Tobacco Documents Online

Rcsttlts of Rcscarch '1 he proRrcts tit the research fnrlRram hat hecn reflected in a cnn- tlantly Prnrwinp numhcr tit hnhlithell fahcrs th.rl nre ahc/r.rctc/l inJiviJrrally rrnd lictcd clccwherc in this Report Ncverlhelea, in order tit rrnvidc snme pcrtrcclive trf thc Rlan and «rrpK rd the prnrr:nn and tit Ihc hrctcnt statc of knnwledRc, it scemt pertinent ala. to ttnnm:rritc the finJinRa anll tech- niquet in tevcral imf+nrtant frelds or inveclipalinn At tnmc Ixrinls the tum- msries may Irnrch upon work whnse resul/s havc nr+t yet been puMithed in full Naturally, mrt all the work under w:ry nr crlm/rlctcd is diccucud hcre. 7hese sumrnaries sre: I Smuke Inhal:ttimn Studies: II 1 unR Pathnl- nRy; II1. ('arcinnpenicity and Ilinattay: IV, titcuc ('ulturr; V(->,rdinvas- cubr Rrcrarch, VI f'aychr+ f+hyaiolrrpital Stuncrt, and VII Miacrllancrnrs 1. .Smtrke InllrrGrlirrn SIrrrlie. 1 hr I I R(• hat ttir.narlrerl /r mnnlx•r erf ttnrhet in which e.lx•rimrnlil animalv wcrc rnrlnccrl Ir11tIh:rlr l rPa/rtle tulnkc Sr.ntc trr lhctc ire f;n enrruph PhrnR to inrlicalc ccrlAin finrlinR. In line ttully .cienlielt ethlree/l mice r+f twn alraint tit ciparrtte snulke inhilalilm in i m:lllunc whitIr lrrrrlrnlt Ilrc rrrllinp cnnditirmc Irr timul.rtr elnacly the mnnnt•r tit hurn:m tnrrrkinp, fra rcrinrle ai-IrrrrathinR Ihe entire nnrmal rrcar,n nf the anirnalt aftcr weininR Nn IunR cancert tit the tyhe prevalent in hum:int were fnrrduced I nnf ademrrnas tit the type thil nccur naturally in Ihcte micr r,ccurtell nm mme freyuentw than in unr><pr+ud mice Another researcher afwlicd Ihc efTect rrf srnnke inh:llalinn by (T, mice which were iltn piintctl un the akin with Ihc potent c:rrc'imrl!cn, mrthylchrd anthrene Nr+ syncrPislic cfTect was nhartved In a third atutly twn ccicntialt tcl ur thc necccairy rnichincry frrr intrrl- tlucinR frceh ciparcltc srnrrke directly intrr Ihc lunps rd drrps thrrluRh irlifit i;ll t+peninRe in their tr,chc:rt 'Ilre tnurkc w;tc rnxlucrll unJer carefnlly crm trrlllcd cnnrlitirrnc rrf RuninF vrrlrnuc, tlrn;rlirrn anJ frcrlucncy in r+rdrr trr aature Ihm Ihe cr+rn/areilirm rrf thc vnwkr wrurlrl rctenrhlc c/rracty fl.:rl rrf trnnke nrnmally inhalrll hv hnm:rrra Ihr tUuly wac trsntinncrl frv rurrrr tll;rn Ilnrc yt'art inrl im/ivirlnal rL.p( rrlclvcll .rnnkr rrf /r1 ?/I cip:rrcllc•• ll.lily frrr nriny mrlnlhc Nrr Inrnp cincrrc rlcvrlulrrl In artnlFhrr Ieluvalrlry acicnti.lt h.rvc rcc'cntlv nnrlrrl.rlrn t r.nlyct/ nrirr• Irr t i/•.rrrltc trnrrkc rnlr:rlatirrn hrr :r trrrul-whal dr/lrrcnl I+nr/urtc Il.rvm/• Inunr) Ill:rl Ihc tu,r t phhrlity rrf nrit c In Irmt• :ulrnranea rd Ilrc tNl r IIr .1 l.r.n 1•r unlu, r~I F.v I... Ir•"• rt.r nr urr Ih.rn, .l. y-,-l•. ul,~~n rb, •.rr1~IJV id nr.n nr Ithrv with trr dclcrrnine whethcr any ingredient of hd.icco, amlrkc t'an influcnce thc effective cufrldy nf thit vilamin either dircclly tit inllircclly. Anrrllrcr invcstiR:rtnr h:n dtrnc the mlrst e rtcnsivc tludy Ilrat has been sfxrn.nrt•d hy I I R('. rrn elfccft of ciRarclle smrrkc inhalalitln hy mice Crrnupt nf fem,le CF, mice were c.f+tned five lirnes a week tn Ihe snutkc frum four to six ciFarclles over a fverirxl of nearly two years. No invative carcin,rmat nf the lung were found, although sontc mice devehrl+cd a hnon- chilit. 'I he txcurrcnce of >,dcnnrms in Ihete c.fxtced animafs was ntr greater than that nnrmal to the strain without smoke etplrsure. ll. Lunlq I'aIboloRy Work in the field of lung pathology hat been nf two lyl.ca: tludics rrf hnman hrnP litsues acyuired at aulrtpty, and sludies of anim:,I Iunpc fnlhrw inl; crrnlmlleJ snulkc e.lxnure. STr/IIIF.S f/F IIIIMAN I.INVI: 7'LC.q/F.S f?arly in 14SS twelve palhnlnFictc located in hnspitalt in varirrns harlt rrf the cnunlry from clllst to enatt undertrxrk e ccwrnlinaled sludy tu deter- mine what kindt nf abnormalities occur in the lungs of human suhjectt thal cnme trt iuhlpty. The incidence of such ahnormalitics wat ta he dclcrrnincd and the relation nf the incidence to >,ge, sett, tx•cupalinn, tetir(rnce• envirnnmcnl, and eaute of rlcalh was to he dclermincd as f.r at prrttihle. Six clattificationt of cellular ennditinns were >alnpled and alx.ut 2000 N/rmps were cadlccted and e><nmined over a period of two and a h:rlf ye:+rt II was ftrund Ihat data could nnl entily he pooled I+ecause nf diRerences in Ihe classifieation tit litcue seelir.nt hy diflerent nhservera I he.e different'et were revealed hy circulating two sliJe cnlleclinns under crxle for indclx•ndcnt claaiftcatinn hy severaf pathuhopiafs. f rcliminary cr.nclusitrnt front Ihi. stNtdy were: 1'1 here w:re no aFe dilTerence in the prevalence tit clranl•ct. ctatccd :ta "hylx•rfdisia tit mclaplacia," at any ape nhrrvc 2% yr:rrc I ccs Ihan 1/1 lx•rcrnt rrf :dl catcs ttuJicd, inctudinr Lrrlh .c.ct and :rll :rprc. h:rJ mucutae cl:raecQ aI "nurmal" in :rll lire .ct lirrne Ihal wrre ccuninrlf 7 M.rlcs thlrwt•t1 chanpec deRarting flYlrm "n..crn:rl" mrrrr rdl,-n than frrn:rlca. hut htrth mrtal+lasi:r aml hylx•rlilaaia rhrl rrt cur Irc qut•nrlv in frm:rlra I Cip:rrNle amr+krr.In Ihi. ahnly femlctl tn fclvc frwcr "nrnnr.rl" crt'lirrm th;rn rtrm cmnkcrc. •1 Ilv i rrruph divitinn rd trctur:lliuna into "h~r:nrLrrrt" Ithrrtr wlrir h mx. Ir.rvr .r hi/•h r/carh r:dr Irrnn Innp t ancrr 1, Il.-r irr Inrrn in/•. :rn•I ulhrr., nrr t'nnaralrn/ cqrca rlf rncl;llrl:r.r:r r~r Irl,lvr1,t.r.r.r ;rl'lu-:rrrrl m:ulv nl rhr.c Ihrcr 1•rrrnllt Ix

I n N S StudV nf the Ix'currcntc elf rnrlaf,l:rtia nr hv(•crl+lati.r by Ihe ti7c +d lhr I:rrFrtt city in whitIt Ilrr c:rart ever rctidcd revralctl nn sipnificanl diflcrenccs. 6. Me/if+litia wa rresent rnnre frcyucntly in thntc tlyinR frnm InnR cancer than in Ihtxe who dicd from (rtl+er canccrs or rrnm III trlher cautct. 7. "('arcinnma-irr trn!' (a cl.rttificatirm Ihal h-it hrcn utrd hy snmc r:+thnl,+Kittt In detcrihe a cnnditinn thit Innkt rnicrnact+~ically like c.ntcr hrrt has nnt shown invativc grnwtlr) w•:rt rarcly diifnntrd hy any elf Ihctc 12 rathningitts, and Ihcn utn:rlly nnly when inv:rtive cancer w:rt ,la, prctent. One pathnlr,pit/ it cnntinuing a part nf Ihit ttndy by nrakinR a more minute eRaminatirm nf his collected IunRt by serial srctinn ('nndilinit of the IunRs will he con+pared in relation tn retidence rnvirnnmenl 1 he relation nf ine/aftelaia or hyperl+lasia ln cincer is unclear hrr autc elf the diflerinP cr,nt'rf,tt as tn how cancrr :Iritct in tittoe OI+ininnt rliflrr widely at to whrtl,rr tuch tnmlitiunt :+rr tn F,r (r,ntiJt•rt'rl :+t "l,rrcan crn+at'• in any trntc c1'lrl)If•:S OF Il1'lnf ll, r.trrv(:.C r f'rnm tturlirt t,f Ihe cellulir cnnrhur,n of mnnte lunpt h,llnwin` ct pnure nf Ihr rnitc Ir+ ciprerrtte Imnkc inh:rl:rtinn trnrlrr rcl:rtivcly vcll controlled cr,nrhlirmt. Icvrr:rl nnl,r rr.,nr lin•hnl•t 1,ucr rctnltr rl I Snr»r elf the nrirr rtlv"rrl I„ vn,•tr rnh:rl.1l+•,rt rlcarl,+(, hrr'n chitit ~1 c hrnnir inll:rmm.ln~n +,f thr- hnn,t lu.rl Inf,rt f Itlrrrt tlrnw no changc flum nnrrn:,l wh.rtr.rr 2 1he intirlrnce elf hrrrnthilrt rn Ihr nnrr vitrrt (•tratlv frnrn one Rrnuf+ tn enrHhrr even Ih,~ul•h thr rnrm.rlt :rre frt,m inlncd ttnckt presurneti Io he identical anrl have rrtrrved Ihc time diclt, care, ind treatment tn far at known 1'f he numlKr nf cases of hrnnchitit in any Rrnup or Ihe tcverity of the inflirnrnalir+n tccnrt to hcar no relation either to the intentity of the tmnke dt+taRe or to the length of tirne thnt the ecpoture w;rt cnntinued. 1. The hrnnchi of rnice with hrnnchitis tht+w varinnt dcRrert of hyf+crplatia and mctarilatia very timilar to that nflcn fountl in humin lungt. S. Cnntinualinn t+f the am+ke inhalalinn tlurinP thc entrre life span even nf the hrt+nchilie mice has not prnJucrd cancer. 6 When amnke e.l+nturr it rhtcr+nlinueJ m Ihe elte r+r I,rnn chilic mice. Ihr almnrmilitict (hyl+rrl+lati:rt :rmi nrclal+latiiatl trnd tn ditappear. Thetr „Ltrrv:,/innt c:+ti tlr+uht nn Ilhr inter/,rrt:trir,rn 1h:+t havr hrern nly+hr+l l,y .+une I•+Ilr„Ir,~itlt tn tinnL+r ;rl nnrrnalrlirt in h+nnnn Innrt at "1•rr1.1111rr."lt Ihr n,.,nnrr rn wlrith „nly tert:tin nritr rlrvrlol' hrnnchitis when exfaned to smoke points strongly In a di/lrrrncc in drrtr-rpnhiricy in the mice Ihcrosclves, of a nalur0 not yet ditclnted. A I"nttihlc hyl+r+thctis, which it being pursued, is that st+me uf the anim:rlt may have a latent virus infection that becomes active The e><planalinn nf Ihit phennmennn may produce some valuable leads for human studies since hurnans alsn arif.car to differ greatly in their resrCrntcs Io smoke inhalation Ilr+wcvcr, these cal.criments so far reveal no rcla/ion between brnnchilis antl cinccr elf Ihc hmg in the mice. l:nnferenre on ('Irr..nlr LunR /)i.enae. On Scplen,her 11. 1959 an informal -conference was held for dis- cutsinn of chronic lung discates at possible antecedents to carcinoma of Ih- lung The conference hroughl together hoth eaperimental scienlisls and clinicians Inr consideration of the prnhlcnt from these opMning Jirecliont of apprnach. 'Ilre slimulut nf Ihe settinn acrmt likcly to Lear fruil in Ihe farm elf new retcarch 1,1ant for allack (tn tevcral pIratet of Ihit prnhknr. Flesides memtxrs of Ihe Scientific Advisory Ilr+ard, the following were present: 1)R CYRIIS C hRI('KSON, t rolettor of ralhnlnRy, university of Tennettee, Mrmphit, 'rrnnetsee 1)R. WAI ll:k I INKE, 1)epartn,enl of McdKme, 11he (ienesrc Ilntlalal, Rtrchcttcr, New York 1)R. r111R(:IiSC I.. (;ORI)ON, I)irectnr of fducatiun, lhe love- lace hnundalion, Albuquerque, New Me.ico 1)R. IIARRY S. N. (iRP.liNl:, I'rofettor of 1•alholnRy. Yak l)ni- vertity School ol Mt•dicine. New llaven, Conneclkul 1)R. l'F('1111: 1111('IIIUNRIiR(:F.R, Senior I1inlnRisl anrl ('ytn chrmitl, ('hiltlren'f Cancer Research 1'oundatiun, Ilnttnn, Mat)achnteltt DR AVI:RIf 1. A 1.11: 1 nOW, rrnfetanr of 1'rrlhnloRy. Yale llnivrr sity Schtx.l nf Medicine. New /laven, Connecticut 1)R. BIARNIi PhARSON, Profettor of 1 alhntnpy, Wayne State llnivenily ('nllele nf Medicine. 1)etroil, MichiRan I1R. ti/1111)ON (' SOMMURS, PnlhrdoRitt, Maaathutctlt Mrmn rial I Ioy.il:dt, Notlon, Mattachutelt. 1)R. 1)()ll(31 AS 11 SI'R(1N1, 1'rn/cttor of Pathnh.Ry, ltnivrrtily uf I ennratre. M emphit, 7?nnestee 1)R AR I It1/R 1 VORWA1 O, Prufetanr and ('hairrttnn, 1)rt„rr ment r,/ InduHrial Medicine r.nd Ityltiene, W:+ynr St:rte llniver trtv ('rdleKr ot MrJit ine, Ihtrnil. Mit'hiRan 1)R k11S%/ 1 1 W WI 11 Uk, Ifirrtrnr t,f I~/w+urlrrrir., 1 I,Lrat. ('„n+munrty /1„ynt:+l, /'I,f.r.da, 1'rontytv:rni:r lll. Crrrr'inrrgrvrir'ilv rrnrl liinre..ny C/rin frnir.rin~.. K1:rnv cllr,rt. Ir:+vr f•rcn rn.,J,' hy v.rnnut invrtti~:rlnrt In drlcnnrnr, I 21

through animal ex)+eriment, whether ciRarette smoke ha• any direct cancer- producing activity. The most common type of test has contitted n( painting smoke condensates on the akins of animals, etpecir.tly mice. Widely diflerinR results have been obtained by diflerent retearchers. A few have reported cancers resulted on tkins of aome nf thrir tett mice aftet very InnR painting with high concentrations of smnke cnndcntates. Others have reported that no skin reactions occurred. One InvestiRatnr has painted Swiss mice with cigarette smoke con- densate, with and without mechanical irritation and with and without irra- diation with X-rays Some benign and malignant skin tumors were pro- duced in all Rrnups so painted regardless of coincident irritation. In Swits female and (',II male mice, inlense irradiation of  smalt, ditfant skin area increasrtl the tcnsilivity lo trnnke crmtlentatrs. 'fhe interpretation of Ihete experiments in trrms of their nvaninR for humnnt it very rtil)icnlt fnr tcveral reatnnt' (a) the mctht+dt r+f tmr+ke prntlnctinn have t,ftrn been tuch at to rai[e dr+uhtt whether Iihe chem- ical cnrnl.r+tilinn it cnmparat.le In • that of antr+ke I,rralut'rd in nmmal Ihu- man trnnkinR; (h) the rlif)erencet in [uttel+tihiGty n( mice anJ I+t•r,plc are to Frt•ol tl+at nt+yn:+nlil:rtive tr+nclu[ir+nt tan t.c drawrt ttrnn thrtc mnuae exrcrintrnI[ cr+ncrrnrny h:vartl[ (r+r m:rn frnnt tnn+ke inhal:rtit.rf• (t ) Ihc ttr+[:iRrt u[rrl irt trc:+ting ntr+u[c akint are tr+ prril Ih:tl they I+Cir nn re:tli[tit' relalinn Ir, Ihc ktnJ[ 14 [nnrlc Jr+..t~ct :+tlrctlly cncrnnttrrcrl I+y pcr+(+Ir in rvtlin:+ry [mr+kint•., :snrl (tl ) Ilrr Irrnr• h:tt an tnut lr n„+rC tllit icnt c/r:rmnt• r.ncch:rni[rnt IF,:rn Ihr akin Ilr.tl rlrr,t/ t+~rrt.rct nf trm.4c trmatrlarnt. ..ith Iht' Inng it rt•I.rlivrly hrrrf 2. Othir Afrrhorfr nt Rinn..nv. ftccau[c nr Ihr uncertainty of mnutC [kin I+.rintinr :+[ ;t Icd h,r the c:tn cer activity of a tnhalnnce, numert+n[ t+thrr methr+d[ havc hcrn et(+It+rtd Ir+r a tlnickcr• mnre rclc,t+lc• ;tnd nunr ca[ily intrrrirt•tcrl Ic[t A tc[t Ih.rl wrndd tic mcinin(-Iul in Icrm[ nf hurn:tn ctl-cricntc wr+nhl hc :t valtcrblr cr+ntrrl+n tinn nnl only in thc cr+ntirming luhattrr rc[t•:rrtlt, I+ul Inr all Ihc r+lht•r [uh- a/ancCt trr wltith /+Cnlde :nt' t'trr+[ctl in thcir rlay It+ rlev hvinlt, If• at h:,[ ht•cn arF{,cttctl, we livc in a"[ra nl tarcinr,fcnt'• it it ctrrt'ntrlv iny,rnlanl tt, lintl a way In rlctcnninc Ihr iticntitic[ inrl tlu:tnlilict td Ihrr[t' [ufrtLtnrrt Ilt:rt mey Ihave att t'tlrtt r,n la•r+(,lc I wn [, rcntialt have [cwn I+rllrt. Ir( Intb:tctt+ intr, tlrC n ccck I+r+ut hct r,f Ir.tnr[rrrt Ir+r I,n,r Lt-rir+d. t+l Iinrr 1,111 nr+ t:urtcr[ h.tvr hrrn I+rralutrrt l hc [entr rnvc.trl•.rtr+rt Ir.+vr aluAu l Ilrt' t,rl,l+rcatir+n td titr trh:+trnu[ ui.l. „f .i.i. , r.n I„ ~t,- It Ir.r I„ . n r I.,nur ,I I,y .+Iln r and their ahility to auppress these Rlands in the skins of mice. An ext.nalve study, hnwever, showed the tett to he low in power of dixrimination. Mc>rv over, the test was unreliable because some substances known to he carcino- genic gave negative results and vice versa. An eRort to rate tobacco amoke condensate by this test gave an indea number of 20 for ti•re smoke from a whole carton of cigarettes as compared to a rating of 10(10 for the weakest known carcinogenic hydrocarbon tested. On Ihis basis, ciprette smoke would be considered virtually negligible in activity in terms of this test. In another study. Spra6ue-Uawley mate rats were fed diets containing 2-acetylaminofluorene to induce precancerous changes In the liver. One Rrnup was eapnted to inhalation of cigarette smoke and another was injected with a IaM+ratnry preparation n( smoke condensale (probably abnormal in coml.nsitinn ) prepared by bnrninR cigarette tobacco in a glass funnel. llnth lubaccr, tmuke e.powres scemed tn delay tomewhat the n(,pearance n( hrccanttrrtua liver tlranRes. Similar espt•rimcnlt with a smnke (+reparalinn frnm a csrefully reRu- I:rlcd mathinC that c'In[ely dnl+lirnlct huacns tmnkinp were rnatlc hy injcclinR lhe rrrr,:rralit+n inrn, or painlinR it nn, m:Jc alhinn ratt on dictt containing either 2 arctyLnninnflunrcne or 1'-mcthyl 4 dinrcthylaminnhcn7cne. '1 his cnnJcn[:HC h:rd nn ellccl on Ihe ratc or incidcnce nf liver tumnra in ratt fcd either anhtl:rnce. Ili(/er.•nrrr in .Snruke (:nndrn.nr.•a I hCtc fintlirnFt cmph;r[iac lhc ditlcrcnt't•t in varinn[ tmt+ke cnndcn• [:ttcc ;md illuttralc the nccc[tity nf u[inR smnke prndut'ctl undcr nnrmal ctrntlitinnt. Othcr invcttiF:rtnrt havc tturlicd the (vrtt[it,lc cn c:ncinngt•nic t•I)t•t It nf nilrnr.Cnnns ct,nrivnuntlt frnm tuh;rrcn (in ( t) Ihc incitlCntc of ttinn I:rncr,ut rulnn,nary adcnnnrat in Slrain A mice, (2) nn urelhane imtncrd I,nlmr+n:ny atlcnt+rna[ in Slrain A mite, (l) nn X•ray indrttt•d lyrnl+hnncrt in ('S7 hlatk mice, nnd (4) nn tdlravinlet (iFhl induce•d tkin ttnnnrt in Swi[t nritc Nrt arth cflcclt were fnund. l7rrv havc fnrrntl that injcctinn nf fincly tlividrJ carhnn pnrlirlrt inlr, thC hlra+J[lrcant will rtrcally increate Ihe numhcr nf Innr, lumnrt Iltat n.+rnr.tllv tMtnr in Srr:rin A mitc A nculral fractir+n nf t,d+atcn amr,kt• :rd [nrhrJ on [uth c:,rhnn I+:trliclCt trlnre injcclinn tlit-h/ly drrrrntnl Ihc nnm hrr of lumrrrt lanrlutrd I+y IhC carf.nn It w:n :rl,r+ Irrnntl Ih:tl a niarin tleficit•nt dicl in Srr:,in A ntite will frrally int rt.r.r- Ihc intiJcnct' of [I.r,ntant•r+ut IunR n1lr/+nr11:1t, wltrrr.lt :+ vrl+/+/rmrnt r+l ni:a in [crvn[ In I+t• I+rrdrelive I rrvtinr. 1 I+yrirtyl nrr•thvl Arb.nr, :,n r•.+L,ri n/+rr,+lutl nf nitnlinc 111.11 cr+ntt'ivaldv t"trlJ :trt :+t :t ni.+t in :,nlnuct.rbr~lrtcl a1+1+c:vcA tu :+Iltvi:tfr• IhC ni:trin tlcliticnr v:tnd dr

I crcice thc Innu+t int'irlcnce 1 Irr ~r+aal~Ic :It tinn (if whi+lc inhalr l smc+ke as in inri ni:rtin aprnt is nuw unrlcr .Imly Anuthcr acirnfial hat e.Fh+red acvcril mrlhnJ% that mighl Jrveh+F inlrl nu•lol hir+:rccay Itthniynrt frrr mc:tanrinp, carcim+Fcnicity llsinp a suhculinrmn airhnnth for Inrnrrr Irinapl.rntatn+n, hc has mca.meJ the effecte c+( Inr+wn c:+rcinr+Rrnie aRenfa in enhanrinR trr inhihitinp• Frrlwlh. fohiccrl amr+kr c(mJrnsates sn far emphrye(1 have ahr+wn no actit+n Smme c•nnrplicatirms hivt• dcvcltq.ed in the np(+licntitin nf the metht+(I and il hat nul yet cvr+lvrrl rntr+ a whnlly talit/aclrny ted rrr+t'etlure •I hr Utrrine crrvu nf nltCe hai been uaed as a lesl tisaue (nr rlclermininR the r+t)tency t+f apenla susf.c•ctetl (if tx•inO earcinnpenic. lhit tisa/e re- semhles lunR lissue more closely thin dr+es Ihe skin (•iRareue arnnke cnn- dcnta/es were applied In the eervix and uFl.er vaginal area td mnrr than 21m) UI/A I mite r+vcr a I+critwl of many mt+nth.. ('nnlrrdt receivetl a+lvrnt alr+nc, mrthylch +l~nthrrnc in the same at+lve•nt, t+r twahhinR with A dry cnlltrn Iil+l+er1 al+f+lic:rlr+r l hcar nlit'e f+rr+vrJ a+ Le trir srnailive In firnrhlce a valid /cat sintt• Ihr trdvent al(mr rt tht• dry afydicatrrr rraullctl in r»rne tumnra Ih.~n diJ Ihr alqdicati(+n nf 111, anu+kc crmdrncalcs In view r,f theae resulls, it has been necrsaary nf cnurte trl :Ih:tnrA+n Ihis rnelhntl as a valid tt•ct While t+thers have crrnsidererl sipnifieant the intluctir+n nf tumnrs at this cilr with smr+ke ci+ndencatcs, thc hi{•Jrer incidence (rf /umtrr induclicm with a pI:rin arplic1trrr in Ilric wrrrk raiacs scrinot dr+uht as Ir+ the validity t+f any such cunclutirrns ('nrrln.rRinr.i. In r.ynrph•1.ar .Inlnrnfa (i>ttensive studics have been maile erl carcutn~enesis in ducks and chickens by mcrhylchnlanthrene api+licrl In variuus tissncs •1 fre resl+rmaes of animalt eq ripl.c•J with !c alhrrt insleatl trf fur anrl IackinR lyrnl+h rlanrl% were ctmsidcred wl+rth tlnclyinR frrr ct+nlr:rst willt Ihe mtxe f1rniliar re- tF(+nsrs t+f marnrn:rliin sFeeica M:/ny inlereslinp nhservalitrns nn tht in duclinn t.f tunrnrt and on their behavior have hcen rcrnrJed Mt,d rele- vanf perhiFs is the cnntrasl in aclir+n r+f rnethylch(danlhrene inlrtnlutrl intn lltc Iracht•i in I+canut t,il sr+lulinn :tnd that tlf li+hacct+ srnrrke cmnrlcn aatet intrrrtlute(I in Ihe t:lme vchicle -lhe nrrlhylchr+l:mthrenc qirickly lantlucra :t very inlt•nae in(limm:rti+m whilc Ihe tir:rrctle vn +kr ic I+rac fit:rlly withoul r/frcl Another invralip~tnr i. ttnrlyinr al ll :rnr+lhrr I+hrnnmcnrm that aly+r:rrc Prnmicinl• :+. .1 I+t.ia fi+r a Ir.l ncll+0 11(• L:r% r~harrvcil Ihnl trtteirt Irnnrua whi+h r.innnt nrrlinerily F.c Ir.m.ld.rnlcd Irr a atrain nf mi,r in whirh Ihcv u' .ilirn wi1) "t:rlc•• an.1/•rnw i/ thr :mim:+lc :u,• fir•t t+nm/r,l (ni fr.l1 w.ih 1 m hy~hn~:+rl.nna lur :r Ivri.nl n/ Innc I+n.•r In Ilhr ?I i Ir:Inal+l.rrV I hc time tlurinR which fhe trancldant will Frtlw is tclalcd In tlre dr+a:r~r r•f hythr+catlHrn given Wilh cullitient drr.apc, evcn nnrmal skin (trnn Ihc :rlicn str:lin can he Iransl.lanted suct'ctdully fur rcrintls rcLtlyd lu thc lh+a:rl-e 1 his nlcthtKl apl+c:us Itl be wcll suitcd Itr quanlilatiun and its evahctlinn fly ctnnpariam r+f a large ctdlet-titm nf Iv+lynuclc:n hydrn- cathtms is undcr way- One scirntial his undertiken to Ruide fnrlher sludy (+f a carcinn- Fcnit'ity ataay IIIrI111NI h:Itetl trn Ihc rcallrunc nr a pttdt.rrran (I'rnumrrrlrrn rr+rJunrnr)l Irr ullr:rvitdel light frdluwinR ealxnure in Ihe tlark lu a prrly- nnclear Irydrtcarlarn. •Ihe resrt)nte is reputed Itl he related Itu carcinogenic :rctivity (+f Ihe hydrtrcarhem. Cnrnfiarison tlf a large numher of such hydru carbnns is to be made in parallel with IPtts by the mclhtrd deu-rifred in the preceding paragraph. rrrnna.ny Cnnf.rpnre A ctmference waa held St•rtemher 10, I9t9 for discussitrn of car- cint+p,enesis and hir+issay methnde ('ritical an:tlytit was matle trf hilhrrln Frevalcnt mt•Ihtala and nf recent dutlics supFcatin(; new al+lnr+athes to Ihe prtrblen,. '1 he discnnsion retulletl in the planning td several new cn t+rdinalctl siurlics to compare the resullt nf different ntaay Ieclmiques. fletides mcnthers of the Ilt.ard, tlrc following were presenl: 1)R. R S. 11F('KF••R, A.u+ciade Prnleasnr of ('hemiury. Ilniver.ily nf I lnutam, I lotrston, 7 eaas I)R. R K. II(/111WF11•, l4.arciale 1'nde.aur of Oncoh+Ky, llniver- aily nf Wiscnn.in Medical Schnr.l, Madhnn, Wiac•nnain 1)R. (7IlISFPPr°. 1)Fl.1,A PORTA, 1)ivisinn of Oncoia{ty, Ihe ('Ihi eaRo Medical Sehonl, ('hicaRn, Illinais hR. I(11115 h. rIr-CUR. Prntesan cd ('hemiUry, Ilarvard Itniver sily, ('amhridRr• Mas.achuactts 1)R. I RF1)1)Y 11OMIIUk(iI R, PreaJent, Nio Reartrch Inuiwtr, Inc , ('amhridRe, Mas.achuaus 1)R. A W IIURION, Aa.nciatt• Prnfestnr of Indu.rri:rl Itralth, lluiver.ily of ('incinnari ('tdlege of MeAicine, ('incinnali, (Ihir. I/R. MnItRI('IS LANI)Y, llcad, 1'ntyaacchariJc Scctinn, I al.nratr+ry r+( ('hcntical I'harmacnluRy, Natinnal (-ancrr bnrnute• Ilrrlrr. la, hlaryland 1)R MI I VIN S Nf'WMAN. 1'rofet.nr r+f ('hemiury, Ohin Clac l /nivrraity, ( r.lumlac., (/hin 1/R. Wlt I InAI 1~. 1•/)1 1, kr.rartlr At.rai.rtr in ('h•uPr, 1:,b,+r:rrr.ry (r+r I%t+rronenlnl ('.rrcimq•rnrait, Ilnivcranv r•( 1'dlabnnrh (:radu.itr titluN+l u/ I'rJ.lrc Ilrallh, Purahurrlr, P,•on.)Iv.,ni.r 11R FtI NIAMIN A NIIIIIN, naar.l:nd 1'r,dct.r+r rd I{•idrrni.d,41y, Il:rylor Ilnivrraly ('ulk{tr nl Mrvlirrnr, Ih+minn, /r.aa 1)R LII/KR,1Y ) 5111'AR, ( hirf, 1 nl,.nrlnry t+f ! hrorir.J 1'h.um,r tnb•Ry. N.+tn+nal (.rntrr Inalilnlr, llrthrart., M.uylnn,l MI\\ /(/nN %Afllll, (Rc{+rra- r•rin{• Ilr 1/t/ Cninrl,•ur. If•t+.i1 rnrnl of 7rwrtuRy. Indi.na llnivctvty, IIln,rminRl,+n, InJh•m.1l 25

I)R t'AtII 1? S11'IN1:1(, 1•athnlnri.t, 1hr tna,rutr fnt ('aatcr Rr- tr.irch• I'hd:rdrll,lri:r• 1'rru,cylv.u,/.r lyR (' S Slll'l1ANt1, 1lircttnr r.l krct3rth• Strl,h.rnn I+rr,ll,rr.• Inc, I'hilaJcll•hi., 1'rnncylvanis 1)R IOIIN (' S/I RII• Acanrrar 1'rnfct.r,r t,f 1'h~rmscolntY. 11~1 hnu.ir llni.rrtrty, Il.rhla, Nov.+ Ccutia f 1', Ti..rrr (:rrlllrrr In Ihr hnl,c Ihat Ihc olncrvatinn nf hurn:rn lunf lictne Frnwn i.n t•itr.r nnrl ttudy nf itt rc.pnntct tn carcinnFrnic and t,thcr aFcnts ntight prnvidc ncw nntlcrtlandinR tit thc nilure nf catcinr+fcnccic, thc cullure (it cuch tit- au hat hccn undcrlaktn. (iranlc have hcrn maJc ttt hnrr lahnrnlnricc h,r ( I ) traininp, f,crsnnncl in this kind of wr,rk, 12) :NtctnrlinR tn c•lahliah sttaina nf v:,tit+us httman liscuet, csficcially Innr, tic.uct, I 1) rrt+ccrvinR Ihc n:rtnrr nr t hanpct Itnrn nnrn+al h+ matirn.,nl tr1h, and (d) t+hsctvinp :,ntl tksctif.inr Ihc trct,t,nact nr tuth littnc lu Inl•:utrr crnr•1C inkrcJicnlc and tHhcr aFcnlt 1'. ('rtrrGrrrrr.Prrlrrr IT.•.errr.-h lhc Scicntrfic A,Ivicmy Itr,.url h.rc t•,nlinuctl ilt :rclivc ittlCrcct in thc ficld r,( c:rfthr,c:rttnl.rr rrcc:,rtlr wr11r ./,cti:rl It•fctrnt'c 1r+ 1hC c(Ictt td nicntinc antl tnn,krnr ,n tht• tirtnL,linn /(r.c:trch )'r:rnlc h:rvc hccn tn:rtlc hy IhC 1 1 I2 I lr, cnl,l,nrl wr.r1 rn 1b tcrtlt'r, t.mtcrnrrt wHh c.trtlir,vacculat rhycitdt,Cy antl ttc rlnr•rtlcr. lThc I'M Rclnnt r•t Ihc NciCruriit I/rlCtb,r cont.rinctl tlratil,+ita+c r+/ lltc «'ttf.t tttul, vthc-n 1c:trl.rblt•• thc rc.nltc nf tnany ((ojctlc cnlq•ntlctl hy Ilht• 1 I 11 (' Sincc Ihcn, a nnnrhrr tit (,ul,tit :rlrntnc havc :+~) r.trrtl in Iht ct icntilit (itcrltntc :tml atc ~h.tr.,ctctl in Ihrc I(cl+.•rl G,mc tlc:rl wrth h:r.ic rr.•l,lr rnc in c:trdinv:rccnl.rr I•hy•ir•h•Ry whilc rrlhcrc art• tnntcrnc,l with tlran)•t•c in thucd hy nicntine :+ntl Ihe snnrkin}1 of ciF_:ucttCc In view tit Ihc cl,ctul:Hnrn :rhtnrl Frt'.rvy cnn,kinp onrl dc:tth. (1r,m ttx,+n-.1ty diccacc, :t 1•rit-1 rcvicw t,t ccitlt-ntC• rclolmC tn thc Cllr•cl nf nrc"tmt• anrl vnt,kinp, nn Ihr cnrr,n:rry t ircnl.rti..n :tnt1 h:tccrl r.n Ihc rccnltc rr 1„+rtcrl hy I I R(' €tanlct•c, nt,)thl t.e •4 yctial intert•tl hiJjrrrnorr. In Rr.pnn.r Sincc tnn,Arnl' .,r Ihc rnlrttr.,n .,f nur,linc rrn,uu„nly rt-tinlt. tit :+ rc tlrrt/ir,n in Ihr cnl,t•tti,i:+1 tittnt.,In•n• .+\ i+r,lit'.rlrrl I,y Llrlhyat,,.•)•r:rl.lut nrr:rtnrcrnt'nlc r,l thr h.rnr) „I hy :r f.rll m.kin Icml., r:tlruc. ment h.rvt• cnntirlcrrvl nit,qrn, t„ l•t• :r )'t n, r.r1 v:+vn „n.Intl„r .tp, nt I l,t. „vrrl,,,,k. Iht• 1_rtl Ih.rl Ihrrr• .,rr /•rr.,l rlrlicrcrnr. in rh.• rc•.)•,•n,c .,1 ,hl)crrnt v,"r ul.rr I.r,lc t,. rn.,ny r I,rnut nl .,)•rn1\ It h.r. 1,.n)• In rn knnv.n Il,nl 11„~rc i•, a tc, tt• rt,t-:tl :tc'tirrn I,ctwccn Ihe vatnnutlt.t lnnt tit Ihc dt•cp and arrcificial vee- sclc '1 hat is, whcn Ihcre is cnnslriclion in one arca, at durinR aneslhttia tit atpltyxia. Ihcrc is dilat;clit+n in tht olhct. This rerttttn(h tin asfxct tit hnmrr,tl:rrir rr);nl,lir+n Ihrnuhh which the total f.eriphtral resiHanct .nJ thc copacily ttf tlte v:tscular syslent rcnmain ct,n.tant 'I hus Ihc cirtliac nutput antl l+ltw+tl presnnc m;ty hc liltlt aRcclctl in the fact nf rclativcly IarRr tltangcs in pctil.hct:rl tcai.t:nxt nr tht+.c ntikinatinR in citl,cr thc dccp nr tnf.crfrt•ial va..cul:rlurc( lltcrt is qcncr:tl aRretmcnl Ihat, in the knlatcd htart, nicntint added Irr tht pt•rfucinp, tncdiurn resulls in clilnlation nf the cnrnn:vy arlerict I Ittw- evcr, it w;tc nt+t ju.ti/icd tt+ aaunrc ftrun this td,urvalit.n that anth is thc c:r.r in Ihc inl:+cl :rnirn:tl, since nicr+/int allt•cts rtlhcr cltut'lurcc that ntay ccctrnttatily inllucncc ta+c ctat+naty hltw+tl flt+w. 'Ihut the ctlcclt +,f t),inc• hhrinc t.n Ihc t ircul:rlit+n rcccntl.le in m:roy rccfut'tt Ihtnc of nictdint•, and sintc nict.tinC .tituol;+tc. thc atlht•n:tl Incdulla, it it I+rt.hahlc Ih:d thc cf,inc Idrrinc rrlc:tcctl ctmuil,utcs trr Iht eh:rngrt t+h.crved 'I hcrc it a faitly extcncive lilttalutc tin Iht tffcct tit smttkinR on 1ht crat+nnry cirtul:rlit+n Much t+f Ihe wt+rk turn whii h Ihis is hatcd is nnl I,rtq,c•rly ctrnUtdlctl :unl ncctl ntH l.c dcccrih(•tl hcrt:. Ilnwtvcr, tctcnt ahnlicc in hr+llh m.rn and r+lhct m:rmm:dc Ic;rvc nt+ dt+uht that nictdine hnA (-Ir:Irfllr cnn+kc tcarlt in an int rc;t.c in ct+ttrn.+ry hht.+d llnw '1 he siFni/icancc ++f 11hik nt•t•da Inrtht'r cnnciJt•t:rtinn cincc Ihcrt• is ;rlstt an int'rcacc in hc:rrl r:rlt• :rnJ in thc ft,tcc trf t t+nttat tir.n duc, :tt Iratt in patt. In a dircct atclit+n r+f nir++tint ++n ittlr:K:rrdiac •frtrcltlret In vicw n( thc f:trl Ihat nictttinc inctcacts cattli:,c wt+tlk, 1hc Iprcclit+n :Irict•c ac In wht-Ihcr, undcr Ihc.c circnrnttancct, Ihc cirt:ul:rlitrn kcCpt pacc wilh tile ntcl,ltidic tcyttitcntcrHs td the htarl. In dt+Ps, intr:lvrtlnl/t Infntlt,nl td rticrrtinc aml tlirccl injcctinn intrt Ihc crtrrmiry :utcrics recullctl in e dc/inilc inctcasc in ct+trmary flow. In thctt c%i.crirnt•nts thcrc w:rt a t-nr- rc.l•rrntlin(• int rc:tcc in cattli:rc wtnk, hnl hccaucc in cnme inct:rncct Ihcrc wcrc ch;tnyt-t in thc A VlnxyFen tliftCrcncc :+ntl invrrcir.n trf thc •1' wavr. thcrt m:ry h:tvc kbrt•n tnmc inrcrfrrcnct willr Ihc ulili~:rtiun nf t,tvrcn a r++ittt +Ic~crvint• „f (rtrtlhcr alttcly. f urnlrlr. (. ri..n ..f /yl.ulinr 1hc tlcrc.tr,.n r.l I.I:nlit;+1 crnnrrn ic lltc c(1t•t1 tit cmnS,inl. r.n tort.n:+rv 16,.v in rnr.rn 11,r :u lu,nc rrf nir nUnc :rrc cr.ml,lrt nn.l int lrn)t ttinur Lrtir.n tit tlrl+r..•.r,.n nl v.+rir.nc 1..a1% r,t thc nt-tvr,ns cyslt•nt :+mt Ltvil.lhcr:rl tlrtn I,nt t cur h.r. th, mn.r Ir. :rn.l )•Lrn.lt I lt'nt C, rt it iru/,nrlnnl t,. .Ir Ir rrnmc whel 1r rly.r n•. In Ilhc t nt..n.nv t irt+rl.+lir,n nnrlt-t nnn+,.rl i r.mlrtrnn. r.f cnrnf<in)• I tl•rrirnrnl. h.rcc hccn c:rrrictl r•trl n/iliiinh Ihc Icrlurirlnc r,f T .r 2) ~

inccrting a calhcler Jnectly in/n the coron:lry cinus lhe dala nhleined ahnwed 1th.r1 amokinR resuhs in n aignificant increaae in the cr+rnnary hlrx.d f6rw and a siRnifit'ant declinc in Ihe crnrmary vascular reciclance. 'Ihete wac a fall in myocardial nsygrn e tlraclitrn, hnt since thia was prnror'innal Irr the rice in cortrnary hlrrrHl fkrw, it wnt concluded that the r+tygcn con- snmrlirrn wat not .ignificanfly changetl 'Tlhc rxfrriments jvst menlioned are in accord with the r.hcervalion that rlcctrocartliographic or hatlislocardioRraphic changes are not se!n in healthy individuals aa a retull rrf smnking. Ilowever, when the coronary arlcrict Rre discacrd, tmokinR commrrnly prnchrcec ch:,nges in the electro- cardiogram charnctericlic of anoxia, and Ihis has been employed at a lest of coronary funclinn lhere is aho the fact that in an cccaaicrnal patient with anRina peclnris an attack of pain may he precipitated hy cmoking or c.thrr activitirt I hrac nlncrvatinna cugResl th.l Ihe elleclt of .mrrking rrn the diarase hratt may md always he the aame in heilth and This is an irnh-ntanl frrr+hlcm for furlher invesligatian Sinrr tome ri.k miy Lr invrdvcol in cnr li:/c cathrleriyalirrn in the iarccncc (if crmonaty diaeacr, nther Icchniyues for Ihe mcacnremenl of hlocrcl flnw arc under sludy In Ihe rncanwhile a ctart hns been matle rm laboratory studies in which the rffcc/c (if nicntinc h.ve hern tected in rahhitt rnatle athero- cclerntic F.v hipJr cholralrrrrl tlirls 11 hat been rerv<atcd that in the mamal hcart, i+crfucirrn with nicr+tinc rranltrd in a brief drereacc in coroniry flow that gave way to a more rirr+ttinprd incrcice in the ratc (if flow fhe lattrr phaae, refireccnting a rlilatation r+f the cinr+nary arlrrirs, wis ahccnl in the atlhrrocc'krotic hearl In another dnrly of rahfhifc main/ainecl on 'a high chnlcctcrnl dirl, the oral nclministntion od nicoline rlid mot aRecl the Irrum cholrctrrvrl and phrrchhnlirii(l valuca (if the tlcr-.rrc of arrrtic alhcrtrcclrnrait, hul d 1 rranll in an incrciscd mrrrtalily and incrrased incidence (if fiilhnic.pic,l ch:rnPcc iii the hcirl and reriphrril vascnlatnre Similar exrvetimenlc in chickens, hut with IarFrr rhnes (if nicrrlinc. pnwluced nit significant carrlinvascular l.athtrh+pic changca ovcr Ihrrcc rrcnlling from the hiph chnlrctrr<rl dicl ;rhmc. '1 hc rrculls of hnthrr aluJira :rhmg thcac lincc arc nwaitrd with ai ct ial inleresl ('.nrfinr•n.rrrfnr ('..nl/rrnr• (irI ntrca nnJ r~11,-r a<irnti.I( di6 nr rru:rrrIr in Ihr t.rrrhn1•.r.rut:rr f rhl ntrt /r-r :r r-nrr, lditcu..i-n I nr I J 1'/1'/ In .~ I lili n In n rrirl' rra 1.1 Ihr ccirnllfsr nIl% i.my It,~:rr,) Ihr f~dL~winp wrrr fnr.rnt IIIt 1 Itr~t',t rr A t Iltlr,l It n, 'a-, ( nv /t. .1 Il".r... I •.1.. • . I 1)R KI/R I 1)i'. ('R1NIS, Grddwaler Mrmorial Ilnapilal, Welfare IJand, New Ynrk, N.Y. hR. f'RANK W. 1)AVIS, lR., lohnt liolrkint Univertily Schrxd of MeJicinr, H:Jlimore, Maryland. IMrml,rr, ('ommiltre on SmokinR io Relation to ('ardinvatcutar 1litraae, Amrric.n /lrarl Aauciatiun) 1)R 111OA1AS R I)AWIIF.R, National Ilearl Intlilule, flcthr.da. MarylanJ (Mrmher, ('ommit(ee on SmcdtinR in Relali.rn to ('ardiovaacular 1)iseatc, Amcrkan Ilear/ Aasnciation) DR. /A('K I RI.UNI), Medical ('..IIrRe of VirRinia, RichmonA. Virginia UR. 1Ah11 S GII I fTTfi, I at+Mrralory of C'hemical Pharmacology, Narional Ileart Inslilule, 1lelhcada, Maryland 1)R IIARVIiY 11. /IAA(D, Medical College of Virginia. Richmond, V irRinia 1)R. PAU1. S I.ARSON, Medicll ('o1kRe of VirRinia, Richmnnd, Virginia 1)R. ANI(1NIU fyE 11'ON, PhiladelPhia General Ihxpilal, Phila. drlPlria, Pcnntylvania OR KI•t I.Y I McKF.E., Merlical ('ol/eRe of Snulh ('arnlinn. ('har Irclr.n, Grolh ('arolina 1)R /11 RIII RI MtKI?NNIS, Medkal College of VirRinia. Rich mond, VirRinia DR. I:.I)WARI1 W. PFI IKAN. Rotlnn l/nivertily Schnnl of Mrdi cinr, Itnttnn. MaacacAn.etlt DR. WAL I FR RF.UISCII, New York University--Rcllevue Mrdical ('entrr, New York, N Y. 1)R. SFYMOUR It. RIN-7.I FR, ('ornell lJniveraily Medical ('ollrRr, New Yrnk, N.Y. I)R. l1 RKY f. S(.'IIMII-IIII?NNI:R, l.ankenau Medical HuildinR, Phila.lrlphia, Pcnntylvania hR. ('AROI INF H11>F11. IIIOMAS, lnhnc Flopkins Univrnily Schnrd of Medicine, llahimnre, Maryland hR. lAN1 1' IRAVI:I I., (brnell Univertity Medical ('nikRe, New Yrnk, N.Y. I)R. 1)IIANF . (i WFN71'.1 , llniveraily of Kan.as, I nwrrncr, Kanaas I)R. 1. F1)WIN WOOI). Medical ('ol/rRe of GrnrRia, AuRucla, (irmria I'l, I'.yr/to-phyaiol-roRirnl Slri(1ir+ 1)uring the course of the pasl year several new sludies were inaug,ir- rated in the fic6k of psychrdoRy or of ptychrr-pllysioh,Ry. Onc un,lcrl:tkinp is lo ctudy smokinR practicea nf yrrung coIlrFe dudrnls in rcl:ltinn Irr C:unily hislnry, type nf secnndary t'hr>,dinr, ac:rrlcmic inter eala, :It'n/tl'/lllf :Il hlfvrrnNlt, an1l tnrlal relal/11n{hil+t. Aeurthrr rrmrlr ic e+ldnring 11rr la•havinral rlfcelt rrf arnokinp unJrr atrcas conAiU -n. Irr drtrnuinr whclhrr aurll c/1ct'Ic nrt' trnryr,tr.tl.lr I, thw'r rrf rranilnilr7rnr. Aro/•a Iln,ly m.n1.Fh.. l.-l-y (n rrLrli"m t'r tirh:trtn u.r i: nrtw Ihr ar,hirrl nf .r al+t'cial invrcli/-aU"m 7y

rr, tn C> fJ A)tilnl alutlv rll cnnikinp h.lhitt annlnp f.lllcr pcrtnnt ic 1,rinp. nt:ltlc Ithtrnl/-lh Iht' Al-i ( t'nlcr tlf Ncw 1 nl•I;tn.l r rr. nri..-r•rrr)tlt•rrtt. rinQ nn thc cancct prt/hlcm irc onnmiri>'rd hcre. Scvcral alutlirt hc- Unr tcirnlict hat I~crn invcdip•,linr Ihc ctftrarr ftf varinua tracc mrtalc in ht+man hmpa and li\cts in «arch td ptlstihlc cluct to the rrcvilcncc of p:trticular diccicca in cerliin Incalilics. I urlhcr invcctiFmtnn hat hecn tnadc (tf how carcinnFcnic arn flycs arr incnr(+nralrtf into crrlain protein cnnaiiluentt of the liver. A scicnlicl hm ntidc a hacic tt+nly n( tl+e mechanicm nf hvf+c'rrlacia and retiatincc Ilr hac chtlwn how irrilminn will ftrcl prndnce protein dcrlrlinn f+1 a lictnt• ac rcflcclctl in citculatit.n nf ccllnlar rt<+tcint at pttlhu- lirlc in Ihe ccrtun, Ihrn increaced rratlanCr to fnrlhcr tlirnipr. Ac rccict:•ntr inrre tccc• t11e irtiti.tl hvl+crpl.talic rrtl+,+ntr faNc tdl cha+l+ly antl Il.e tc citt.tnl akin Itltcc ill hyl+rrf+l,tcia "kin rr\I+ttntft ill tflhatcn cnntltr rtlnctt a it rlr,rt In nlhcr nprntc /k hacic ctully wav mitlc frf Ilu ttnthnlnpy of human t+ral licalrt, rc rrci.dTy ic trl.llcrl Ift ,pinp (1h1 Chrlt X t.ly (+Ilt(-t t.f f,rttr+nt Mhn wrrr rvrfltll.llly (I6pn"tcrl 1% havinp Illnp c:lnt rr wrrr tlnrlirtl 1}tc tn.tin rtlrf•r,ct• waa tn imj•tt+ve Ihe intctf+r{t;llil•n t,f llrr t'.IrIu.1 , 1. rlllr t.Irlrrar,r rJ hrnl• r.rm f'r :1• rl rr.llcil hy ritliulnpy At I hy (,r-hli I r•1 It- .lu•1, .vl nn I1\tr+ wat tn:trlr r,( Ihr IYctltfl;ltirlnt trf tl1(' 1+rfl/+f1[ t\ll.~ll' Irr•1.•Iri +\\l /r' r r`Ilrr Ir'rl I I11• l/rr.Nrrl th'il pcrtunt whrltc rr t nl+.lrwn. tnhlrt tr,l Ilirrrl t„ nltl.rlnlinn 1,/ rluvc im1 fUtnet wetc nmtc IiLclv 11+ t+r hr:l\v tttt,•krl. llt.tn t•t'relmc nol vl c.lrrr.rrl AnilVlic.il atutlicc wcrr rn:1Jc ill crrnllt:trc Illc Lratra ill rfdynntlrar llyflrt+cnrlrfrnt in mainthcartt nnll aVtlrt}fcanl tmt+kc f+tt+tfncctl nntlrr v:uinua crtnttilinnt lhc e1TccIc of tmnke nn Ihr ciliary :tctivily ~rttl Inut'flut flnw in ianlatrtl hrr+nclti ill crvcral animal tl•ccict :tlct+ were t+l.ccrvcct Frlfnrr.frff. Prr+Rrnm lhe rnrtlical aturlrnf fclhtwthip prnptam, tttirin:tlctl in IQSS ttf+nn rrcrrrnmrndalinn nf thr Scirntific Arlvia+ty ISn:tn1 anrl tcncwccl cach ycat tincr, ctlnlinucd In chnw enctrurapinp rrcnltt in I')Sr/ 1 he lirnpram it tlrtiprtctl It, tlimniatr intrrc\I in t.:ttii rcacmt FI amr. nr nlrrlu:tl tchr+nl tlutlrrtlc whtt, willh Ihcir aJvi.frrc, flrcirlr nn tht tul.icr tt Ir.r ahldy Rctillirnth /,f /hr /rllrrwthil+t ;arr crlrtlctt I+y thr tlr:tnt ill Ihr mrrlira) alh.u.lt Irq wrrff< ill lllr trln+lnt~r r.t r.tllt'r n/1 1+tnt lirlrr in tllr f.lhul.rl"vrrt t,l t.l•r rirn. r,l r .. rrlr•.It Crli,6 nr• w1r.. I/nvr t~.util il, rtr ~I m tl.r lury.r.rnl 11.1vr ,.r~r. n 1•,1• ~ ~.. 11„ n r.r Irt It .1,~1 ,..nrr ,d I11, r 1,.1\r 1•ct'n t.rrl,ll.llrrl rn r . /1bst t•acts of Rcpc>r1 s Fach recipient ill a•T<thacco Intluctry Research ('nnmtiltce Rrant ic tccPnncihle htt thc inilial prcscntation or pnhlicalirrn nf thc retuttt r11 his tetcarch in cv:icntilic meehnRs or in afpmpriate scicntific jt+urnalc. FolhtwinR are ahctrat•tt, appnwal by Ihc aulh,rrs, of rrtcara'h.rcl+t+rlt wilh acknnwtctll•emcnt af cnpptttt (rcnn the 'f ( R C. that have arpe:uctl in ccicnlific jttnrnalt tince the f,isl Rcporl and IhruuRh July 1959. Ahttracls t)f earlier rif+crt by Frantect which appearcd in previrnrt reLnrls of the Scientific hircclta arc lictcd af Ihc entl (if Ihis tection. -Ihc namc uf Ihc ccicnlict Irr whutn the I I R.C'. grant wRs tnaJe is Rivcn in p;ttrnthetis where tcynited. lhctr rthshnclt have hccn grou(,cd under five henllinpt /('ancer Retcarch: 11, Ilnroan I.unr, StuJiet: 111. Ilc:vl antl (:ircul:tlitar; IV. "Itl hac'cn (•Itt•utiatry: and V (thet Sludict. 1. l'nn.-Pr It errnrclr "T"ISSUF SI'I'('If K'ITY 01: SF.R(IM ('OMPONF ' NlS." fly S 1) Yrrl, M I) , W I: Scll•, It S, C. IltrRt,l. A tt ,:,nA F. W. IIAPNra Ilk , M 1)., wilh the aid of R. Rtlttrtutrr>tn, M f)., 1)cismlrncnls ill Mctticinc antl Phytiu- 1ttRical ('hcmictry, 'I hc Inhnt Ilnpkinc ( Inivcrsily SchtN+l .tt Medicine. II:Jtirnore, Md .•/ A(. .1. Arfhll'r,t n/ Jnlrnnd Afrdfrirv, Volume I(11, par.cs 411.V4R, /unc IVtV• (T 1 R.('. gr.mlee: I4atncc) !'urf+o.r n j.rrnf.: Scrum prrtlcins incorporate amintt aciAs very raf+idly, anJ it tcernt jnatiti:thle 141 cnncluJe Ihmt Ihie prrKCas likec place within cells. linder a Ityf+rllhecit derived frnnt a Iheory uf cell retlwmce Itl tlanctRe evttlvcd in thic lahoratttry, thc teramt Rlohulirts havc a ccllul:tr t+tipin Itt+nl a l:rr fe variety r.r LWrhart all of Ihe litcucs of the h.K1y; they cai:t(+e :unl circul:NC in Ihe 1wtJy Iluidc, and Ihen reenter Ihcir recrcclive cclh ttf nricin In rrtume Ihe (olc in prtacin nrelalHtlictn in which they were involved before leaving lhe cell. 1:><fx•riulenls were devited Io Iesl Ihe thenty that the ct++n- Tv.nents nf notmal hnm:ro cerum I+tnecss tisene afxxcificity. 1•r.rrrdnr..! 'I iatncc frttm hmnan nrF:mt (kidncy, muaclr, tkin, thyroid) were obtained frcchly in the r.peratinR rrKtm whcn prtstihle; and hunt:tn heatt, hrain, liver. cpleen. lyml+h nr.de, at+rla tmd cr+nnective licate were nl.tained Lt+t1 rm+rtcn. Fta injcctir+n intn rahhitt, thc matcrial w:ts utrd firsl ac a cutf,rncirtn in c:ttine anJ I:rlrr in the It+rm of a eenlrilulteJ aul+cr- nalan/ nf Ihr cutfrcnairtn Imrnnniralir+n of Ifhe r,thhils (trnccrtfcrl until an adrqnate level rlf :rntihttdica wat ehuwn ('tnac rraclivily wae temrtveA It,r aetlain tanpea nf tlihttL+n t+f anlircn arnl anli.ctttrn 1 he I+rrt'if+illn Icat w.te nscr) ttt rttintatr 11Lr Lr+.crhlr lintila t.f nnknf/wn arrum fq ft/ ;tnti/v-n fhlu /ifnt ami nlaft (ft .I/rlnf•cinl.tlc Ihr ttrtlrr rrl rnnpnilutlc t+f Ihc antiprn .In1lhnJy I+ret ipiLtlr Al+lrr/rlai.tlr t nnrrt4 Iealt :thn wcrr ettnlfnt IrA (lr..finlr•r Itlt• Irtulta tll..w Ih.d Iltc auti\cta Itrclt.+rct1 rrt,m :tnr+lhr•r tltc circ, willt rt•I:rtivr tf.ct tlit lly frn tvanf+t+ncntc ill a ainp/c Mnn:m tlrp.ln, will Ir:tclinnalc ft:lrrt tl1 Ihc .rrunl ftrtrtcinc nl inllivirlual Ilrrtnnt hy ftrt/~lnt t/r.n {I

nf rret-ihilinc lhc tctrtlt[ art rcl+rr,tlucil.Ic: alart c.rch ftt•tcc.n at t•arir,nc lirncc fhat i tlillc'rcnl I+itlcrn nf t+rccil+ilin fr:rt'lirtnc, Int•:tcurt•rl I,y lruri( n1 scrnm thlu(7nn 'Ihrcr fnttt imlicntt Ht,rl acrunt ptntcinc atc cttt:tinly nnt hrrmnRcncuuc f+ul can t+e tlivitlcd inlrr many indcpcnJcnt fl:tc/ir+nt I+y anti- lictnc tcra, antl he11, In cnnfinn ffte cnnccf+t divclr,f+crl ftr+n+ wr,rk /+n litanc d:ttnne thul (,rnlcrnc rlctivctl fn+tn ntctny ticcucc tircnlalc at [crunt prr, trint lhe rccnllt ilctr fur+virle furlhcr cvirlcnce 111a1 titcnc tpccificity tlr.ct titt in Ihc tuarurnal U/hrr I:rnnfrrrr: Ametifen Cancer ScKiely (Natitmal antl Nlaryland I)ivicirtn), Americ:rn Ileart A[st+eiatinn, N:t(inn:,! Imlilulcc nf Ileilth, Oamnn Runyt+n Memr+rial l-uncl• Millnn M. Frank I-nundalinn, an<1 1he Nnt)ema ('nrrt,nlir.n "-IIIM(/R-11OSf RI{I.A'CIONS htIRIN(i f)F.VII(/fMFNf ANO A1-- 1FR ftT (7RFSSIUN tW 11(I? TttMt)R " 11y 1 rnctrltt R C'Fnrt+t>,+. 1'.ttWARtI 1t/1ftNlr K nnll f'I,wAtttt 1 S< Illrn/ Ki, f)cl+,lrl/nent of IfirKhrnt itlry, I'ntdh:tnr I/nivercity, New Yr,rk ('ity (1)r ltrecnitk it now 11 (he Wclltnmc Rcac:rtth I ahrnatnticc. Iu/k:thnc. N Y 1.4rrlucrt of llin,lrern irrn, nn.! hinlrht.ir r, Vrrlumc R1, fi,pct 4•1 S\, )uty 1'1S~>, ('1 I R(' Rtan tre ('etccttl,+) 1'urprr.r n( .Nnlr: f'revirwe ctutticc in /hic I:thrrratr+ry hive chnwn that ciRmficanl than~ct txcur in Iltt wcil•19 antt alan in (ttc nnclcic aciJ ct+ntcrn Iralinnc (if [I,ccdic tictncc tlurinF Ihc 1.•rr,wth of Iunrrut in ihe ral, anrl tha( fltt(+resence n( aul•l'1r1:1ntn1/t h1lnl+tt c11tt('c MCeta[et in (f1e llcncytll+/tnttctetc nci/l ( 1)NA I et,ncenlrahr,n nf Ihr Iivrr :tnrl Itmp, where:tt rtrncenualir,n 1+1 rihnnucieie acirl 1 ftNA 1 nray r+r tnay nr,t chanFe, tfcltcntlinr nn I/te t t(+t uf Itumar. ln view uf tht n:tture ind ncwrihulirrn of (.r+/attium antl ite inl- pnrtance in cellulir nrrl•rhulient, it. 1rvclt wcre ft+untl tt+ 1+e rcl:+tetl In nllter rhennmena characlcriatic t+l ner+ldatlic rrr,wth It wac decitle'l Irt t.:uninr Ihece facttrrt in ct+nnrcturn wilh Ihe prrrwllr :uu1 rcl•rcacinn of v.1lion[ n'n rlacia in rntt nnd mice I'rnrrdnrr.: '1ht Murf+hy Sturm Iymphrnarcnrn.j wic Irancptan(ctf in Ihe f+ecloral rcFir+n of m tle 11r+tVman tate hy tntant of a trtrc-m antl tttc )cntcn sarennri in flluc Slrntce f arm[ tatt Suy.cncit,nc c,f ('14r)R rnvcl,tiJ lenkcrnia ct•II[ were inrrcolaled in the ri)'tlt fcrhaal rcRir,n nt malc ('57111 / ft1(11)2 mice f.iver[. hrnR[, kidneyc and [Idcenc were u.lirpated after the anintalt were cacrificrrl, antl tf+t'cilnent of hrrne m:trrnw and h1tMNl a1.n were Iakcn ('hemical antl rhycinh+yical th:+nt-cc duting dcvelr,l,ntcnt and afler rePrettit+n t+/ thc Intntnt werc [Ihulicd 1'-inrf7nK.: (itrrwtlh of 11rc 1vrnplnrc;ncr,ma in Ihe tat wat accntnrmnitd 1+y an incrt•act in 1)NA ctrnlcnt of livcr, lanp antl cl,lrcn anJ a dccrrict t+l I)NA in htmc ntnrrnw; rd lhe litcucc mcnlirmed. t1,lecn alnnt• th/.wcrl a clrar.`c (incrra[t•1 in c,axcnir:ttirrn r+l 1(N1; Ihc I+,+la[tinm cr+ncrn(ralir+n uf livcr ntlarr rr+cc (',+ncrrn(ralitm nt I)NA in Ifrc lunf rrru dnrinp Iht• rlrvrl O, rn f. r. nf,rnrnl t,t thr Icn.rn a:vtt,nrl, whilc I(Nn tctnainctl nnth:tnrl•d; fhrnnt Plnhin, ef,etilic prac•ity, anrl Irdil tnlirk rd Ilrr blraHl were rlcl,treactf tn:ukcrlly. aml a1l:mtrtl rnininrum Icvt'{c wlrrtt lumr+t circ tccr(hrd 2(Ir: ++t Ihc l.rK1y writ•hl If,r Icrrktmi;r h.rrl n„ cllrtl r,n 1hr 1)NA n/ livrr n, Iulnr, rn Il,r n,.,.,•. 1-, u..1n,i,1 t rnr ur tmr/• tTNn .,n.l a.Irlrrnv m „1 Ilir .r tr•..nr r t When thr•tluce afnre-ntcnli.nncd u+mnrt tegreaced, cach of the chanRes lcctril+cd w:t[ rcvcr[ctl and n/.rrna) pal(crns were re cslalrlishcJ ONArr Rrnnlrrr: Nalirmal ('anccr Inslitnle. "A('(ION OF ('1(iARlil'17: TAR ANI) SMOKfi ON ('111:.M1('ALI.Y INI)Il(•f~l) ('Alt('INO(;1?Nf~SIS." fly I(t1WAR1t 1~ IIt/1tMAN and A. ("I AwK (ir+rt / tN, 1)c~:vlmcnl of C'hemislry, Stanfcrrll l/nivcrcily, ('ali(nrnia. Prr[rnl alJdrec.rc: tiunt t.ahcxalory, f:. 1. du Pnnt de Nemunrt & ('o , Ncw;trk, 1lctaware, anJ I)cparlment of Ilinclrcmictry, (lnivercity (d Te><at MO. Antlcrctm 1(narilal and '1-umar Inditule Tetat Rrprrrrt .rn IlirdrrRv and Afrdit rrrr, Vul 16, pages 333-145. Fall 195R. (T I R.C. Rtanlce' Ciriffin) Pnrlrnrr nJ ,hrdy: Ac certain weak earcinttaent or nnn-carcinnpent have acted hath at tyncrgittic and as anlaRnnittie arcnlt in animal e.(.cti- mcn(c, it wac cnncidcrccl tkcirahle In dclern+ine whelher ciparclte crn/,ke or ctmdcn[alc wr.uld enhance (or inhihil tbe ernrrse of a wcll cttahlicfx•rl c:nt'inr,genic tcrlurncc, namely Iha/ rc[ttl(inR fram feedinF Itt rale a Aier tt+ntaininh liver c.rrcinrrgt•ns. • l'r.r.rrhrrr: In thc /ira/ e+lxtinttnlt Iwn Frt+upa n/ SpraKnc 1).twlrr lualt ratt wcrc ft•d rliclt cnnlaining I/AF (2 atclylamintrflnnrcru ) (t+t Itt•nlxlc of (wtt and Ihtce m/.nlht. Onc Rn+up wat c>tlarted ttr the srunkt• /d claml.ird fillerlets cipatrrte[ cannked in a rnachine at the tnte uf 20 eiRatettec an htrur, R hnnrc daity, fnr 12 tn 14 wccks. In tuthcequtnt Icslt (he ratt rrccived amnlee al tF/e rate of S ciR:rrcltct nn htrur. R hnun daily• 1 he uther Rnrur n( ra(e wac injectetf nn allernnte t1ayt with (11 nrl of n ennclencale rre- rarrcl by hurninr ciparclTC Inhat•co in arlaa (unncl: Ihe cnntlcnca(c waa sutftcndcd in Itt•hnut oil at a cnnccnlr:rlinn ut S11 mR./ntl. ('nntrlds rtcciveJ Lear,ul nil nnly. 1n 1he secnntl exf+t•rimenls eiaaretle smnke eondensale, commercially preparetl in a smokinR mrchine cltxely duplicaling httman smnkinR, was in- jcctctl in matc :rlhinrr ralt nn dicts cnntaininR tither I)AF or 1'.Mc11AF1 ( 1'-tnclhyl-4-dimtthyliminnltentenel. Other tals on Ihe samc rliclt werc rain(t•tl Iwice weekly wilh the tamc cnrtt/cnsale on shavecl arcat on Ihe hat'k of Ihe ncck. FinrlinK..: lnhalalinn (if ciRarelle [rnoke antl injeclilrn of thc lahura/r,ry ciF;nellt cnnricn[-.1te tfclay the al.f+t•arance of the prccanccrrnr[ [Ia1e in raft fetl 1)AF, nt ctrn in frrrcc tlam:tpe to the liver and in delay n/ tihn/lyvin h+werinR nf prcc:rnccr•+uc liver Nn protective actinn tu( laf.crralnry ctmr(cn t:tlc w:rt tdncrvctl in r:t1t fcd 1'-McUAFI, however. Atlutiniuralitrn ld thc cr,mrnercially prrl.:tred cil!arelle [mnke enndene;tle trt ralt Inl eilhtr car cinnp,cn dirl nul alfrc/ thc ralc of cnnccr indnclinn of Ilre (inal Inm/+r irtci drnce 11 nrutl t+c r(.ctq•nirrti Ihat Jiflcrcnl clmtkt lar frat'lirrnt v:rry cnn tirlr•taldy in c•rnyurtutir.n rlcl+endinR 11114111 n Ihe cnndilittnt of cl+tn(at[linn and n(fher (.rr/.qt, "t(YAI l/ftt)NA I I IN-1('( IVI' S1'RUAI)IN(i ('Al'1(tR OF f•IIIRINI: t:N1)11M1•((tl/11 CI('1(f•111)NN 11111Itt)N11" fly F. IlrrKrnl,lRr:rP . M S(.R/K[KIAH, ;IrIrI P (' IIARrt t, Ilin Rtatatch (mlilulc, Inc ,('arn hrirlrr, M.rat, an,1 1>r+[tt.e II )alktnn Mt•mrni:rl I thrrr:rlruy, F1nr Il.rrhnr, (tfr f'r..r rrrlrrerr .•( Ihr S,r, rr fr f.•r ( t1•rrirrtr•n6d nt.,f..pt• rnt,f Mi dn tnr Vnl t)'), r.r/•r. t.+,S r,hR. 1)rtrmhr r 1'/tK ( 1 1 R(' rr:trtlcc' 1h,ml,tirl.cr 1 11

Prnfrn..• nf -trr.lr: Ihe erpcrinrrnrt wcre tlctil•nrd hr rnracnrc the clTrcf rd ulert+nc in tl.rciding Intlin ink in file rlcrmic uf Icct animilt antl to cluci- d.ttc itt n+rthini.m lhic rt•cc:uth it intt•ndct/ lt+cl:ttify r+hccrvafitmc rnatlr during tfuJn•c td hi+Jr+gic activifirt rd t'n+h+ntctrial cccrctit+nc (ntrr++nr) t+htiint-tl f+y ccrvit'aI lipatinn in mit'c, which rcvrilcd thal crntle uft•rtme t•nhancec inlrndt•rm J clrre:rd nf lndia ink. I'...r.•.fhrrr: Inrh:r ink w;rc injt•ctrJ inlt:nlcrrnally in Rn+upc t+f rnature malt and frmalc RI M antl IIAI It 'c micc Sit grt+uf+c cnmfxitinR ?7 1(I M malrt rccciveJ India ink nrarker cnntaininR 611, I?lt, SIIU aml IINI(1 of hyilurtmitlace, (1Vytl:rcc), and fhe cprcat) w:rt cr+rnhatctl wirh thal rccult. inP fnrnr cerum t+r RinRer't solutinn. Five RUM milrc rcceivcd India ink ,nd frcch ulcrnnc trt+nt micc rtf the aame tl.t•cicc, :+ntl rhe ytrc:td w;tc c++mparcd wifh thtt in mice receiving Intlia ink anrl tcrum. FfTcctc t+f utcr- r+ne frnm IIAI ItIc rnite wcre rneaanctl in 19 m:rlr intl IS fcmalt rnice t+f that tpecirs given India ink n+arkcr aml utt•rt+ne in five difTerrnt cr+nccntra- litmc, antl the cprt•ad was conrpared with India ink and scrurn injrctiont FiRht IIA1 11/c rnalct were given India ink antl hyalurtmidate diccr+lvrd in utcn+nc frtnn mice r+f file tame cla-cicc I urlhcr It•crt were rn:ttlc in dc:+tl fiAI Il/c mice ckin (•t+ntnrl e>rcrimcnlt wcrc c++n.lutlcll in t:thhilc. file standard accry aninral I++r the cprc:,Jinf I,tfnr. F inrlinR.: I lie rrcullt indicutc th ct+mrnt•rcial 1Vyrlocc en!h:mrcc Ihe sf+rcat!ing td Intlii ink in thr dcrmit ~+1 f mice rnnch at it th.cs irt file rnhhit. Intratlcrn+al injct li.+n t+f rnnrint• ufcrrmt• frtnn IIAI 11; c rntl Rl fv/ mict• enhancet tKrcntlinR nf India ink in live mice of thete trecirt IIAI rl ic utcrnne rv+Irntialcc file ryat•atlinr t•fictl r+f Wytlicc in livc 11A1.11Jc mice. hnt is wilhtmf cflt•ct uf+++n injctlit.n inltr dr;trl IIA1 Il/c ckin ItAI It/c uler- nnc dt+cs nnl drltt'Ivrncrirc I+valurt+nic :+ri+l irr r•in.r '11rc pt+trn/iilitm nf Wydatc hy ntcrt+nc t++n4d hc cr!+Ltinctl hy incrc:tcc r+f inrr;t tlcnnal laccanrc ciucctl hy infl.in+nr:tfi++n nnrl t'ncuinF wiJcr tlrltuci+.n nf thc en7vmr. ht•nce a grealcr tfircatt 1 he nalure t,f file cnrnrt+ncnt r+f utrrt+nc rec!tnncihlr h+r prnvt+kinr. inl!:unnr:+li..n rcnlaint tu I+c +Ictt•rrninr+l :rnJ rn:ty wt•II hc a nrucr+~rnfcin. • RAlOA('AN111I1NtA I'Xf'I:R1l1f N1A11 Y INT)ll(•U1) WIIII A11:11IYt ('lll /! AN I11/11 NI: IN 1111 ('Itl(-Kf N" Ity R 11 Rv;retrN, M f), 1'rn(racr+r t+f 1':+rhnlVRv. I/nivcrcily t+f Icu:tc Mctli( al (lranrlt• C:tl. vcctnn ••1 MA .4rr lnrrt rrf f)nrndh+l. et, Vrtl 7'), Irar.ct 11').147, ( c!. rnary 1959 'lhit r:+!rcr ditcncuc the cimiLrrily nf a alnarut+nc cr1l tuntnr frt++luted in file tkin r+f (hitkrnc aflt•r h+c:tl afq+licilinn r+f rncthyhhnl:tnlhrcnc ttt thr kcr:ut+actnfhrmri in rtnn "1111: ItI Sl'IIfA IUftl• til•S11 M IN I111: N(112MAI. WIIIl'1: 1TKIN I111(.!( •' Ily It I1 lttr.ru+v, 1)rl+:nunrnf nf I'ctfhr+hq•.y, llnivt•raity r+f Ictac Rlydic:rl Ilrint h, G•tlvrclnn I'nrdrr r C. irvn r Vrd 1>t • I+al•ct I'1!+ 710. J tn uary I')tq. "•n1f'('IIANICM (1! 1tfM(rVAI O1• I t tffl) ANI) rAlt l lClft A I1 h/Al1 1(fAI 1 ROf\1 1111: ftI Sl'IftAltlltl• IItAr 1OI 1111 I)I/CK " Ilv It 11 Itu.rw+rj I At /.4r, /rnrt .f I'.rlln•L rv, V.•1 67. c I r1+ru:uv f'rn f..... ..~ .In.ll.. ,\n.+ln+++it .rl I+n.ln+l•. n+.lrtt +n Ihr •.Imly ++I inl+++r+l I 4 I ' carcint+grnecic in Ihe recpiralnry Iract af file white 1`ckin thrck m.ide if nececciry In cclal+Iich Ihc "nnrmal" for this hird While 1lhc analunric ttruc tarr l,f the req+u,lt+ry cycft•rn ic similar in many wayt Itr thal f+f rnammalc. Ihere arc cerlain rnntl:nncntal different:es Iha/ tupgctl afotrssihlc v:rrialir+n in funclit+n l.inlc :tflcntinn hat been given to file mcchanitm trf file rerncrvcd nf Onid anA p:trlicnlare nr:Nlcr frrrm the retpiratttry tract nf hirdt. Pr.rrr.lur.•c: In llre first tludy I:Hen was injected ttt protluce rnnltlingc (tf file rt•crir:rtnry tr:xrc td duckt. Tt, study hhaKl capillaries in the InnR, an atlult hirrl wak cacrificed and salinc injected immediately into Ihc pul mr+nary artery; wht•n Ihe saline returned fYnrn Ihe pulmttnaty vcint free t+f rcd cellt, India ink was injected into the pulmonary artery; after the ink h:rd ctnnrolcted a tr:rntit, secfinnc uf Iung were preparetl fnr histologic ttutly. In the tecttml ttntly itntnnit saline, flnnretcein stxlium, saccharatcJ iron t,xidc, India ink, liquid petrnlatum, .nd l.iptvdium spnres were given intralracheally tn sep:tr:rte grnup~ nf duckt, which were sacrificed after varying intcrvalc of eafyt'turet. lhe thoracic and abdominal vitcera and fhe air sacs were nhcerved under ulu,violct light for flunretcence in the IunRc, air tacs, liver, gallhlatlder and intetlines lhe Irachert and hrngs tuhce- ynently were renn+vcd intacl, and scctitms were taken Grr hislningic stndy FindinRs: lht•re are nn lymph notlcs in the duck, unlike rnantrnals 1here are lymrh channelt in Ihe lung which drain inln the larger lymphaf- ict, which in turn cnnunnnicalc with Ihe thnr:rcic tluct and then ernply intrt the vena cava When particulate matter is put into the Irachea, it rnually can he dcmimcharcd in the dilatcd parahrtrnchi at Ihe(+criphery tuf Ihe lung and in thc larger air tact. l he cilia on the ervilhelial cellt in the respiratttry tract degencrafe rapidly following deoth, sn care mutt he e><crcisrtl in e.prescing an t+rsinittn trn Ihc ciKnificant:c td Ihc ahtence of cilia frtrm the will of the Iraclhca. In file ccctmtl ctutly, taccharafed iron n.itk and flunrrtccin ttkliurn p:rccctl direclly thrrrurh fhe ervilhclial layer nf the recpirnttrry 1rac1 inlrr the ctruma and Ilutruph file wall t,f Ihe hltwwl ve%sclt aml/t+r lymphalics P:utirh•t nf India ink, Flt+hulct nf l+t•Iralatunt, antl I ilawliunr cf.oret nroi gr:rtt'd 1hn+uFh Iltc I:tyer of epithelinnt and cither cnlercd the hhw+d vetat•Ic antlinr lymhh:rticc ,hrectly t+r were pFhagtrcyti,etl within Ilre ttrnrna hy fihrn. hlaclt anJ hictrK yfrt. 'I he Irancfer nf Iluillt nml patricnlatc m,tler frnnt Ihe rccpiratt+ry Ir:u't Ir+ the v;ttcular syVem nccurreJ rrin,:trily in Ihe air cact "('AN(T.It O1: 11I1; I lIN(i - 1111[ SFX RAfIO A RFVII*W OF '1/1t: . 1'RO111.1AI " Ity I lrt rN Klar tntt r ind R 11 Rrr:rx)n., I)t•partmrnr nf P,Ihr+h+py, llnivt•rc+ly nf Ie.:tc Mcdic:d Iiranch, (ialvcttt.n 7rtnr ltrpn.tt rrn /1..rL.et urrJ Afrrlirmr, Vnl. 17, raFct 2'1 4R, Slain(! 1959 (•1-1 R(- pranlce: Itirth+n) '1 Irc nv:tiLtldr lilcr:thrrc r+n Ihc cex rnlin ttf cancer nf the lunr, ht•Iwcrn IR71 and 10S) t,ac hct•n rt•vicwcd 'Ilrc rnalc tn ft•rnalc rntitr in 1(IR atuttict 117.6119 t;rct•c t+f Iunr. c:urcrr 1 v:tricd frnnt (1 7. 1 Itr 21/ 1!. 1, with Iht• nvrr +( r r,+li.+ Ihvt• rnalr t.rct'c It+ t+tnc feur:dr t:rte I rnm fht• l+v:ul;rhlr tl.+ra it n1+IK•:u. Ih:t1 file int rrntr in lmrl.. c':un rr hat hrrn rrralr r in rhr m:+lr Ihan irt file frm:Jt• IIr+Wcvrr, flle IfUt•tlJt+n mav Ihr ;t%k r+l hr+tv n++r. 1t +•/ Iltit thtfrtrnt r It rt•nl antl huw rrrnt h ic nnly a(+ I+.trcnl'r Ihi, rt•vrrw .ht+wc file clalt• nf t:nnfncir+n rclcr:tl.lt• A+ file inci+lcntt• t ( 15 14

rd Inng can(cr in fbe milc an<I ft•rn;t(c. I)ita are avail:thlc tn chnw th:lt the malc frnlile "mnrlality rRtcs'- fnr tunr rancer w•cre i1 alwnrt the camc Irvcl in Ir)14; f,y Ivl() Ihey werc 1 7:1 anJ in IVNI hacl increiccd t<+ 4(, 1(('utlrr, 1. Am Stat. Acsn t(1:7(+7-2R2, In reviewing all the tlali, it <Inec nnr af(,e.r cnrrect fr+ accer/ Ihis r;,rin of 1 7: 1 a4 a ctirling pr,int It w(wld arrrar fr<,m this tevicw Ihat the malc-ftmale ratin of lung canccr w,c arprn.inrelrly t or 4 /n nne in 1`)<x) inrl 5 nr 6 tn nne in 1955. "1Yf•f:S Uf KI Rn1tN17A11ON IN llfl' I((/MAN CfN(71VA." fly ). P WitN+,IANN, M I) , and ) Mr n R, Ph 1) , 1)ivicinn nf (h:rl ParhnlnRy, l/nivrrcity of Iliinnis, ('u/1eRe of Dentistry, ( hicay,o Inurnnf of lnvrsfiRa- ti.•r t)rrrr4lft,LrRv, Vnl 32, p,ges R7-94, f"chru:rry 1959. (T I R('. Rran- tcc: 1)r.lsaac S(hour) )'rrr/+nr• o/ rtudy r in sludying thc cpithclial cntfacc in the human RrnRrva, four tyl,cs of staininR rcaclinn werc fnund. 711rce cnrrespnnd fo tbc prrvinucly rccnRnhed dicfinctit,nc of hrll kcratinitalion, par:+krtatnaic, and nqn-kcratiniratinn, which atc ct,nsidcrtd as nnrmal varianls nf rhe RinPiva. 1hc fnurlh hsc nnl been dcscrilrcd hithrrto, and thc tcrm "incom- flcre pinktr:,lncis" ic cnFRcaled h,r it In tadt•r In clarify thc cr,ndiliunc in which thesc tyl.ca of ktr.nini?atinn t*ccur, i1 ii necec.ary lo suhdividc the gingiva inln analnrnically diarinct tcFinns 1'rn-,furrr 11ir,(.cy af,ecimcnefrr,m (hc cusrid reRion t,f gingiva or 32 rnen 27-711 ycan of age were sturlird microscnpirally. ('rlycorcn cnncenlra- (inn, tsrimatcd ae the dirlcrcnce in PAS fx.citivc mntcrial without and with diaHaac trcatmcnl, an<I the t/rprce of inff:rmmsliun in Ihe undcrlyinR cun- neclive tiseue, wt•re clacciticrl ae O, alifltl, antl r<,ncenlrated nr scvere. 'llte ennlycic includcd crcu and nr:11 cnrfaec nt the frce I-ingiva and Ihe alr:rcheJ PinRiva -__ the P<,rlinn in ri:rrl atl:tchcrl fn thc t,n,lh antl in f,arl tt. Ihe hnccal c,r linl;ual cur(acec <t( thc alvct+tar hr,ne FbnfinRrr lhe type nf keritinirntinn wac aaterf:,ined in a trrtal nf 214 rcginnc nf the RinRiva 1he relatinne hclwecn <lcgrce t+f kerstinit:,tir,n and Ilre ~,resrnce nf Flyct+Ren and inRamrrrslir,n diflt•r <lunnlitativclv, but nnl yuatrtativcly, in the crecl, nral, rond atlached areas 'Ihe dictincti<,n r,f "in- cnmf+Icte parakcrala.ic" -- madc p<+caihle by very careful ct:lininP It•t'h- niquee -- Lcrmiltcrl ecrirafe dudy nf aht,ut a Ihirrl nf nce par:<krratulic JrrRinns f'arakcralncic clill rcmaincd the sinFtc mncl ftnyncnt type nf kerntinitatinn. riccnrrinF in a litttc nvcr h-l1f nf the camrlr. Othrr Rrnnr.rr: Natit,n.il Incritutcc n( Ilcalllt 11. llrrnrnn l,rrrtr ,Srrtrlir•. "I tING VOI.I+MI' IN SMOKI'ItS ANh NON SMOKf 1tS " Ily IIr NRy IIt A( KnIrRN, M I) ,)rKll: ItRt171 R, I'h 1) , nn,l Itt NRV 1. l'AVt r+n, Ih I) I alw.tal<,ty t,f I'hvair,lnpit•at 1lvpicnc, llnivrraity nf Minnca„I:r, Minnc arnlit ,4nnrr/t r./ Inttrrnnl Afrdirrnr• Vr,lumc 5I, papca GR 11• luly I')tr) ( 1 I R(' f•r.,n(rr (Ir<,tc4 I I'nrpn.. ../ .tn.f.: lrrhattr, ann,linf- h,rc Irrnp t,rrn .rrtl,rrlyd :,a nn rlirdr,r.ir (:r<n,r in rral,ir:,lnry awnl,tr,ma nn<( l.rraxl,r,l,,,lnn.n:rry <litraar• l..rl•cly r.n Ihr haaia r,( t linir:r1 iml,rrai.,n It w.n r ra,vrlrrrrl 111m mr:rcurrnrrnt nf .,n.,l.rnrit (unp r r.rnt,.nlmrrn/t in rddr-r im/rvr,ln.,l. mirlrl fht 1 91 r exfxcled lo prnvide cr•mc infnrmati<,n concerning ulrimale lifclimt effects of smnking on brnnchnpulmonary function. I'rnrrfirrr: 1):rta were cnllecled for 221 business nnd firufessit,nal men of Ihe -I win C ilicc aged 47 lo 57 who participated in a lQ-year longitudinal study nf cardlnvascul.•rr aging. All were actively empl<tyed and were fsee of manifesl heart diccase, hyperlcnsinn, and grnss parenchymal lung in- vnlvement. All fi(Ied uut a questionnaite on smoking ha(.its ctvntparahle In Ihat of Ilamn+nnd --llorn of the Americin Cancer Society. Vital ca- pacity rf each cuhjecl was determined at reat, antl residual air vulume was delerrnincd a(ter forced expiration with the suhject submergcd in water in a s1inR sen1; 1wo tror more preliminary tesls were miJe to "train" the suhjer•1 so that minimsl vahtcs of recidual lung volume might he obtained Aftcr Ihe final immersinn, the subject was raised and breathed 0, for seven min- utes. Residual volume and nitrugen cacretion were Ihen measured APe and body si?e were elirninated as variahles in the lung rnfnme comparisons F7ndinR.: Vital cnpacily was smaller in each caterry of srnnkers. The diRercnce from non amnkcrs rt:xhcd a statidically significant level fnt all smnking categr,rics cnmhined. ResiduallunR volume was larger in alt cate Rnricc of amnkcrc, htd not conciUtntly at slatistically ciRnificanl lcvels 1'nlallung raltacity was not siRnificantly diflerent hetwecn Rrtmrs -Ilsc tatit, of residual volunu to total lung capacity was significantly plealer in smokera. ln a group which had saceesafully stnpred all cmr,kinR. Ihe lung cnmpartment values were similar to those of a group who had never smnkcd, and the r:+tin of residnal volume to tntal long esr:+cily was siFni- ficanlly smaller than in the current cmnker.. Stringent scrrcninR of lhc samplc for alhn<srrnal reapiratt.ry m:tnilestalittns, such ae hiatories of clinical asthma, puhunnary Iutxrrnhrais, chrunie prtNtuetivr cough, anti ehesl de• farmily, etcIudcd 11 suh)'ectc (22 smnkers and 11 "Never" n( "Stnpf,ed" smnkers): this left a rrcitlnal r+f (RR men in whom the same onler af di(fer. encec in IunR vnlume prevailed between cmukers nnd nnn-smukere as in the lotal samplc. The diflerences recorded were in the direetinn to he expected it amt.k inR is a facNCr in prtalucinR a furxlional increase nl airway resialance Jlhlhrr Rrnnt..r: Nati<tna( Flentl Inctihde "IIIf? [:1 11'l'IC O1,~ SMOKIN(: (IN '111F. RPSPIRATORY SYSII M IN NURMAI. INI)1VIfyl/AlS." Ry KFt.r.v T. M( KFr, 1)cparlrnenr of Medicirte, Mc<Irca1 ('nllcge of Snnth Cartdina, C'harlectt,n ,Cnurhrrn Rfrdi rnt lnurn<d. Vrrl 51, paf-es 111(1.11 (5, Seplemher 195R. 1'urpr..c rr/ .rurh: Itcc:+usc rtf the aancwhal cnnnicting cr,nclucinnc tlr:lwn frnm a numla•r nf aludics mea•urinR varinns napcclc nf I,ulmr,n:,ty functi<+n, it accn,c<( w<,rlhwhi(c tn sludy -1 rrrnr(, nf nurnr:rl inJiviJu:rls, cmr,kers nnrl nr,n crnrrkcra, tn dctctminc whrtltcr any cir'nr(ic:,nt tltl(clrnlr in t•aaily nrcaaurt•d vrnhl.llnty cnnq,nncnrs nf hrc:rllrinf cnuld hr nhtcrvrd itn 11re lwrt ~rnuf,c I'r.r.r.hn.: h1r•.,.urrmrnla t,f the vital c:yonr ity nnd m,r.irmrm 1.reathinf c:r(,aily wrrr t.,nir<I ,ud in 171, yr,unf, mrn :+(trrl 7(1 In 41 (RS^. wrrr 21 7R), in<turlnrr t.lt nun amr,krrc. 7) r.( tlre an,r,krtc .na 1cd Irt,wrut t,nr aml tw<r t,.r<k. rd ril•.:ucllrc d.uly tnn<) thc rrrnaininp 44 nnr h:r11 Ir, 17 1 r, ~ C.