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ftr data, ~indi- le hene- I estab- ~ation ratory i 'spects Im tlie. Ey ob- ~nong egory. ; The jsk of ist as ~adon ~ence laceo: be p resent in relatively high~ concentrations in cigarette smoke; inlarge ,1u,1ntities in: the~ air of industries in which workers have high-Tung, ,•~mcer rates,, and also in the air of urban communities. Sterling and Pollack(~86)~ reviewed theeffect!sof' air poldutionon, ,leath rates! from lung cancer. They suggested that partielesresulting, f rom the combustion of' organic fuels may be more strongly related to thc incidence of lung cancer in the populkation than cigarette smoking. 'Irhe eumulat'ed epiderniological dat'aregardiiircigarette smokangand ltnu; cancer were not considered by the authors in this report. Asbestas. Ogarettesmoking asbestos workershave, ma~rked2'yelev~ated Iung(I:uicer dleath rates compared to: nonsmoking asbestos workers. Berryi6) examniedt.he combined etfcct~of asbestos exposure~ and smoking on mortality from huig cancer among 1,300 male and 480 female asbestos f„lotory workers over a 10-year period. There was no significant i'n- cr.ease in llung cancer mortality amon~g smoking or nonsmokingn orkersn-ith a law-to-moderate exposure to asbestos. Ho«•ever; among smokers «-ho had heavy exposure to asbestlos,, 32'. lung cancer deaths occurred among 663 men (9.9 expected), and there were 1& deaths among 292 n-ouien (1'.4 expected). This confirms the greatly increased risk of de- veloping lung cancer among asbestos «~orkers who smoke cigarettes. Autops y and'Cy,tolog,icad Studies f'an pol'- 'the the 'clic and y as in- ata ?es„ sl'ic ser to! The respiratoryy tract of cigarette smokers examined at autopsy flre- qttentIy demonstrates epithelial changes consiidered to be precttrsors of bronchogenir; carcinoma. Such changes include squamous metaplasia, atypical squamous metaplasia, and carcinoma in situ. Herrold (35) studied histolog~ie~ types of prirnary~ lung cancer~in, U~.SL~ vete,rau& who .vere~ subj~ects~~ of~ the Horn study. Q!f~ a total of, 2,241 wh~ite~~ male~ vetr~ eraais who died of lung cancer over an 8-year period~ histologic mate- rial «-~as~ a-v~a~ilable~ fbr.~revie« in 1,477 7~ patients. Histologic types were~ rroul~~ed according to the~ Kreyberg classification of Gsoups~ I anld H tniil,ors. Group I tuaimors~, epidermoid and oat-cell carcinomas, were~ prePs{>>it in 2~7::3'~ percent o£~ the~ 55~ nonsmol.ers~ and were~ present in 57~.8~ hercei~it~of tlie~~4l72 "cnrrent~smoke,rs~~of cigarettes~only.?'Thedi'tfere.nce \v~as statli'stically~ sipnaifi~cant (P<0.01?1~):, confi~rming,tlic~strong, associa-~ tion behveen cigarette~ snioking~~ and Kreyberg'Group~ I tumors. 71 ;Q tj O

- ~i Auerbach et al. (2) examined epithelial changes in the bronchial tree ~ of 456 men, and 302' vr omen who had died of' a cancer other than lung ; cancer. There were 72 ex-smokers among the men, all of whom had '' smoked for 10 year&or more buti had'quit smoking for at least 5 years prior to death. Atypical ceils were present in 93'.2 percent of the current ~ The prevalence of atypical cells (hyperplastrc and metaplastic) in the sputum of 1221ma1e and 128 female «-orkers was examined by Rob- bins (72). These smokers, all under the age of' 10; were mat'ched' with a control group d~rawnfrom a population ofcollegestludents. Atypical cells were found in 14 percent of the smokers andl 5' percent of the non, smokers: smokers; 6.0 percent of the ex-smokers, and 1.2 percent of' the non- I smokers. Areas of epithelium composed entirely of'~ atypical cells devoid It of' cilia were found in the bronchial tree of'. 8 percent of'the current a smoke:rs, 0.2 percent of the ex-smokers, and none of the nonsmokers: ~ TJnusual cells withi di'sintegratiing or fading nuclei were found exclu- ~ sively in 15 percent of the ex-smokers. Oral Cancer Data from the large ,Tapanese prospective study by Hirayama (37), indicate that mortality rates from cancer of the: oral cavity among males are higher in smokers than nonsmokers; A dose-response rela- tionship: was demonstrated for, tiheageat initiation of'smoking. Thestlandardized mortality ratio among cigarette smokers was 10.0 for men (P<D.001) and 1.22I for women compared to nonsmokers. These ratiosare not stable due to the few deaths that occurred from oral can- cer in thss study. Certain relationships between cigarette smoking and' cancer of the oral cavity, pharynx, and larynx were investigated by Moore (59). Over a 15-year period', 1,000 patients with invasive squamous carci'- nomaat these, sites were, treated ini Kentucky. Of thesepatient~s; 203: . had a history of cigarette smoking and had had no recurrence of cancer for a period of 3 years or more. This group was further dividedi on the basis of' current' smoking habits. Of the 122 who continued to smoke,48 (40 percent) eventuallyy developed ai second cancer at these sites,, whereas onlyfive(6 percent) of'the81 who stopped smoking de- veloped a second malignancy.. This sixfold' difference is~ statistically significant (P<0:001).. The survival curves for t!hese two groups are presented in figure 3. 74

ii ial tree ~ n lung pm had ~5 years lurrent' le non- devoid urrent iokerss exelu- Lic) in F R'ob- wit'h ~pical! ~ non- I I I . (37) long rela- I The Ifor 2ese pan- t'he F9),. Fci- 1~03 Ii,o,f, L'ed t.o ese ~e- ~y ,re Figure 3.-The survival ofl ex-smokers and continuing smokers who were treated for a primary cancer of the oral cavity, pharynx, or larynx: 100 90 80, 70 60' 30 20 10 0 4' SOURCEt NAoore„ C. (59). 5 6 7 8' 9 Follow-Up (yr) 10 L 1i 12 13 Martinez (57), studied the~relationship~between smoking in various f orms and cancer of the oral cavity in a retrospective study of 153' p,rtientlswit!h this disease. Dose-response relationships were demon- strated for the amount smoked,,the amount of' alcohol consumed~ and tiliadevelopment of cancer of the oral cavity. TyIdesley(90) examined the prevalence o£' leukoplakiai among, 402 English coal miners of whom 280 smoked and chewed tobacco. Tobacco chewing was commonly found to be a substitute for smoking in under- ground' conditions where smoking was impossible. Leukoplakia wasf found in 3.6 percent of the chew.ers,,-whereas no leukoplakia was found among the nonchewers.. Nelison and Ship (62) determined the relative influence of eight vari'ablefactorson the development of oral cancer in relation toagEat t!heonset of disease ina population, of 191 patients.rithacanfirmed diagnosis of a primary squamous cell carcinoma of the oral cavity. The factors considered inclhzded age,sex;race~,, consumption ofalco- holandl tobacco„ certain systemic diseases,and oral trauma., Thelprevalence of'heavy tobacco use was more common among the younger patients. «'hsle 91 percent of the cancer patients under the age of 45 smoked more than 20! cigarettes a day; only 59 percent of t~hepatient!s, over 65 smoked this heavily. 75' ~ K.'w

Reverse smokihgis a~ common practice in some parts of India, whereby thelh ;htedl end of a homemade cigar isheld inside the mouth. Pindborg, et al. (64) conducted an epidenriological survey of 10,169 villagers, in the Srikakulam district of south India and~ found that. 43.8 percent of those interviewed practiced reverse smoking. TLeuko•, plakia was~ found' in 818 percent of reverse smokers compared to 0:1 percent in nonsmokers. The 10 patients found to have oral cancer were all reverse smokers. Reddy, et al. (68) found that rev.erse smoking rvaspracticed by73. of 100 patients with orali cancer. Reddy,, et al. (66, 67) reported characteristic histologic findings of' the oral' cavity in biopsies obtained from reverse smokers. In two other studies from India, changes in the ultrastructure of the oral' mucosa of chewers (5h), and smokers (G5) are described'. Cancer~ ofl' the~ Esophagus In the Japanese prospective study, Hirayama (3'7) reported that ~ ~ male smokers had' a mortality ratio for cancer of the esophagus of 2.24 compared to nonsmokers (P<0:001)'.. NTartinez (57) studied the relationshipbetween smoking in various, forms~ and the development of cancer of' the esophagus in a retrospective study of 179 patients. ~ Dose-response relationships were demonstrated for the amount smoked and alcohol consumption and! t3i~edeWel'opment of cancer of the esophagus. Cancer Qf' the Larynx The mortality ratios for cancer of the larynx in the large,Japanese prospective study were reported by Hirayama (37) to be 11.0 for male cigarette smokers and 9.0' for femalie cigarette smokers compared to nonsmokers (P'<Q.001).Stell (85)1 concluct~ed'' aretrospectii've study of 11W patients tiv~itlii carcinoma of' the larynx. Only 13 percent of the patients were non- smokers or ex-smokers compared with 4!1 percentof'the: controls. The relativerisk ratio for heavy cigarette smokers was 3.48 compared to nonsmokers. The relative risk was 1.34 for smokers of pipes and cigars. b'Toore (59) reportedi the occurrence of second primary cancers in 203'sol:okers whoAiad been surgically treated forcancer r oftheoralf cavi~ty;pharynx,orlarynx,,witkout recnrrencefor.a period~of'3 years. 76

yf Iindia, e mouth. bf' 10,169 tnd, that Leuko- ~d to. 0.1 cancer moking ~~ i; et ad: l cavity iEs f'rom. ~ Ihewers i I ' that, ~u~s' of 0 the ~ment xentsi ioked f the i nese, nale 1~ to. ¢ith~ ion- rhe red, nd «'i'tttin an aiverage~followup; period of'7~ years, 40~ pereent'~of t'he~ 122'. l,atieirts who continued to smoke developed second primary cancers „f t i,E.~ uhper~ respi~ratory or digestive~~ tract, but only~ 6~ percent, of the l,utirtits who stopped smoking developed second cancers. A total of :,oi l,utients «•ith cancer of'the larynx underwent lar3~•ngectomy. Of tl~t, ~ 16 «1'lo~ contli'ntied t~o~~ smoke,~ t'~ltree~ developed a second' cancer,~ wiu,reas, ~ none of the~ 34: ' ex-smokers~ without a larynx : developed a. -,,cor id primary malignancy.. Cancer, of Uhe Pancreas I I'iray.ama (37) reported a~ significant association between cigarette =m0king~andlthe~~develbpment~of'cancer of the~pancreas~, The~~mortality n,itios were 2.05 (PC0,001) for men and 1.91 (P<0.05) for women.. Krain (~,47')~ reviewed a number~ of~ environmental factors~that may~ lbr associated with the~~ 15~~ percenti~ annua~t increase~~ in~ the death rate f roni cancer of' the pancreas~ found in the Uhit~ed States. The strongest , n~<I~ociations~ appeared to~ be~ with cigarette smoking and certain „(Tupationali exposures.. Cancer of the Kidney andl Urinary Bladder Hlirayama (37) reported a mortality ratio of 2:71 f'or cancer off thekidneyand bIdder in women whosmokecigaretties(P<0:001,)~.The mortaIity ratio of 1.07 for men who smoked; compared' to non- smokers was not significant';,however; the fe.v deaths from this cancer atnongmen in theJapanese! study did not allow conclusions to: be dra~wn. Hoover and Cole (39) examined the strength of the associ'ation between cigarette smoking and': the development of bladder cancer in successive birth. cohorts of' men and «omen, in the United States, Denmark, F.ngland'y and Wales. Increasingrates, of bladder cancer wer.e observed in populations characterized by an increase in cigarette smoking among successive birth, cohorts.. The association was con, sistent in both men andl women, andl wasalsoconsistentf'or diffierent national'ities and urban and rural groups. These findings suggest aa causal role for cigarette smoking, in the desxelopment of bladder cancer: Iln a retrospective study from Germany, Fischer (27)examined thesni:okinghabi'tsof1,02 men with bladder cancer and a controLgroup of 198' men who had benign prostatichypertrophy.Ti'herelative risk 77

, ratio was 6.4 for smokers of fewer than 15' cigarettes a day, andl 27.5 for smokers using more than this amount. Only 3 percent of' the men~ ~ with bladder cancer were nonsmokers.. ~ Xipell~ (1Q3~~)studied renal nodules~ in 2~5Q~patients~ in AustralM who came to autopsy. Benign adenomas were the: niost common 1'esions f' and were found in 22 percent of the patients: The remaining nodules ~ were cysts, thrombosed veins, abscesses,, granulomas; and metastatic ~' lesions. A, statistically significant difllerence~ between the smoking habits'of those with adenomas and those with the miscellaneous lesions z ~! was~~ reported (P<0:012)1. All the adenomas were~ found in smokers. C~ole,~ et~ al. MY conducted a retrospective~~ study of~ 461 persons~ ~ with transitional or squamous cell carcinoma of the lower urinary ; tract., After the~~ data were~ controllled~: for cigaret'~te~ smoking, occupa~-~ tional exposure appeared to contribute to M percent of' the lower ~. urina~ry~ tract cancer among men aged 20 to 89~ compared to the~ 39 percent attlributedl to cigarette smoki~~ng~ in n7err~ in a~ previ'ous~~~ report (15). T Werf~-Mfessing~ and K~atnl~en, (100) examined the association of' occupational exposure~~ and smoking~~ ini t~he~ development of bladd'er cancer in 346 males in the Netherlands who had' this disease. The { sm~oking~ habi~tls, of cancer~~ and cont.rol' patients in each group~ «ere~ ~ nearly ident'ical ; however, patients with, bladder cancer had a longer ` exposure to hazard'ous~~ woi•king, conditi~ons~ th:an~ di'd~ controls. Experimental Carcinogenesis Experimental~ studies, ma~inlyy in animals; have, added t~o~ an under-~ stand4ng~of! m<Rny~ of'the processes~~ia7wolved, in ~tobacco~ carcinogenesi's~~. Possible~~ mechanisms~ of~ chemical carcinogenesis were~ reviewed by Miller and Miller~ (58)~, Ryser (76)~, and Leone~ (5l). Electroni spin resonance studies of carcinogenesis were reviewedl by Swartiz (87). Franke (28) discussed the posible rolle of hydrophobic interactions of~ polycyclic aromatie~~ hydrocarbons~ with, protein in~ chemical car- cinogenesis. Chemical carcinogenesis in Sy~~rianihamsters~wa~s,~revietiv.edl by Shubik (82) and'$omburger (38).. Re:spiratory Tract Carcinageneais E~pidemiological~~ cli~nical, and au~~tlopsy~ data from studnes~ of~~huma~~ns have established cigarette smoking as the major cause of lung cancer in the j'nited States. One: ofl the~ reasons~ it~ has~ not~ been possible~~ to 78

lia who lesions aodules ,astatic noking lesions iokers. ersons rinary ~cupa- !lower lie 39 . ioious ler- sis. by y'in. 7). ins lr -d rliaracterize fully the mechanisms responsible for this causal relation- ~k, iE> is the lack of an ideal anian.al model in,%vhi:ch to study respiratory t~ract~~carcinogenesis~in the laboratory. Exposing~~ animalsAo cigarette~ anokc~ in a closed chamber d'oes not~ repTica~te~ the~ kinds of~~ ex~~posure~~ .ru0l-ing ~ humans~ recei.-e,, although sorne~ recently dieveloped smoking , dr:mibers provide conditions similar to the exposure experienced by Iiuiiran smokers. 1Tany animals are obligatory nose breathers and,. irr tlrem. a large~ horti~on of tlli~e~ partienla~te~ phase~ of cigarette~ smoke ~ nri' V he removed by~ turbulent precipitation ioi~~ tiLe~ na~~sa~~U passages~ or l,I rN-nt: before reaching the sites~ in the lung, most c.ommonly~~ exposed irI liumans. ~V~uerbachy, et a1L (3~)~ first demonstrated that~ malignant~ liing tuai~lors~could be produce& in smokinh, d~ogs~w~ho «-ere~~ taught to~ ~runke through a, traeheostomEi. Severa~l investigators have~~ recently ,~xuuriiiried respiratory tract ca~rcinogenesis~ in aniinals~~ using~ intra- tr;i(•l'ie;rllinstilhiti~ons~of~chemiial carcinogens found in cigarette~smoke, irucludtinb benzo~~(a)pyrene~ and! 7H-di~benz~(dl,g)carbazole~. Tumors~ re,rilting from this type: of treatment are~ freduently ~ simila~r~~ to~ lun:g nuriors found in humans (wl~ 32. 33. 36, 77. 8l1).. H~arris,, et all, (33~)~ examined the~~ acute ultrastructural effects of herrio(a)~py,rene~ carripd~ oni ferric oxide particles, ~ on the~ tracheo~- !')r()uclniall epithelium~ of t~he~ Syrian Go~lden hamster. Test su~~bstances, . were adaninistered by intratracheal instillation. Fe.rri~c, ox~~idie~ alone rt"sultedl in some~ focal replacement of' columnar~ epitheliilm~ with laol,'.-gonal basal cells. This~ effect w~as~ reversed by t,erm~iinati~on of th:e~~ treatment: Aftler treatment with benzo(a)pyrene and ferric oxide, t:ncal replacement of the columnar cells with pleomorphic cells oc- 1,rrrredi These pleomorphic cell's~~ lcadl the~ ultrastructui:al f'eatures~ of' rtY~pica~l sq~uansous cells~,ancfi. were siiYlilar~ to~ t,he~ hy~~perplasti~c~epitlreli'al '-cl~ls~ described' in the~ bronchi of smoking , dogs and the~ neoplastic~ ,~lliuaanous eells~ found in human bronchogenic ca-rcinoma.. In an extension of this study, Harris,~ et al. (~32)~ reported that vita- nrin A deficiencY or~ the~ application of lienzo~~(a)pyrene~-f'erric ox~~i'de~ tiirourh ilitratraclieal! inctillation resulted in-squ~annous met~aplasia of tlie~ trachea. I3oth lesions~ appeared to~~ be~ morpliologicaldy~ similar~ by liglit naicroscol>tir,~ but~ at~ the ultrastructura~ll level si~,*nihcant d'iffer- 4~nces Ive~re~ observed. Squamous nnet<aplasia induced~ by benzo(a),py- rene-fcrric oside~ was~ characterized by~ defects~~ in tlhe~ basement me.ml5rane; enlarged nuclei with cy~t~~oplasmic invaginations, and pleomo~rphi'c~nuclcoli not~ seen followii<zg~vitamin A deficiency~.. Sellak~u~ma~r~ and S'hubik~ (~80)' treated' Golden Syriani hamsters w~ith~ %1:~eekly intr,ltracheall instiillationsof~ 7H-dibenz~(c,g)~carbaz~ole~~ (7iH1- UI3(')~~ suspend'ed with equal amounts~~ of~ ferric oxide~in~ a saline~ solu-~ ti~on. Une group ofl 35 hamsters was treated with 45 mr~. of' the~ Carcino~r;en and a second group was~ treated w~ith~ 15~~ mg: llore~ than ~s~'-) percent of~ the a~~ainra.Is~ in each group developed respiratlory~ tract. 79

tumors. Most of the tumors occurred in the major airways andi were;' single~ and' rnnltiple~ applications. A single administration of~~ 37.5 mg., ous concentrations of benzo(a)pyrene and ferric oxidW were used in~ , Saffintti,,et al. (7'7')~ eramined, the careinogeni'c~ effects of benzo (a) I pyrene prepared as~ a~ suspensioni of fi'ne~ crystal2ine: particles at- ~`,i tached t'o~ ferric~ oxide in a physiologic saline~~ solution and admimQs~ tered kiy~~ intratracheal applications to~ Syrian Golden hamsters, Vari were found less frequently. squa:mous cell carcinomas. Adenocarcinomas and anaplastic c.arcino~nas ofbenzo(a)py.rene, witli12.5 mg. of ferricoxideresulled in five broncTiogenic carcinomas and five histologically benign respiratory tumors in a total of 61 hamsters. Following multiple adn-vinistrations,, bronchogenic carcinomas inchtd'ing anaplasticandisquamouscell types were induced i ~ all dosage ~ groups and' a~ positive dose~-re~sponse~ rela- tionslii'p~~ was~ demonstrated. Feron (24)~ studied respiratory tract tumors~~ in S'yrian~~ Golden hamsters folloiving, tracheal instillati~ons~ of fizrfurall and/or benzo,(a), hy'rene. Of the 62' hamsters. 41 developed respiratory tract tumors of which squamous cell car.ci'noma, of the trachea wast~hemost freq,u~entt type observed: Fiarfurall it, combination with benzo ( a) pyrene resulted in a hinheryieldr of tumors than was seen with benzo (a)pyrenealbne. Furfural albne possessedd no carcinogenic activity. Shabad (8Z): andl oneof'his, _ col2aborators,. Y''anysheva,, produced benign and malignant epidermoid lung tumors inratsfollotivi~ngsinglea11d muiltip1Je administrationsof' benzo(a)pyrene byintra- t'racheal instillation. Dose-response relationshipswere demonstrated: E~'xperiments in Mice Cigarette smoke~~ condensate (CSC~)~,, various fractions of CSC, and, many chemical compoun& identified in CSC~ have been tested f4r~ tumorigenic activity~ in mice by~ aa variety of' methods,~ includi~ng~ skinn pa~inting~~ and snpcutaneoir:- inj~ectioirs. Complete~ carci~nogens~~ and in- complete~ carcinogens,, which i~~ncl'ude~ tumor initiators, tumor~ pro~-~ uioters, and tumor accelerators have been described. Several' recent.t studies~ h<nre~ been conducted using mice~ as~ tlhe~ eaperimental' animal which examine~ furt~her~ the~ mechanisms involved' in tobacco carcino-~ genesis.. T.ee~ and O'NeiIl (50)~ nleasurecl the, effect of duration~~ andi dosage of~ benzo (a) pyrene applicationson~ the rate~ of~ dev.e:lopnient~ of~ benign and malignant skin ttmiors~ in m~ire: 'Z'he~ incidence rate for tumor formation Nvas' d~itectlyy p~roportGonal~ to~ lioth, time~ and~ dose. q'hese~ data conf'ormedl quite~ closcly~~ to postulated mithematic<<I models of the rate of tumor dev elopment.. 80 ~. t ~ ' I c.

t n d were hcino~nas ~ enzo (a) tles at- dininis- s'. Vari- used in 7.5 mg; in 6r,eiratory ations, , 1 types e rela- t l'olden ,zo ( a) ors of' quent tulted' ilone. iluced' wi ng ntra, 6ited. land for >kin in- )ro- ;e.nt na1' no- tge gil ,or se of' I)ii~~-ies aiid «"hitehea.d (17) studiedi the effect of altering the "tar" ;iudi nicotine ratio of cigarettes on experimental carcinogenesis. No. ~i_nuiticaut difference in tumor yield was found between condensates 4)k,i;cined fronr the smoke of cigarettes containing 16.6 mg, "tar" and nig.~ nicotline and other cigarettes~ cvntaining~~ 10:0~~ ing:, "tar"~ andl 1~.a I~n1(r. nicotine.. '-~everal studies by Bock,,et al. (7, 8, 9) have examined the tumor prowoting- activity ofl a number of flractions~ of~ cigarette sm~oke~con-~ :iens,ite (CSC)~.~ A number of~ subfractinns~~ of the: neutral fraction ,if~ ('S(" were~tested for~tu~~rmor~ promoting~acti'vity in mice~~ pretreated %O~tli 1-1,1•3~-dimethyIbenz(n)antihracene~ as~ a tumor initiator~ (8).~ The, . niost, poTa~~r~~ subfract~ioiis~~ and the fraction: containing~~ benzo(a)Ipyrene~ «ere the most active tumor promoting fractions. In another stndy (,)). the weak acid fraction of CSC'' was found to be a very weak ('0uihl~ete~ carcinogen which probably ~ acts primarily as~ a tumor pro- inutiug~~ agent. The promoting activity depended primarily: on the nuriVolatile constituents of this fraction. ilTore recently,, B'ock, et al. reviewed the tumor~ promoting~ effects~ of CSC and extracts~ of' t~"b,u,co leaves. _V combi'nation of t~wo~ subfraetions~ of the~ tobacco~ ex-~ t ra(•ts. ~is wel2 as five majpr fractions of CSC, were foundi to have tininor promoting~ activity. Tlie~ fraction containing, the polynuclear~ ;re~otmitic~ hydrocarbons~ was~ found to~ be.~ a complete carcinogen. Tw~a. >+ii>fraetions~were~ found to~be~ strongly synergisti'c~in their~tumor~pro- u,ot~i~irg~ activity w~hen applied simultaneously to~ mouse~ skim Lazar, et al. (49) found that hy,droquinone applied to mouse skin in conj,iinction with the active fractions~ of CSC accelerated the early last.ologic changes that result from the application of "'tar" or its fractions., Van Duuren,~ et al. (97')~ have~ suggested that "'cocarcinogenesis"' be differentiated fromi "tumor~~ promotion"' defining~ "cocarcinogenesis'''~ ,ts~ tlhe~ production of ~malignant tumors by ~ t~~o~ on~ more~ agents a~pplied. simultaneously or~ alternately ~ in~ single~or~ repeated doses ta mouse~ skin and -''tumor~pr.omotion"~ as a single~ treatment with one agent foll'owed by single or~~ repeated treatment with a second agent.~ Using, these~~ defiiiiti~ons, the~ a-trthors, found severall tumor~ prom~oting, agents~ to: possesscoca~~rcinogeni'c actiivit~y..~ Roe, et al. (i:/) studied' mechanisi.ns of mouse skin carcinogenesis~ using benzo(a)~pytene~ and a~ neutral fraction of OSC applied singly or in various combinations with each, other: Skin tu¢nor~incidence~rates~ ialcreasedwitih the dose~ of applied niaterial for both~ the~ neutrall frac- tion and benzo(a)~hyrenef l~I1i'xtures~of the neut~zal~ fraction with benzo-~ ( a)~pyrene ~ (lid not act ind'ependently~ ini the production of~~ ma]lignant sk~izi~ ttuuors~ l'nut syncr-~istically;~ su(,gestiidh that some. of~ the~~ compo- nents~of the neutrail fraction act as~~cocancinorrtins~~ rather thEUi as conrl- plrt~e~carcinogens~. ar

Schmahl (78) found a direct relationship between the dosage aq duration, of subcutaneous injections of tobacco smoke condensates and! the development of sarcomas in rats. ~ Maenza, et al. (56) studied the efl'ects of a combination of nickel. subsulfide (~ i3Sz) and benzo (al) pyrene on sarcoma induction in rats. `' The interval between administration of the carcinogen andl the de-~ velopment of sarcomas was significantly shorter (IP'<0.001) ini male~ Fischer rats given injections of a combina,tion of 10 mg. of M;S'z and'T 5 mg. of' benzo (a) pyrene than in rats given either ingredient alone. ;. There appeared to be a synergistic interaction between nickell com- ~' pounds and the polycyclic aromatic hydrocarbons. ~ Healey;, et al. (34), added further refinements to a technique for v measuring, the nonspecific esterase activity of mouse ski¢xi following appli~cationsof various chemical compound's:~~°~~itlr few exceptions,, , changes in esterase activity reflected the known tumor prodbcing activity of a number, of polycyclic hydrocarbons and tobacco condensates.. ~ Sydnor, et alL (89) exaxni'ned' the effect of' an aqueous extract of' ,- cigarette smoke eondensate,on benzo(a~.)pyrene-induced sarcoma in, female Spra:gue-Dawley rats. Benzo(a)pyrene was~ injected subcu- „ taneously in various concentrations of' 12.5 µg: to 400 µg: per dose dis- ; solved in sesame oil. Injections were given on alternate days for 30 doses. The mean tumor induction time was accelerated in five of' `: seven groups given the aqueous extract of CSC' in their dirinking water. A:nimals given any benzo(a)pyre-ne eventually developed sar- ~ comas at the site of'injection. Dose-response rela:tionships were demon- strated for the concentration of benzo(a)pyrene administered. It appeared that aqueous extracts of CSC contained one or more com- ponents which functionedias cocarcinogens. Aryl Hydrocarbon Hytlroxylase (AHH) Certain of the~~ch~ernical componnds~ found in the ga~s,and particulate~ phase of cigarette smoke are absorbed through the lung or oral cavity into the general circulation. Possiblv through such absorption some chemical~: carcinogens are~ carried to~target~organs~~ not directly ~exposedl to cigarette smoke.~ S~ame~ of these chemical compound~~s~ are~ probably.~ excre~tedi unchanged while others are~ metabolized t'o~ v~ariousdegrees~ by~ enzyme~syst~ems present~in the~ liver andl many~ other tissues. Tlie~ ~ microsomal mised-function oxidases are~ key~ enzyme, systems~ for the metabolism~ of' a«id~e~ variety of chemical compound~s~~ ineluding~ the 82