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TABLE OF (:()NTFNTS I P.gc ()bservations . . . . . . . . . . . . . . . . . . 5 Rese.rch Findin6s . . . . . . . . . . . . . . . . 16 Abstracts of Reporta Carcin<isenesis Studie. . . . . . . . . . . . 29 C.rdiuvascuLr Studies . . . . . . . . . . . . . 32 Studies at the Cellular Level . . . . . . . . . . . . 43 Pulmonary Physiology and Anatcxny Studies . .... 45 Psycho-Physis>Jo6ical Studiep . . . . . . . . . . . 48 Tobacco ('hemiatry .od Biochemistry Studies . . . . . . 49 Pharmacology Sludies . . . . . . . . . . . . . 51 Other Studies . . . . . . . . . . . . . . . . 52 Recipients of (hants . . . . . . . . . . . . . . . . 55

ti('If:N'1'IFI1: AI1VIti11Ftl' I1/1AItI1 tr, Tl,e ('uuncrl for 1 ut,acct, Rctcar( h 11 S A K1iNN1:"T Il M1=RR11.I. 1.YN('I1, M T) , St I) , 1 I I) , l'hu,rm,,n ('h,mr rllrrr and 1'rnfrrlr- of 1'arhnbrty P1cd,cal ('u1kRc nf South ('arolina, ('hiricstun, Sr,uth ('irr,lu,a FIUWARh 11 nNl*RVONT, St' F). Sr irnn(rr F.Jr(r., lhe lournal of the National Cancer Inttrlutc lTcthrula, Maryland RI('I-I^RI) I IfIN(7, M T). 1'rufrrs(x ond Cha/rmon. Tkparlmcnt nf Medicine Waync Statc Univcrsity ('ullcRc t>t Mcditrnc, Iktruil, MrchiRan McKTTN ('AT"T1'1 I., Pt/ I), M 1) 1'rnfrtnrw F mrriluf of 1'harn+exv,lnxy (-rrrncil tlnivers,ty Mcdreal ('r,Ilcgc, New Yurk, N Y . lTON 0 lA(`OBSnN, M I) !'rnfrrJtrr and ('hairmon, fkriartmrnt of Medicine Tlnivcrsity of (Ticago lhrr,rrrr, Argunnc ('anccr Rrtrarth Ilutl,ital, (l,icagn, 111,nuis PA1,1. K(y1lN, M 1) ArrtMlOlr 1>,trrlrn 1- frr1J 'Irr.,lrrr NjI,r,nal ('rn(cr In.wutr, II„h( ..l~. Meryt,rnJ ('I.ARF?N('F? ('(X)K I IT11 1', Sr h, 1 1 I) , I t r 1 L) Sr irnri(rr' llrrrr fr>., 1 hc („unt,l for I r,hat cn Rrscart h I I S A 1)irrrl(or Fmrrirur, Rcnctx Il lit kson Mcmurial l.alx,ratury Flar I-farhtx, Maine STANL.F?Y P RF?IMANN, M T)., Sc T). Dirrr(nr F.mrrilut, l1x Irtttitute for Cancer Research Philadclphia, Pennsylvania W11.LIAM F. RIF?NFIOFT, lit , M 1) 1'rvfrsx,r E.mrrirur of ,Surgrry Johns I-lopkins T)niversity Sch,wd r+f Mc,licrnt, Italtirn,ac. M:,rylanJ L?F)WIN Ll. WIISON, PRt 1) , 1.1. 1) 1`rnfrtrtw F.'mrrifus of Viro1.Sl,uitrirr Ilarvatd / Inivcrsity, ('amhrul}•.c, Mea.r, I,utrttt ttOItFf( 1'f Illu KI I 1, I'„ Ir 1 M(tR1tIC()N Itltn(1Y, M 1) I„r+ nrlr Cr rr,ur/rr I Lrrr rr+ , i Obscrvations A dccade has passed since the Tobacco Industry Research ('ommittcc, now called 'IAe ('ouncil fur Tobaccu Rcscarch-ll S A., anJ Ihe ScicnUlic Advisory Iluard began their wurk. During these ten years a majur rescarth program on the rclatiunships uf smoking to health has been initijled, arnplified, and has gradually assumed clear-cut shape and directinn. Research on these and related problems has sirnilarly eapantkd undcr nrany other auspiccs- Federal health agencies, voluntary hcallh and sci- cntific orKaniratiuns, universities and nretlical schtwds, anJ Icaching and research hospitals. Significant advances have txeurrcd in scientific knrrwktlgc and untler- standing It now seems appropriate to review thc prugress anJ thc laublcros of this first tkcatk, and to a,nsitler thcir implicatit,as fnr the future. Perhaps the mosl significant aspect of such a review is Ihe rcalintiun that Ihc passage of  substantial period of time-and the accomplishmcnt of a substantial body of work--havc not changed (he fundamenlal prub- Icros. As is uften the case in hasic scientific caploration, intensive rescarth has raised more new questions than it has answered. Ihe task before us is, if anything, larger and more conrpkx than it appeared a decade ago, and the majta research problems underlying the rclatirrnships uf smoking In health, though sornewhat better dcfined, remain Formidable. At Ihe time the Board was establishcd. Frrr c.am)tte, when epi dcmiulugical studies reprxtin6 an ssrxialion Fxtwecn eigarctte smoking and cancer uf the lung were being advanced as a majttr suplwrrt for the hypothesis that this relationship was causat. the nced for inlentivc resc'rnh in nuny areas -bitsassay, 6erxlics, palh<,h,gy, hirxhemitlry and t,thcrs ur er<plnrc this nd alternative hyptNhests, anti Iu clucidatc hrsic undcr lying biological mechanisms, was evident In the intctvcning th'cdtk cRl,crl rucntal wrak in the vatit,us arcas has raised nrany new iatues 'I hc nerd for (nlther InuwlcdRe (withtnrl whi.h any hylwHhcsis will latk crmfinna tiun) is still clcarly evitknt After ten ycars. Ihe fact rcmains Ihm Inr,wh•dKe it intullicirnt rithcr lu (nuvidc atkyuatc prrNd of any Iry/,trnccnis lit lu dclntc rhr th.ttit rnrth.tn i.m. /1r IlcJlttl anrl ditcatc wrth which we ar: crrnccrnr,l It r. Irnc nuw t it w,,t in 1'!t•j tfhal tnntinucd retc:,rth in all arc.,t whrrc 1m,wlt'dl;c it Jcfit ra nt „Ilcrs thc ht•sl h,ya• for thc futurc S

I Whilc the suhstantive arcas t+f rctcatch, and shecilic rr:rarch resulls have v:rncd widcly dunng flns dccaJc, cctlarn hrt+aJ firintrtdt•s h:lve crncrgcJ which scrve as a uscful RuiJe It) furthcr planning Arn++ng thcse nlay be litted Ihe fullt+wing: ( 1) Thr f/nrhnnRlnr Narurr u/ 111.ro.r ('unccptN+ns tit disease vary enocmously with changes in methods nf detecting antl tkfining Ihcm. Every new techniyue-anJ there have been many- /nr the tklcctic+n, tkscriptinn, analysit, treatment rrr hrcvcntion uf a drs.casc enthy tends to alter. to tnmc c.tent, perr rprinn of thal cntity. l hus it is easy to forget (but im(+nrtant to rcnrcmhcr ) that thc buvr nururr of that entity- whatever it is - rcm.int unthangcJ 'ihe naturc c+f Ihe intr.ccllutu haxhcrnital I+rtxcss Ihat inuutcs Ihc dcvck+f+n+cnl t+f a tqoamnus cell circinnnra tit the ItmK, /++r ct:uul+le, was the s.rrnc in 1664. 1764. I Nh1, .nJ 19fh1, dctpite all the t I+jnKcs in k nnwl- edgc .ntl view t+f it that h.rve t+fturrcJ durrng that timc sl+an I hrs undcr- lytng crrnvacncy rd the basic prrtcss rnust hc :rpprcciatcJ tlurrnR thc search ft+r fartrrrs whn h rnay inrtrate, xcrtcr:rtc ++r dcl:ay its cx'currrncc II is cyually irn(wtrtant tit Le awarc that any r+/ tlkvc nurlrfy+ng fatnrts trnrhl t+ngina/c, int'rcite, d+n+v+rsh or tlrsal+f.c.it wrth the passaRc rd tirne and with thange in tnr+ ttanl t't-nJ+ln+nt, antl th.rt tht.c rvrutt ttwhl rn turn Ir,ttl tu th.nKcs in the rrl.rtrvc /rcyucnty rd Jrflt•rrnt dncates lhc clucid.rtu+n r+f suth f,utrus iv in+lw+rtant in Iltrctt hrr.lwrrlitm to Ihe cxtcnt that they thrnw light t+n Ihe has+c and as yt•t tmlx•rfcctly UnllerstlwNl rnrc'hanisms whith thcy aflect • (2) Thr I1i.rlnrtiun ffctvrcn l)irrrf ('nu.r, I'untrifLufinR Cau.r, ARRrnmrinn an.l Nun 4prririr A..orintion 1hc intfwatancc nf these dittinctrttns in the scarch fur hasic knt+wlcJhc has alsrr I+ccr+rne evitlcnt during thc h.rst dicaJe Ihry mutt ir+llucntc r+ne's tlnnkrng rtnt <+nly with regard Il+ hacic n+rthinit+ns t+f drsratr hul Ast+ with regard In cnntrul, prcvcnfir,n ancl Irc.iln+cnt. 'lhe (xt+hkms raitetl by tt+mhutn+s which have hrrn idcntified as luim:rry causes" tuf a (trseatc entuty (tt+r etemVIc thc tuhertlr I+atillus in tulK'rcuh+tis ) are scirnlifx ally tlmtc dilfrrrnt f+t+nl thu.c r:+r.rd hy ctm tlninns wluth h.rvr Leen iJrntdirtl a acnnr~ tit trrt:+rn n+•Lrntrs, tit hy ct+mF+tit+nt i+kru+liid at nrrn yx•trtfit.+lly •+tttrrelcJ with e Jrtr.rtr cntrty 1 rir+h~ r +h~- frrr•1•Irrn. •1 1•y nt. wh+t Ih .nt• rnr m tht'r/ .r, ., il, JJI. r. nr Ir..- rL...r ulm h,ut• r/•1 •„... r,.n nr I.•...I t.••r...... n I r r 1 he I:rtler are maners trf universal ctsncern, whilr Ihe h+rmcr hKUs ancn lion on the need to tlefine the mrchanisms of selectivity and thr n.turc tit Ihe susccptiblc purtitm of Ihc IrNal population. Yet another type tit pu+hlcrn is raisctl by facttrra which through association may appear tit tre seleclive hut which are not c/fcctive agcnts in the discase at all, for caantple, the t'ating of cnrn and pcllagra. Again, the distinctitsn between agents which act "causally" and Ihrne which aggravate or exacerbale the prugtess or devclapnrenl of a disease once it is established is of obvious imptrr/ance bWh to an untlcrstanding uf mechanisms and to the design of effective intervention 1}scse diatinctions underlie every ctmsitkratinn uf morbidity, mnrlality and prevention of disease. 'I hc+e disrinctirsns have ntN heen adequately investigalcd in connec- tirxt with Inng canccr, cardiovascular or txMr discaus, hy the types af study which can yickl Lcttincnl data, and the design anti cunduct tit such study ren+ains a ntajttt prohlcrn for the future. (3) The fmportance o/ Ilorr Forfor. In IN..n.r R..puna Although the esscntial role of host factors in disease resprmsc is rccug nired, very little organized research to tk6nc and analyze these factt+rs fras been or is being cunducteJ in the area of amuking and hc:rlth 1 he fact that such research~is dilf.cull, costly nd Iimc-consurrsing has unduuhtedly been a deterrent; one may recognize the practical infltKnce of this situation on the individual research worker who naturally prelers to sckct prtstslcros towards the xrluticsn of which nKmths rather than ycars, and years rrthcr than a life-time, will conlribule. I lrlsl facttxs promise particular pertinence in cRploration tit the prohlcnl of Iung cancrr, which trccurs in pcrams who have never lxrn c.fxtsed to dlc alleged c:+usative agents, antl which also occurs in only a very small pro pt+ttit>tt ur those who have been so eraposcd, so that a nlajnr st'irntdic tyucstinn ccntcrs ttn the "why" anJ "huw" uf the dctet'titun and sclcctit+n t+f irtdiviJuals who will tkvelt><s lung cancer '1 he available evidcttt•c dernands attention to gcnctic, constitulirxul and other h++st facturs Snch knuwleJge is lacking In the devchtpment of Ihrs knnwlrJge t+ne 11111,1 toe realistic and palient lhe nurulx•r tit Jrllctcnl Rrnctic rrr tunstitu nrmal patterns amrmg hunlan inJivitluals it vust, and the drtrrnr urm Irctwrrn nmN nf Ihem by any siruldt• r+t trmvenrent mcthr+./ rs nr+t as yet I+f.rttit:a 1 hcy are unhkcly h+ t.c tit thc gcnt'tic'ally simlJr tylrr whn h r'ln t.t• +1r1ct IrJ hy thr rnrlhrrJ. tit nrlh+alut Mcntlclrnn :ur.rly.r., Ilr+ y wrll, m ull prr.h,+hrhty, tt+rtlrrhnlr tn tht• dranvcry tit hurht•nutal tyl+r. th.+/ crn Isr ~.aK r.rlrtl w+lh tclet+vcly mt rc•+.tvl tit ttrt rca.cJ rrtk% tit .+ hr.t n mJcvrJu.+l 7

(4) 7Ih7 lYerd Jor Accurer•y o/ I/nro 7he nceJ hx accurac'y of data r% such a hasic scrcntrfic prcccpt that it scrmt Rrrtuitrrus trr stite it-and yet it has sr+ rdtcn been uvcrhwrkcd in studies in Ihe smr k inR and health field that it must cuntinually be emphasizcd Often, in epidrmir,ltsgical studies rm large human populations of in birr clinical studres with individual human subjccts, it is tinrply nrrl feasible to nf,lain clala of tht desired accuracy. Thcre are ohvirrus ethical and practical Innits tn the estent to which human bchaviur can he crrntrolkd or human bcinss suhjccted to esperimental prrrccdures. This intrinsic limi- lation in research design does not, however, alter the resprrnsihility to apply rigrvous standards anJ to set careful limits on the intcrprc.atinn of the resulting dala Problems of this scsrt of particular pertinence are the limitations of pent Mrc classificatiixr (e If , as in death certificatrs) as cnmpared lo direct obxrvatrnn (e g , antopsy ); Ihe culkclicxs of data by trained persrsnncl whose accuracy and reliability pf obscrva1/tN1 have bcen estahhshcd by the usual uicntific prncedures; the lailure in statistical analysis Io takc account of many uncontrolled variables A parlicular problem in the currcnt slscc'trum of research on smoking and health is the lack of intert.ive, direct longitudinal study of various types of smaller f+rrpulatirrns asscrnhlcd and cr+ntnslled, mcasured, tested and oAsetved frx the origin anJ development rtf chanRet in physiological processes of pcnsihle significance as precursors to, or steps in, the origin .nd development of chronic disease Such studics require hmR tcrnr eflurt by highly trained personnel ancl they are ctxtly; yet the urder of accuracy of data frnm such effrxts is likely to make them much more important than further repetition of less esact types of studira Fufure Research There are several ways in which the main lines of future research may he listed and discussed Nut nrr malter in whal way this is (fomc it shrruW he remembcred that many uverlapping and inter-relatcd Io,mct and problems will cross the h.wndanes within any attempted clas.ilicvtirm At the present The ('snrncil frw Tuhacca Rescarch is esl.eciAly con- ccrrsed with the initiation and supfwrrt of rescar.h under the hrlhrwing broad headings A More direct observational clinical pathrrlrrgic studics rrf special cr+ntrolkd pr.f+ulations It Iscflrulr.,n •nd evaluati,m r.f rnr'lluwls of t,ruassiy ha whwdr unoke and rt% pr-.ducts, mslu linK chcnnial analyti% of snurkc I t (' I:pidemiologic and statistical :nalysis of nrorbiddy and mortality data. I) Study of psychophysiological differences as host facturs of pn- tential importance. A. l'Unicaf-P.rhologlcd StrdJe. Hack of any eBorts to devise and develop better and mrrre meaningful research in this field lie certain factual observations of detcrrninative value I.ung cancer is a rare discasc. Of those who have never smoked, a very snrall fraction develops lung cancer; smoking is nnl a necessary precursor to the discase Of even the hcaviest sntokcrs bWh in amount and in duration rrl the habit only a very small fractirm develop lung cancer. ()ne prrrhlcm therefore is to discover what characlerislics (chcmical, physiulugkal or psycho emotional ) the people have who develop lung cancer, both srnrrkers and non srnokers, which other individuals do not 'Ilsis utvulvts a type of dtrecl, observational clinical study utilizing tests and analysis of indtvid uals over ksnt periods of time. There are many ways in which new and more promising studics may !x set up. For esampk, if certain conttcslkd prspulatiuns in large medical centers could be under frequent direct observation and tests, clues tu significant factors in the origin of constitutional or chronic disease such as cancer, cardiovascular disease or chronic rrspira/ory disease might well emcrge. A pikN study along these lines is already in progress. It may he necessary to focus the attention of any such particular espanded clinical study on one or two objectives chosen from the following: lung cancer, cardiuvascular diseases, chronic respiratory diseases, psycho- emolinnal types Wherever possible, however, data on all of the major problems should be gathered. It should also be noted that the use of twins involving a comparison of identical and nexs-ieknlieal pairs is a valuable technique which has not been used nearly to the nptimum rkgree. Various factors as to which data are already availahlr in epidemio- lugical studics should also be borne in mind and shrruld he inclurkd wherevrr the prospect of obtaining pertinent and valid daln +rcros RrKKI AnurnR Ilsete m•ry be listed history of previous lung infcclions, inhalalirm vs mMr inhalation, family history of rnruhidity and mortalily, ru-cupatiuoal hazards, etc. It. I)rfinJtir-n ond F:r-nfuntlon o/ MNhodt of llloe..ny :nnrr yrars .rt- the (li.tingurthed bira'hernitt I)r A 1 IlrraKrn Smn stated lu the ti.icrHrtic Advrsrny Ifreard to the 'luhaccu IndusJry Kcscurh 9 ©

(lonumttce thal istd,rtir+n uf nlrnttti:rhlc chcmtc.rls frtim tuhactr( snurke and itt Jcriv.rtives wtwlJ not hc J Ifitult Ilc lurthcr rcmerlcd th.tl Ihc Imrlenti:J nurnhcr nI suth thcmrcals wuu1J be great anJ that the real luttrht-auan trf chcmnal /ratuunttum uf smtrkc is the vahJily :utJ aphhcahrlrry ru nun td the rnctMrl of rtxthtxlt tJ hruassay utcJ in measunng the phyutdtrgn.rl cflects of Ihe.c vatious suhslanccs as they appear in u,haccrr srntrlc. KnnwlcJgc td thenriaal compositinn and physical prtyr•rnes iuf srnuke it in fact vcry rnuch more advanced than the techniques lur hirtingical ssay of /t+r evaluation of the eRects of Ihc suhstanccs un living aninrals. As assay techniques gradually are improved or Jcvised, including assays for measuring ptysible "carcinogenicily" by even scmi-quantitative nrelhtKls, our gcneral plan has been /iru to measure over all cflccts n/ whole snntke and then. whcn a Istnsihly significant hitdr1n.d cffccl hrs Ixen Jcte.teJ, tu trace it Itr thc specific suhstanccs ur prtKxrtict that may hr reslwmsrhac for it 'T hc sINN hrhl of emhhasit has thcrclurc Irccn cunsistcntly tar Inuingy ralhcr than tin chrmittry In actr+rJ with this gencralplan, frw etample, 'The ('unncil has cnn- ccnlratrJ much mnre altcnlitrn upon the tcst and trial of systems ftrr cvaluaring thc Nnsrhlc cartmoKcnrcily nl whole smoke nr uf smukc con- dcnsatcs prcp.rrcJ undcr vcry c,refully Jrfinctl and rcprtrtlticrhlc cnndi- litrns, than ul+nn the nnt.ruon anJ rJcntih, auom nf suth hrssvhlc inFrcdicnts as ppdynutlc.r hytlrrKarlunrs Whrlc scvcral hyJrtxarhrmt elf this clats have been rJcnufecJ in crlrcurcly tm.i11 tr.urs ut tigarelle tnurkc hy in- vestigattxs unJcr trlher s(won.ur.hrl+. Ihrst rJcnuhtrturmt heve nul an.wered the htime qucstnrn whelhcr suth tratcs atr ahnve thc IhreshtrlJ of hiuhrgrcal srFndrtance undcr thc attuol tunddwun ul hum.tn life Ilcnce etrncenlratiun ulxon htuassay still cotnmarrJs attentarn tit a rnuch gteatcr degree Ihan does chemical analysis -Ihe Councd fur -Itthaccu Rcsearch plans tu ftrevs majtrr attention on critiquc and frank evaluation of Ihc prescntly uscJ mclhtrtls ul hnraasay. I here would seem In be certain ratnmal conclusiuns that can be drawn in the primary selection rtf nrcthrrls anJ assay 'Ihrcc td Ihcsc are as folluws: I Whcrcver possihlc, the nrpan trr fiauc which tihnwt p:tthngcnie changes in man should hc tlu targct tnK:rn ur listuc rn litc annrral uud 11 Whcrcvcr ptnsihlc, thc aKcnl of ayrntt .ucl.ctlcJ of ctud"gic•al ( athi ~cntc calracily in m:rn %huulJ IH ulqncrJ In .inim.tl% m 11hc s.rmc thnnical furut .s Ihjt rn whfth it is apLIicJ I,- m.ut, cg. whulc tnnolc t ( Ill Whcrcver possihle, the suspected agent or agents shuuW be applied to animals by the sarne route that it is applied ar man l his dtrcs not mean that other methods or assay may ntN tte t-x/ul trr valuablc 11 entphasites, however, that if comparistsns between animal cRperitncnth and man re to be made under the most valid and scientific cundilirtns which are attainabk, variables should be reduceJ to p minimum and similarities be increased to a maaimum. Though dilleretsces amung animal species tested will always prevent their simpk and direcl eatrapolalitro ttr humans. data gained through such tests certainly can aid understanding uf basic bitschcmical processcs and suggest clinical observations that should he made directly on humans. Whenever and wherever artificially isolated or prepared fractiuns or crrmptsnenls ur the naturally tsccurring form of a complea suspecletl agcnt are used to prove the physiological activity uf that agent certain princtples scent tu apldy: First; it must be shown that a similar isolatitm or chcmical process lu that which artificially protluces the Jerivalive, takes plate naturally in human snroktng. Results obtained with  rxsn-equivalcni Jcrivalive .rc clcarly ntq comparable to the actual problem in vivu. Second; it must he shown that any efiect of a prcp:rred derivative or component can be and is obtained by a less amount and by dtrsagc equivaknt lu of kss than that which actually challenges the hunun tissue Iligher cnn- centrations or larger doses rd the challenging nulerial create an entirely Jd(crcnt sel of circumstances biochemically spcaking, and Iherc/ure are nut cuntparahlc with or quantitatively transferable to the proltknr in humans. 7 hirJ; Ihe melhtxl of application or contact with the challenged tissue must Ite of Ihe same nature as the natural method of contact or applica- titrn in humans 71se eRecls of possible mechanical ur bitkhemical trauma in •a Jillctent e.perimental procedure must be recognized as variables not naturally tsccurring in man. If an eapcrimental target organ or tissue Jieerent from that of man is selected, the rcastxn for the choice must be stated and eultlaineJ Such factors as greater convenience, economy and other material advantages must Lc lrankly laced, evaluated and balanced againsl the scientific varia- hles and dilTerences involved Faeltxs of this sort have a slrnng frruttirul ahlsCal I'tcmalute or erroneuus cunclusitsns drawn humm isnsuunJ prcmi.es t:rn, huwcvcr, cunstitute a great ubstacle to Ihe search (ur Ihe truth Nu maller, IhcrcftNe, huw long nJ arduuus may I.e the rtrad ttt a lunfn•r cvahratirrn of mcthrxls of hinassay antPlu Ihe rlcvcl'qrmcnt of a trrunJ fHrsla•tlivc in thcir inlcr tclatiumhifrt, Ihat trraJ tntust l-c IravcltJ lhc ('tnmtil intcnds to du its Ix•sl tu see that this is /he case' II I (1

('. f p/rLntlurnRy and Sfnrl.ti.n! Annly.l. 11 is generally ctrnccdcJ scientrfically that cpidcmitdngtcal data cin mrutalrry are nrrt the h»is for dctcrrninmg the origin rd the drtica• es in which lrrhacco has hccn asscrtcd Io play a mle Such data will hc suhjcct trs continu- ing stuJy antf evalualirrn by "ilsc ('uuncil for I t.hacco Rcxarch and by othcr gcncies active in supprating laborato.y or clinical restarch Fnr esample, statistical findings have suggestcd future rescarch needs alung a numhcr of lines. I Methrals fur definite quantitative measurement rd rhe extcnl and dcgrcc of inhalation need to he devised in order tu facilitate the determination of the rnk. if .ny, which that pmcrss may play in any estimated or observed physirdrrgrcal activity uf smukc The presrnt "4ucstnrnnairc" rx "I+Crsonal opinusn" mcihrrl yd csti nruing the amuunt nf inhalatiun is mN as accrnate as would he uthcrs that can hc rkviuJ In such n impcxlanl issuc as the quantitatinn of the claimed effects of snsoking, the nrrst precise and imptrsrmal rrxahi.ls rd mcasurcmcnt which are avarleble are csscnlial to snund scrcnttfic cvaluatirm 2 It wrruld he imfw+rtanl to Jctcrrntnc any cumulattvc cllccts of ex- ppxurc Irt smrrkc and whcthcr accuntnlatitrn if any prrx'ccds at a study nJ nuthcrnaur.rlly f.rc.lntahlc ralc Studres ate tKing, and shrruld conlrnuc Irn ce, m.r 1c In hnJ whcthcr any "thrc.hrrld" rcla- litmship ctists 3 A mak csccss in inciikncc uf and in rnurtality frtrm must if not all respirattxy discases is particularly nlarkcd On what is this de- pendent? To what degree are cndrxrine factors involvcJ in Ihe genesis or ckvelcKsment of these diseases? 4 There is ample evidence that confusirm exists (in a witksprrad nnd quantitatively significant scale in mrxlality records because of failure to distinguish primary cancer of the lung frurn sccondary rw mctastalic canccr in the Iung Addrtirrnal crmfusinn csisls in that lung cancer is not ckarly distingui.hcd frum ulhcr h.lhological ksions which can Ise cnnfused with it These siluaur,ns must tx cnrrecled before an accur,rle piclure rrf causahve or crrntribulory factors in primary lung c:mccr can lK• uhlaincd S /1lthrwgh the actual numhcr rit dcaths frrtm lung cancer is irs- trcasmR hcrausc rrf Irrlrulrurm yr.rwth anJ hcrau~c rrf larger numlrrs rd Lrr,nn, rn thr hrphr-r •t•,r 1•rrwl,s, Ihr r.r. uf incrcasc in tl.f .Kt tnrrrrltd rk.lh r.ili- h.r, lac'n stnwtnK rl'.wrs %tntc 1V111 0 0 v t r*~ n , IZ U ,,, o , 1 his declining rate of incrcast, viewed in the light rd actual and per capita consumption of cigarettes during this pcrirKl, raises a serious question concerning the validity of the simple causation theory and dcmunstrates the need for continued study and observatiun. Undoubtedly new `roupinas of data, new types or techniques of analysis and indeed new typea of cootrolkd popslaliuns will suggest and develop other probkms of interest and importance for further investigaticsn lf the limitatic„ss of epidemiological research as well as its suggestive and stimulating value are kept in mind, increased activity in such studies will be an impurtant contributor to increase in knowkd6e. Il. P.yc/io-PAy.leloff" SrreHa. T here havt been eonsiderabk numbcn of studies in this field, all of which suppcxt the belief that snwrkers of diAerent types and rkarecs may dtflcr frexn each other and front non-ameskers in psycho physiuWrsksl characteristics reflected in habits of living. ('ertain ckments, inherenl in the nature of probkms of Ihis usrt, make their solutirns comples and difTseult, however. 71sis fact, while a rkterrent to undertaking research in the area, does not constitute a valid reason /ur neglecting to recognize the importance of tho topic or to take the steps necessary to its further analysis. A promising hypothesis is that types and degrees of smoking, as well as the practice of smoking versus nun-smukin6, are retkcliuns of characterislic reactions uf the individual in his adjustmenl to his life cnlrcricnce Scientific study based on this hypulhesis might find different categories rr! biucirernical, ncuroluKital, psychological, endocrine and emo(iwsal drives or needs which the individual experiences and which he Iries to satisfy or to control by one or more uus of, or abstinence from, a number of things such as lubacco, alcohrrl, a,ffce, trarsquilizers, esercise, narcotics and frKxl. Such study mitht also find that the heavy cigarette snsuker, the moderate smoker and the non- smuker will prove to he different in their psycho-physirrksgical characteristics, as the parallel groups under the other eatetories of re"msive hchavira lu life e.pericnce may also he. Personality analysis by queslirrnnaires rrr by lay interviews have been mark and these have pruvided kads which are suggestive and which nray be developed by more refined nsethcxls of research Uut it is unlikely that it will be sufficient to try to cnmpkte the analyris of probkms rrf psychrr physiu Ingical nature by Ihis usrt uf npinirm-baxJ evidcnce. In Ihe prrKCss of rktectins, recurding and sekclinR significant drfler- ences in ways that can be undersUKKI and analyzed, there are certain guides I3

which may probably hc accehteJ frnnr the uutcet Atrcntinn shnulJ bt ftrcuscJ tus thc earlier statcs Itf individuel Jcvclopmtnt durmR whith the innatc charactcristics are easier 14) identify and ttr separate from those prtafuccJ by or largely tkl•entknt upon the strcin-ectrnurnic envirtmrsmcnl In this way rnc might t.c able to mcasurc and record various JcRrccs tt/ stahihty and in.tahdhy, aJjustmcnt and matadjustmcnt and control and lack of con- trol which might well devek>p into factors of great imptulancc for adults or atlnkst-cnts. II is interesting that rssnst physical anlhrtsruhtRical studies which attempt Itr ctnrclate morphology and psycho cmolianal traits have been ntatk on adults In the adult stage the tkteclirrn and measurement of the psycho emtNional category o/ traits is complicated by the invtdvtd, cumula- tive resfarnsc to all the cr.m(.kritics and changing elements uf the stx-in- ecnnnmic cnvirr.nmcnt that the indlvidual encuuntercd uvcr the years Such rescarch is usrful and interesting It would Lc much mnre so. hnwevcr, if a htumlatit+n of critical studics of thrldten and adoksccnts was built under It by future rescarch a An attempt sht,ulJ he made Iro, tn fiml and to study charactcristics whrth invnlvc clt+sc cnrrclatirrn rrf mcnl.tl tu ermtHirm.l hchaviur with variatrun in srrmc dcfinathlr: rnd nrr.ri,nr.rlrlc huKhcmic.fl rrr Ithysittlogical prrxcstt•s ( "rrlr /u.irrry llresc arc a few tr/ the nr.rnv vtrrnlrh, larrhkmt trr fht- trrntrtrntcd as the research conurnres rtn Ir~h.utrr u.r nnrl 1110111.101 hr.rhh Ihc Inhaccn Industry Rescarch Ctrmntillcc hes been an uhsirvcr anJ tnitintnr nf re- search in this field over the penrKl nf an entire decade lhe c.rcriencc gained during this period shtwld aid lhe Ctruncil ftst Tnhaccu Rcsearch-- U S A. as it carries on this irnfnrrtant work ('crtainly the research prob- kms to be faced arc diflicult -Thcy are the pruhknrs ptnt•d It+ medicine by the very nature of constitutional and chrnnic diseases llse etiology of these distases must he sought cwl .nJ idcnuficd amtmg 311 the lacturs Ihat ficct human health from the hr,l Irr the final decade trl thc human life span Iltrwevcr, thc nulhvrk fr+r a snlutinn Itr these mcdical ptr-tdcrns is mtae erscuuraRin6 ttaliy than it w.rs when thr lt+haccu InJu.uy Rcsearch (•umnrince was founded ten years ago New agencies havr jrrincd in the scicntrfsc cflrnt In unJcrslarsd /arrblcros rrl tnh;ttttr usc rnd hutuan health Ritcnlly rhe Amrrican MrJtc.l n%.rr i.tttrrn amtrrrrncrrl a rnulrr rnrlhrm Jnll.rr /r.r.nr h t/L-,r Ihr I rrlrr.r1 (irrvnnnrrnl r. rttr.rnrhny rr+ -rwrt .ulr1.nn1 rd tr-r rri Ir rrr rtu% rrr.r I1hr rr is rvrrV rr.rtrrn In F.chcve Ihel I hc Ctrurnttl fnt 1,•1 Ir, I II\ \„rll N. •rlrl. Irr -rlvr.rlc .nrrl t•Ilrttrvcly c'rr tn t urdinatc its proRram of research with thosc of other intcrc.tctl aRcncics Thc result can only be an increase in medical knowkdgc which nuy resolve questions regarding lubacco use as well as increase 1hc Ihcrrlreuuc and ptc ventative resources of human medicine itself.

i i Researc•h Finclings The Tobacco Induslry Research Committee was formally organiud 10 years ago to create a pragram of rescatch into fundamental health prohkms. The program was espected specifically to develop facts regarding the effects r.r tobacco use A panel or ycientnts and physicians agreed to serve as a Scientific Advisory Board to the Committee, est.hlrshing pl+licy, lkfining problems, seeking investigators well qualiAed to attack such prohkms, receiving appli- calilms lot `rants and selecting those which the &rard approved for the award of research funds. The Committee has not attempted to devek><+ any laboratory facilities of its own It was dctermirsed al the outset thal the research of the ('ommittee would he accomplished through  program of pants in •id to inikpendent researchers working in their own institutions. 'Ihe ('osssmittce's Ixrlicks .nd activitics have continued under its recent rcdrsignalilra as The I'lwncil for -1'ahacco Research U S A, a After s decade of support of research it secros appropriate to review some of the scientific findrngs that have been rn.de TTirough the end of 1963 Ithe Scientific Advisory Hoard recommended almost S(K) grants for rescarch sturlres and 7hc Clrurx'rl has in turn made awards totaling s6.o]g,0U0 The actual output resulting from The ('ouncil's program has taken the form df scientific papers and repixts published by individual investigaton in medical and scientific jewrnals. To date such publications have reached a total of more than 350 reports It ia to these rcplrrts Tlse Counci. must turn in attempting to evaluate the accomplishments o( its prognm. ()( ecwrse, it is impossibk to list sll of the achievements or'Tlu Council's research Flowever, this review will attempt to cite some significant illuslra- Iive esamples. Rinoaaoy /or TumoriRrnic Action A major difficulty with attempting to deduce a causal uHSnectioo from the stulistical asslKiati/M betwcen cigarette smoking and the incidence of various tylres of caneer, especially cucrnlrma u/ the lung, is that there are a number of other rsonrausal reasrms for ,bc esistence lsf such an associa• liun which can he postulater) nd rnutt he eullurkd bcfure ny final judg- mcrrt can be rcached Suur rhr trmlrkal rtlrlarialr.ry hyl..,rhrait rviyinally adv.ncrd was Itre I,.~.~~lul~lv rh., r i~J-.n,.' tn- lr nupLl he.r - t.vilv a% a rtnrrl tnnlaet ear,-..'r- • t.r y. n.n..l., r..f h.n~ 1., , " %L-ni"n1 .1 rn the eflrrrt Ilr develop reliah(e and yuantitative mcth/k1s for assessing such possible activity in clsmparislxl with that of uthcl substances and nsistures that are common in the environment and whose lumorijenic action is known. I. A survey of mechanical smoking devices was made and conditiuos de- fined under which a relatively uniform cigarette smoke condensate could be made reproducibly. The conditions were so specified as to fall within the range under which normal smoke is produced by human cigarette smokers insofar as poasibk. Inattention by previous workers to the importance of combustion conditions to the chemical composition and biological activity of smoke condensates may have vitiated Ihe results o/ many other earlier investigators. 2. Painting of smoke condensates from commercial cigarettes and frnm cigar tobaccos and pipe tobaccos smoked in cigarette form on the skins of mice has shown that their relative activities are inconsistent with the statistical association between cancer incidence and the smoking of cigarettes, pipes and cigars. Moreover, the high dosages of smoke con- densales required in these esperirtsents, nd the nearly life-long treat- mcnl periods required fot minimal tumor production, attest to the weakness of the activity of all such preparations and raise doubts as to whether normal human smoking could ever produce a dosage such as to elicit this type of action. 3. The painting or feeding of potent earcinornic rubstarsces has been shown to increase the tolerance of mice to transplanted tumon or normal skin from other mouse sarsins, which transplants would be rejected in the at.scnee of this pretreatment. This response could be related quantitatively to the dosage of carcinogenic substance and (hw used as a hioassay tool. Standard cigarette smoke condensates tested by this method were inactive. 4. It had previously been shown that several carcinogenic substances in- jected intravenously into certain mice would produce lung adenomu in numbers that were a simple function of the dose of carcinogen given. These results were confirmed In a study sponsored by The Council -ihcn standard cigarette smoke eondensales, freed rrom alkallrids so /hat they could he given intravenously in large doses, were administered in the same manner to Ihe same straln of ndce. No increase in the numbcr of lung adenomas was observed. S A one cell animal, poromrciunt touJoru.n, has been shown to he rapidly killed by esplrsure tu ultravilrkt light after overn(Kht contact with many carcinogenic suhsunces of Ihe prdynuclear. hydrocarbon family in estremely small cl+ncenlratinn. ('ltuncil projects have re- 17