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CTR HN 011431

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TARI,F OF ~(Y)NTF,NTS ~ aN Ln ~ ~. m m J"'k Ln m Preface by f)r. C. C. Little . PaRc Progress of Research Cancer Research . . . . , . . . , , . . , R Ifuman l.un6 Studies . . . . . . . . . . . . . Ib ('ardiovascular Studies . . . . . . . , . , . . 17 Psycho.physioloRical Studks . . . . . . . . . . . 22 Tohacco Chemistry and fliochemistry . . . . . . . . 22 Other Studics . . . . . . . . . . . . . . . 21 Ahslracts of Puhlishcd Reports Cancer R esearch . . . . . . . . . . . . . . 24 Ifuman Lung Studics . . . . . . . . . . . . . 12 Cardinvascular Studies . . . . . . . . . . . . . 14 Psychu-physiolnRical Studies . . . . . . . . . . 49 Tohacco Chcmistry and Riochemistry . . . . . . . . S(1 Other Studies . . . . . . . . . . . . . . . SS RcciPicnts of Orants . . 60

SCIF:N-TrI-Ir AnvIS(lRY Il0Afen tco the Tobacco Industry Rtstarch Commillce KF:NNRTII Mf'RRIF.F. LYNCII, M.T)., Sc f)., 1.1. 1) ,('hnirnrun ('hnnrrllnr and I'ro/rtvrr of rnthnlngy Mrdical ('oIItRe of Snnth Carolina Charleston. South Carolina RICIIARF) 1. RIN(7, M.D. rrn/rttor and ('hai.mnn, Fkpartment of Medicine Waynt State 1 tniversily College of Medicine 15etroit, Michigan McKFFN CAl'i F * F.1., Pn.D., M F). I'rn(rttnr )"rnrri(r+t of rhnrmornlngy Cornell llniversity Medical ('ollefve New Ynrk, N Y. LF(1N 0 lAC'nBSON, M.D. I'rrrfrttnr onJ ('hoirmnn. F}tpartmcnt of Medicine. l/niversity nf ChiceRo a 1)irrrmr, Argonne Cancer Reaarch Fknpilr,l CTricaRn, Illinois PAUL KOTIN, M f). rnnf rrirre I'rn/rttnr n/ rofhnlnxy llnivtrtity of Srnilhtrn ('alifurnia. School of Mcdicine F.os AnReles, ('alifnrnia C'F.ARF.N('f C(X)K 1.ITTl.F., S(- f)., I.L..h., l.trr f). $rirnfi/ir 1lirrrfnr,'Itrhaccn Industry Rcstarch Comntillct Pirrrrnr l-mrriru., Roscnc 11. lackaon Menrnrial I.ahr,ratnry Flar FFarhor, Maine STANLEY P. RrIMANN, M.n., Sr D. l)irrrtnr Fmrrifu.t, The Inditute for Cancer Research Philadelphia. Pennsylvania WII.LIAM F. RIENI/nFF. la.. M n. rrn/rttnr F-mrritut of .SrrrRrry lnhns Ifni.kins University School of Medicine Italtimnre. Maryland FI)WIN R. WF[ SON, Fh1. F)., 1.1 F) rrn/rarrr Fmrrifut of IVifnf .Ctnrivirt Ilarvard I./niveraly ('anlhridRe. Ma%aschusctts Rtllll'R"T (' Ilf)( KT:TT'. Pff I) 1 Mt)RRISON IIRnI)Y, A1 f) rr f ' I )i i .4 rr, ~w inrr St irnrrln 1)rrrr Inr r rrr r ,~(.cnr infr .~rirnfif I Preface A monograph on cancer morhidity', issued by the ltnilcd States Puhlic Ilcallh Service, commented on statistical and epidcminhrFical data as follows: "In the ctudy of cancet, a disease that apparently can be induced by  multiplicily of etiological agents, one cannot teal- istically expect to do more than identify factors that appear to he frequently associatcd with cancer. The prooF of an etioloRical relationship must then he sought through more intensive clinical or experimental studies." 7 his is suhstanlially the position adopted in 1954 by the Scientific Advisory Nnard to the Tobacco Industry Research Committee. It was rcaffirnled in 1960 and remains unchanged al the present lime. It is a prtsitinn Ihat Also ia held by many othen, includins slatisticians and rescarchers. i Evid.nre oJ 1'nrlou. Poufble Ferfor. During this period siRnificant evidence of various possible contributory causal factors in lung cancer has been accumulating from both statistical and experimental research. Previous lung infections, air pollutants, genetic factors, stress, hot- monal influences, viruses, diet, and other possihle influences are being invesliRated further and, as they are, a more accurate perspective of the whole picture of lung cancer causation is emerging. These factors arc not cited either to answer ot to evade the question as to what role. if any, tobacco may have in the origin of lung cancer. They do not and will not deter the Tobacco Industry Research Committee fronl continuing to support independent reseatch which is trying to answer this question. l.nnR ('nnr.r Origin l. Compfet nnd Ob.crre The present situation emphasites the truth of what we and othcrs have said rtpcateilly. 7he origin of lung cancer is complex and slill obscure. There probably are many contributing factors. Ifewever, development of research into various aspects of the lung cancer propram has had to t+c carried on in an unusual and somNimes dif• ficult psychological clunnte. This came ahnut becau.e /herc arc Ihosc who would insist on accepting ns a proved fact the hyprNhesis that ciRarrlle smnkinR rePrtsenls a primary causative factor in IunR eancer Ihis p-niP "'MnrMJHy hnm tnncrr in Ihr Uniftd [t.fr.." Puhtie Itedrh 6lnnnriaph Nr. th It C 1)rp.rlmenf of Ilerlth, 1 ducalion and Wrlf.rr, ION, W.dhipRrun, 1) (' PiRr 4 5

makca t,nc rd Ihc rm,.t dcfinitc and hlunl dctiRnitir,na nf a tfx•t;ilic c:trrac that h.tt hccn adv.rnrcd /r,r any nt:rjnr ry(a rd canccr, and Ihcy dn an .tt t tirnc whcn acrt'ntc ia till trying In dctcrmine file h:raic miFint of thia diac:rac l hn%e whr, rnnat '+clivcly prnntrrlc Ihit hypr,thcaia have cr,naiatcntly ipntactl nr, al hcat, have minimi?cd the fact that numcn,ua directly rclcv:rnl ctrt'rirnrnla eithrr havc f:tiled to auril+rut the hyPr,thcaia nr h-.tvc rn,vitlcd only wcik nr nnccrt.iin data. -1 hit aitnatirrn hia tcndcd to nbscure the reil nahrrc rtf the prr,hlcm antl a1au file aipnificnncc of resc>trch findings Ihal are not ctfntidcnt with prc- cnnceived attiluJct toward tnhacco . Since itt incc(+tion in IVSA, the T I R C. haa advt,catcd devcln(,ment nf en accruate and ohjrctive (+ertpcctive. T hit pnlic-y it reflected in Ihe tluality t,f file acicntials who Inve hcen Riven rctcarch Franla by file Sci- cmific AJvianry Flrr.trd• in the kind nf work they arc duing. :urd in Ihe acr,rct of rcacarch rrlu+rlt they have publiahcd in Ihe lileralturc. llrc ctmtplcc nalure t,f cancer nriRin it itaclf a tlclnyinc f:iclr,r :tnd no imrnrnt of cnlhuaiatm for any t,n4 Ihcnry can either h:talcn tn lacvcnl Ihe evcnhral dclcctirm and analvaia of the variuua comfa,ncnta antl t•Icmcnlt thit are involved Trmrnrn nnd f'nnrrr /1nolhcr f:utr r trf imf+ort;tncc in the Fcncral paychtrlr,Fic:tl climate thil aurrrruntla thc Iung cancer fon,hlcm it thc tovcr cntph:raia t,f thc nde allriF+ulcd tn irritatinn in Ihc c:+rcim+gcnic prt-t•caa. 1 tic mnllcr ia trf great intcreai ttr the clinician. 1 he t,hvirnra Irauma ciuacd by x-tay hurna or Ihit tcaultinl• frnm the ariplic,tir,n td ccrt:iin chcmicala tt+ the akin trf LrF.rx:rtray anintak ia a atriking phcm,mcnr,n and quite naturally attr:rcta file altcntir,n nf Ihc rc- aearc'h wnrker nr clinician. It ia well trr rcntcntbcr• huwcvcr• Ih:rt any kind n/ nhvit,ua irritation rrr ir ia not nccea•:uily or even utually a prccurtnr to the caatntial inha- ccllular chanfc r+r chinpet thit cnnatitutc whnl it c:rlled m-lifn:tncy If it wcrc, it ia pn,h,hlc Ihat hum:tn bcinFa wt+uld hmg irtr have l.ccn wi(,c'd t+nt hy canccr In anv Ir:ruma r,r area nf irritalir+n there :tre cr,nccntric rinFa nr h:tnda r,f tiaaut' crrmrr.actl t+f the following lyfvca t,f ccllt: (a 1At file central Ix.int of the Itium:r. cclla :rrc killrtl and Im,ken down 'ihcy e.innnl form cancer /1, /(lhuairlc n/ theae are d:rnr.rped ce11a wilh im/,airc,I funt tirrn and rrilncrA fv.wcr nf crll Jiviainn f hcac :trr nnt I,r, t ur-ra r,f r:tnrcr (c) Surrnuntling Ihc whnlc :r/leclcd area arc nnrm:rl cclla cntircly un:dlcctcd (tl I 11 t rrrnr rr rK urrt, ir it /rnrrrr.f in dteorrrr w•hir h lirt Artyrrrn (h) nnd (r ). lMrr inrrn r anrl vitiAfy unlmrrned rrflt nrnv hr rrlra,rJ /rn.rr t rrrrrulizrrl runtrrd anJ oi•tuulh• mrry dirrrlr• nrnrr rnprrl/v rlurn rln the nnrma/ onrt. In the pnrccaa uf uncontrolled and, up to nnw, uncontrollable j;rnwth tnat charactcrirca cancer formalion. there may be obacrvcd t hangca in the mrmhcr and rnnr(+holt+Ry of the chrnmcnomct. From time In linrc auch changes have been contidered to fx of etiological cignificance. Such changct arc probably of little or no actual significance in cancer cauaalinn. 1?tere nre many recorded obscrvalinnt of hiehly malil•nant tumnrt with file nttrmal number of chrtmnnomcs. -Iherc utc nlar nrrny tyf+ea of mm lumnrrnrt cells with striking abnormalitiet in numhcr unJ/t,r ctmft.rm:rlirm n/ Ihe chrnmtKomet. Science nruat lunk inuJe the ccll't mosl minute nnd dclicale atrucrurca nnd mual analy?e %nd e.plain itt fincat and mocl inlricatc /unclitma fx(urc the dillcrcncet between the nurmal and nraliRnant cell are undcrtltw+d. l•:1ri.fem7nfnRirn( Crpdi.. Naf f:nnnR/. It it tmyll wnntlcr, therefore. that th: data derived tt,lcly frnnr cpi- dcminltiRic:rl studict leave much lo bc dcsircd as a fnundalitm tin which lu I+:rac swccping and dttgmalic hyptHhcacs nf cancer c:ruaaliun, Scicnliata. phyaici:tna, ond the public arc rccnRnitinR that fact in ever incrcaainy num- IK•rs, and are admilling the need of far more knowlcdcc th:ut we mtw ~traacat bcft+re thia crwnplc>t probkm is fully untlctattMnl and thc :rnawcra ttr ila ntany ch:dlcnRes can be expccted. While the'anawcn we « ck are slill not within tnrr Frnap, we now have a far better umkral:rndinK of the yuettirmt. ('karly. prt,Frcat it fn'inr m:ulc 'I he findinFa t+f thr patt ycar, aa rcfmrled by acicnliala lhrtnrEhnul the ctiuntry. intlic:ile real htq+t• fnr eventual tulutinns tn thc ch:tllcnf•ct t,l c:tnct•r• heart diac:rae :rnd rrlhcr conalitution:d nilmcntt. I wiah tt, t•xprcas tincerc Ihanka to my aatnciatct nn file Scientific Atlviaury Iln:trd. :tntl In thc asauciatc acit'nlifrc dircclura uf Ihc I I R ( ' . ()r. Rnlx'rl C. Ilrx kctl and hr. 1. Mnrriann Iltatly. Dr. I lr,ckt'tl• whr+ h:ra been tlnacly aaat ciatcd with the Ilnard't reaenrch pnrFram fta eiPlit vcara. Ict. m:rdc ru:rny valu:rl,lc cnntrihulitma Itr the review trf rcac:rrch rtn Ihc payca fnllnwing While Ihia rcvicw illualr:ttca the acrIfx• antl ct•nnrlcaitira td Lrrrh Irma heinp invt•atit-.ttcd, it it eaat•ntially t,plimialic and At'acril.trvc rd Kr•nuine IunFreaa. C. ('. I itllc .Crirnrr~~ l)irrrlrrr 7 F,

"1'lrc Progress of Rcsearcii Prngrest nf Ihr 1-nhaccn Indudry Rescarch (-nmmittce prnRrim, as dcvchrrcd and carricd out by Ihc Scientific At)vianry Ilnanl, is rcllcctrd only in p:rrl hy the incrcasinR numf.cr of paf.rrs puhlishctl hy rccipicnts (if Rrantc Since the 1964) Re(xrrt, 60 new puhtishcrf parcrs h:rvc :r(qvc-arctl. hrinFinR the total In 222 Abslracts of the new puhli.hcd wnrks are in- cludcd in annlhrr tectinn of this Report. Mere numhrrs of papers, however, do not mcisurr thc siRnificance (if rescarch prnRrett A review of complcted and cnnlinuinR research Rives rcasun to believe that some of the )car's develnpmcnts open more direct patht loward discnvcrics that may he expected to contribute practical m; a- sures for coping with certain formt of cancer and cardirrvascular cfiuascs lhis review estays to estimate the state of prnRrest in sevcral fictda, to asscss the intpacl of certain findinRs, and to define the nature of tontc un- tnlved prohlcros The discustinn is divided into 1hcse scctinns: I Cancer Rescarch. 11 Ffuman I.unR Studics. III Cardinvascular Studies IV. Taycho-Phytio- IoRical V Tobacco Chemistry and 11ir+chrmiatry VI. Other Studics. 1. (:anrPr RPSrorr•h In planning cancer research it it helpful to tlislinRuish two differrnl levels of attack A full and final tnlution of the canccr prnhlcnr may he exrcctrd to ennte only when we une)crstand the hasic hinlnRical mech- anisms of cell differentiatinn and or the regulation of metabolic and cell divisinn prncesses 1 he most fundamental investiRations of the day are at this level, and more effeelive participation in such InnR-range nd hasic research is definitcly nne goal nf the 1 I R.C.'s program. At the same lime, research at a less hasic Ievel can be e><pected to produce uscful infnrmaliern and snmetimes to yield immediatcly applicable mcasutet for partial control or delay of cancer in Ihe human prrpulatinn Many snch measures have indeed hecn dcvelopcd in the pasl. Wrll dcsiyncd cxperiments at this level may he succetsful in nfprait- inf the relative rfTrcts of many controllable e+ttrinsic, as well at inuin.ic. I:rctnrs ulx+n the level of incidence of particular fnrms nf cancer in animals f'crhaps the he.l hope td developing control measuret fnr snnu fnrmt uf moiiRnancy in Ihc rrlativrly near future lict in sludirs nf this tyre. Scientific hiatury Inmiilca many risct whcre tuch reaeatch nnt nnly tnlvcrl inrmrdi:rle Lr~~hlrma hut al"r Irr-Jntrd .cicn/ilir by trrr~luc/t rrt rvcn rrr:ltrr ultimatc i value. Pasteur's discnvcry of induced immunity may hc Iraced to his origi- nal attack upon the practical problems of Ihe beer and wine industries. 1 he Scientific Advisory Board, along with other scientists, has cnn- sistently held that pathogenesis of bronchotenic carcinoma must be a compkx phenomenon and that real profr,ress toward solution must be c.- pecled through discovery and relative evaluation of a whole serics of con- trihutory factors. Thit position has sometimes been misconstrued as im- plying that no progress in the control of lung cancer could he eapected until the whole cancer prohlem could be finally and fully solved at the hasic level of biological discovery. This is far from the true meaning nf this position. Tl/F, F,X/'F.RIAfF.NTAI. AI'PROACII The several reports of statislical associatlons between cigarette smoking and lung cancer incidence made it logical to develop research to sce if smoking could play a direct, primary role in the etiology of the disease. To be s.ire, statitticians worthy of respectful attention did point out many anomalics and inconsistencies in the statistical picture. Some even yueslirrned scriously whether hiascs of several kinds might not invalidate the reprtned relationships. lhese legitimate questions about the statistics could, however, he left fer eventual resolution by qualified experts In Ihe field of epidemi- oloRy and statistics. 'Tlie testing of the question concerning tobacco as a pntsihle causative factor called for e.tensive eeperimental research in the laboratory and clinic. Stntf.rfrnt A..ocfnllon f:ennot rroo.l;euaedlon The point requirinR re-emphasis is this: Even if a statittical aaocia- tion is assumed to he completely valid, It does not and cannot dcmnnarate that smoking is actually a factor In the etiology of human hrnnchnRcnic carcinoma. 11 has been shown, for example, that there is an excellent corrclatinn between socio ecnnomic class kvelt nd the incidence of "chronic hrnn- chitii' in flritain. No clinician or stalittieian would suRRett for a moment that the amount of money a man receives per annum could of itself cause any disease, unlets he were actually infected by microhes frnm cnint rrr paper money. We automatically proceed to consideration of such mat- Icrs as dietary aJcynacy, housinR conditions, kind of clnthinR wnrn, nalure (if enrplnyment, level of medical care, amount of rest or citcrciar, nature of recreatinn, exf.oture to the elemenls and othrr factrus whith rnay he nnrrtrd by incrunt' Hnt1 which in lurn ma) in/lut-nce incidrnrr ri/ Ihr diseate. m U1 q 9 c> ~n

llre c> istcnce nf a slatiatical acsociation drxs nnt ditcl</sc the numhc•r nf intcrrnrdiatc variahles that may lie hclween the end resull (tliceatc) and the cnvirtrnmental factor orRinally taken into accnnnt 'ihe useful function of finding such a cnrrclation thut lies in the clues and hints turncd ull which may hc further and srparately validatcd. "Fnllnr-y of Ml.plnrrd ('nncrrt.n..:" In the particular illustration just Rivcn, the impnsaihilily o( a dircct cautal rclationship is sutficiently obvious to prevent investiRilnrs from mak- ing premature or feke inferences. In the case of the refxorted asancialion between tmnkinR and lung cancer• the statistical evidence is actually no dif- ferent from that nf the income-hrnnchitis situation and does nnt, nf itaelf, permit any more reliahle conclusian with resf.cct to direct causation 1)r. Itrrkann his callcd this fi?ure u(+nn the nrfrnrrntly nhvinus aa an esample of the "fallacy of miaplaced concreteneas " A allrmiae thm smokinR could hf a prime cmuaativc factor in IunR canccr cnuld hc uard only aa a wnrRinR hvrrrrhrsir hut not m. a proved fact. Neverthclcsa, thc habit of ucinp, Ihit hypntheaia frnm day In day as a Rcncr- atnr of e:herimentil tlcaiPna aecma tn have induccd tnrnc « icntiats In forget itt wholly tcntntivc d.:etut Fvcn pa an hvputhcaic, it acrn.lllv c,,ntainrrl l vrrv arri luc limit:rtinn- Only a very tmitl lirnrlrrtirrn nf r.en tlrr llr:lvlro ~rnwkcr. cvrr rlcvclrrps Ihis dlSfaac and it akn nccnrs amwmF m,namlrkrra 1 hia ia actlnllv drnng evidence that the etinloRy of the Ihtf:rtf ic cl+rnplcx ind that a mmtf.cr nf influcnces muat act in concert in iti Rcncais lhc irilplicition ia atronF that there must he factcrrs determining the drgrce of atcccfrtihility or rfaiatincc in individuais. It would arrcar to be a rromiaing enterrriae to determine what thcac factnrs are• with the view nf utilirinR Ihcnt in control nf cancer. Yct this f+rrttihility has hcen largely ignored in rraclice. lhe rclativcly low inci- dencc of IunR cancer in heavy srnnkers at well aa in the pcncrnl r-Pul.thon hac been attrihutcd rather f+re-emptnriiy to "natural diffcrrnccs in cut- cflrtihility," as if thcat were unirnf.ctttinl nr inaccccaihrc to aturly Gilliam's recent nhacrvatinn of the diminiahinR r:rtc of incrc:ne in hmF cancer in- cirknce auOPrata thf ftradn:rl diaaprcarnnce nf i partic'ularly au.cfftihlr pnrulitinn Animnl tnhnlntinn Tr.r. Con.i.t.nrfy 1YrRerlrY One way uccJ to dudy the hypolhesis that cigarette smoke might I.c a prime causalivc factor in the gcnesis of lung cancer was animal e><rcrimcnta- lirm '1 hc mo.l directly pcrtincnt of these experiments were the nurncmus studics in whit h anim:lls of several spccict were made to inhalc fresh, whnle ciRarcltc sn.okc at frequent inlcrvals over ksnR'perinds of lime, often JurinR the whole n:rtural cpan of life after weaning. These cxrerimenls cnnaistently failed to prr.ducc cyuamous cell carcinrnnas of the type that arc most prev- alent in humans. lhcce failuret• in view of the numher, extent and duration of the testt hv many able nnd experienced invettiRators, militated nRaintt Ihe aur- mise Ihar Uohacco smnke could be a primary factor in the inductirm of auch canccrs Ilnwcvcr• the prohlcm of species diRercnces in susccptihility cnuld hc raiccd• and Fencral iRnorance of thc effects even of strnnR c:ncinnrenic aFcnts nn the lunr tiaaues left the reasnnt for negative rcanllc uncertain. Fnrther work has helped clear up the uncertainties. It was Inpicat to extend these studict to investiFatinns in which ani- mals were madc to inhale aerosnls or fumes of potent, known carcimrr.cns, includinr mcthylchnlanthrene and l,d-hcnzyprene. Such c.pcrimcnls rm rats by Kuschnct were alto negative. ARain, the rcsults cnold I.c intcrpretcd in sevcrat wayc. The efficient lung ckansing mechanisms (inclurlinF mucus /1r,w, phipocytic activity, and absnrption, metaholian and cxcrftinn) nf thc healthy animal might not permit a contact limc, nt effective dntaRe, adcyuate for carcinogenic action. The prnhlcm of sfacies diflcrences In susceptihility cnuld f.crh:/p. atill he raiacd• though Andctvont had IonF hcfnte shown that syuamrluc IunR carcinomaa could he induced in C-S7 black mice by IranafiriinR thrrads im- preFnatcd with 1,2•S,(.-dihenranlhracene through the IunR 71rit had dcm- onctratcd that mrrusc IunR cella are biologically vipahle of tranaformatinn into maliFnant tisaue of this histoloRical type. Riftton and Shuhik have shown that larye tlncfc of carcinorcnic hy- rlrr+carlHmt introduct•tf inln the Iracheat nf duckt and ham.rcr% rc.fa'ctively in nil cnlutinns will prrxluce cancett of varirrua tyfns Simil:rr fffM'rlnlf/lla u.inR tobacco tmrrke condentatet have failed tn pnKluce cancer 'I hfae citf.crimcnts have, hrrwcvcr, further cnnfirmed the L•rcl that lune% of .cv cr:/l :Inim:ll apfcirs are hirdnPic>,lly t114cffHthlc tlr m:rlipnant ch.lncc whcn rlrlaa~ca Irf kmown tartimrrena are auflit'irrtl and rnnlact tlnlr ik l/inl• cmrnph I Itt I I

Trnumn nnrl ReR.n.rntfon Po..iMy (nrotr.d Anrlcrvnnl's studics and their extensinn by Kuschncr using thread trancfixion inarnduced the additional factor of trauma along with increased contact time and interference with normal cleansing mcchanitms 1 he relatively high incidence of squamous cell carcimnnas in these eRf+erimcnts drew attention to the possihie role of trauma and Ixrhars of attcmptcd regeneration in susceptibility of the lung to carcinoRcncsis. Suhsequently, a series of studies showed that a number of radioactive and potent chemical substances can induce epidermoid IunR cancers in rals and mice. Thcse studies are not directly illuminating with respect to the ctiuloRy nf epidermoid lung cancer in man, because they were carried out on animals and they employed very powerful agents not widely en- countercd by human beinRs in ordinary life. The studies do, however, dispel any doubts about lack of species susceptibility. Meanwhile, clinical and epidemioloRical studics of human suhjccts by a numbcr of investiRators pointed toward the possibility that damage to the IunR, followed by reReneradnn, might be  predisfxning factor in human lung cancer, whether the damage was due to tuberculosis Iesions, infarctinn, or mechanical injury. Winternitz long ago pninted out the frequcnt occurrence of severe mctarlatias in the lungs of persons who died following influenra in the 191R-19 e(+idrmic and had called attention to their "precancerous appear- ance." Several investigators had attempted to produce lung cancers in animals by repeated influenza infections hut, th<wph metaplivic ch:rnRcs were produced, no truly invasive lumnrs developed. (:nnr.r F:xprrlmint..rith 17ru.e. fly ctrmbining repeated influenza infections with inhalation of syn- thrtic smog. Wisclcy, Kotin, Fnwler and Trividi have obtained invasive and metnatatic squamous cell carcinomas in the IunRs of ('-S7 black mice at a suhstantial level of incidence. Almost at the same time. Martin and his crdlafx.rators showed n synergistic action between scveral viruscs and a sfx- cific chrmical carcinogen by obtaining tumors when combined small dtnes nf virus and chemicals were given. Given separately, at the tame levels, thcsr aPents failyd to induce cancer. Stanton also htas repcssted the induction of syuamnut cell hmR car- cinnmas by chemical carcinogens administered intravenously into rals in which nrrat of IunR infarction had been produced. lhrar rr,rnl rvrntt err citr l to illustratr the ral.id Irvrli-l+inrnt nf n„ lh-1. f,.i "-1, „r .,lu.r.u•ui crll a ari 'n„n..I m I n.ni. it InnFt These methods provide a basis for evaluating the relative rRccts of many other extrinsic and intrinsic factors on the rate and level of incidence of bronchogenic carcinunra in animals. fly suitable desisn, it should become possihle to evaluate the effects of aae, se><, nutritional atatus, excess or defi- ciency of hormones, stimulation or depression of the reticuhocndolhelial system, cancer prornotinR aRents, various types of trauma, irritants, mucus cnmfxnition and ahundance, activity of cilia, efficiency of detoraification mechanisms and many other factort. Te.t. (:ontfnue on ToAorro SmolrP Tests of tobacco smoke In this experimental biological system have not yet been completed. So far, the indications from these and many other tests of the activity nf tobacco smoke, are that the smoke is much too feeble to play a role in the etiology of lung cancer as a direct contact carcinogen. 1 his does not necessarily exclude tobacco from having any role at all, nor is any such role established. More investigations are necessary on the suR- :Restions of possible indirect, contributory roles for tobacco. As the experimental systems described gradually permit the relative evaluation of all the f+ossibte external and internal in/luences listed atxrve, it ahould become fxnsihle to determine whether and to what extent tobaccn smoke can cnntribute, whether as irritant, promoter, modifier of ciliary activity, in/lucncer of nutrition or by any other means. It is a task of con- siderahle maRnitude, but the rneans now seem to be at hand. The fortunate spect is that, as the contributions of the various suspect factors are evaluated, melhods of nullifying or blocking snme of them may become apparent. qr course, the f+rohlems of species diflerences and rele- vance to man will remain to be resn(ved. Nopefully, effective methrKls of reducing Ihe tnll of human lung cancer may become evident from this type of work. C1/RRt;NT CONTRIItf/TInNS FROM T.1.R.C. 1'RnCR.4Rl The program of cancer research supported by T I R.C. Rr.rnts pro- duced several significant developments during the year. The suggestion that some transmissiMe agent is pr«luced by ccrtain tumnrs has come from further study of the increased concentrations nf deorayrihonucleie acid (f)NA) in tumor-hearinR rats In tissues distant fnom Ihe actual tumor. F.tracts of IunR, kidney, liver and splecn rrf rats f.enrinR Ihe Walker 256 carrinnma and the Jensen sarcoma have been hrund trr ini cnrl+runte Ihymidine It` more rapidly than thnte frmm nnrmal rats, inAiiat. inR a fxrstihtc influrnce frnm the tumnrs. I. 11

In three diRcrent laharalr.rics, c> f+nsure (if culturrJ cclk h+ murke and mm Srnnke yatct wat studicJ witlt dcccriflirm rlf rnnrLhrrlrrFicil changrs, alteratinnt in Rrnwth ralct, and mr+Jificatinn rrf mrKl.rl v:tluct of chrrmi.anmc numt.ert. Fflecls nf irratliatinR human arnninn ccllt havc been sirnilarily de- scrihcd Since rnnrphnlnRical changcs and plniJy rd chnnnrntxnc cvnctitu- tinn are nrd simply or Jirectly diagnostic of maliRnant mrxlilic:rtirrn, it it e.pcctcd th,l future studies at the cell anJ tissue cuhurc Ic"lt unJcr T.I R('. tuffxrrt will place increasing emphatis (+n changes in thc dynamict of the living cell I urthcr quantitative cytnchcmical studics on the rcl:rtirrn of f)NA to varinut patlhnlnRical ctrnditirrnt also point trrward thc crrnclutirrn that Jcviatirrnt frnrn ntirmal in amtrunt and tlittrilmtirrn tof 1)NA irc nnt tf,ccifically draPnrrdic nf maliFnant Irandnrm~tirrn, hut r:tthcr rof /•rnwth rir rcPcneratirrn rrPardlets of cautc, nr (if f)NA virut in(cttirin Nn lernR Cnnr.r. In A/ire f:ip.Ard to Cmnke A new summary revietved the hittolnRical, cytrrlnRic:J anel cytrrchemi- cal slndy (if the Irnchcnhrnnchial trcc and IunRt td mice exfx),,cJ Irr ciRa- rette smrrke It confirmed the Irrcvir,udy rcl+r+rted variability (if respnnte, ranging frnm ahccnce of siRndicint hitlnlrrRical chanFc. IhrouRh mild bronchitis with swnllen epithelitim and mild hyf.erplatia. Ir+ severe hrnn- chitit with a typical basal cell hyrerplasia, tquamont cell mctn flatia anti occasional dysplatia or "carcintvmn-in-titu " Invasivc carcintinra was n.rr found "ihe extrcme variability of respnnte, regarJlctt uf thnc anrl Jur:rtir+n (+f exposure, pointed to ennuihutinR factnrs, such as latent virut infectirmt. characteristic of the individual animal. LnnR-contiuucd studies with the white Pekin duck have culminated in rrtxluction of nnn-metastatic ncoplatmt of varied type in the IunRt (if hirdt given methylcholanthrene in fxilysorhate Rl) by inlratrachcat infutinn. lrt- haccu smoke condensates timilarly infused have not produced lumurt. RIl).4SSAY AfETIIOI)S r , Ihc Ihntt. "Rclvivc potency." therefore, implies cnmparisnn rrf activity within tnnrc ficcJ or stanJardi,ed hiohrRical system. rach such tystcm will prtxlnce itt own scalc, since there are wide varialit.ns in rrnctirm Mrlh arrnrnr and within species. If several tcalcs hatcJ on diRcrcnt,biohtgical phcnnmcna, other than actual tumnr prrwluctinn, are scl up. Ihcre, is no guarantee th:tl any p:rrallclitm will exitt between Ihem in the relalive fxxititrnt astumed by Ihe varinus agcntt tested. If a degree of parallelism should cK-ctn amrrnR several tuch scalct, it might encourage cnnfidence in their tignilicancc, ctrecially if nne a1 least is baseJ on actual lumor prutluction. Ohvimrtly a mcthnd more rapid and conlrnllahlc than rnuntc tkin painlinF, and rrquirinR only very small quantitiet nf tesl tuh.tancc, wnulJ l+c ,rf great praclical vcJUe in sf+tedinr rescarch. In thc'1 I It ('. Rranl proFram nver Ihc past half drvcn ye:ut, a acrae (if mNhrwrt have f+ccn tried utd in the attempt to tctt fur thc rcl:rtivc "carcinnFcnic rntency" of tobacco smoke and other subtlancct Such in- fnrmatinn would, it was IhouRhl, hclp atsett the hyptsllxtit that tuch amrrkc cr+nlrihntct In human cancer as a contact careimrFcn nnJ help Jcternrinc where emphasis in retenrch should he direcled. None nf thctc earlier :tltcmprt proved tn he tatisfactnry for relative quantitative ev:tlualiun. Mr4at, hu1 nut all, gavc complclely negative results. llul even thnuFh not whrrlly satisfaclory, these many sludics produced an nverall impression thal tnhaccn smnke (if nnrmal character, In its Icnunut state, it Itxr weak a carcintr'cn. if it is nnc at all fnr humans, to act in thit capacity as a Rcncrntur (if human lung cancer. i F.nrortrnRlnR Rf'-ar.It. In Tflr.e Aren. Now the hcncfits of this work arc coming to fruitirm. lhc retcarch fnr more tntisfactnry hit.assay methnds has entered a new ph:rte which apfn•nr% encouraging alnnp three lines: I. A mclheKl based on the activity of "earcinugenic ayenls" in cnhancing growth of Iran.pl:mtcd tumor anJ nnrmal skin yraltt - hat hccn shrrwn capable of quantitatinn, and an "activity scale" fnr a IirPe tcrict (if highly purified fwdyeyelic hydrncarhnnt is in Numernus studies have been supf+ortcd by Rrants in the eRrxt tn canttructinn. nhtain a more cxact quantitative mcthtrtl nf testing frx relative nver-:+II 2. Frnthcr ttandardi?atinn is in prncrtss Irrr a pnitrrm:rn "carcintrRenic portcnciet" (if varinut suhttances and mi tturet, includinR natny /ra carcinrrFenie hydrnearhnns, hased nn Ihe resprinae rd m tn trrhacco smnke and enndentatet I'unnrrrrrurn r.nrnJrmmr In ullravirrlct anJ rclaleJ radinlinrn frrllnw- On a ttrictly thenrctical hntit, "eareinnFcnic prrtency" is nnt an in- inf c.hrrturc Irr thc hyrtnrcarhtrnt in hiFFt dilutinn A actr nrl r. hrrrnt prr,pCrty rvf a chrmical arrhoancc It:rthrr it it thc rcl ult nf an LrrtcncV sc:rlr is :rl.r- trr 1r enntlruclyd hy Ihit mcthrtil, with ute intrrattirm rrl ~r,mc kind Lrtwccn on agent anrl a tlynamic IivinR entity -- ,rf thc tarnc s:rnrlrlct trf hiyhly purilictl hydrrK'nrhrms m tn © I4 IS m