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CTR HN 01 139*r

_or ro- 1960 REPORT o J t ji c SCIENTIFIC DIRECTOR /a.A1tF:N(:F: (YH/K t,l'i'ii.F., Rc.tl. •runna:O iN1/11ti'1'ItY RFaF:AIN31 c(IMMrrrFF I

SC.iF:N-rnFI(: nlrV1M1RY rs0Altli to the Tobacco Inttusary Rese>,rch ('ommitlee KRNNf?III MI?RR1(.1. I.YN(TI, M h., Sc.h, I-1.1)., ('hairman ('hnnrrllnr Medical ('olleRe of Smnth ('arolina ('harleston, Sr)uth ('arnlina R1('IIARI) 1. RING, M.n. rrn/rrtor onJ Chainnnn. Department of Medicine Wayne State I)nivenity College of Medicine I)ctroil, Michigan McKEF.N CAT'fF1.L, f'tt.f)., M h. !'rn/rtn» F,mrrllus rr/ PhormnrnlnRy Cornell (iniver.ity Medical Co11eRe New York, N Y. L.fON O. JA('OIISON, M f). f'rrn/rtsnr n/ AlrJirinr, University of (?tica/,n !)irr(rnr, Argonne Cancer Research Ilospital ('hicaRo, Illinnis PAUL KOTIN, M 1). 1'nrrl I'rircr 1'rn/rc.nr (P/ f'mhrd.lev I/niveraily of Southern Califoanii, Sch(xd r+l Medicine l,os AnReles, ('aliG+rnia CLARENCE COOK 1.11'I 1,17. Sr I) . I1. 1) , I rT T 1) Sr irnrifir l)irrrtnr, 'Trrhat cu In Iticlry Researih ('ornmittee /)irrrfnrFnrrrirur, Ruact•e Fl lackarn Meniorial I.ahoratury liar Itarhor, Maine STANLEY P. RFIMANN, M 1), Sr 1). f)irrrrnr linreritut, The Inttilute for Cancer Research Philadelphia, Pennsylvania WILt.IAM F. RIFN1IOFF, 1R , M.f). .I snu-iorr 1'rn/rtrnr of Suurry lohns Hopkirn University School (,f Medicine Baltimore. Maryland EbWIN fT. WILSI)N, Prr 1) , 1.1, n. 1'rrrJetcnr F.mrrirut ol Vitnl Srnriuirt Ilarvard Oniversily ('amhridRe, Mnssachusetts ROIlt tt 1(' II(K'Klil-f, I'll 1) 1 M(11(RISUN IIRAt)Y, M I). .1 ,in, i,ur tr rnn/n Ihrn rnr Anoa rrur .\s irnNfilr I)irr, Inr t Preface The year 1960 was one of great interest and activity for the Scientific Advisory Board to the Tobacco Industry Research Committee. As general lines frrr development of promisin6 research have become evident from ccumulated eaperience, a program consistenl with Ihem is being rapidly evolved. During the year, the T.I.R.C. responded to a request from 1he Board fatr additional funds for research grants by increasinR annual appropriatirnn to SR(Nl,(KIO. T hece additional funds will be for Support of further study in the fields of viruses, psychn-physiok>Rical Iraits (conslilulional diRer- ences), previous chest and lung infections, bio-assay, and tissue culture. (:nr.aotlon TArory of Cmoklng (Inprorrd The cnr,tinued failure of evidence which is qualitatively dilTerent or of increased aiRnificance to appear leaves the causatinn theory of smoking in lung cancer, heart disease, and other ailments without clinical or e.peri- mental proof. Meanwhile, evidence of the crrmpkx factors involved in the origin and nature of these diseases continues to increase in quantily, depth, and scientific significance. The result is that the tobacco theory is rapidly losing much of the unique importance claimed by jtts adherenls at ils oriRinal announcement. It has not received definitive support in the clinic and laboratory. One 11nr.i' Fnrf: Mnr14 Mer. Mnrf 6e Found Out With all Ihnt we have learned in the laboratories and the clinics, work- inR with aoimals and chemicals and people, e><plorinR a variety of avenues nnd approaches, the one hard fact that we must face up to is that there is so much more to find out. We will not find out from over-simplified and pcrhaps super(icial conclusirms as to causation. Such an allitud- would only stille or delay needed retearch 1o find the baqk origins of lung cnncer and cardinvascular tliseaacs, which are most powerful, diversified and deadly enemies to nur wcll-txinR Nor will they he s.dved by puhlic prrmonncemenla or by reu.lu- tirtns or by rcview committees that concern Ihemselves srdcly with suRges- tive nr inctrmQlclc dala. The answers will come only frnm the ;tccumuLatirrn :rnd ciwndinalinn of creative knowlrJp,c acqnircd in many fielda rif endr.tvr,r atrrr palient, careful study 5

SrnflUirnl Ilnfn R.qulr• Clmrlii. In hfhrr Arrn. l'he mrmhcrs rrf the Scientific Adviany Ffrrard h:rve rclx•att'dlv nraJe clear they feel that the slatistical Jata thue; far advanccJ to shnw a sr.nrirrirnf nrawinrinn between smoking and various discascs are sullicicntly suFReslive and important to juslify and, indeeJ, tu require a Rreat Jcal of further reacarch in other major areas. 1 his is necessary in order tr+ evaluatc thc e.i+linR data accurately and to make (rnsible a more scicnti/ic definition anJ analysis of the problems involved. In spite of thesc often-rel+ealed statemcnls, there aprarcntly slill exict mi.understandinRs and misstatements of cwr attitude in this malter. 1t may be of value. Iherefore, to suRFest certain s/eps in research which can be taken Its prnvitlc evidence that will have a higher degree of scientiGc value and that should help in the necess:rry definition and :rnalycis to which reference has been made. R..rnrrR Sfrp. SuRRr.red hirst, further eflrnls should he made to see whether cancer can he in. duced in animal tiseue by the direct kislication of whole smtrke instcad of by artificially rerersareJ cnndensates td smoke. Secnntl, epirkmir+InRical tlita shrtulJ he nhtaineJ hy direct clinical r+hservation rather than by qnevinnnaireet and hc:ntay opinion In such Iun,,ituJinal clinic:J studics, factr+rs anJ hahits other than smrtkinR shrrulJ also be included It is as important In knnw, for eRamhle, why the nver- whelrninR nrajnrity of heavy ciRarelte smrders dr+ rrrrt Jevchrp IunR c:rncer :s it is Irr know why the enmp:uatively amall percentage of srnrrkers Jtt. lhird, pathtdr+Rists need tn make concerted effrvts to imprrrve and aRree upr>n criteria G+r classificalion ttf human lung trnnrrrs into types such rl adenom and squarnnus cell cancer srr that stuJics n/ relative rates of incidence and of prtseihle cnvirnnmental anJ other in0uences nn such rates could be made more mrnningfrrl. Such recearch is entirely prtssihle It is aJrnilleJly Iime cnnsuminR anJ difficult hul it is a necessary tteppinReh,ne toward a level rtf knnwledpe which mud Ix attnincd on the rr+aJ trr arhrtion of the prtrhlcros that may he involved in tnhacco uce in relation 1r, health. Rrp.+rr fry rlr• .Crrrr.trlSr .Llrrl.nry IT.rnrrf 71tis year, for the firsl time since ite form:rtirtn rn mid l'/S4, the Scientific Advisnry llrrard m.rde a ft+rmal report tn thc I nhaccn IndrnaLry Retrarch ('rtnmrittee. llriet rclwnl, whith l.rr.ins trn (•:rre A. ctmsidcr. the rhanrrc Itiat h.vr rK i uurrl in Ihr l.rtt rvrrn yrart in thr alatrra rrf knrrwlrrtt'c ../ Il.r ~rl,ir~.nr.lnt. .•( .n...l-y 1,. hrelll, ir.irw• Ih. ll...nil• %ta'nlltit Ilrn Pram, and diicuscec the nceds and Jirectinns for furthcr rc-carch. l lu ISnarJ states in its report that so far as a linal srJutitm rrl cancer and heart Jiseate is concerneJ, scien(ific honesty reymres acknrrwacdgmcnt that, in the ahsence of greater knowledge of the fundanrental processes invnlved, a simple answer Iir what are not simpk Qucstitrns is unlikely in thc near futme. The Hn:vd has been fortunate in maintaining the scuuc personnel who jrrincJ it seven years ago. Recenlly, however, I)r. Julius 1t. ('nmrrx, /r., a member of the original Bmrd, found that after moving front Pennsylvania Irr (:difornia, the cnmhinalion of increesed professional reslxmsihilitics and genRra~hic distance was making it impossihk for him to attenJ ISoard meetinRs in the east with the regularity he desired. Ile has, thcrefnre, re- siRneJ frnm active memhership while retaining the same active interesl in Ihe Scientific Advisory fluard's program and the willinRness to help it in an advisory capacity 1)r. Comroe's Inss will be a very real rnx, for his kntrwlcJRc anJ originality are Rtea/. Appreciatittn alu> is e>tpressed for the eonstruclive ctrntrihutinns of -I .LR C. Rrantees and scientifie ennsullants, and of p:rrticipanls in the enn- fcrences splmenred by the Scientific Advisory FtnarJ. "I he rrmemlxrs of the 'f I R('. alar are to be commended for Iheir eontinued, Fcncruus auplxul of Ihc rescarch proRram, and fcx enabling Ihose of us reslwrn%ihtc for the frr+gram Itr work with Ihe most complete frecdom. l heir Iru.t in the mcm- hcrs of the Scientific Advisory Ilnard is stimulating and warming. C. C. Lnit r Cr irnliflr I )irr. tnr 7 ti

Report Iry Ilre S(;1EAN7'lFl(; AI)V1S()Itl' It()Alil) to tlre T/11IA(:(:(/ INI/(ItiT11Y It!•;tiFAR(:1/ f'Of111111'ITF:F. At the end t,f itc firtt tix ycart t,f r,reratit,n, the Sricntific Advicnry flr,artl dccmc it ndvic:,hlr In takc tlt,ck t,f Ihe chanpcc which havc r,t currt•d tluring tllit f,t•ri„tt in Ihe ttatut nt nur knnwlellyc t,f Il,c rclatir,n.hil, t,f tmnking to hc:,llh. In review i1t scicrltifrc prt,gram, and tn cnncitlcr thw needs and tlirt•clitm for furlher wnrk. At the rrnlr IIIr Itt,:,rd wac ectahtichcd, cpidcmildt,fica( ctuttict rcfxat- inR in acct,ciatit,n hc-Iwccn ciR:rrctte tmnking and cant'cr t+f Ihc IunKc were LcinR e><tcncivcly pul,licired 'Ihc hyptHhccic that thit rclatit,rr.hip mip.ht rcfreccnt a cantal t,ne wat hated in part u(,tm cupcrinlcnlal ttwticc ill whith it wat rc(,t,rtctl Ihil thc pruh,nFcd appflcaYl,n t,f ccrtain cirnrt'ttc crnt,kc ctmdcncatcc In the tkin of the mr+uce wac c:,l+:rhlc nf prnttucing malign:lnl chanRct. 11 it frt,m thit f.cttpcclivc Ihat arlv:rncct in nnr undcrcl,n hng nf Ihc prtr},Icnr dnrinp, fhc I+ati cix ycarc mutl Lc evalunIrJ. Maj.ir elTort h:rc hccn dcvtdrd In the inrlcpcmlcnt itrvectiP:rli,m td the two Rrcat fichk I+f cancer and t,l cardit,vaccular Jitcace. Ilterc have hecn dc/inilc atlvintrt in knt,wtcdpc and imprnvcmcntt in Icchniqnc. So f:,r at cnrtccrnt n final ct,lntinn t,/ Ihe prt,t.lcmc, ccicntitic h„nrtty rcqnirt•t ac- knt,wlydgmcnt that, in the ahccnce t,f Freatct knnwlcdfe uf thc fumlanlrntat prnt•ccccc cnnccrned, a timplc ancwcr tlt what are not timplc yncctit,nc it untikcly in the ncar fufure. F,rtrnrrdrd Rr'.a•nr.-h (Iffrr. Rr.tt llrrlrr ('nntinuctl clltatt in ttimuIafc Ihc hrnadeninc antl tfcereninr, I,f re- cc:,rch in aII arcat whcre knowltdy.c ic dt•ficicnt tdlcr Ihc hcct ht,f+e fnr L',c futnrc Much tut t,ur rea•arch lanl,r:un hat f.ecn funtlmmn•ntal nr ha~ic in char:rctcr -:,n arc:r where pt,+rtete it Irtc (t-rl.lin hul IIlr fw,c.ihlc rcwardt rre:,tcr. '11hit h:,c hrcn :,chievcd wilhnut ncl.lt'clinp t linit :tl pruhlcnrt ar'J trthcrt having (uattical aly,licatinn. N;uurnlly, it takct tintc fnr n vcnturc nf Ihit ct,rt Ir, P~t•t unltrr way, h,rt il ic n,+tc.vt,rlhy Ih:,t gr:mtt Ir:tvr I,ccn matlc It, mtnr Ilh.,n ItN/ cticnti.ft rln :,h„ul 11) mrtlit'al tthtm,lt and tdhrr rrtt•arttr in.tiuwi mn. Ihttarl4l„nl ILr ,„nnltv. rrl„rNrnlin/• an nvtf:,ll (Irnantult .nf,la,tt uI nt':,rly t•1,/NN1-f/l/ll Already appr.,aimatefy 137 cnnfrihutinns presenting Ihe rctults of work dnnc undcr Ihit tuphtat have been puhlisired in Ihe ct•icntifiC literalore. livcn Iht,up.h it mutl he admitted that the effr,rl thm f:v hac barely scr:ttchcd the turface, e.cellenl scientific studies have hccn reported, and it can contidt•ntty he assumed that the facls revealed will ullirnatcly cnn- Irihute to Ihc totutian of the broad yuestions which concern uc. Hul per- haps the mnct tignificant development has been 1hc general recognition that we do not yet have the answers, that an association between the extent of tobacco use and the incidence of lung cancer does not prove a cautal rela- tir,nchip, ttctt cwpcrimenlal veriRcatinn it ctsential and that lhcre are a numher nf other factt,rt which need to he concidered. We are not satitfied tn Ict the problem recl with statistical reports suRRetling that heavy srnnking increacet the rick t,f cancer of the (unR; we are intcresled akv in knt,win6 why the overwhelming majnrily nf heavy smokers do nt+t contract the dicease dctpitc their smoking. We are also vitally interested in the meaninS uf the rearltt, derived from Illc +tame dala, that only a tmall fractit,n of the repurlcd cxcecc dcatht in the heavy smoking group is iItributablc to cancer of the hmg. I,nnR l'atlrrrlrrRy Strr.ly oJ 3,000 Casrs In revicwinR the resu(ts of the scientific (+rt,rram, a few c(,cciffc con- trihulit,ns will he selected which are ilhnlrattvc of the v:vinut linet of research undcr way and which have contributed to a changc in viewpt,inl. A ccx,pcralive sludy of tung pathology on aulopry ntalcrial in -l,(NN) catcs frtrm 12 hospitals in notable in several respects. It reveated wide dilfcrenccs in interpretation uf the same slides by ditferent rnernhcrs of Ihc grntrp. II demunstraled a high incidence of epilhelial changes in the hrtrnt;hit,les, evcn in the rounger aRe groups and, while the incidence of hyrcrptacia and mctaplasra waa urmewhat Rreater in Ihnse with a hitlnry u/ heavy cmt,kinR, "carcinnma-in-silu" was seltlom secn. An experimental sludy in which mice were e><pnsed fa cigarette smnke daily retulled in chrnnic hranchitic in a variable proportion of mice in each group witlr cpi/heliai prnliticratiun which in tnntc instances rescmhtctl "cart:int,rna- in-silu," hut never proRrested to carcinorna and reverted to normal when expt,cure to snu,kc wnt dict•anlinucd '1hcse studies were significant ( I) in tlemnnstrating Ihe need for 1nt1(rer sludy of tittue pathology wilh reference lu Ihc rtttc uf infection and the unifnrntity of inlerprrlaliun, and (2) in hrinFing irHn yncclitm the validity of 7desi6nating hypcrplastic chanFes in lung epithclium as precanccrous. ' A large noml,er of differcnl biological systenis, including rnnuce-tkin painting, have fx•cn tried in Ihe attempt It+ ettahlith ttnnc relative fwltcncy rating Inr eifarrtte tnwke cundentate nn a rational senle r,f carcim,r.enic activity 'f he srnnke cr,ndentale hast proved to he inactive in mtrsl nt thete tetlt, and in tcvcral cates dre mclhndt have been found untalitfaclt,ry for Ihe intcnded purf>„tr. Nn dcfrnile eviderree eaitts Ihal Ihe retpnncet uf painted mtrute tkint ate inlerl,rclahte indicators t+f earcinnRenic harardi h,r the human lunr: ('nntrtyucnlly, we hnve selcctctl a few trf tht• rnntt `tttl rnitinr. hir,atcay Irchnitluct fr,t ftulher sludy nnd devetnl,menl in the Itu(,e uf I+crfet:ting a mnle ral+id nnd tcliahle atcay. 'Ihuugh it t_cuvlut be r A 9 J ©

I said that a relative potency titinR fnr cigarette smnke eondeneale has yet been achieved in any quantitative scnse, the exten+ive aSSay crprrience has created the general insfiression nf auch kehfe activity as tn shift the hxus nf attentinn to olfier plausible mechanisms whereby tobacco smoke might contrihute by indirect means to the palhtrgenesis of cancer. Studies nf the influcnct of smnkin6 on Rastmintestinal function have ahnwn that there is no signiacant effect, either in normal pcrsnns or in ulcer patients, on the eompenition, amounts or rrt.prrtict of Ractric secte- linns as indicated by eight measured paramelere l hcse findings suggest that the reported statistical eorrelation of cigarette smoking and peptic ulcer may reflect association between the ulcer-prone temperament and a tendency to smoke rather than a causal contribution of snntking to u/cer Renesis. The cardiovascular research program has shown that the response in man of the peripheral vascular system to nicotine is usually, but not always, a diminished blood flow in the skin of the extremitie., while dila- tion occurs in the deeper tinues. Changes in the coronary artery circula-' lion, when nicotine ahsorptit.n is sufficient, are in the ditectitm nf incrrased hhxxf flow sutTrcirnt to meet increased (uxyRen demand altendinr increased ntuscular wnrk. 7here is sorne indication that these tesfxtnses may he modified in the presence of a croscknnis Measnrements nf cerchral blood flnw in healthy persons stowed nn significant ehanges induced by smoking. l1i f)t'rrrtr•r•a Rr/rortrr>t Rrrur.rn Smokrra nr1r1 Nrsn-Smnkrra Evidenee has been collected in show that smokers, esl.ecialty heavy smnkers, differ in Icmf+eramenl and personality fhnm IiRht or nnn smokers. More recently, an assnciatiun hclween -.mt+kinR patterns and txxly build has atso heen demnnstrated. lbcse nhurvalions conform with earlier studies on twins, and lend snpporl to the concept that at Icast sttme part of the assrxiatirins nf smnkin6 with particular rlisrases ritay reflect a ctanrnttn enn- stilutinnal predisfxnition rathcr than direct contribution or srnukinR to causation. Studies of pulmonary physiology as affected by .mnkinR have shnwn no consistent significant changes in hhwK1 gas eachanle at rest or after one-minute step up exercise, hnt some fall in oxyRcn urlake dnrinR tread- mill e.ercise after smokinR. Pulrnanary compliance has f.een varitrusly re- ~+c.r1ed as decreased after sntokinR and Also a1 unaRected in normal fxratns. In emphyscma and chronic hrnnchilis the changes induced hy smt,kinR are pcater. l.onR•lime smokers are rernrted to show snrnewh:tl incrca;ed residual IunR vnlume, and hrwly plethysmnRrarh mcasurenrrnt indreatrs snmewhat increased airway resiatance fedlnwiny, srnttkinF, an rtlcct not dnc in nicutine A etrnsideralrlr mmrher of ha.ic uuAics have trccn efrme whit h rel•rr- +ent imiMtrtanl cnMnhulittns tct r,ut rcscarch prt,pta+n. F.ul which wi/l not be dca'ritxd here in rlrtait Some nl these are in the Pencrnl arra nt chrniic:tl synthesis and hrcakdtown of the ct-nstiturntc ttf tnlraccrr inclurling mrrhyla- linn trattittns, mNa,,,li~rn r.f fiyrirlinr cnml-inrMs, rntyrnntic fii,tu„rn r+f ((),, .nd rhr IMJyl,hcnt'l ct,nlcnl trt Iravrs ()thcr slutlies have c„nicrned If/ t fnndamental aq+ects of eareinn6enesis, and include observations on the early changes in the lunils of tumar-bearinR rats, the cyarluRy and nuclear dcowyrihtnnrctcic changes of skin and lung epithclium exposed tn catcino- gens, and the action of carcinogens on cultures of huntan IunR lis.ne. With T-.I R C. suppcxt various aetivities, designed to pntniote the ob- ctives (+f the Scientific Advisory hoard other than through research 6rants, have heen initiated. These include the preparation of a"slandard" cigarette smoke crnndensate produced under eonditktns of natural smukinR, thus makinR available to grantees a uniform product. To overcome the shorlate of inhred slraim. of mice needed in the research prolqram, a gant was made tu expand breeding facilities. In jorrtrel (:on/rrencea to Fxc)renRe Ideas, Knowledge rot the purpnse of promotinR the exchange of ideas and to evaluate the atatus of existing knowkdge, a number of informal conferences of workers in specific topics have been held. A conference of pathnlnRish, meeting to cttnsider the signifxance of changes in the lung epithclium, has Icd in a crMrperative sludy, mentioned elsewhere in this rep,srt, which has bcen the suhjcct of scveral additional conferences. Three conferences con- cerned with the cardiovascutar effects of nicotine and smnk in6 culminated in the orRaniration of a three-day public symposium on the subject held under the auspices of the New York Academy of Sciences in March 1960. In the field ~f tissue culture, the topic of two informal cnnterences, there was recognition of the shortage of trained pursonncl and provision has been made to enahle several 1aMxatories to train additional workers in the spe- cialired Iechniques required. Other canferences, all of which have contributed lo the scientific pro- Fram of the Uoard, include two on hioassay of carcinogenic compounds, one on the role of infections in the senesis of lung cancer, and two on the hcarin6 of constitutitmal or psychological diffetences on smoking habits. lhe T.I.R.C. has also rrovided funds to make possible a symprxium on At- musplreric faclors in disease heW lanuatp 1960 at the University of C'ali- furnia under the litle, "7he Air We flreathe." With the object of encouraging able students to embark on a career in science, an annual grant has heen made available Iro ench ntedical schrKtl in the lMitcd States tu provide a felluwahip for wrrrk durinR Ihe snrunur nrnnths or other holiday perirxl, unrestricled as Itn subjecl. lknrnher si/;niticanl conttiMrtitm has been a Rtnnt 1u make I+t+ssihie the prcparatirm r,f A hntrk nn the hiolugic effects of tobacco and nicrrtine which will I,c puhlkhcd in the neAr tuture. This larRe valumc, hnsed tin a very conqdete review of the wnrld's literature, shrnrld scrvc as nn invaluahle scauce htNtk fnt infurmalion on Ihe suhject. Alrrrry Itrsr•nrr•ir Arrna /irinR Stttrtfrrl 'I hc Scicntific Advisory ftoard has Itivcm mtich crmsitlcratirrn tn the dirrclittn nnd enel,ltasis of ils rescarch prrrl rattl As it can rnrra latr/it:ihly he developed in thr ycars immediatcly Ahcad In nrtttt inalant'cs stutthrs ntrw unrlcr w:ty rnncl I,r ctrnrrinncd bul the Ilnard it cit(rlrrrinR nnrl, in st,mr cnscs. Itlatts nte wcll ctlt+nR tttt c tltandinR, certain lines nf wurk and atddinK t,thcrs II

t hrxc tcccivinR rnncidetalinn arc: I I hc fx+cail.le role tit t,rcvinus infcclir,nc tit injnrics in the nril!in tit 2. IunR cancer. Vttcnsit+n nt hinacsay r.ncth,Kls (nr carcinnRcnic activitY. A crunrarative stndy of Ihc activity tit Pipc, cigar and ciparclte hrh:rccn cnrnke condcncatcs prnduccJ undcr idcntic:+I cnndititmt. 4. Imprnvcn,cnt in t1i:rRnncis of early IunR Iccianc. 5. 1 he tx+ccihle rt,lt of viruset in earcint,Rcntcic. 6. l he qucetinn of threshold dose and latenl time in chemical car- tinnKcnccis. ' 7. 7hc hiolnfical activity af smnke in termc of the rclalinnchil+ he- twctn its varitnrs cnmf,c,nenls with a view tn throwing Figt t on p+aeihle anticarcinnRenic influcnces of analnRues. R. litttncinn nf the /icsuc culture techniquc for ctudyinF nnrntal and ahnnrmat Rrowths, includinR utilizinR the newly l+crfcclccl .yn- Ihctic m47116. 9 I'urlhcr ctuJics nf the influcncc tit anu,kc and nthct atmr,cldretic Ixdlulants On the IininP tit 1hc Mt+nchi, includinR tlhc atrrvity of Ihc cilia . I(1 l t+i,lerni„Inp,ical ctudies in relatir,n to Nhnic, sncial, cct,h,Rie and cuhural rhflcrcnces. 11. A pithnlnRic study nf urhin and rnral po{,ulatinnc. 12. ('nmrncitinn nf cmnke with reF:uJ tn particle cize and cnncentta- tinn nncl irritant aclinn t.f cr+t++y",ncnts, singly and cnrnhincd. 11. Mtch:tnians of parliclc nhcurlHiun and tr:rnclxat hy rcci+itatnry ctllc, nf nnrmal and altcrnt mucr,ns cectelinn, tit nnrmal anJ al- Itrcd ciliary activily, antl of nrrrntat and altcrcd ccllnlar rcrcn- ctalinn, 14. The tnle nf thc r,utoni+mic ncrvnus tystcm in modifying thc tntal hnet respc+n<e and that of Ihe resririlt+ry cl,ilhcliunt 15. Studies nf hum:,n twins (nr the purpnsc nf analyzinR heredilary and envirnnmenral factors in diceaa.. 16. Pnssihle changes in moulh and throat micrrN,rR:rnisms in srnnken. 17. C'artlinvaccular respnncea tn smnkinR in snhjecls with :,Ihcrn- scltrosis and othcr disardcrs, including a dircct stu,ly nf rctinat vcs+els. 19. InOnence of smokinR and nict,tine nn the cr+mflncitit,n and prnp- erties of blood. 19. Cnntprricon tit the (+cythnrn~iraI And I,hycinlrrRicaI cffccr. nf smukinR with Ihn~e t.l Iranyu,tircrs 20. lhe qucstit+n of tx,scihle a1lerRic rtactian. ti. Ir,hacc„ tnuAe 21. A ct,mparican af thc I+hycical, carnlinnal unrl I-ythoh,pical char actcricticc tit cmnkcts with nun-smr,kcrc 2] 11u r/1r,1~ „l Stnl,l.inr, cm„kinp I r T.I.R.C.'. Support .lppreciated In concluding this repnrt, the Scicntific Advisory Board wishes to record its appreciation to the Tobacco Industry Research Committee for prnvidinR large sums for research and for approving all its recommcndatinns withnut question. fl is appropriate to make brief reference to the Board's experience since its establishment. "The Ilnard has held meetings at kast quarterly since its organization, and has awarded considerable money to investiaators, but this prl;sent com- n,trnication is the first report it has made to its sponsoring organization and this withrntl request. To u1 forth an evaluation of accomplishment made by this approach 'o the suhject, whilc the credit does not accrue to the Board or its memisen, certainly one of the most siRnificant occurrences is that a major business indus(ry has organized itself to determine so far as possible what, if any, effect its prtxfucts have on the health and well-being of ils customers. We must continue to search for scientific taknt dedicated to thc seeking af knowledge and support it fully so that it ma~ be freed of insccnrity which may hant.lrinR il. We must continue to kt it be known that we are in that search, and applicants for projeeled research ahnutd t.e supported if their idcas nre prnrnrsrng and their opportunitka good. We musl cnntinue effnrrs In stimulate broadening and deepening of rexarch in all of the nress where knowledge is scant. We must not be disturbed by inconclusive andlor faulty «porls, nor resct against them defensively. We must continue to promote true basie research in the inlrncellulsr processcs tit life and in the multice11u1ar living organization even thtwgh, in some inslanccs, this will have no obvious or immediate connection with the practical quection of tobacco and health. At the tobacco industry continues ils support of the search for truth and knowlcdge, it must recognize. as is Iways the case in true scientific research. Ihere can be no promise of a quick answer. The imptirtant thing is to keep on addinR to knowledge until the accumulative Iacls provide ttx basis for a sound conclusion. Kenneth Merrill Lyrxh, M.D., ScD., LL.D., Chai.nton Richard 1. Bing, M.D. McKecn Cattett, Ph.D., M.D. lxon O. Jacobson, M.D. Paul Kotin, M.1). (larence ('a,k i.itllc, Sc.D., LL.[)., Litt.D. Stanley P. Rcimann, M.[)., Sc.D. . William F. Ricnhnfl, lr., M.D. E?dwin 11. Wilson, Ph i)., 1.1,.1). 12 13

Results of Research The constantty gowing number of puhlished papers on sludics sup- ported by the Tobacco Industry Rescarch Conrntittee is a mcasure of the prnRress of the research proRram. These papers, which lotaled approxi- mately 137 by the end of (ktnher 1960. are ahatracted individually or listcd elsewhere in this Report. An additional 22 papers, given at a cardio- vatcular conference held during the year, were subseqaently published and re listcd on page 22. In this section are summaries of the findinRs and major points in several important fields of study. At times the summaries may cov-r re- search not yct puhlished in full. Not all the studies in progress or com- pleted are tliscu.sed here. Thr%r aumrnarirs are• I(-ancer firse>trch; 11 Ifurnan I unR S/udics; III Ilcirt and ('iTculatn+n; IV. Ptychn phyiinlopieal, and V Tohaceo (-hemidry 1. (:onr Pr Resrnrr•h Sevcral studict on Ihe effects of tobacco srnoke and of smoke con- dcnaales nn anim-A liccues h.ve been rcptrrtcd JorinR the pasl year, at well as a number t+f cnllatrr:rl atudies in the cinccr firld whith diJ not involve the use of tobacco Tobacco smnkr c~ ndrm~trt in Ii.lurJ f ctrnl;rlunr wcrc intrniluccd into Ihe trachea of young adull duckt tl.rrlv rwer hurR rrrinds ul trme ann en- cnmpacsing up to 110 injcctiona No changes WFr.cctinR ncoplasia dc- vclnped, thnugh .nme acute and chronic reactions occurrett Mnh amnng treated docks and in same untreated birds as well at in some receiving only petrolatum. M one of a series of control sludies, ducks were also given rncthylcholanlhrcne in aeveral forms by the nra/ route. GaslrointestinTf system tumors were not pr«fuced by Ihcse means. An ex/ensive study was ctrmpleted to deterrnine and compare the eRccls o( various inhaled gases and aerosnls on the activity of the cilia of hrnnchial epitheliurn and the rate of flow of the mucuus slrcam. Various inh:rled aRenls, including tnhaccn ~muke, were (ound to he capable of /emptaarily inhihiting ciliary activity nnd delaying movement nt the mncous htanket. Tbe eorrclatinn o( Iheae effects with meupholagic chanRes of the reapiralnry erithrlium was nhrr heRun 'lhrse ohscrvatinn+ have cm/+haaircd the need (nt further wttrk tn evaluate the hmctierns r+f ntucaa ae a prr+tective mnterial, the drf.cnrlcncr of iti functinnt ufxm c'hcrniral anJ I+hy.icnl cnm f++ni/ir+tt., aftil ,I+c (:+t lmt whith t'~n nmatify cr+m(ti~tilinn T he tnrch.rni.rns I , that influence ciliary activity seem also to call for further elucidation, af dtxs the overafl tofe uf ahe ciliary-mucus system in proleclion against exlraneous inhalcd careinr>Renic aRenls. New studies have been authcxired along such lines and an investigation of the effects of air ions upern cilrary behavior has bccn undertaken. Smnlr. ffnr no E:erct on Mnn.e /,unR Ad.noma. Two scientists, reporting further on their tobacco smoke inhalalion sludies, (ound that the incidence of Rrossfy visible lung adennmas in female CFr mice is unaffected by prolonged snwke exposure. ('ollateral studies have included extensive observations of the chrom- osome numbers and pbidr of human and animal cells cultivated in virro, and obscrvatirrns on the responses of mousc and human cells cultured in virro tn acetaftkhyde eapenure. Another researcher has nhserved the sensitivity ot Ihc rnnuse fore• stumach to carcinoRenie hydrucarht+ns painted nn the skin nr arlrninisleretl orally, and has suRgested the utilization of thia scnsitivily as a hnais for  bioacsay technique. An eRperimenl has shown the enhanced ability of lissue slices from several organs of rals bearinR (he Walker or Jensen tumar to inccapotate labelled Ihymidine into deoayrilxHSUckic acid (1)NA ). Annthcr investigatnr ha% reported detailed pathohrRic studies of the interrelations helwecn inflammation, keratini>'atirxr and RIyu+Rcn deposilion in alvcnlar mucosa and gingiva. l:nn/.r.ncr nn (:.ll nnd Ti.aue Calturr TTre T.1 R.('. has been supporting research in the ficld ol tissue culture (or some time. I he wotk las included attempts to eatahlish strains of dif- ferent human lissues, especially lung lissues, so that reaponsea of such lissues to carcinoRenic and other agents could be ohsetved. It is hoped that this area of endeavor will provide new and helpful in(ormata)n a(xwt the mechanisms of carcinogenesis. (irantee+ and other scientists working in cell and lisare culture or related ficlds of reacarch met for a diacussion nn May 24. 1960 AmonR thuse present, in ,ddilion to members of the Scienlific Advirtrry 1lnard, were Ihe folltrwinR: OR. PIIt1.IP ('(x)PI: .R, hR. IVY (IO11)RIN(i, MR. MORRIS KI I:tN, Mt.erl F.indein ('olltRt td Mtdicint, Ntw Ywk, N Y. 1)R. (iFUROI O (',f Y, 1)R. MARY Rt t7O, M1SS Itt:.t)A I INI)1'N, I innry ltu.•rll ('.ncrr Rr.cuth I slw.nurmy. Ir.hn. /IopAin. lt4..pil.l, 1lallimnrc. Maryl.nd DR. ('1 ( 11 W i 111('II It N141•R(;I R, ('hildrtti% ('nncct Rt.c.'r.h 1'uunAation, 1luslon, hta.iachusNl. 14 IS

f)R. AI.VIN S I IiV1NV, Indiana (In/ver\Ity MrJ/l':d (-rntrr, Indlan- qrdis, Indian. DR 1111 1. P. MAI)UROS, Ihc Itrktncn Inaitute Inr kIrdic.t Re- je.rch, ChicaRo, Illinnk DR IX/NAI 1) M. PA('fi, Inainne for ('rlhdar Rricarch, ltnivrrmity of Nchreak., I.inculn, Nrhra.ka DR O I fOI I AK• DR. lAIStrO K(1K1t1111, MRS PAICY S Mf1RROW• IMvcr Medical Re.esrch ('rntcr. Inc , Unver, 1)clawue I)R (-. M POMfiRAT•, 1)R. A. AWA. DR. Y. OIINUKI, lhc llni- 1)R vcr.ily of I c.a. Medical Rranch, (:alve.t,.n, I curs AI.AN S RARSUN, Pa11x.k+Ric•Anatnmy I)cPartmcnr, Na/innal In.titurei of (le.llh, Rethe.Ja, Maryland DR. SARA/1 E. STF.WARI, L.horatnry of RiolnFy, Natinnat (':rnccr Inititurr, Rrthnda, Maryland 1)R. ('HARIIY WAYMOUfll• Rmcrx R. )ackurn Mrnu.rinl I aMor- tory, Rar llarl.nr, Maine I'IrnlnRy ( an/.renre On May 21, 1960. an informal conference covering llie suhicct nf virtnes nnJ thcir plrssilhle relaliunship to human cancer was hclJ I)iscus- sinn centerrd un the present slatq nf knowledge concerning the role of viruses in c:rrcimrFenesis, and prnmisinR areas for future rescarch. Meml.crs (•f The Scientific Advisnry 11narJ attendctt the sessitrn, as did Ihe following recipients of l I R(-. Rrants nnd nthers doing research in Ihe ficlJ: I1R, 1/1(/MnS P ANI)I RSON. Ihr InditWe for ('ancer Research, ('hil.Jclrhia, Pcnrnylvania 11R. 1'I111 II' 1)R IVY (i()1 1)RIN(:, AIF.rrt (?invcin ('nl- IrRr nt M"hcinr• New Ynrk, N. V. 1)R. (il'(/R(71? (71:Y, DR A1ARY Rf1.1/, I innry Ilnwcll ('ancrr Re- nearch I alx.ratnry, lohn. Itnpkint Ilntrit:J. H:rllimnrr, tvlaryl;rntl 1)R. ('f('I1 I(; I 1:(1('1111'Nf11 R(i! R, ( hildren'. ('anccr Rc%carch 1'ounJatKrn, Rnitnn, Ma..achusrtti DR. AI.VIN S I 1?VINE, InJirna thtiversity Mrdical ('enter, InJian .I+olis, Indionn DR. R111. P. MAf)URf1S, The Ifeklr.cn Inaitulr for Medical Rr fr.rch, ('hiuRo, Illinois DR. ('IIRISTUPIII:R M MnRIIN, I)ivision of Infrctinus 1)i.r.ers• Scton IIaIt ( nllcRe tlf Mcnccrne, Icrsey ( ily, New )rrsry 1)R C. M POMFRAI•, The Ilniver+ity of lr.a MeJical I)rnn(h, (:alvcdon, Ir.a. DR. AI.AN S RA/ICON, PalhnlnRic-Anatrmty 1)cpartmcnt, Nati.m:J Inslitrnrs of Ilralth, I1ct/,csJa, Mnryl.nd 1)R. SARA11 Sl1 WAR 1, 1 ah.xarnry nf Ili.d.r~y, NatinnA ('nncrr In.litutr, RrrhrsJ., Marylnnd 1)R. IIt)WARI) M 11'MIN, 1)ivisiun of fln.lnr.y, of Irihnnh.Ry, PaV/JCr1J, ( NIIlnrnia (':Jilnrnin Inatilulr I/R ( IInRIIY WAYM()(/III, Rrn...r 11 ),"'n Mcrnnnll I [:ven prior to this cnnference, increascd emphasis had heen placed upon rescarch to evaluate the possible rnk of viruscs in carcinoRenesu. I he study of virus infections of the respiralory system of rnice in producing tlysplasias either with or without smoke inhalation had heen undertaken as an t•><fension of the smuke inhalation sludies. Investigatinns of the inler- aclinn of pdynuclear hydrocarlXins and of trace melals with viruses have alsn been sf+trnsnreJ. Synrpmium on "TR,, Alr Rt'. Rr.ethe" On January I(i-18, 1960. a conference was held at San Francicco on '•Man and Ilis I?nvironmenl: lhe Air We Breathe" under the combined auspices of the llniversily of Califnrnia Schrwl of Medicine and University F:atensiun-I)epartment of Continuing F:ducation in Medicine and IItalIh Sciences. Partial financial assistance frx the meeting was contributed under a grant aprrnved by the Scientific Advisory Hnard. 'Ihe Ihrec-day scssiun crmsirkreJ the environment as a whole and frtwu Ihe widcs/ birrla8ie point nf view. Seienlisls came hrnn the Uniled Statcs, FnRI:mJ, Wales, ('eru, and New 7.ealand, and many disciplines were represented. Among those present were physicians, palhnlnRisls, physiodo- gists, ecnlogists, town planners, and engineers. 'fhe problem of air pollution appeared lo he uppermnst in the minds nf virtually all the participanls, and the subjccl nf smnR was stressed in many of the papers. ll)e statistical analysis of lohacco in relation to lung cancer was the theme of a discussion by two scientists with cnnlraslinR views. Une siynificanl report was made by a New Zealand scientist who Jis- cussed his finJinRs on lung cancer among EnRlishmcn who miRratcJ 14, New 7.ealand as compared with nalives of that country. Itolh Rroups had the same c~mstilutinnal or hereditary makeup, the snmc way of life, at>,1 sintilar eating anJ smukinR hahils. Itul Ihe former camc frum smnR-fillcd industrial alrnnsphere into an unpolluted atmosphere. 1'he incidence nf lung cancer was J/) percent higher amnnR Ihe iatmi- Rranls generally Ihan arunng the native-born white residcnts 11ut imrniRrants who came tn New Zealand telatively late in life, n/ler spcndinP llt or more years in 1•:nRlaml, had a lung cancer incidence alxiut 75 prrcrnt ahrrve Ihat for New 7ealanJrrs (tf the same age. The Nrr.cceJinPs of The sympraium are esreclcd Irr l.c huF.lishcd shnrtly. 11. llrtmnn LunR Slrrrli('. lhe nrrrl fnr mnre ndequa/e and comprehensive mcthr"ls for nrrn%ur- inr. nnJ rv;JunUnP hnm:m lun/ lunclinn has FK'cn rrt'rrpnvrJ us rnrc nirans rd irnlarwinP thc study r.f clnrmic anJ prupressivc IunF Aict.r.cs A I 1 RC O. A r r, 17 J 4~

I i Rtanlce haa I+uhh.hcd Iurllier wttrk rcf+outinR :t hattcry tit tuch teats with irnrrnvcrncnta and rmKlilicatitrns. I hc cflccta nf amtrkinR nn cuth hulrntmary functitm h:v:unctcri have Previt,ucly I.ecn rcht,rJCd in a nunJrcr cd puh- Iiahcd .tudic+ New studici havc hccn undcrt:rkcn ttt crnplny lihc IxK1y plcthycmoRraph for mtnc prcckc dctcrminalion tit airway rctistanc'r and reaiduml IunR vtdume, 1'articipaliun in a prtrclx•ctivc study nf chrttnic hing discIce h:r% alco been cllcctcd in the cxf.ectatitrn of attaininR morc prcciac t/clinitittn tit these clinical cf+ndilit+ns, IK•tter relalive ev:rluation of etitdugic factrrrs Ihat cun- trihutc tu their oriFin or aRFravatitm, and fullcr undcralantlinR td their intcrrclalinnshirs, natural hictnry, and Ircalment. 1 I1. llr•arf and (:irr•rrGrfirrn A cr+naitlerahlc numher u/ investiratitrnc in this field reacltcd puhlica- tifm durinR thc year, nf whic'h mmc than half wete nf a fundnrncnl:rl n:rturc LcarinR no drrect, immct)i:rte rtlation Itt tobicco clfectc hnt hn+:tdcninR the hasc uf underclandinR of cardittviyular mclaMtlism and funclnms lhel c arc dcacril.cd amnnr the eh.trac/c hrllnwinR Ihis seclinn. One Rrvrup trf ~t:icnticlq his ahnwn a cftrrclatinn between allergic re- actiont to Itrhacco c%tractc in henlthy tuhjccta :rnd their circulitrrry rc- SLtlnse4 tn amnkinR at mcisurrd by plNhyamtKrafhy, h:tllislnc:rrdit,l:rafhy, and tlcctrtt arditrRral hy 1 hctc rccults aukl-ctl a title of tnh:ucn ccncilivity in dctcrmininR the individual ditfcrcntcs in cardittviacular reaf.f.nacc that have hmp lxcn rcflcctcd in 7filircnt diccrcrancict amnnF thc IimlinRs tit dilfcrcnt invcstiKittrrs . The cnnalitnliftnal and heretlitary comptrncnta ftf rrctlitlxnilitm ttt cardittvatcular Jiae:tte h.tve rcccived furthcr clucidalittn thrmuFh the ctathes tit another invctitir.attu. Fvaluatit+n nf facttaa influencing scr.rrn chnlcsterul Icvclc frt+m (1ay Itt d.ry has perntittcd further cttntirmaliun nf the corrcla- titm between high mcan and rel:rtivcly /luclvalinR chtdcsterol Icvcls and thc inciJcncc t+f ct+rtm:ny tx'clu.it+n Familial tcntlcnt-ics in rcC:trt) trt hftth ttctIuvitm and hiyh aerum ch-clcstcrol were ohscrvcd Il.•rrrlirnry Unrtnra nn.f Snr..kinR /trhnri.rr ('nnstilutinnal tlifTcrcnccc between vnrrkcrt and mm anurkers have Itcrn rli%cnvcrcd whit h suyFett Ih.tl hcrcdit:try lat tr r. Ll.ty a vi/;ni/ic.tnl nrle as dctcrmin:trtta td %nntking f.clravitu within thc cnvirrrnmcnlal Ir.rrnrwruk uf Antcric:rn Ide Ile,tvy ciF:vetlc vntrkcra alwrw a.Irikinfly hiphrr in- cidcncc rit thc ~,cnctically dctctmined al,ility 141 I:t0r Inccnyttltinurca -Ihc .vm-kt-r.:t1.n, av .1 rr~nil., rntnc.ftt n P.ivr a ln%t.rry rd hvla-rtrn"wn tit I,trcntt Iht-y lr.rvr hrl•,ht•r ruc.ut v;ilncs hm hrarl ratc artd Iwl.c lactttnc, hil.hcr thulcstcrnl v4luea, annpri.c a IarRer profwxtitm tit heavy individuals, and mtrre rtltcn report e.pcricncinR anRer and an urRe tu eat when under slress. 7 hc crRt+metrinc stress Ictl for tcvealinR cruunary insuniciency in Lcrcnns with early coronary disease has been furlhcr stutlicd by trbscrva- titrns rtf thc cllccls tit Ihc drug on isolated ht:rrt% of chttlcslerul-1cd rabbits. Crtntparisnns with Ihc actitm uf vasopressin and nicotine have been carried nul. One researcher has reported the occurrence of lipid infiltration into thc iris of rahbils fed cholcslerul as a dietary additive. Additiun of nicotine to such diNs did not obviously rnodify the cfTect< of cholesterol. f:nrdifrr.vrrrufnr Sympoaium A cnnference on the "Catdiovascular Cffccls af Nicotine and Smoking" was held under the auspices of the New York Academy rif Scicnces in New York ('i1y, March 24-26. 1960. with a grant awarded by the Scientific Advistxy Hoard. In the expressed opinion of the participants, the Rreatest achievement of the mcetinR was to assess impartially the effect of cmt+kinR nn the heart and circulatittn. Thirly-four pafxra were presenled by scicmiatt engaged in cartliovatcular research, and two panel discussions were hcld an importanl phaces of this work. The crnnference, Iherefore, includcd an excellent repre- scn/alic.n of the investigators who have been studying Ihe effects of nicotine and smokinR on the heart and circulalion, and provided a funrm for dir cussinn of Ihcir eapcrimental findings. lhe evidence pre%cnled gave no indicatinn that smoking has an adverse effect un the normal heart or inlerfcrea with the ctxonary circulatittn. 7 hree papers presented tlala suMslinR that the tRccls of nicotine are allered by the prescnce nf coronary artery disease - an iml+rntant topic for further investigation. II was generally agreed that smoking shnukl be diccouraFed in patients with peripheral vascular diseast because, in many such pcraonc, smoking may result in vasoconuriction in the skin. Some evidence was presented to implicate an allergic basis for symptoms frnm smokinR when Ihey occur. Also or ttut.tandin6 interest was Ihe finding that differenc•ea in response to smnkinR apiKar to be in part genetically delerntined. Another sludy ahnwed that ndrninittratifm nr large dntes of nicotine to animala hrr f.rnlnn'ed hcritwla did nnt rcauh in palhnluFic changes rtr inlerlcrcncca with Prowlh. 'Ihe 14 (talrcrs presented al Ilre Ihree-day cnnfcrence, a% well as the cnnnncnts m.rde in twit panel diccusaiftns, were puhliahrd in full in the Serteml.cr 21. 1960. isave nf Annnh rrf rhr Nrrv Yr,.A .If f,drmv r~f .~llrnfrJ. 'Ihis ptihhcalifm's table tit cttnlents. IistinR the pafxri by lille and authttr, is given on page 22. t' 19 19 tn