc.and lip neo- plasms, 361-365, 367' relhtionship of tobacco usee and neo-plasmsofl oral cavity...361-365, 367 relationshipof lung neoplasm to~smok.- ing,k air pollution, and residence in., 253-254 457

Sheep pregnant, nicotine injection and smoke inhalation.effects on, 414 Smelter workers see Occupations Smokers (former)) see also Cessatibn of smoking atypical nucleii in' male esaphageal epi- thehum in:, 379-380: CHD mortality probability in, 46 incidence of CHD and mortality in, 46-48' lung neoplasm mortality ratios in, 241-242 lungneoplasms in., ]owetedlrates; 11 mortality rates from COPD, C75'5 mortality rates from lung neoplasms, 276. Smokers vs. nonsmokerssee dso. Nonsmokers bladden neoplasnrsin, 293-295, 381-384 cell rows and atypicallcellsin vocal cordl of, 280, 359-360. CHD'mortality in,. 21-22'2 comparison of abortions, stillbirth and neonatal death in, 390, 405A06 developmentt ofCOM in., 14!1~„ 145, 1!95-205 differences.in emphysema types.in; 154', 156. effecrt of cigarette smoke onn postopera. tive pulmonary complications, 175 effect of sexx onn mortality from. CHD~ . 28-31 esophageal epithelial cells with atypicall nucleii in,.292 esophageal.neoplasm mortality ratios in, 290-291 exttetion off tryptophan metabolites in.,, 297 frequency of esophageal neoplasms in, 238' frequency of' kidney neoplasms in, 238 frequency of mouth and pharyngeall neo-plasms.in, 238 fiequency of urinary bladder neoplasmss inl 239 group, characteristics in lungneaplasms and smokingin,.240, 244,:329-333, laryngeal neoplasms in„ relationship to tobacco use, 354'-357lung fibrosis development in, 161 lung neopfasmmortality, ratiosih, 240-243 lung neoplasm mortality in uranium miners,..256morbidity ratios fiom CHD, 24'y mortality from cerebrovascutar disease, 67a00 marta8ty from, CHD., 24„26-29 mortality from. CHD in Swedishh twins~.,. 51. mortality from. IAryngeall neaplasms; in, 237-238 mortaliiyrates,.3 mortalityratiosoflCOPD in, 142-14V3mortality4 ratio &om~ laryngeal'l nea- plasms,.278-279mortahty ratios from pancreaticc neo- plisms.in, 298 myocardial infarction relationships to physicallaotivity, 44 pathological andd cytological changes.in respiratory traat of; 258-263 pepticc ulcer in, correlated amountsof tobacco use, 427-028postoperative hypoxemia in; 174', 2300 postural hypoxemiamechanism in asymptomatic,147 postoperative pulmonary campllealians in, 174-1I75, 230 . pulmonary alveolar phagocytosisin, 1165 relation.between CHDand.serum.choles- terof level, 43 relationshipp to infectious respiratory dis- ease, 172, 226-229 serum.lipidsm iq 41, 98,102 surfactant activity in lungsof, 172, 225 type of lung neoplasms in male and fe- malc, 250 Snuff dippers~ of,. relationship to neoplasms of oral cavity, 287, 361, 364-365 Social adjustments in~, children of smoking mo thers, 407 Socioeconomic relationships in COPD,152=153',.216-217 Sold'ierss see Occupations South Africaa esophageal neoplasms in, retrospectivee studiesaftobacco use,.378 occupational exposure and smoking,rela- tionship to COPDD in, 219 retrospective study. of methods for.lungr neoplasmsin., 328serum lipid differences in smokers vs. nonsmokersin, 99~. Spontaneous abortions see.Abortions„spontaneous Squamouss cell carcinoma see Carcinoma, epidermoid Steel.workersseeOccupatfons Stearic acid suspected earcinogeniragent of cigarette smoke;.266. StHlbirthsabortions and neonatal death and; in smoking and nonsmokingmothersy 30,405-4066 effects.of maternal l smoking, 415 Studentss see-0ccupations Sugars see Glucose,mucopolysaceharides Surface tension aee Respiratory system Surfactants see Respiratory system Sweden acute effects of cigarette smoke on: human pulmonary4unctionf 168 blood pressure differences=in smokers vs. nonsmokerss in, 104 CHDD mortality and morbidity in., 97COPD morbidity in smokers in, 203.,.205 effect of cigarette smoke on animais.cili- ary function in, 221-224esophageal neoplasms in,, retrospective 455

Nickel. workers see OceupationsNicotine atherogenicc.effects of' 1120-122 effcctt on blood &pids,.123-1128'. effectt on $lo od.pressure, 366 effects on cardiac rhylthm, of heart, 36effectson cardiovascular systeml 56-58, 107-118 . efl'ects.s on catecholaminerelease from adrenals„36„119 effects.on.heart.rate,.36 effects.ommyocardium: oxygen demand, 38 effects on myometrial~l strips in gavidic women, 408 effects on: peripheral.vascularl system,.72, 75,.1133:134 effects on pregnancy,.411-014 urduction.ofn neerasis.in arterial wa0s,63 neurogenic effects of, 57 Nitrogemdioxidee pulmonarychanges.in rodentschron- icallyinha0ng.,.161.,220Nirtrogen.oxide effects onn resistanee' of squirrel monkeys topneumococcus, 1173 4dVitraquinoline . lioxide . alcoholic solution of„ development of papillomasintnice drihking~ 292~ N-Nitrosamines carcinogenicity in cigarettes smoke, 264-266 esophageal neoplasms induced in: animals by. 292 Nittosopiperidine see Piperidine,nitroso-Nittosopyrrolidine. ' see Pyrrolidine,.nitroso.N'methyln icot'marmde urinaryy excretion' of,, smoking effects on, 297 Nonsmokers see also Smokers vs. nonsmokerss carboxyhcmoglbbin effcctsons oxygen uptake, 61: . Norw'ay' lung . neoplasms .in„for~ pipe smokers, 244 lung.neoptasm mortality in„relationship to tabacco:use'.,,245-246 tracheobronohial tree xhangesin stnokersand nonsmokers of, 259 Oat't cell.carcinoma see Carcinoma, oa2cell. Obesity. relationship to CHD mortality, 43 relationship to smokingg and CHD, 4345relationship: with smoking~ inn peripheral arte rio sclerosis„72 Occupations.aee afsn:I ndustrial hazards asbestos workers, respiratory tract carcii noma,256, asbestos workers,.lhng neoplasm mortel- ity in smoking, 257 bank.k employees, smoking andCOPD,. 198 coal miners;, impaired pulmonary func-tion in smoking, 163 coal miners, respiratory tract carcinoma, 256 coal miners;, smoking andCOPD, 153, 197, 218-219 coal miners, smokutgandg ventilatory function,.207flax mill workers, smoking,and COPD, 199 governmentt employees, blood pressure differences in .. smokers vs. non smokers, 99 longshoremen, mortality from smoking- related cerebrovascular disease„70 longshoremen, mortal'ity rates from CHD in, 28 ]bngshoremen, smokingg and.COPD, 200 longshoremen, smoking and ventilatory function, 208 medical students, serum lipid differences in smokrs.vss nonsmokers; 98. medical students,. smokingand nicotine effects ann blood.lipid level's, 124 medical'., students,. smoking~and tkrombo- sis relationships, 1300 medical students; making andd ventila- tory function, 209-210 nickel workers,.lung neoplasms in, 256 physicians, bladder and kidney neo- plasms imimoking, 293, 294 physicians; cessation of smoking effect on COPD~ 1142' physicians;:COPD. mortality rates, 149~ physicians,, decline in~. cigarette smoking rates„48 physicians,, mortality from smoking- related cerebrovascular disease,.68 physicians, mortalityy rates. from. CHD, 26 physicians, mortality ratioss from. esopha- geal neaplasms, 290' physicians, mortality ratios fromm peptic ulcer in smoking and: nonsmoking, 424. physicians, pulmonary functionn follow- ing cessation ofsmokiqg, 149 physicians,, smoking and venlilatorg function, 209-210, 2113 plant workers, occupational exposuree and'd smoking relationshipss toCOPD; 153,218„219 plant workers, smokingand COPD{ 198plant workers, smoking andl ventilatary' function, 206-20g post office workers, blood pressure dif- fierenees in smokers. vs- nonsmokers,. 104 post office morkers, smokers and ven tila-roryy function, 209 post office . workers, smokingand.COPD~, 200;202 prisoners, serum. 8pid differences inn smokers vs. nonsmokers, 100 prisoners, smoking and nicotine effects on peripheral vascular system, 133' railroad employees; coronary heart dis- ease, morbidityy in smaking„34 railioadd employees, mortality and mor- bidityy from CHD, 97 raitroadl employees, mortalitgrates.fromi C11D, 28 smelter workers, lung neoplasm mortal- 4511 I

i Roi in l 4' in st smi plc Ilon CH n Bio a fro fro to ity frormarscnic exposure, 257soldiers; smoking and COPD, 197 steell workers, COPD development fmm, dust exposure, 153' students, carbon monoxidee effectss on blood lipids, 1299 students~ infectiousrespkatorydisease in smokers vs. nonsmokers,.228•229~ students~ . mortahty fromm smoking-related cerebrovascular disease, 66 students; martalityrates.from CHD, 28 studentsi.smoking and COPD,,201 students; smokingg andi nicotine effects on blood lipid level, 125' students~ . smaking and thrombosis rela- tionships, 1.30 students~ smoking and.ventilatoryd func- tion,211 telephone companyemploy'ees smoking and COPD, 200 textile workers, occupational exposure and smoking. relationship to COPD',. 218-219transportatiom employees, smokingandCOPD,198„202'g tmnsportatiom workers, air pollutionn re-lationship to.COPD', 216 tr'ansportationn wnrkers,., smoking and ventilatoryfunction, 207, 2d2utility company employees,. CHD mor-bidityin smoking, 300 uranium miners,, lung neoplasms in smokers'.and nonsmokers, 250veterans; bladder and kidney. neopWsmss in smoking; 294L295 vetcrans; COPDD mortality rates, 143 veterans, CHD marbidit-vin smoking, 32 veterans, . effects ofl smoking om twin, 50 veterans';, lungneoplasmg mortality in smo kec and nonsmoker,.241-243'. veterans; mortality rates from CHD, 26,, 38 veterans; mortality from smoking-relatedd cerebrovascular disease,.69 veterans~ monality ratioss from esopha- geal neoplasms, 290 veterans,, mortahty ratios from peptic ulcer in smakersvss nonsmokers„ 424' Oleic actd I suspected carcinogenic agent.in cigarette smoke; 266Ohve otll penetrability of tienzo(a)pyrcne in micee esophageal epithetlum, 292 Oral.cavit}+neoplasmsl estimated incidence in IIIS'~ for. 1970, 284 mortaBtyfrom in1I967.,.285 relationship of tobacco use,. 285, 289,. 361-367 Organs culturesof, cigarette smokee effects om cell growthand reproduction„ 267,, 343-345 Ompharynx neoplasms frequency in smokers and nonsmokers, 238 Oxygen seee a(so: Hypoxe mu . myncardial consumption. of,. following 452 nicotine stimulation, 58, 75, transportinbodyyt carbon monoxide effects,.60„75 uptakee ih: nonsmokers with speciEc rar boxyhemoglobin. levels, 61,.75 rvure hamster„ C-14 labeled smoke particulates deposition in, 2811-282 Pancreatic . neopla sms relationship tosmoking,.13, 238 relationship of smoking, tomortality from, 298-299 Papain pulmonary effects on rats exposed to~ cigarette smoke with 163 i~ , Papillomav development in mice drinking.alcoholirg tienzopyrene,.29:2'. formation fallowingsking paintingg with. smoke: tars,.337-339, 341 indltction in hamsters exposed too tlen- zo(a)pyrene,346-347 Pentolinium blockagee of nicotine cardiac.stimula4on, by, 57' Peoples Gas Light and Coke.Co.. study of Ct®, serum cholesterol and.d smoking relationships; 43 Peptic ulcer antacidefficaey and heafmgg of, effectss ofi cigarotte . smoking on., 423development.in: smokers, 13 mortality from, in. U,S- im 1967, 423 mortality ratios from,, in smakersands nonsmokcrs; 424 retrospective and crossrection study methods for smokingg relationship.to;. 425-027 Peroxides, suspected.carcinogenic agent:in.cigarettet smoke', 265. Personalit y characteristicsrelationship to,CHDand.smoking, 48-09, 105-1.06' Pesticidcscontentlin cigarette amoke, 265, 266 Phagocytosis pulmonary alveolar, in.smokers vs. non- smokers, 165 PharyngealI neoplasms frequency in. smokers vs. nonsmokers, 238 relationship to tobacco use, 362-364',. 366 Phenol suspected.carcihogenic agennofcigarettee smoke,266 Phospholipids functionn as surfaclantsin lung tiisue;. 172 smokers vs. non.imokers,39-1D0, 102 Physical activii,v relationship to. CHm andd smaking,. 41„ 43,44 relationship to myocardial. infarction, smokers vs. nonsmokcrs;.44, Physicians see Occupations Pipcridinc, nitrnso- aw t .~4>u>bs

( skin painting, smoke condensatee effectson,267,338 Railroad'd employees see Occupations Rats atherogenio.effects.of nicotine in, 120, 121 blood lipidsin, nicotine andd smoke ef- fects, 128 ciliary funetian im, cigarettee smoke oni. 221,222 BmSO nicotine determination.ih female; 412 lung, neoplasms, from intrabronchial hn- plantingof chtomium.compounds,.258m lung, neoplasms, from, nickel carbanyll and dust infialation, 2566 lungs, cigarette smoke effects on smfac-tant activity;172, 2255 offipring, nicotine and smokeeffects on birth weight;A07pregnant.,. aromaticc compoundd stimula- tion of placental &P-hydroxylase.activ- ity.,414'pregnant.,e fetall wastageandl neonatedeathe in mico tine and smoking ~ 4111 pulmonary carcinoma induction follow- mgasbestos'dust inhalation,2517 pulmonary changes~s fromm chronic nitro- gemdioxide inhalation, 1.61„220 respvatory tract of,.cigarette smoke:in-halation.effects, 268, 349, 353skih painting,smoke condensates etpects;. 257,340 trachea of,, cigarettesmake effectss.343 traeheal ligation of;.eigarette smoke andd papaimeffects.on, 163 traclieobronchial tree of,.cigatette smoke effects:on, 268, 346-349 Reading ability in childrenof smokingg mothers, 407 Reserpihenicotine cardiac:stimulationblockage:by, 57' Respiratory system seenlso Bronchopulmonary disease,, lanynx;.llungs'., trachea acute: effect of cigarette smoke onn human pulmonary function, 163, 16'6d69 animal, cigarette smoke instillationn or implantation effectss on, 268,.346'-348 aruinal, effecf.of cigarette smoke mhala- tion an,.268•269, 349-353 effect of cigarette and cigar smoke on bronchial reactivity; 164'effect of cigarette smoke on human Ni- aryfunction,165,.221-224 effect of cigarette smakeon human put- monaryclearance, 164,170 glossary of terms used.in testing;.2115histologicall changes,in.smokers;15445P iinpnovements's in ftrnction following smakingpessation, 14'8,149 pathological changesin cigarette smokers, 175 postoperative camplicationn in, of smok- ersvs. nonsmokers, 174,-1.76, 230 pulmonary alveolar phagocy.tosis in smokersvss nonsmokers,l65 454 :.: pulinonary infarction inn dogs inhaling cigarette smoke, 271 surfacee tension of, effect of cigarette smoke on, 172,225 surfactant activity of,, in smakersvss nonsmokers,..172', 2255 surfactants in,. definition, 172 te.sts of function of, in smokers 146-147, 206-214'Respiratory tract diseases see also Asthma, broncAitis,., broncho- pulmonarydisease, emphysema,. pneu- monia; tuberculosis infectious, smokingeffectsg on, L72 226-229 infections; prevalency among', smakers, 10,176 pathological and cytological c7tanges~in; of smokers vs~.. nonsmokers, 258-263 ventilatory function~ in, smokers vs..non- smokers, 175 Rhodesia retrospective smoking study of inethods's for lung neoplasms in, 328 Rubidium-84 tracing capillazy ttoww in coronary blood flow, 59 ~ Rural populations, W ngg neoplasms in, suspected etiolagy of increased, 276 Rmal.residenceslungneoplasmincidence in, in Switzer- land,244 relationships of lung neopl6sm to smok-ing'., air po8u tion, and, 252-255 Russia atherogenic effects of'.nicotine.on rabbits in, 120 atherosclerosis.autopsy stud'iesin, 54` cigarette.tar effects.on rat tracAeobron- chial tree in, 348 Saccharudes see TC'ucopolysaccharides Saliva interference in action of carcinogens.on orall cavity, 288 Sarcoma formation followinganimal skin painting withsmoke condensates, 338, 340 ihduction in rats byeigarette smokeih- jeetion,346-347 Scotland see United Kingd'om. Sex ages of cigarette smokers byy.6 effect of,. in alpfa-antitrypsin deficiency emphysema, 151 effectt of, on laryngeal neoplasm inci- dence development, 277effect of,. in mortality in cigarette smakers, 276 effect of, in lung.peoplasms and! tobacco use, 244,:329-333 W ng.pancer mortali ty by, 252 lung:neoplasm development by, f 1I mortality rates of cigarettesmokers by, 3 ratios of, in lungneoplasm mortality in Norway and ritdand,.245:-246

T-AHhE A31 -3umma7y of iztetlmds use.d in retrospective studies of tobacco usr, and cancer of the eaoghaglt_s (cont.) Author, Year, L'nses Controls country, reference Method of selection Nnmher Method of selection Collection of data Hradshaw and 9N Pntienta with eeoPLugeai cancer. :441 Pattents with non-malignant disesee. Hoepital interviews by Schnnlend, 19G9 trained African mcial , South Africa wurkers. (41). Mertinez. M. 120 Patienta with confirmed epide_rmoid eao- 360 l20 mnlu, 59 female patients In aeme hos- Interviews by trained 1960. F. 59 uhsgealnuncer disgnased in 19GG. 177 . liwl with n n-cencerous diagnasrs. pexeonnel. Puerto Rieo 240 mnlr, 118 female member.a from eame (1Bs). eommunity. ~-- - osPss4eo

TASCE A35. Summary of methods used i e osFecEFtie silnties of smoking and c2ncer of tltc bladder (cont.) hnthor YeLLr, Ciaa C.atr0la coLLntry, xxtexa_ne_e _ Sex Numbe _ Method of aelection Numb¢r ~ Methad of aelection 9tsszewski, M. 150 Y atients with histologicaBx confirmed bladder 55p Undefined suurc€ age-matcAed. 13G6, _ _ cnecinama. . ~ Nland (Edl). Deelev and Cnhen, M 12t Yet'.enta with histol_ogically confirms_s1 bladder Pt4 Pxtienta in ssme hosVital with nan-caneerous 1066. anrcinonla ar pulmnnnry diseese matched for aga. England (551. Yuahida et al., 163 Catients with 6ladder cancer. 163 "Comparison cases." 196s, 29 . ._ ._ .. 6n Japan (s3o). Kidu et e_ 1.,_ 88 ~ Admissions to 15 h_osuitula ia North Fukuoka Selectad fmm patients hospitalized in_ same re- 16ta. 26 Uretecture. Sfgion foV llun-urinar5 ailment9 and age- Japan (144). matrhed Danhnm etal.. 334 Adminslone to New Odeuns BasDitals with his- 350 Admissions to aame hospitals with npn-neoplae- tl6R, 15V tnlogic diagnosis o[ bladder carcinonsa. 177 tic diseases and diseases unrelated to g€ni- .~ ll.S.A.tasy. tnminnrz tnart. Anthony and Thomas, Patients with nauilloma and csnc_er. ot bladder '276 Surgical patients without caneer previously i_n- 1990, England 13). at Leeda betwecen 1958-67. tervicwed for lung cancer etudy.

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