Tobacco Documents Online

34 CTR HN 0112*r5

~ EXHIBIT / CTR HN 01 127G

1 REPORT of the SCIENTIFIC DIRECTOR CLARF.NCE COO}: trrTLE. Sc.D. Chairman. Scientifie Advisory Board Jul-- 1. 1956 • June 30. 1957 TOBACCO INDUSTRY RESEARCH COSUIITTEE 130 East 42nd Street. \e.. York 1-', 'N. I'. r •y ••',, CTR HN 0~. ~•~• ,f

i SCIE\?IFIC ADVISORY BOARD to the Tobacco Industry Research Committee CLARENCE COOK LITTLE. ScD.. LL.D.. LtTT. D. Chovman. Sctenttfic Advisory Board Scienrific Director, Tobacco industry Research Committee Director Emerirus. Roscoe B. Jackson Memorial Laboratory Bar Harbor. Maine McKEEv CATTELL. PH.D.. M.D. • Prolessor of Pharmacology Cornell University Medical College New York. N. Y. J' L'L'S H COMROE. JR.. M.D Director, Cardiovascular ResearA Ins:ttutc University of California Medical Center San Franctsco. California LrON 0. JACOBSON. M.D. Prorerror of Medicine. University of Chicago Director. Argonne Cancer Research Hospital Chicago. 1lltnots PAt1 KOTIN. M.D. Arrocratr Protersor of Parnolop L'nrversitv of Southern California School of Medicine Los Angeles. Calttornta F:ENNET}i MERRILL LYNCH. M.D.. Sc.D.. LL.D. Presrdent, Dean o1 Facuirs and Protessor ol Parnolog. Medical Coliece of Sou:n Carolina Charleston. South Caroitna STANLEY P REINfAN"N. N'. D . S~.D Scrrnnr;,; Drre;ro• rmrr:rus The lnstitute for Cancer Resea::~ D,recro• Er*.rr rus Tne Lancenau Hos-.itai Rese;irern lns::n:te Pauadc:p^ia. Pcnnsyivar.;a W7LLIA',! F. RIEN'HOFF. Ja..,l.D AlJOcrar[ ProreJso, of Su/Ffr% Jchns Hecktns L'nrversic% Scliooi of %1ed.cmc Baltt^ore. Mar.iand' EDWIN BNk1LSON. PH D. LL.D Proltssor Emrrrtus or Vita: Starrsrres Harvard L'nrvr.s r. Carnbre:e Nlassa:huse:is ROB---RT C. HOCKE 77. Px.D Assocrarr Screnrrc: Drrector C T~' N N 0 112-r--" 1 6

Organization and Policy . T:'e Tooacco lndurt.> Relearch Com,'nzrtee is tne sponscnn; of a researct: program into questions cf tobacco use and health 1: aas orcan:zd in euly 1954 b% representatives of tobacco manufa;:;:rc-<j irros+crs and warehousemen The Committee itself neither operates an. research faciluy nor has any determination in the scientific procrar•: c.n-r than mai:ng available neccssar. funds The 5crenriFc Ads•iron Boo.d to the Tobacco ]ndust-y Resear:- Ce-:natee bas full responstbil,e} for research polu} and prog•a^:n:;c: This Bcard consists of ntne tcde;enden: sctenttsts. doctors and ee ;:;;r Khc r:;a:n:a:n their respe:nse u•.s:::caona: af`itat:ons T-ne eha=-arn a,s_ serties as Sc:eat:5c D:re: er of :..: Tcca;;o Industn Research Cc rr-,::et The Sc:e^::^.c Adv:son Board ..oes .,... :tseif en_¢a;e in resear;r. 'cr :. Teea;;~ l:,e::str. Researc- Ce-.r:,::e- A:. research n;en:. is ^-ac.__ _.. ._.,,......_nda:,on cf __ S:._.... Ad%u:n Bcard tc caal:-~,e~ .n. , _ ..__.. YSt:f]:c:s uCrY::.g ... es;:: llsGed r':ed:;al S:hOols. un:%ersil:es ar.~, Other researc,', 1nSta~UC.^.s R: :e-ts of Tooac__ Researc., Co^tr^t.^.e- g7a:::s a:. assure: c,,:rp;e:e s;:cntt^; frrec~r.. ... ,,,nducueg thetr tnvesu¢attons an: repor.:ng the resuiis of tr.r:r rescar.n :n t1:e accepted sc:eetifc manr.c- thro.g^ a:eC:;ai an~ an~ sec:eues The u:vestu¢atcrs rece:v;r.E pants !re^ tn: are aiene responstbic for puciun:-: or re,cr..^.g t^e.. resear... ._._ .• CTR ~~~ t~11 ~ ~

Summarv Dunng the 12 months ended June 30. 1957, the Scientific Advtsor. Board approved 52 ¢rants-m-aid. aneludtne renewals, toultng 5550.000 Included is $35,000 (or scholarships to medical school studens for medtal research work in any held of their choosing One scholarship u ot?ered to eau: of the nation's accredited medttal schoois to encouraae medica: rescarcri a; tvtiaes. S:nce the start of the grant-in-aid research program in the 195a•55 fis:a: sear. the SctenttFc Advisory Board throu¢h June 30. 195'. bas niloca:%~ Sl,''15.200 in specific prole: s-to 6' tnLesu:a;ors sn S: of ::.e nauons ieadtn¢ universities. hospttals and rescarch mstttuuons During this same period, the 7obrcco Industry Research Cerr:rtttte.e has appreprtated funds amounting to 52.200.000 (or research g;a.n:s. tn- clud:nt a supplementar} 3200.000 appropriation requested by the Stsrntufic Ad%tsor. Board tn the 1956-57 fiscal year to meet spectal needs (or new F:rants DIRECTION ~oF RESEARCH P:;,marv attention has been given to developtng* research pro ect.s re- la:trc to cancer and hean aiimens. since tobacco use is one of man. fa::crs c.` modern-day life being generally investigated in the study c.` tnese daeases Pro: ess of medical researc!: is slow and patnstak:ne ;ianv promising a%enues must be followed before find:nc one that opens t,~e way io new ar.~ usef::: inewieCce No knoµn formula wiL' ou:cki% work out the s,-,n::e ans+er .o hu,^.,an health prebiems .Adsances are made b~ s:a.es . seme•+ha: as one would cut his way through lun¢?e under2rowti*i Sci;n' medical and ezper:mental knowiedee of tobacco use :s re:a- tivei- l:^::ed. a: ttnes contrad:cton, and often eonlenural rat.ner than fa; ua: Too little is known about mam• factors. includtne whc veor.e smokc or what kind of peopie become part}cuiar.• heav~ srnokr,s (Pages 1C-::. 16-1S.29-30 ) ON CANCER RESEARCN T„e probiem of causation of anytvpe of cancer is complez anC ;e anaiyie Al: research on this so-caiied eonsntuttona'l d:sease is. and mus: ^e. patnstaktng and ttme-eonsumtnE There is not knoa-n todav anN or eutck %.-av to answer the question of whether anv one factor has a roic :n causing human lung cancer (Pages 1:-13.) C CTR t ii 1 0112t-~ti..+r

0 Despite all the attenuon pven to smoktng as an accused fac:or trn human lung cancer. no one has establuhed that cigarette smore. or an. one of tts known eonsutuents, is eanccr<austng to man. I:evcrtneicss. :: was ruognsted as desirable to encourage scarch for possibte sutxtances :rn tooacco smoke that might sn some way be ancer<austng Antmai tesu have been eontradicton• and ambiguous in sndtcattng whethcr coocentra:e: smokc condensates produced under normal combustion condtuons can tn- duce sun cancer in experimental arumais. In an% case, it is kno4r ;.ia: antmai tests are not dtrectly zpplrcable to men. This situation ied to con- s:den:ten of the general probiem of devetop:ng bet:er uays to tes: ar sumtances that might be suspected of having a cancer-tnduc:aF eacc: e. man. ana to measure tne reianve potene:es of such sues:ances Enceura.e- n:ent and suppon have been g:ven to tissue culture tecnntaues tna: raa pe.^r.:: the groatng of living lung tissues where thev can be suomt::ee :: caaiienges .nd observed dtrecQ~ (Pages 11-13• 20-.6 ) S:.^stiarly, linle has been known concerning changes that rna~ oc:_- tn the lungs of human beings in the normal course of their lives A ia::e- scie .tiot investigation was undertaken. with preltm:nan resuits t~ia: tung tissues in Iaree percentages of peopie of all ages. but esrec:a. 25 %ears and older• shos+ observable deviations from norma! uhr: are r.c• obvtousiv related to any spec:fic environmental or occupauonai facce:s (Paees 27•29 ) ON HEART RESEARCH A:u`touch some observations have been made u; the vas: er. e~rca :f smoktng. and espec:aiis of ntcotnne. on tt;e eard:o~ascu:.r s%s:r- c r:as xen recogntzed tna: mu:a re-a ns unknown and tha: mar•- ca:. :• -. ~ are contrad:c:on Prel:c::r•arn res::lcs cf ne%+ researct. .nc::a:e .r._ some -.revtouslv held concepts concerntne the eftects of toba:cc c.n car~:o•ascular svste:n were over-st^•.ol ;icd. or do not app'1 ger.r.•:. (Paees 26-.' ) Rcsearch is continuing not onl% or soeri`:c e?,ec:s of s.^...::n_ biood vesse!s anC coror.ar-a f1ou, in nurnan tests as we.. as 1. laccra:orn ar,:mals. bu: aiso on µnolc population groups -._ fa::ors. tncudtne hcrcd:rs. d:et. recreation and work habtts. tn adau:c- smokt.^.g. are being considered in relation to incidence of card o~as:c.c d:seases ON SMO}:TNc n-PES Constoerab e atten:ror has been g;%en to -avs o.` earr:tng eu: s:::c : on pcpuiauor• eroups to ee:cr-n:ne ..netner there are anv ps)'cno-pm 6 V •s \ 1 { • N 0 11 ia•• W' .ti.

olopcal diflerences observable between cxcepttona0v heavy smokea rnC moderate smokers or non-smokers. (Pages 16-18. 29-30. ) Several studies of populations were found already under way tha: could be enlareed to include specific study of smoking hutorus of the individuals tnvol%•cd. Out of one project came a report. pernaps the flrst based on sctenufic study, showing a stgnificant rise Ln body we:g.ht fcr men vno stopped smoking as compared with a control ¢roup of men vhc contsnued tosmoke. (Page 41.) OTHER AREAS OF RESEARCH Some gJants have been approved Ln cer.atr•, othcr areas c`. reiat:.^g to tobacco use lnvestiEations ar: being supported cercect;^, en: ttssues. 4hich ma% lead to revised concepts concerning tne ra:e e` ussue mat^.tenance processes tn aging peopie. Studies on the eRec:s of smokmg Ln relaucn to gastric functions have been completed %+•tth repons snowmg that c:garette smoking by patients with duodenal ulcer did no: produce stp-.:5cant eban¢es Ln gastrnc secretions. Similar or related wori is bc:ng connnued Prole;ts also have been tr.ttuteC tnto such matters as t::: con- sutuers of tobacco leaf and the chemtstr% of tobacco smoke (Page 38 ) C I "f Z M N

The Research Approach The'public's interest in the relatton of tobacco use to human is naturally great. !t is certain to remain so. Broad and specific a=usat,ons and elauns of harmful eHects from tobacco have been made. and the sn- corTectness or correctness of such statements must be proved• no ma::c: how long or how difficult the efiort may be. !n the active and continuing discussions about tobacco use and 6eai~. .!%:-c seems to be nearly complete apeement among sc:enttsts on en.% c.n.e potnt: The need for much more intensive research into t.':e su^ e:: To this need. the Scientific Adetsor% Board to the Tobawo Inecs-r• Research Committee is devoting its efiorts. The Board has responstt,,:;::.e fcr advanctn¢ and encouragine to the limits of its resour:es sctent:^; research into all phases of tobacco use and health and for maiiag granu- tr.•aid to qualified research scientists from funds made avatiabie b. t.`.e Cemmtttee. This 195' Report of the Scientific Director provides an opporrun::y :e dtscuss in some detail the progress of the research prograrn which u- ezr.pt t::ally got under was late tn 1954. Searttng in 1954 wwith nothing the mandate to erant funds. with no strings an.aehed, to mdepencen: sc:ent:sts. the research program hai through June 30. 195"• acuvatez- rese3rch pro)ects totaling S 1.'• 15.:00 in the field of tobacco and hea::'. O`. this amount. 5550.000 was for 52 separate erants-tn-atd approved :r. .... .: months ended June 30. 1957. Mans• of these were, of counc. r- ne•ja:s of proiccts prevtouslv started. tndreattng the ume-consummg na _rr ::I!s ty;.: of researc^. 1 ne 1Y3r covered bv •hIs .^c: t als0 saLL' lrldCr'enden: pl:o',:cY::On . :n~es::¢ators of manv papers repcrlini worK whtch was A1rJ'r+e.^.e~. a: ICaS' :r. :ar•.. with grants frcm the Tobacco lndustn Resezrc^ Ccmr.:::~:c A-.s:racts e` these publisned papers. as approved by the authors. are :r .. ~:~ la:er in this repor. APPRO4CN TO RESEARCH PROBLEMS The nine sctenttsts who compnse the Scientific Advtsory Board have had complete fre:dem in planning. seiectune and develootng ^,hases c` ez"rtmentai resear;^ The% have pooled their knowled¢e and t.:e:: ei• ^ene.^,ee and their dtsctpitnes to deveiop the research program T*eN ha~e a;sc eonsu;tcd frequentiy with manv independent sctcnufic coliear.res. boe.t :ndjviduallv and in conferences 8 C ~sR t~4~ 0 1 ~.~'~:~

They have Etven first attention to those areas whtch are presentl} of most concern to medical science as well as to the general pubitc-the questions relating to cancer. and specifically lung cancer. and to heu: duease. 1lembers of the Board take the general position that definitive con- clusions or predictions of individual risks are unwarranted bv the pre:sent imperfect state of knowledge in the complex 6eld of lun¢ cancer causation !n regard to heart disease. they take a stmtlarl% open-minded azutude toward causation. consistent with the expressed positions of such or¢anu.a- uons as the American Heart Association and the Nattonal Hear, lns::rae The program of the Scientific Advtson Board is one of bas:c and ur.c:ased research It is not plar.ned with a preconcecved pvr^ose of orovsnc teoac:o innocent or ¢utits in tts e3ects on human hea!th Its purxse :s sole;v to obtain new information and to advance human know!edee in even pesstb:e phase of the tobacco and health relationsh:p There is for any program a surrounding framework or backpound o.' proolems and of unanswered quesuons These questions should t-e con- stantuy borne in mind until thev are adecuatelv answered It is often vm eas% to forgel, ignore or b}pass unsoived phases of a probie:n w•htie .r he: pursuit of some parttcularls allurtnc theory or h.pothests It is. howeve:. the dutv of experimental scientists to maintain balance in thts rype of srtua::en and to distribute e^iphas:s and evaluation wisely and fattlv trn re:a::cnshtp to the uhoie ^,rco:eT. Cr field involved I SCIENTIF7C. SOCInL(~GIC>L FACTORS Before presennnc :he therefore. tt wil! be desLrab!c tc d:sc.ss bnc9~ sor.:. c.` .... :a:..,rs tha: sur:ound acd .nt'......: ar, croad and eont:nu; , ra^^. c: r:s:ar.,, tn thu tntcres: _ an_ c-ai::ap:ne field of toDacc: use an-, iea;:n Some of these fac:ers are µne!,% otoiowc. Thev deal w:th t.^.e c..^m- piezttues that are mhercr: in c^sen:nr and anaisz:ne a haott utun m.an% .arub:es in its reiartonsr.:^ :~ ca:~ses tnr: arise qute:iv and subtls -~t-ti:^ .. ::ocv and tna: c,,..::c.:c :. .e a: r c' tne bods. d:sturo:n:. unba.anc:r.: a.^.C :~rnaps destro\m_: : s n.r-3 `.,r;nen and tts survival C1(nel factors a_ri 1*"'^-ov" 'I ^es: tnvoive, among oihel t.~1:fS. the atutuces and react:ons c' :r_,•.._'.,a.s o: d:fterent types to smoking. ene e.` mos: -tdesercae an: -,.-.an customs that has developed as a pan c! our wa\ o' h!c . •-j- :^rce centuries It is destrab,e te :^. c e sor.s of factors clearlv distinct in ou: seiec::en and eva:uau,r e s:e.. ..ese3rc6, proo:eros ..`.V. demand our bes: eaer:s These pro;:c : a•c sober:ng ar.d impressive sn tne:r 9 C TR HN 0 1 ~ ~~4.'

own ngnt. but they become matcnally tntensified and confused when tne•.c is a flat and complete acceptance of an incomplete degree of analys:s of their elements. or when mixed standards are empioved whtch obscure tre:r origins and component pans. Such bctng the ease. the Setentihc Advisorv Board will continue to maintain an open-minded approach that encourages new methods of tn- vesugatton. recognizes the long-time factor in obtaining direct expcnmental evtdencc in this field. and refuses to subscnbe to. or endorse as conc/unve. incomplete or rrstncted evtdence. even though pressured to do so T^c need of protecttnc the public by adherence to a conservative. att::ude wtl:. we hope. become evident as this Repor, progresses THE Ct:STOM OF SN101:I.',G Dcep-rooted and widespread human customs have some reason cr reasons for the:r adoption and continuation This is undoubted:y true cf smoking It may be unnecessan or impossible to discover or de.'.ne al: of the underivtn¢ motives involved, but it is necessan to attempt to dete.^r..ne and to evaluate any influences for ttood or evil which our habtu mav ha%e on heal:!t and well•betng There are. fonunatel%, some helpful pnncaptes to g•utde us in such effons. Beause the reactions of individual human beings to any babt; var. t.hrough a wide and often unpredictable range. cer.ain inherent ltmt:azter:s in the da:a and restrictions in tnterpretatton must be eoostdered before appi}tng anC ex:endtnE am con;iustons derived from s:aust:cal stud:es on ii^tted pepulauon eroups Swec::ng tteneraitzanons as to the sociological appltcanon of or as arc us a... :.' nc: alwass. unwa_ and tne~!ccuse Tt:es are aot to aro::sc .esr.....,...' ar:~ :emp:aao.^. .,, de...., or to eircl.'mvent rePJIa::C.^.s The ^.gh: et sei'-dete.^n:nattcn is a ser% s:.en, tra:t in ,^e Amencan p;...... 1: has e.•.arac:er:zed our benastor s:nce :... caNs ef our ort_gtn as a na:tec. and it wt;: cont nue to do so TASh OF GET7TNG SnC'ND DATA Recc_c::z:t:, thts. the e~ora of the Sctenn.^.c Advtsorv, Board ha-e been and ~,1: conunue to be directed tow ard encouraging sc:enttsts to acqutre and -oublish su:'`.ctcn: data to help provide a basis for sound and votuntan oec:s:on b% ei.e t;td;v:dua: las•man as to wna: c:s attitude te%2-rc tooacco use sF:ouwd be 1: v. `.' ta:e a lonc :.^e ar:C ,..,...n cren:t~e a;tnkmc to devtse and tc carr. ou: :..: ex~crrne tts or. Ua:;rn co:^~tc:e answers to the mult:nide of !n C T R_ H N 0 112-8 E

o,uesttons can be based. Many tndtvtduals. skills and tecnntques will be requtred. It is not necessary, however. to wait for aeswers to all the ques- tions before one can bectn to formulate tentative opinions or worktng hypotheses. In fact, the reaction and degree of receptivity of tndtvtduais to partial or incomplete evidence varies just as much as, or perhaps more than. their rcactton to use of tobacco itse!f. The right of an individual to determine his own level or threshold of convtn: bthty is unquestioned. There are and will always be individuals who are convinced wtt':ou: the need of experimental evidence that all tobacco in an> form ts ev::, nez;c;:s ar,d toztc. There are individuals with a ss:r.:iar att:tude :o%ar:! zIcohe:. coaee. and the use of drugs. sera or medicines. T-r.e are at the other extreme individuals who. after pernaps 5v years of life ezpertence, will not admit that even excessive use of suc.`h agents has a de:e:ettous eftect. Neither of the extremist gsoups is likc!s. to have any last:ng ef!eet on the behavior of the vast malonty of the public and netuner w,i;. in :.".e lons run, contribute much to a more intellieent and une:-tottonal anai%sis of the role of tobacco use in today's living. DISE,ICES OR1GINATIN'G a'ITHiN THE BODY I: is well to repeat that the diseases with which man wil! be chte.".~ concerned in the foreseeable future are those which ortgtnate inside of htm b% some unbaiance, derancement or distortion of function. The cells and ttssues involved have been present before the disease occ::rs and t: , re-,atn as a part of the bod\ orrr, the disease is reco¢ntz.able. Th:s makes it doubivi certain that the btolo¢tcal and biochemical na:ure of :he ,nai"duol v.tll be a factor of pr:r^e tmpor•.ance in :he ert:tr.. and .,....,,rne of eard o%ascuiir diseases. u;cers, cancer. menta: tiir•.ess a^d e;°e: e:seases of eneogcnous or:gin .A:: these facts co^tb.ne te m:ke clear the g'eat and unavc:c3^:c res:c.^.s:'.:itty of the laberaten and clinical tnvesu:atcr .,n de^^:n. .ne de:ree to which conclusions reached b% him can proper!} be eztenee~ or Fecerai:z:d to cover the whole population LUNG CANCER AND CIGARETTE S)tOF:fNG Smoking as a human custom has existed for a number of eentur:cs. and lung eancer as a disease has eusted for an tnde^ntte numbc- of ce-tur;es- eeratnl. .m..a^% more t.`:an smoking The apparent increase in lung cancer. espectall% among middle-aged e: old:r men. has been retated b% some srattsuctans to a cornc;:ing tncrease in the total consumption of cigarettes CTR HIN 011266

It is evident that much of the numencai increase in reponed iunb cancer cases represents an increase of people in the suscepuble age grou:s and tmprovement sn ability to recognize, diagnose and report toe disease !:o one has shown how much. d any. of this numerical increase is an ac :.•a: rncrease sn attack rate. Some individuals, however, have accepted t!!e apparent increase as being almost 100 percent rea:. They tlso have c.n• stdered that statistical data showing a somewhat paraLlel utcrease in cigare::e consumption indicate a cause-and-eHect relationship between exceu:ve c:garctte smoking and lung eancer, when taken along wtth reports of a .".tc:^,er percentage of smokers among lung cancer cases than among ot-,er g: oups used as controls. Such assumptions stimulated some investigators to bcgrn sn e•etts - as:,c hunt for the '•component•' cr `ce:::ponents•• m tooa::o smor;e luna: ca- be blamed for the unproved cause-and-eae:: relattonsh:p as weL as fer the reported production of skin cancer in some ezpe:.ments o*::.`. certain strains of laboratory mice. The limited experiments with m-ce are of doubtful sig;ttficance :r ezLrapolauon to lung cancer in man. However, the report that highly c:n- centrated tobacco smoke condensates can induce skin eancr ut mice unde: ce^atn eQndittons has led to a search for a specific substance that may. be responsible for this w tth the definite implication that it would also eause lung cancer in man. The skin of mtce-especially that of certain stratns-reacs by cancer fa.^-auon to a whole host of chemical compounds It ezhtbtts uncontroi!e: grc-th with unique senstnvttv and speed compared with the skin of ines. c: .; e other animal species whtc!t have been tested. Tebacco smoke. like the preducs of burning an. eo:npiez vece= c s::_s:ancz. contains a eca: numoer oe cnemical compounds To dr:r:: tsr•a:c. analyze and assa% such compounds is the present m:er-.s: ac:, of a number of research scientists rJes^ae t!t;s. no spcr5: const;:uent of tobacco smoke has been four::, :na: accounts for the re~one~ btolo¢:c acttvttN on the sk:ns of mice ORIGr, OF C,LNCER L1I:.NOQ1 1: ts verv human and natural for people to hope tltat a single. stm::c ca::se of an.N type of cancer can be found and neuvaiized or eitm:nate~ Aicn; with entrustasm to find rnr cause of any type of cancer Lhere is feur:;: ra:.-a!;% a g:ea: pub,•: neµs-appcai for an% and all theones. eia:r.u ar:: eti;eencc of anr ser: pernttne in that direction. Durtng the past fes% years we r.ase had man% eza:::p;es of thu fac:. 12 C TR H N 0 11 2 E30 7

L ntorrunartiv. hot- trtri all nidtncr troni both loborarorits and ciinre s tndreatts rnar tiit probitm o/ cousorion of on.% t.%pt o/ conctr 1s compies anc d prcuit to anaiti;t. It is fatr to sac that a ph:losoph% of over-stmpiificatton and an attempt to convince the public of a final solution or of a lethal r,sk not eemonstnted b% ezpertmental evidence are neither kind nor accurate nor W se. Those who maintain the less glamorous artttude of tns:s::nc upcn pat:en:. urne-consuminc progress toMard the wnoit truth µ-:ll suFe: te!7• porarni.y tn pubi c opinion compared Mtth those who hold out the hc^e ci more rapid and sensational solutions The~ ma% e%en be ciass:ncd b% so^•.c as =e:ne eb::!se and obs:ruct:or.a: Tnz: fac:. hoMeve:. does not chan:e or Aeaker, the bas:: so;;neness cf t-he e;d adace. Mh;ch applies comp:cte:} to the control and cenzucs: of the so-ca:iec constitutional diseases such as cance:. that sa%s the ioneer wa% arounC ma\ be the shortr. K,a% out. It is perhaps heaith:er. bc::. men:aii% and sptntuall%, to accept and adhere to a phtlosoph% of pat:ence anC unerr.ouona! skepticism until the various fac:ors %kh:c': contr:octe to the e::g:- of eance: are knoKn DANGERS OF OVERS111PL1FICATION 1N' SCIENCE To ove:stmpld\ our concept of the et:oloe% of an. of these diseases ts a_an,r:ous precedure fo: a: ieas: two reasons ia 1: tends to !t^:: the extent anC d;re; :on e` tota, rese3:c"h e.°.or:s te uor/, baseC on a r:n_:e n%pothes:s 1: .e':ers anc e.^.•.:cas,zes :esearc.^, e~or:s in tr.e c: a:..a n: ;e s es:an;a;, e.~e, of % ;eu I` ._^p.ex,t\of e::oicg} Is la•er ^ro~eC anc ...- s:rr.;,:c shc\%n ._ _, :naeequate cr tnco^n... conr•,cen.. in tae p: .. .:~ anc su.-.c::e:s ot tne simpie tnecr•. is snaken and future conciustcns ., cc__.ed Te a tesser bu: st..: in..,.:ant de_ ... pubi:, ss:ep.,ar,. ul:. ....., .•..;u~e .^.1L... if ne: a~.. ot,,.:t:se.....' as \te!i 1: c:a% oe he:~; l to d,scuss Cnea% s,;:^e of t^c factors that reed! :., be eens,cered and e%aiuated in tne prob;eni of lun¢ cance: causation beiere a soluuor, can ae cu:meC 1. SEX A\f) %1kR1TAL STATL'S T.-e:e ap;eaa tc ,., c:ea: e,:cc:::: .na: .,en s:^o~ a h:g.^.er moruht. ,::a:o:\ e:seases ar.C al~o from easa:o- from iung car.ce: anC aL o:ner res- vascuia.: d:seases. ~.an do ~o:ner. l: is aso true tna: Nhen ad!usunen: is 13 CTRt ! t't 0112266

made for ace. both men and women who are divorced shou a h:e^e: morulttv from these diseases than do those wno are married Why are these things true' Is it a redectuon of d:fterences in hor-nonal makeup betMeen the sexes or between balance and adiustmcnt of hormonal acuva. related to marnal status' Is it that men and divorced people ave a more tense and exposed l:fe respectrvely tnan do women or married people' Or are there st:li an unrecognized (actor or factors snvoi.ed' 2. EFFECT OF IRRITANTS Acm:tanc fer the sake of arpu^:ent•the exten: Of a still unana;Nze~ en~ ee:a:at:c increase of lunc canc:: in uh:tc ma:cs. what ma% be the pess:o:e e'ects on cancer incidence of former lune tniur., fre^ frem -cured'• pneurnon:a or tuberculosts or exposure to mustard gas. from combustion products of gasoline or diesel en¢:nes. or other air ;oi:utants and ensuonmenul a¢ents' The fact that statisticians find these e:ements d:f`ccl: to measure and that macs, therefore. completely tencr: them tr, the:r s:ud:es does not automancail% el:r.:tnate them as poss:tie factors to be stud:ed. Arnone en.•ironmental e'tects of possible significance mus: be included t1; reiauvelv recent increase in exposure of the lun¢s to x•ra%s These ra%s are known to be a carc:n2cen:c agent and their eftect appears to ~e cumt.;ianve In an+ sampie pecu:auen the individuals who 6ve in c:ues or nea: ¢ood dtaenosuc centers a:c ^tor: apt to receove x-ras d:a:res:s or trea:rr:en:. and tt:s rn t.^.ese ar:3s :',a: lung eancer a;.pears te bc :r.os: 3. S)lOK(NG X ER~-L -r, OVERQ EIGHT ~::ere is evtdence tr.a: cessa:icrn o.` the smoking habit ma% be ioiio-et r~ a s:_cn:.^,cant increase :,. ._. 4e:ce: There is also ev:dence t.ha: over- w; -. peopie are -crse hea!tt: risk in boa; ca^... -n= car-;oscscu:ar disease tn-^ jr: :t cse •~ne are not What ts the corr.arae:%e Ca.^.:er SC t^C CSYrAeIQ.'.: a'•Z: t: 'C S-'.~ACf' 3. ~'N1ntiING HABITS ~ver:or.: a_ere:s :`a : ea: ind:%:dua; de°rreocei tr- sc:ei<Ln; haons and that th: .r_ and evaiuanon of suc` ha::cs vtvoi, e a %L:)ole grist c' O', :ousi%. a person Mho smoxes to the but: a fuil pacK of c,care:::. :~r c_ recer.es a d:flerent amount of smote from cne Mhe smokes a 1,... ;,a:. to ona half Icnvh or to quarter-ienc:h The temperature and con^e : ,' smoke also var, a: difIerent leng:h of the e;¢areae Hab:rs c` !rczuenc----Cepth and retention 0 CTR HN 0112611~'.~

the smoke in the lun¢s-also vars creotlv In ae:ual fact the onlc thtnc :na: %ke can tx rei3uveh sure of in class:ncatton by "pacl consumpuon'. is :na; the two-pacl a das smokers reach for and ltFht (or give awav) a-^ ctcareues. the one•pack smoker 20. and the one•half pack 10 Are these re:c:tons. therefore. indications of dtflerent levels of nervous tension anc of response to it rather than accurate qu]ntuitts'e measures of tobaccc smo:e exposure' 5. LATENT PERIOD I 4nc:her eo:^^!tc_.:ne f]ctcr in lunc eance, r_usat oa the_..es :s d:r'e::nc[ of opinion conce:ntn_ a latent period of :G er mere se3:s `. I ::s:zed s s:]:tsuc:]ns who relate the app]rent increase in t.^.e d:sease :r ,..::easeC consun;puon of ct¢arettes A some%%h]t stmtlar situation existed tn the incidence of cance: amerc : eari% ..orl.ers utth x-rass In both cases it is evtdcnt that some sort of ehan_ees in the ussues c.` .... .re s:duai rr:ust precede ann trtccer eflect of the reai e: :hccrc:::a: ~c aeen: ir, bot:s cases the nature of the exposed ttssue ac.ocars to a i]c:cr of m]ler tmport]nce Of all of those exposec. no more taan a vcr• s^a:: ^tnorus of heavs ctaarette smokers and onl.. an unknoun fraction c` i-::'• AcrKers deseiep cancer whtch can be rei]ted even stuttsncalis ut:r. .... 'a::; or ocCllra:ICr T: fccus 7:..':UCn on the accuse.a, oe:uvatlon or haba :s. t~e.:fC... ._ ~•. - a or [^C"]S:S to a pCssi~le C3U13tI%Y faC:or that is 1^'^o;:.^.: a".- e in :.•: sas: .ma,er:;% ci c3ses Sccn dtstcr.ed e^:r::as7s :s ci c. __ • .._c cn_-1 ._., itad to un'::;ur.a:: nee`ec: o' rne:: srr: es :a:s .: i - 6. NIETHOD= OF kzc>1' OF CARCrNOGENE_I5 ~s N:: no sans.`]:;on r.:e:hod eztsts of obser.'tnc the course o' c:,anr-: .. ss.,. tr ,.. it.; acc T,•. Sc:cnr.,,'.; Adstscr• Bca:_ :s. ...-.- s.;:~er::r.: researcr in;e tissue cu;;ure of adult human lung t:ss-;c .,. •..- .. : and :r_: o~sersauon of the response ef iunc t:ssc: tc sar:eus chai:erces 4n cn are prestous to or eoncurrent with ooser.a- r~::. _- ,^esr.c,e and'r:.,...; as a ste; in the rt¢^: dtrectter. ir. ;cc r-ear.:::r.e. ccftairn res.!ts Mtth, animals serve to e:r.7ras1_1: %ar,:~.s ouesttcrs a. Proier,:c~ e_z-,csure of t~e iunes of rodents to masso-e doses of e:care::e s:r.oRC has faued to produce bror.chocer, c cancr. C iz [`ti i ii Z 0 112 ..+• O

(b) Tobacco smoke or smoke condensates have failed to pro- duce cancer even on the skin of suscepttbie strains of mice when applied in the quantity and at an exposure rate tttat would stmulite conditions of human smoking (c) The extrapoDtton to the human lun¢ of results obtained by patnune of or tn)ectton into the skin of mice is dectdedlp questtonable. It is-++ell known that mice of ccrtatn strains have hieh carcinogenic skin susceptibility to scores of atcnt% no; proved carctnogentc to man. The skin of the fingers of cicarette smokers. parucuiari% hea%} smokers. is due:::. exresed to smoke but there is no record of an% smoker es•e: hasmc . t:;^:or. e:tner malignant or benicn. on his finee-s as a result of this exposure Yet the skin of humans has reac:ed in this was. to x-rass. showtne that it can become the sea; e` carcinogenic atuvu% under proper ehallenec. "- PH1'5IO-PSI-CHOLOCICaL FACTORS Alt!toueh the isolation or sdentificauon of ph%s cal. psycheloncal and emct:er,al human classification types appears to be remarkabis d:fFicu!:. t.^.e recognition and tmponance of indrviduol human d,je.ences tn thesr r:s;e:;s are unr.ersal and impelltn¢. T.^.ere are undoubted!% important individual variations tr, the re.- t:lara. order. temoo. tntcnsin and eumuiattve e."ects of ner,.ous an: response to life snmul wh:cn not onis influence ha:::s c: _.r.astcr bu: un:c~. tear d,rcc:is on t::c health and sunisal ^,respe::s :. .... .-.... :~..~. _-..r:s to oe:r. ;nc and te :^eas:::e oroeesses c.` t!i:s n;c are cc: , n ,.x c:ex in tne:r oKr. ncn: out are snl! essenuaiis "pioneernnc ..• .c ef a large mass of iuerature in t^e gcneral hcid Howes'er. even %L::r. ... .r.^naestmai amounm of werK accempi:sned. tncrc is enoucn suc¢esti- es:ce-:e e.n. the extstence of d:~c:ences between so-ealled heass s^:oKers ar:: no.^.-s^':okers to encoL;racc ..,^unutd, creat,s extended and cecrer:c: .esear,,. on tnese asne::s e.` tne heait^ prob;..,M broadt~ speakir.c one mas reason toward an approac^ to .^e ;.rob:er7 as fc::oN'S . . a T:^.._ ar. :nd:sicua: d;~erences in surtitsai pe:entu; and .., onse .., 5:....~.. and S:.ess ` Tr- n:a!...... .. ...,, ha.e suc:essfull\ ad:ust:d tner- sei%es so tr.a: a%era.c life span ci man has tncreased b\ de:ades o%e: vas: na!f<entur. 16 C1 t`rr t i 1 `l « 1129.S.

(c) There rematn a large number of indrviduals who reac: in such a way as to establish and maintain internal unbalances or inadequate adjustments to streu and frustration The tn- dtvrduals who reacted to combat by shell shock, battle fatteue and various neuroses are clear examples. It is not necessary, however, to encounter such extreme and evident st:muli as those of combat. The higher death rates of both men and women who are divorced bear silent but tr^^res- stxe witness to the delicaev and wlnerabil:tv of the nervous and glandular mechanism of hu:nans and of :.^e lasting tmponance of these mecnarwsms in tne maintenance o! he3lth. Ezcesses in various types of behavior are one of the reflecaons c' the presence of neuro-hormonal unbalance. Thev are not t2he primar. ca::ses of such unbalance and thev do not furntsh the cure. Tnes are ar: ou:uard and visible si¢n of an inner and invisible crisis of some so:: Ezcessrve use of tobacco, alcohol. eofiee, or other agents. may therefer: be ;.::rnarrlv a symptom. not a cause. The more nervous. restless. frustrated and harassed people mav be : r^.c-: the bad health risks Adjustment to life ph%stcall%. emotionalls and rnen:all. reduces. avoids or dissolves the stress and strarn wh:c!: are c::n:ca'.lv experienced by the non-adfusted. Of t^: three types of smoking-pipe. ctcar and ctcare:te-there oouid be ecn:ral acre:rnent that mechan:cs alone µouid sugces: .::a: nenous and restless peopie wouid be more ltkea te use etgare::e: l: :s ..,.. .,casenabi, to look fcr .^.e he3sti' clcar_:te ha^.. to be a-n tnc:ca::en that the individual involved ma_% be ezoresstne his ncn-adius:- ...-... :: seme phase or phases of life. C~nstder. for ezampie, those statistical data which aptxar to sho%& assec:anen between heav% ctearette smoktne and death from various :sres C: :an::: (:;;n;. lannx. phar,%nx. esophaeus. toneue. mout^. iip. biadde:* pres~::. sto:^ac^. pancreas. ltver, gall bladder), pneumon;a, tnr?uenz:. aer::c aneunsm. duodenal ulcer. gastric ulcer. tuberculosts, eoronar: ar.e^' dtsease. asthma. cirrhosis of the liver, and automobile acadents Tai::- at face vaiuc. such data would provide clear evidence of the fac: :.`a: '.r- outward anc vts:bie hao:t of heasti smoktne is a re9ecuon of sucr. a LL:ec and var:ed pamut of tnternal d:s:urbances and unbalances tha: n-: pess:bie spec..^c. caurar:tie value becomes reduced almost to an absvrdtt. Newever. its potenual diaenorrrc vafue as a danee+, signal requtnne physrca: zad ps.cnoioc:cai anaiys s and explanation becomcs evident and tmpennvc Lr I' . 1 i!~ ~`~

!t is entirely probable that other habits of excess in the use of iumulanes. sedatives and vanous dtcury etements will be Eood danger stgnais of a sunilar sort. So.is excessive activity or tnacuvtty of hormonai systems (e.g.. sex, thyroid, adrenal. pttuttary ) or excesstve asceuc1.sm a: the opposite end of the curve. We should recognae, therefore, that in a conunutng propram of rc- search on the relation of tobacco use to human health we are dealing vnt.`h evaiuauon of a habit. Such a habit mav be, and in this case is. a %isible and str:i:ng phenomenon on which our investigative mteilec: se:zes With avid:r% tccause it craves a vitibie and ranq:oic opponent against Mh:cn it can .'s analvt:cal power %k c must constantlv remcmbc:. however. that the boa~ or mm,,i v.h;;:~. Ke are stud%tng is the reactor-the battleground on hcaitn anc d scase fight for control These bodies and minds are of an tn^n:te nurnoe: of t.pes and potentialities, and it is these dtfterences in :nd:vtduais or. -A h;:h st:mulus mLst act. In the face of our existrnc ignorance. which is vast. we should tr tndustr:ous -in research, cautious in interpretation of results, and hc:n::: u•. recommcndrnc alterations in smoking behavior as claimed prevenu~es of :n:crnal and naturallv occurrtn¢ unbaiances and health rtsks CT R HIM 0 112 cz, 3

The Research Prouam %.1 7-ae orpanuation of the Scientific Advisory Board as prcsently con- ststuted .+as completed in August 1954 and shortly thercafter the Boud developed the policy and procedures under which it makes panu. Since the scope of interest was broad-all aspects of tobaeeo use and h::a:an hcalth-it was necessary first to define general areas within wt;,c^ appiicauons for research grants should be considered. The three continuing areas of investi¢ation withsn which the research g:a^u are made have been previously set forth. They are. in bne.': 1. The phystcal and chemical composition of tobacco and us com- bust;cn producu. :. Tissue changes in humans and animals. a field which encompasses a vas number of laboraton and clinical expenmenu reiattng to the lungs, c:rdtovascular svstem, dt_gesuve tract. mouth. throat and endocnne glands, bc: r.c: iimtted to these ?. Smoicine and other uses of tobacco and the emotional and physical makeup of smokers. Recog;suing the advan:aces of flezibility in the groo-lh of a research proca^:. the Scientific Advisen Board has continued to adhere to this genera: plan of investigation W::.hm this broad prozram. there have been shifts of emphasis as :he need and opportunrt% for imper.ant research possibilities developed SPECIFIC AREA_Q OF RE~'E%RCH 7ne subIect mattcr e` erants has br_n speca4c Spec:al er:^!;as:s has been placed cn ezocn^ents relating to ezpenmental cancer a.^.d urc:nogentctty. to aspects of cardiovascular disease, to the stud~ of hu-ar: iungs, to the b ocne^, s:n ane chemistry of tobacco and smoke mg'ed:ents. and to t^e sr.;o• c' Ero.;rs of peopie who are smokers and ncn•smoiers T*e general trend of ,"c reseirc^ proeress in these fields is dss.-t:s;cd beiow rn some detail. As ~i r. a:mos: all scientific endeavor, quick results frcr: inese prolects are nc: :: tc ezz~ecced. and most are still in progress T--:s Report goes tn:: cens ecr3t:c detail on one aspec: of reseasc.`.: na.me:}. that of ezpenme-ta. caece- and earesnogentem assa} This is done because aeneral tay and sc:ec::`.c inte.est his centered on tbu phase of actvnry, and some of tnc prc.:c-.s encountered are frequently not full% appre: a:ed This empr.asis ,rn rc;crar:e does not imply any lesser interest to CTR HN 0 11~'91 4

b} the Sesenvfic Advisory Board in the otner areas of researc^ be:r:_ supported by the T.1.R.C. grants.. I. Experimental Cancer and Carcinogenicitv Asso. GENERAL CONSfDERATION 5 The current wave of intense interest in the posstbtirt. of a rc:at,:n between tooacco and bronchogenic cancer has stemmed pnrrsartly from a senes of recent statistical studies on thts sub:ect. Althoueh full r.tt:cal evaiuauen of these is still far from complete. it has neve^^e,ess bccn r_r.- s:ecred in the public interest to undertake a numoer of direct expe::;r.c^:a: st_d:es a:.^.:ed at determtning whetner a specufic acent ca:c:no¢en:c tc ...-r. :ar. '--e dete::ed in tobacco smoke. and eseectall% in c:;~re::e smcce% tilans research workers have under:acen suc.^s ex.eraen:sx a^d :-.r reso'.:s of a feµ studies have been published. aithou¢^ the r;alor:tv a:: ' su:: in proeress and have been reported oni% in a preitm:r.a:-% manr:er c: nct a: all. The diff~culues involved in destrnmg and executing s:e:;:^,cant ci- pcrnrnents in this field are numerous. Avatlable techniques have not cnr. been tnadequately standardtzed: thev also involve basic thcoret:cai ::.^s ce:amtues and are time-consuming For these reasons. dcfintttve results have been slow in emeratn¢. and non-specialists are inclined to ask wt•. a conclust%e answer has not vet been announced. The S::cnn^c Adv:scr• Board to the Tobacco Industn Research Committee feeis a publtc ob::..- t:en to explain some of these dt!Fcutt:es and to create a better pe:s:ec::•.: u;,cn the question of whe:her tooacco smoke is or is not carc:neger::c '•TOBaCCO TAR" 15 A MISNOMER One ma,cr d;ff;cult% stems frcm tl;e fact that t•tie tooacco s:nece ir. :nam expc;.......a is ne: a ee^n,te c^_,,.,cai ent: , b... ...r-s c_.. .- a-c var:acie mtx:ures of numerous substances The te:7 "tecacce ._ :s in fact a mtsnome:. and apoarentl% has artser, because s:-~eKe when trapped and condensed is a dark-coiorcd. vtscous lic::td l: .._. ,.,TcaraAic to ot.^.er mater:ais commcni% knoun as tars. s_cr. as :- ;a: an„ coa! tar. wh;cn arc produc:s of the desc.rucnve dtsnaa:. .. ..' cr- r..a:er:al in tne absence of a:r. Tobacco smoke as produced in the normal burning of a ct:are::e c_- s:s:s of tv.e phases. Onc, virZuall~ invisible. is a complex mixture of Sases and ti•apers The et^v is a par.tculate phase. consisting o` m::TOScc: : i:--,utd droplets suspended in the atmosphere. The visible pa,^n of the sT,oke cons sts chie.°.% of these suspended parvc'.es Each dropiet is a rn:. compiex mixture of chemical substances. 20 ~~9~ I HN 0 11~9EI

The m.tertals called "tobacco tan" usuallv arc condensates eonsssune chte"s of tne pan:cutate phase of the smoke. trapped by some method sucA is cntlitne to a low temper3ture The method of trapprn¢ is one factor that oe:ers:tnes Mhetner some part of the Fas phase is also eaucht alon: wt:h :he particulate portion of tne cmoke. A simple exampie is water vapor. %%hich is always present in the gas phase of the smoke and which wtll be condensej bs a euffictentlv IoM temperature tfap. The manner of trapping uii; t::us tnfluence the wei_cht of the condensate ootained from eac^ ct_e~rc::e Curned Ncr.-a, smoktn_ of tooacco is a com;iex process that tnciudcs cc!n- ; r.c .-c :r.:c-:o e:e co^^ustior• stmoie d:sttllatton. p)'rolysrS and des:r:;- t:%e ea::•,.:ion Tne smot.c is mod;,^.eo fur:her bs tnterac:,en o' t^e tn:re--:er):s rnmalh formed in these processes Composition of me smoke e^e-::^._ from the mouth end of the ctcarette Mill var, with such fac:ors as :r.e ccaposiuon and condition of tne burning mtxture. the temperature of t.•- ccrr:busuon 2one. the time of exposure of cases and par:tcu!ace m.::cc :e trie high temperature area. the relauve proportion of oxs¢e^ as2: 3e e!re^: t,he air at eac."h point. the leneth of the column of unburne~ teer.;c anc other maternals throu¢h Khtch the smoke passes. the lapse of t;^e v:r. e emerces from the cieare:te. and probabl% marr% others Ir a orac:ica! sense the factors tnfluennnc smoke composition are rcfa::~ :c :ne blend ef tobaccc t%[+es used, their htston. treatment and ...._,..r... :^c additives present as ffaverants or humectants. the size and sr._.c c. -•.c slireds, denstt•• of packene. porosu% of paper. the %c._-•e `re-::enc•• ac~ d~;•ntrcn o! ou"s taken. Ienerh of t^e ortc nai ... , ei: .s r.ake : e^ e:s :c±: :ce rcble^ of :,s :•n•¢ sreke fr.,,M the testtn: ci ar. ~.. r...._. .c.. co r.d ..^.a: car, br f:^:sned to a!', werkers in exac,l, t.:e sa-. .cr•c u.^„ from onc tes: ,., tn. ,•ex: -NInK,NG M kCHI*\Ez used in tes:s c` c cicc:ca: r.n~:t do not smoke so :. .n r.r-essar•- to pred cr smoce b\ rmecean:ca! Cestces Many sr^ok1nC r'.a- c^:nes are quite tncentous anC permit a hte:'t de¢ree of controi of the .c.._...cr.s .._.. ~n:... sr. eK: ,s prccuceo' O:^ers are verv crudc Because ma-• uncrr:ai,:r:; ccs:s of tooaccc smoke are b oto¢:s:s r u^cr :r.ar cncr::s:s t•^.adcc:;a:c aarntton of:en has been paid to she prec..,.•cn of sr.,oce So,•.c na~e e~er: produced tars- b\ methods ut:.r'i% u^:::e c.r:an smo.;r:z s::cc as nea:tnc tooac;o in retorts Rrpons nreis tce~::, c.car:, tne cene:: er s..~.r w a;c^ the so-caileC "t2r"• was produced CTRi i i ; 0 112

The didenag raults reported an: therefore probably due to the fac: that the valsous investigators are not aetually woriung with comparabte matenats. ln many cases it u doubtful whether the tobacco condensates actually have enough resemblance to the smoke puftcd by humans to bear s,gntfiuntly on the problem at all. Organtc matter and chemical processes betng what they are, the mere faet that tobacco served as the onginai source of a complex mixture resembling "tar" does not by any means assure that tests with such a product can shed any light on efiects of tobacco use by humans. In ttus kind of sttuatton, the often-repeated statement that one pestu%e btoiogual test outwetens in scuntific import an} numocr of negauvc tests cannot be accepted as valtd. The possibtitty is far too great that the res_:: uhtch varies from the majority may be due to the use of an aonorma: anc unrealistic test mixture. Present knowledge of human smok:nt mechanus is insuf5c:cn: to per,ntt even the best machines to duplicate exactJy the varied condtuons attained in ordtnary' human smoktng. WeJ-destgred machines. ho-evcr. do permit use of conditions that can be de5ned and reproduced with scme prec;ston and that fall somewhere within the range of the eondtt:ons of ordinary smoking: lf 'he smoke so produced is not directly and immedute!y inha!ed b% expertmental antmals. the problems of collection and preservation bc:crr:e matters of coneern. There is ample evidence thar chemical chanees occ::- .vhen condensed smoke is kept for any lencth of time at room tcr^perature. esoec:al!% in contact with l:eht and air. Although the ma:nttudc and btoioe:cai strntficance of sucr: chan¢es are not known. the% can be r..:r::rr::zcd b%- suttab!c pre_autions A careful account of the htster% c" an-. ;r.:~arat,on used in ex.er:^c.^,ts snoulC Dt Cept ter evaiua::,^c c' dl~ere'.Ces :n actl%'tf'. ^ossltiiv a:_-1nC:ab:e tC c~anCcS dur:rls stcr3:e BIO•>Q__QAY OF S~fO}:E Once a reproductbie method of smoke production has been dev;se~. the prct:erns of btoloc:cal assa% are next encounter.ed. Tne meucrnon of cancer is grnera'.l.~ beiuved to be a resuit of -0:e tn:errc::on between endocenous and exoaenous tn(]uences. E.ndogencus factors Mill taclude species and scatri di'lerences, age. sex. hor.nona: baiance. state of nutnuon, the pantcular ussue tmpl:cated. and many others Exoge.,ous fac,.,rs ar: tt:ose ..:a:ed to ex:ernal challenges T~Lo dt!!erent exoecnous factors may be compared for relative potency with hope of valid conc;us:ons wnen all endo_ecnous factors have been standare:.z.ed and held constant Expenrnentai and conuol populauens .,, CTR HN 01 122917'

must be earefulls matched insofar as recogntzabie factors can be measured and equated. and large groups of subfect animals must be employed to tncrease the prooabtlny of obtaining similar dtstrtbuuons of urtrecogntzaote and unmeasurable factors. In addition. dosages and methods must be standardsud. This tnvolves consideration of whether equal wughts or equi-molar quantities are to be equated. Potency comparisons between two pure. ehcmtczily-de6nabie substances appear relatively stmple: yet very little systematic worK has been cone so far to eiassify the relative potency of even the tx:ter-irnoAr, ehern:ca; care:netens The accurate comparison of a comptez and tncor,- ~ tdent:^e~ mixture such as smoke eondensa:es v t:^ rnd!%i.-:: enext:ca: aeents is eorrespondtn,ly far more difEcui: to ach e~e Mcreovef. r[Jauve potencx rattncs can be eonsneered eni% _ in terms e` a par::cutar tissue of a particular species and stratn in a par:~;uiar condtt:cn. E%ca then, a demonstration of activity of an exogenous earctnogen for some parttcutar tissue of a particular species falls short sctentt^.caiis ef de.^or.s:raunE anY comparable actt,.ns for another tissue of anotner spec,es .4\fN14L ASSAl'S 1\ PHARMACOLOGl' A\D TOXICOLOGY nttsts are aware that animal tests are qutte gencralh used tn \on-scte- the assas of drua. vitamins and poisons. and naturalls wonder 'Ahs t!%e~ are no: ecua!,~ sansfac:or% in the tes:tn_c of carcrnoeens The two sttuat:cr.s are not ciose!% analo¢ous An arn:nai test can be used to measure t^.c o`f a dr__ if tt has bee,n est-abitsned that the an rnal sro,s a resp.ese st.^..:::ir to the hum.an res;onse ar.d if 1: i'.o-, a sa:;sia;:er} re._:,cr,sr.:o :C ...c dcse r.': ..._....._; comDounds tha: tnduce cancer on antma! s'r:ns t!:crc are no ;_.respcr,d ne tests on man to provide a basis for reiattve susce- c,- btL'.• cor.:par:sers Moreover. ereat susc;pubtllty d:Rerences have been oeserve~ amen: various specr_s A¢ents that can tndL;ce cancers on tr.: si::r:s e.' mice re-rrali% have fa::ed to do so on mcnKess cr e;::nea pgs TT.c pro.-:e:^ of ade;ua:e b o-assa~ appites to many neu ma:er:a:s w:th kn::` humans are coming tn:c da'.% contact. and it ;s beccmrn: tnrreastn¢i~ important to deve:ep bc:ter methods to test these materuis for posstoie carctno¢entc actton for humans l;niess be:ter b:o-assa•% technieues cac be perfe;:ed. man% unne;essarv ao.reaenstens r^a,: bc aroused concer.::nc these materiais In a sense. the ouesuon of tooacco smoke earc:nogen:c:v. for humans is e.:} one instance of a probiem tna: is br,cs:nF broaC and gencral 1V the research proram of the S::ent:hc Advtson Board can help estacl,s~ a rat onai procecure fo: solving such CTR HN 01 12SIG

problems, it will have made a eontrtbutton far becond the matter of tobacco use. ~ / ENDOGE\Ol'S AND EXOGE\Ol•S FACT01iS IN CANCER !n the present state of knowledce it is impossible to gauge the relatrve significance of endogenous and exocenous factors in cancer caus_uor. The re!ztrve wetcht gtven to one or the other by an+ tndtv:dua! is protabf.% determined more by philosophical predilections or pcrson_! 6e:d of rn- centrzuon than bv arw avaiiable bodc of setentt^call~ de:er:nine~ e~:cence This tre%ttatl% aftectc opinion as to Mhere ar.t heu pra::ca; a: cance- . control should be concentrated ~: ose Mho are prt cui:ri% impressed u::^, th: roie of e^cece-c_s f:c:crs wtll natur.ll% stress tne tnterna: -ne ph%sioiect;al fa: ors Tne :^,.._ extren:e exogentsts Util feel that "eset~ ttssue has its oMn pr,ce" in terms cf threshoid suscepttbiiit% and tha: the reducticn or eitmtnanen of e.e:: suspe;ted carcinocenic acents from the-envtronmenr is th: pr:^2r• eoa; in cancer prevention. This presents a dilemma wfitch cannot be resoi%e~ a: presen: It becomes all the more necessanto preserne cr::::,~e pcrspe::t.e on the avatlablc evidence and to pursue research alons :ne itnes succested bv both philosophies 5>IOf:E INH.ALAT1ON STL'DIE;-' S,nc: the lune is the ttssur o` ereatest tnte:es: in the presen: eennec- uon. it is natural that mant ueri:ers s:^•ould !ta%e undertaken exper:r.:ents in ~::i;n an:mals Mer: in~ ;:C to m^aie toortco smeke Tnis has t`'.c ae a..tac: of e:^•plo%tne v.r,,., tres-% s-.oke :n a prom. an,, d:.._' rr•:••••.. On the othc, har.,.. an•c•a•s carno: oe ,nd:,.ed to tr^a;e s:-.e.: as hcr7ar< c2 S:.^•.e exposures ha%e eccn -a~c ,rn s^noke chambers. uhr!: ha~e t..e dtsac~an:aee of admtnts:::ir; = arC sem.e::mes s:a:e s:::oke te :`.: animals Othejs have beer, cmace r.,,^es throueh µhtch smoke is eraun from a r•.a;:^•me dtrecti% cas. :n- ci .re animai Dces. for trstanc: ha%e .,..• exoosed to smoxe throu_cn trac^ec:c:ncs Tn:s te;n.^,:ace has thc a• ~.c _.. c tn; an:raals lar¢e enoucn .`c: bronc.^.es;optc cxamtnat on an-- ~ ccs. eu: tne ctsadvanta¢c of enor^scustN greater troubie and eos: Th: of adequate numbers of animals for stata:;:a!1 st_cntF•;ar•: anc it is ur.ce-:ain ut,.e:r.e- exposures can be as aeeouate a fractton of tne l fe span as wouid be des ra^tc Alt,,)ou¢h a lartte an:-a:s e•` dtaere.^.t spec;es and s:n:.^.s hase been lone exposed to frecj:r: ;:;ar::te smoke inhalation in a nursbc: C TR H N 0 11 '4~9 9

of laberatortes here and abroad, no squamous cell carcinoma has be:- rcporud. This is an tmpressi%e observation because of the number and vartett of antmats. the length of exposure time and the competence of the worc:rs Dt!ficult% in proper interpretation of these results arises from the fac: that a Lrrttted number of control ezpertmenu, conducted with antfsaai smokes contatntn_ che^ttcal acents known to produce cancers on the sktr.s o: t.^.e sarr.e kinds of animals. have also fatied to oroduc: lur._e eancr:s s,her: tnna.et Tnis failure suc^_ests e ther thit luna ttssue has a c e^e: tas:r:^s:c resa:~nce tnan skin or. mere likei%. that the luncs are or-:^a::: • outte ef~c:er.: in rerrostn_ ioretgn mattr f:orrn p;o;or,_e' ._r::,:: OTHER Ll•NG E\PF.RI>1EN'Tz S,ncc smoke inhalation and the inhalation of kno~n ea:c:ne,e^ ; ehe:csica.s in smoke form ha%e fatlcd to produce lur.g cancers in antma.s. other tecnntaues hase been tried. Larger amounts of test ma:ertals ale ^e:r; tntrcdc;e:! in forms more like!% to remain in lonc contact wtth iung ttssues Ben:p.::ne or rr.e;h%lchoianthrene dissolved in oltve oil and an!ec:ed tn:c th:e lu.^.zs of rats do produce tumors in a large proportion of the a:si:na:s C:¢3re::e smoke eondensa:es. stmtiarl% introduced into animal lun_cs. h;;%e fat!ed to dc so Ineucnon of scuarr.ous cell carcinomas in animal lun¢s has also been uch:eved wt:h the kno~sn cf:emt;al c_rc:nocens 5. implantation of eel:e:s rr tr.reads tmpresnattd %%tth ;he a^ent These techniques. thouc!t far `rc-n dv.i:ca:. - an% ncr:r.a! cend ::ons o' evposur:. are ;.ermt:..nt: co•,..ar,scrs ,. .,..c- ....^ical e•src,nccens tcDacco smore eonccrsa:es d::e:•., i.. TE-;T; EMPLOY1NG f1THER Tl;--~l'E;' 1n an eaere to broader t.h: base fer btoche.-::ca1 tests of carc:r.e- cen;;::.. ezperments has; been undertaken to expose a number of dt~e:er: t:ss_es .^ severa: spectes of animats Stu,'.ies in ducks and turk:ss ha\_ n,er :....,.-.anon on tr.e reactiens o` feat^::-beannc skin as c_.. pare4 tc the hatr•bear,nc skin of reoents Sites of trea:rnc:t: snc:::cr Icather:C areas as opposed tn unfeatnered areas such as the s+eb o' :^_ foe: lrn mice. the aop!rcat on of a¢ents is betne studted in the utcr:ne eerSU. t„ a:rsa;s under tae s'k:::. and in transptanted lune ttssuc ;re tntravenous rout: ts unce: ecp:orauen in m ce and rats v.t:h fat e^tuisten~ or ^re suspensions of so;:d ads.rceru as vehtcies A fuller evaiuactcrr o' the scoaceous gianC su^,p:esucn tes: as a possible quick earesnogen:;:n assas t:as been under v`a%fer some ume. but its reltabtlttv appe.n to bc dtmustshed bs fa te neeati%c or.e faise posttrve reactions to some agents CTR HN 011300

~ COCARCI.NOGENICITY AND INHIBITION STL-DIES f Several efiorts have been made to determine whether the inhtbttor% ~ action of one carcinogenic agent on another can be made the bas:s of : i bto-assav for carunoeentat}. In one study, the application of c:tase::: ~ smoke condensate appeared to delay development of tumors induced by meth%lcholanthrene simultaneously applied to the skins of mice. Conciu- stons are complicated bv the small number of animals observed and %Lcak- ness of the eHect. as well as the possible existence of true tnnt^ie:crr unrelated to carctnoeen!cttv or of dilution e9ecu. A number of cRe^s tc measurc tne efiects of tobacco smoke condensates when appiteA. alor,: kneu~r. :ar::noeens have been made or are in progresq I 11. Cardiovascular Disease A:tr.euch there havc been reported cenain statistical correlations be- twern tot:acco use and cardiovascular diseases. the various authcr:c:es In the ine:d have refrained from conclusions that these correlations are :!:e result of a causal relationship. There is general a¢reement that knoMied.e of fac:ors involved in eaustne cardiovascular diseases is such that far more invest!eat!on into all elements afiecttnc lives of human beings is necessan. before t.m..piteann: ans one of them. Ir. considennc reseorch prepusals to determine facts about the or s:^o::-, on the cardto%aszular s%stem. the Sc:entific Adv!son Board':.s feund eztrerneh useful trie confercnce method of discussing prrnts:r: r%cr.ues and methods of rescarch A second conference tnciudmc all :: c:;:r^:s ~' :rants-tn-aid for cardirnascu:ar and lung ph\stotoc-\ s:uc:es. %Lac ccnc_::eC on Nta\ 31 and )une I of 195' Attendrnc K'e:e 1 DR ERN:ST O4kTTt\GER. Tufts Lnj•erur. Senool of Medietne. Bostor. , Stassacnusects R G CABRER.1 µasr.inrcor, Ln.enic.. St Louis Mi+sour, DR KL'RT de CRI]IS Ie- Yor. Gnwersn-Post Graduate Med,c3- Sc^oo' "e. lori,. 1,~ Y DR JGHN; W ECKSTEIN Sia:e Lnr.ers t? of lo-a Couese of Mc-:c:rc lo~a C1t% Iov,a DR JOHN u FERREE Amer,an Hrarn A+socuuoc Nc~ York CG"• DR JAC1; FREL'";D Med,ca; Cotle;e of Rtcnmond DR CARL C GRCHZIT. The Graduate Scnool of Medicine. Gn-venn> of Penns.t•anu Pn.iaoc:onu. Penns.t.anu DR SAtiTIAGO V GLZStA'`, Phtude:pr:u Genera! Hospua! Prttaee:;nta. Penntst•ze a DR. JOSEPH H HAFKENSCHIEL. The Lankenau Hospita!• PhJadclPnta. Pennssi~anu DR H1kRR1' HEIM.1NN. L'nrteC States Public Hea!tL Serrv-tce. Air Po!la t,on Medtca! Prot;rarn. D vts,or. of Specu. Health krvius. wain• inttor.. D C 26 . -. : <' ~ .J .. i Y C1R- \{1• 0 1..30 1

' DR JERRY H. JACOBSON. NeW York Eye tnd Esr Infvmary. New Yort, t, t•. DR. KELLY T. McKEE. Medacat Collete of South Carolina. Chutatoa. • Soutn Carolina DR HL'RLEY L. MOTLEY. Un vcntq of Southcrn Catdornta. Los Antdes. Cahfornu DR WALTER REDISCH. Ne. Yorl Untvenny•Post Graduate Mcdtcal School. Ner Yotl. \ Y. I DR. HANS S ROTTENSTEI%;. University of Pennsylvania. School o! f Mer ccnc. Phdaaetphu. Pennsylv.nta DR S7ANLEY 1. SARNOFF Nauonal Hcan Insntute. wash ngton. D C DR- DAVID L 51MO%~ Depanment of lnurnai Medicine Ctncinna:, General Hospual. Cincinnau. Ohio DR C,AROLII~E B THOSIAS. The Johns Hopkins Scnool of ~feC:::ne Bar.,mort. htar.lan-1 DR 1,NE -, TR 0,'ELL. Dcpanmcni of P-arrnacoioly. Cornell Lnwenit> \tcl-al Collc;t. Ne. 1 nr.. 1, Y. DR 1 EDwtN WOOD. Masucnusccis 1•femo-ul Hospitals. Boston. Mass• acnt.utss DR R1CH6.RD L uECHSLER, Momenort Hosp ul lnstttute of Reuarcl. P,:a:,urjn 13. Pcnnsylvanu The conference Mas intended to discuss techniques and progress in reseal:.^.. ratt:cr than to drow any final conclusions, and discussants ag:ced that exchange of information amcnc the workers in this field of research was he:piul Research betne conducted thus far su¢aests that some previously held concepts concerning the e!lec:s o.` tooacco on the cardiovascular system mas ha.e t~cen oter•gencraitze.' For example. while it has been knos`n that n;cc::ne in teta:co leaCs to some constriction of peripheral b/ood vesseis. more extenstse exve::mcr.s now show that this is not true for a;: sub:e::s =.: oc:.rs onn to c.r:ain pccp:c ::nder certain conditions More- eser. .... .cr,s:...nse r:.:: w^... ., c;._rs is easii masked bs ctr.s tnfl.:e:;:es sc:n as tne cens:r.ctne e:?ec:s o: lowered envtronmentai ter^- peratt:re Aiso pern,^ncra constr;cn%: caccts mas be limited largcic to t^e ~ sesse:s o: :.;e sitln rather than to thesc in ;.he deeper vascular beds ( There are indications fur,her that the nicotine eRect on other blood vesse:s sccn as tne coronan arter,es is tus: the oppost:e: that is. it results in a tt;atton ratnc: than a cor:s;rt:t:cn The pha,^nacoioeN of ntcotlnc ts con:p ex and opposite e3ec:s m~ be produced by its action at vanous sttes. so tAat the overall efle;: is a geometric mean of man% actions and reactions Muc^ esocrtmenta: work is being eonunued to unravel these ,.,,. ,,. . among :aocra;or. an;ma;s out also wu`t human sublcc:s III. Stud.N oJ Human Lungs Late in 195.:. a co ruerea:c o` pathologlsts from various pans of the eoun:n was caiied os th: S;:cn:;r c ACstsor} Board to ducuss meatis of ,y="'C7 - CTR MIN 011302

eoordtnaung a cross-country study of the pathologic anatomy of the uacr.ea. bronchial tree. and lungs ootatned from autopsied specimens and surlpicai exctstons. The general question considered was: "Of what tvpe and to what extent and degree do changes occur in the tracheooronchtai trces of a general populatton?" The project. called the Pathologtc-Anauomic Study. w•as set up to examine changes in lunes from a large number of tndividuals of botlh sezes all ages. and living in urban and suburban and rural reglons. The 12 pathologists engaged in the studs agreed that :he tr.i:r-nat:crn a: hand was scant} and incomplete Results of the surve~ couid u} t~e baseline upon whtch continuing studies can be made Acree-:e^: v.as reac^ed on techniques for the preparation of the ma:erlal and :he se:::cr.s to be taken from strateelc spots in each lunc N hlie a mcre er less standardtzed procedure was adopted. each pathologist %lsas tree to use in adetuon one or another of his oMn techniques A relauve!_v st:^pie for- of history was adopted conststtne of a¢e. sex. occupation or ci..n.c c' occupatton, previous illnesses. smoking hablts. etc. As the study pro¢ressed. the need became apparent for a un:.'orm c!ass:5cauon of ehan¢es iound in the lung tissues It was hna!i. dec:deC to descrtbe the observed lung tissue conditions by six classtnca:tons 1. Normal : H>perplasta 3. Squamous metaplasia 4 Atypical metapiasta S. Carc:noma in s:ru 6 Carc:nc:^a The results of s:ud,. on over ;.6GG cases are be!nf f~3;c]eca a-.e-: tne pre!tmtnan observations µas the relattvelv hieh preva;ence of iur.: t ssu: chances among a!i groups and all a¢es studie~ It Mas also nc:c: t^at the condition termed "carnnema in srru" w•ai rare:% ducnesed :~ znv ef the pathologists and then usualk onlv when there was t^%'ast%! .......cma prescn: 4luch of tne w•ori eo^:r.,eaced unecr the Pathoior:c-Anater.t: S:oC•• is be:ng eonttnued. and arrangements have been mace for keeptr.g un.e gToup tntact and for hoiding future meetings. Ccnferences of the coopcraunc patholo¢;sts. thetr co-workers. and gues:s were hc.d in Decc:n^cr. 1956. and June. 195" Attendrn¢ one er both of Lssese conferences were the followtne DRS E M BLTT DORCTHY TAT7ER. Los Aoteies Couniy GrnvaJ Howial. Los Angeies. Calitcrnia C TRH i i 0 11 W7 ~.r~ ..E

DR. WILLIAM H. CARNES. Votventty of Utah Collete of Medicine. Sau Late City. Utah - DR. DEAN CONNOR.S. Untveruty of Wisooostn Medical StAool. t•faduoo. Wqcansin _ DR. DEAN DAVIES. Amerrcan Cancer Society. New York City DR. RUSSELL S FISHER. Uotveruty of Marytand Sctsool o( Med,cme. Balumore, Maryland DR ALFRED S FROBESE. The Graduate School of Medtctnc. Untrenu> of Pennsylvanta. Phtladelpnta. Penruylvanu DR. HARRY HEIMANN, U. S Public Health Service. Air Polluuon Med, ~ ul Propam. Divis on of Special Health Servmes. wa+niorion. D C. DRS. R[:SSELL L. HOLMAN. R.ALPH MEIER. Louuuna Sute Un,- versny School of Medicine. New Oriwns. Louwsuna DR. KE,`ETH P K':L'DTSO1.'. L'oivenuy of washtnpon Med cal Scnool. Seatt e• washtnpon DRS M.AR"7N F:L'SCHtiER, HENRY G $CHMIDT. NYI:-Belierue Med,cal Cenier. Ner Yort. N. Y. DR, THOMAS C. LAIPPLY. Nonn.esiern Unrvcrsny Med nl Scnoo:. Chica{o. Illinois DR. H R PRATT-THOMAS. Med cal Colierc of South Cafoltaa. Charles- ton. Soutn Carolina DR K O. RL'SSELL. The Universuy of Tetts Medical Ceatcr. Houston. Tetas DRS E D WARNER. K. R CROSS. G. K. PALMER. State Univenity of 1o-a. Iowa Cny. lo+Z DR RL'SSELL _UELLER. Ephrau Community Hospital. Eperau. Pennsyt.ania In addition to Ltie Pathologic-Anatomic Study there has been tYSeucb sponsored in the gencral field of lunc phqstologv and respuatory mecbantcs One group reported that under the conditions of the ezpet•tment. scto'r- ing had no sltmificant efIect on the mechanics of pulmonary fuocvon for normal su5uc:s I\-. Population Studies Researc^ projects approved c% the Sc:enrbc Advtsory Board mc:ude several pnpstoiogical and ps}cno:cr:ca; s:udies aimed at determining Khetner tne tendency. to become a nca%-% smoker or to remain a light one or to be a noo-smorer is reiaec-, co ps~c.,1o-pn%siologicai make-up of Lhe individuals Several mteresung leads ha~r ^rern repcr.ed tn a preltmina.n• manner b} some of t.bese investigators O.^.c oci:e~es he has definite psychological clues that may permit a sharp d".erene,ution of persons into two 6sttnct groups in the eulv stages of the;: ss,otinc expenence lf further Wer•r sustains this ooservation. it may tenc ic s^oLL tnat havv smoken and Lght- or-non-smokers may be persons of d:ae-en! constitutional npes. 6•tt.h diflcrent dtsusc expectancies Onc r.ceri ec a group of men who bad stopped smokng, compared wt;h conunutng smokers. tndtcated that the CTR HN 011304

stop-smokers tended to add and retain weight as compared with similar mer. Mho eonunued to smoke. A great deal of additional work wtll be reou:ret to follow out these clues. Early publication of preliminary findtngs is expected to stimulate further investigation by other scientists It is well known and well understood that studies tnvolvung ;-.e ci,- amtnauon and questioning of human populations ars difficult. Any grou; that is available for minute study and examtnauon u likely to be a se:ecte-- group. and thus very probably not typical of the entire population Tnus. it was fortunate that several population studies were aveac• under way that had tncluded, almost incidentally. smoktng histories of :r.c subiec:s %ktth some of these tt was possible to tnauttura:e researc:: ^,rc.e_a tha: %ould retate smoking histories and habits with the otner rna•cr :- - s:.:::t:cna: factors that were alread% under studN- :^c preitmtnary work of these prorects under way has been sucn as to encourage further tnvesttcatton of suitable populations for st;:d•. an-~ of me:nods for conducttn¢ the studies. Because the conference method had proved produc:ive in other `.e:::s of tn:erest. a ph%sto-psychologtcal conference has been scne~uied .`er the fa!! of 19S'. V. Other Research Studies A begtnntn5 has been made in studying the eNects of ntcoune and smoktr.g upon the gastrnc functions of normal persons and ulcer patnen!s Of t~rce proiects under way. one has been completed K:th repors to t^e eaec: :nat c;earene smoking by patients with duodenal ulcer did no: proc_cc sign:^:an: chances in gastnc secretions. O^e stue,. of oral tissues has been carried out to dcscrnbe the c^.ar3c- tr.a:,a of tnese tissues as a'iected bs a¢:ng and exposure to toeacco s-.cr: C'ner stud:es tnc:ude taentincatton of tooacco leaf consutuenu :.._ mec:^.a-:sr,:s of metaooi:sm and of nicotine formation in tobacco iea%es t^e rne:^ar,:srns of nicotine break-down by bacterial and mammaita^ sss- te^;s. teen::C.auon of smoke tneredtents: and collecuorn and studl•, o. .,•.~ ches: X-ra% fiims v.tth a vtew of tmprovtnc dtacnosis of lung disease 30 C TR t i i i 0 11 ..t O~..~

Recipients of Grants The follo-tng is a listing of recipients of grants approved by t"e Sclenttfic Advtsor. Board and activated prior to July 1. 195'. ir.c:ude~ are tncse c;jrrentl~ be!ng supported or compieted since the last repcr. GR0IEE a%D 11 STITLTION D %tLRRkY A%GEVINE >iD. P•o- lcJZo• n' Pcr-o-or•. Lni.crs,ts of k s- cons,r. Slca.a, Srnooi. Maauor.. w,s• cons;r. PROILCT TITLE rY.,.,u,., .•e..r, r.. ..e r ..u.r...: . ...e.. .. .e . +., ..., ..e.,,..• Patr.MoPc-Anzttomjc Study of Ct;iu.ar Cnanges rn Hamar, bronc-,, FREDERIC)i K B,kRNES. 1.. MD. PN D. AJ1of,c,f P.o,rrsor or MramAr ona P,,sz,o,or:ca! C"tmurc, lonr.s Hopc:ns Lno•auts S:noo, of Medicinc. Baiumore `. \faryljn:, S1.%fL'EL BELLET \f D. D,rrrror D,- r,sion of Caro,o,oh. Pntlaoupr.,a Gcn• era! Hos;,u:. Pr.,,adeipn,a. Pennss!- •an,a RICH^RD l Bl\G. St D. P•olrsso, of Nra n-r wisn,nron l ni.c•s:ts Scnoo of ~IrGr.me S: Lou,s UmoJr, \'r.erars ^:-.in,s'raiio' HospI:a S: Lou:s , Fc•-•t- • a• "c Sse-ca; Coi'cre of A,aoa-:a B rm:n~cam ? A-acar-.a G o:;.~. ~t S Se^ c• Ca^:r• Rnrn,r. _. Mca.. Re,.rj•:' In; nos.e rP:•. D-s,oc 8j.:j.c \e. Yor. -.tc slcore, LAMES F B^,;\ER. PH D. P.o'enr• 1• B,o,oc Ca.:.`ornu Inssiiutc of Tr.n- noior~ Pauarna Cal:forn:a JOSEF M BRGZE/. Pn D P,c,rrso• Lanorc:c, c' P-,na.otca: h~r.r^r Ln-ers, . _. Minnesoia Sc!~oc o.' Pubiic Hea.,:t _ M,nnr.pons. M,nrrsoia E f•t 8LT7. M D. P•o,ruor or or,. l,n,.crsn, of Soutnerr Califorr.,a Scnooi nf Mrc,c:^c CA,e' Po,l 0 or . Los Aniars Cour•, Hosp-ia, Los An ;t,rs 33. C:i,fornu K'ILLI,0! H CARNES M D. P•o,n,c• o• Pur•-or. L-eaw, of LC:ar " Irrt of Mec.c:nc Sa.: La.e C,:s L:c' tFormtri% a: Sul Lr.i.c•si:, Scnoo' o! Mrcic,nc S.ar. Franc,sco C.1Itforn'a, The Roie of Hyperplasu m Tissuc Re- sponse to Cnronic Damage Cud,osascular E"ccts of Smotir.s arsC `,cot,nc in EaMrtmcoul Antma,s aaa Human SuDitcts The t'Sccc of Smoung on the Corooan Blood Flo•. and Cerain Pnascs of M.ocard,ai Metabol sm in Pat,e::s ,.,:•. Artenesc,crot,c or H>pe^en."r Carow•ascc.ar D,sease lP, ir.esnja:,or of tne B.oiollical E!cc's o' :.(jrc'...e Sr^AaC Y, Enzsr•^.a::c StuC% of Me!nylauoa Ruc- nons m Pian! Ttssuc b,o,o; c, Crarac:e-a::cs of Men anc 7^.c.r Smounj HaDiu 1P. Stud% of Trace sr1cu1 Storare of P.dmon- ar, an: l:~e• T,ssue er SpcctorrasSntc a^c C-e^aa .N,c:noos Pa:roio;,c-Anatomlc Stues of CtlSular Cr.-Ir,cs in Human Broncn, P::-o.og.c-Anaom,c S,uas of Ctliuiar Cr.antes in Human Broncn, CTR • •N 0 1 I 3

CR AN7EE AND INSTITLTIO% LEOPOLD CERECEDO. PN D.. Pro/ra- aor o, Brocnrrruarrv, FordAam Lntrer- suy, Hr. Yorl !1, ,- 1. HANS T. CLARKE, D.Sc., Profrasor of B,unr .rum, Columbta l;ntvernty Col. Icle of Pn%stcsans and Surgeons. \ev. lort. !.' Y. laee Gonscnau) PHILIP COOPER. M.D.. Aa.oc+ere Pro- lrifor ol Chn,ca/ Surjrn. Boston Ln,- vrrsuy Scnool of Meo,crnc. Boston I1. Masucnusetts. C(ue1. S,r•Irca( Srrv,cr one D,rrrro•. Surnra/ Rriro•cn Laa- oraro•, Ne:crans Admtnsstratson Hos• pita~. Yro,tarnce 8. Rnooe Island HA";S L FA,LK. PH D•.eaniranr Prorrr- ro• o' 8 on,r~,nrr• Ln,.ersrr, of Soutnern Cal,fnrn,a Scnool of Med, crnr, Los Angeles JJ, Caltfornra DANA L FARNSWORTH. M D.. Hrnry K 0-r• Pro/rjaor o! Htr,enr and D,• rrrro• o• C.nnrq,rs Hralrn Srn,rri. Harvar: Lns.ersny, Camort:ie 38. ~Iasucnusc:cs tSee Hcash and Mc- Art`urj FRANK C FERGUSON. Ja. M D. Gmr~an or Drparrmrnr or Pnarrna• co,or+. Ato:ns Medical College, AI- bans 1. \r- Yorl RUSSELL S FISHER. M D . CFrrr Mre,- ca, £ra-r• S.ate of "arytanC. Pro- rrfro, o• Lrr:r Nra,cn,r Ln,.rrs,rv of ~1ar.:ar.C Med,cal Scnool. Baltimore. k1.ryianc B L FREE`^.. Ik\'DER \S D. D:rrcro• c Ccn:r-Rrjro•c', s: Iior.Hos^,ica:. San Fran;a;o IS. Cal:forn,a JA:/: FRE'-',,^. .1! D. Lrrrt,•r•- P-c- nro,or, .crJV,c'! ~n Mre~c,nr !Aet, ea. Co..r,e of N, ul,n,a. Rienmona 19. Virginia GEORGE 0 GEY -k/ D. D,rrcror F,n. nn•Ho. r', Ccnrrv Rrrrorcr Laoo•a. ror Drpa,mrnr o' Jor,ns Hopa ns Hosp,u,. Baltimore. Maryiand 32 PROJECT TITLE A Studv of Earlv Chcm,ql Chinrrs tr the Lunp of Tumor•Bcarsn; R.u and Mtce (P) Proseolvnc Actrvrtses of the Whne Bloo,; Cefls of Man ann tnc E.`•ec: of W r:e Blood Cell Act,vntes of Caresnopens. Nutrition and Other InAucnces tC, A Study of the ERecrs of Cigarette Smoc- sn; on Lesels of Gassrsc Ac,c. Prps.n and Lropcpsun rC-P, Exam,hauon of Ct/arene Pape- a^: C.ra• ret•.e Smos.e Conaensates tor Aroma:.c Poisc)ci,c Hydrocaroons Personal,ty and Smotinp tr. Colleir Grao• uarec,A Fdteen•lear Fojio-up S:ce. tCr Ellects of Tobacco Smoke L'oon tre Func- non of the Card,ovascuur Sys:rm in Animals and Man Patnolofic-Anatomic Studs of Cc:iuiar Cnan/es in Human Bronch, T,e e••a :! ,,:.a- Eatrae:s o' ' Carnnoeenic E9ec+ of Me:^s:c-o•a ^rer:e an-- of Ltira-1-ojec L+In. Ire E."•e:: of Tooacco Ex:raca on Carc:no- /ent: E.'Ie:: of Lreenane-Induce: P:.- monars Aaenomas in S:rair. A M.ce ve l'se of \ arious Sulp!+ydryl Comm pounds as %eu:ralizml or Coun:crac:tr.q 1/e-lts (or tne Poss,b,e Carc.nolrr.c E.".cc: of Tooacco Extracts in M:;c Correlatuon of 11,fultitecnnica' Procc:.ret Performed on tne Pcripneral C:r,.'a- non of Normal Ind,v,duals in Recurr• bent and Erezt Postt,ons and After Es- ercuc Before and After Snam aod Actual Smounl FclloWshtps for Study,nj the Culture e. Human Lung Tusue and ene E.•.ec: of Kno%r, and Poss b,e Cucu+olenlc Agents Lpon Such Tusue CTR' HN 011,307

GR &*%TEE AND INSTITLTION GERTRL'DE Y. GOTTSCHALL Px.D., Atara/anr ProrfN+Or of Brocrrmrnr), Depanmem of Patnolopy and Mtcro- bwtogy. The Rockefeller Inwtute for Mcdsa/ Rexarcn. heW York :1. N Y. (Formens at Columbia Unsvenrty Col- IeCc of Pnysacsans and Surgeons. NeW York, N. Y.) (See Clarke) A CLARK GRIFFIN, PH D• Heae ol Brornrntur•r Drparrmenr. M.D. Ander- son Hospttal and Tumor Institute. Lm- venny of Tuas Medical Center. Hous- ton :!. Teaas MOP.TOti I GRCSS%fA\, PH D. M D. Al7oc.:'r l.,n.c:. P.oretaor or Mcal• nnr Lnr•rrtir:% of Cahfornio Sledical Cen:r:. Los Angc+cs :41• California CARL C GRI;HZIT. PKD. M.D.. As- iocrurr rn Pn.a'o,ors and Prrormaco;- or% L'nrversns of Pennsvlvanu Gndu- asc Sc:+oo: o! Medictne. Phtladclpnia A, Pcnns.ivanta H B HIkAG M D. P•orrllor or Pharma- colof. "cdreat CDllcgc of v'u~Vota. Rtcnmon-1 19. Nuginu JOSEPH H HAF/;EVSCHIEL. M D. D,rrcro• o' Cara,opurmona- L n:r Lanccrat: Hospr:al PAtladelpnu 31, Pennsv.aw HERBERT R Hk uTHORN E. M D. c' Jr~c ,~ rnr o' Su.rr Ln .rrs. ^! Pcrns.nanu Gra w:c Sc.^.ooi cf Mcc:c:nc Pnrudctr:•. +. Penns-an.a CLA.RK w HEOkTH MD. Pnstra•. Dr+c•rT- o' h,vrnr. Harvard Ln- versrts Carestriarr 38 Mass.cnusect~ (Sec Fars-onn and Mcnnnurr RL'SSE« L HOL111N. M D . P•orrssc• on: hr:s c' Orpc-rnr 0! Pornc-c;• Lounuau Su+r LnrvennN S:noc. cf MeC-nc. O%ev. Orieans 1:. Louisiana F HOkiBL:RGEP.. M D. Rrrra•cr, P.d lruo• of Mra'cr.r anc D"ecror Ca,icr• Rrsroren ana Canrr• Connor L n,r TuAs Ln,.cnii, S:-ioo' of s1cd.c:re tie- Er:i:._ k1e:,c.Cenir bos?o-. Mauacr.uuu Sc:enn5c ^uoc au kos- eoe B )actson Mcmoru~ Laborator>. BV Haroo• Mame It.o% Preside.-.: B~o-Resur,r LaDCrasones. In; . Bos:oc. Muucnusc::s PROJECT TITLE Proteolytic Acuvsues of the Wbtse Elooe Cells of Man and the Effec: oo wcr.e Blood Cell Acuvsues of Carcinotecs. hutnitoo and Outer LoDucncn The EAect of E+posurc to Cigarette Smoke oo tne Induction of Cancer by Cncrosca. Compounds (Cr Tthr EAcc: of Smokint on Ccna:n Gas:nc Functruns Pnarmacolopc Studs of Nscounc and Rcr latcd Alutosds (C ) Prcoantton for Puhitnuon of a Booe crn ine Btolopc Aspccu of Tooacr.o ana its Smocc Meisurcment of Corocary Blood Flo- Cardtac work and Cardiac Osygcn and Carbohydrate Metabolism in \ormo- tensivc Subrects Before and "ftcc Inrr" venous Ntcotinr and After Smoc.nl Standard CGpreues Attrmpts to Induce Pulmonan !\'coDrasms in EsDcnmental Antma:s b> Eaposu•e o' trie T racnco-Broncnral Ssstem :c To a:;o Sr,oie Penooahtv and Smok:ng in Coileye Grac ures A Ftfteen-le_r FoiloW•Lp S:cc• rC. Pat!'olo`.c - Anatomrc Stud, of Ccilu:ar Crunlrs tc Human Broncn, A Stud, of the E!!ecu of CGprtne Tars Lpon the Bcna•ror of Transpianta::c Tumors tn Rodents Empiosmg aSc- TecenrQue of lntrautenoe Tumor Tnes p.antatlon CTR i i i i 0113106

GHANTEE AND 1%STITITION JERRY HART JACOBSON. M.D.. Dr- recror Of E/rcrroon-ra/o/or. NeW York Eye and Ear Infsrsnary, NeW York 3. h Y. ANCEL KEYS. PH D.. Profruor of P/rsa- .o+orKO/ H~ywnr onA Drrrcror. (.ao- orerory of Phano/oerca/ Hyrrrnr. L'n venny of Mtnnesou School of PuD• }sc Health. Minneapolis 14. Mrnnesota JOSEPH B KIRSNER. M D.. Prolruor ot Mre,rrnr Lniversrn of Chtpgo Schoo, of Medrnne. Chicago. Illrnots KENti'ETH P KNl'DTSO`,. M D.. Ar- C-r' Lavn.nro- Sr•,rt Vt - en-s Adm,nistra:ron Hosprtal. Searnle. M asrroe:oe Prorrirn• o• Parr'orot• Lnr.ersrt) of washtnpton Medtul Scnoo„ Scattlc, wasrtsngton ALV1N I KOSAK. PH D. Attocrarr Pro- rrrlo• or Cnf/nrlrn , M afhington SoWre Co++ett. Ne% York Unrversn). Sev. l ork. N Y MARVI%~ KL'SCH\ER. M D. P•orrsro, o' Pornoiof•- *-e. Yort L'n'vcrsir) Coltege of Medietne. D•rrr:or o• Pc- rno'oc~ Believue Hospual. Nes. Yort 16.,' Y. THOMAS C LAIPPLY. 51 D..csfor,arr P•n•rfso• o' Parnorot• \on`.~esserr. Ln,vcn t) Medrul Scnoo,. Cn.ca2o. 1litnou PAl'L S LARSO%~ PH D P•c r:sr• n• P.a•-•oro,or Med1cai Co, :r`e e' ~.r ~.n,._ Ricnmond 19, 1 ~r7:n,a CE :L:E'EL'CHTE'~BERCEP P- C Arl::::lr P•o'rfr: • C• C'.': ; i' 'A " err Reser`t L'nirrrsit% S:'.OC. O: ~IeCc:rc C c•c:and e. Oc'c PROIFCT TITLE A Comparison of EJeeemecunop-annv as a Means of Evaluanng the E"e:: o( Vasoconstnnor Drugs Upon Cercera' and Reunai Crrcuutton wuh Osr.cr Techniques for Thrs Dctermtnauoo ( C, Charaeatnsucs Of Men. Inctuosng Smo.- mL in Pooulauons Drflenng in the In- csoenu of Coronary Hean Dsseasc The E!1ea of Tot•ac:o Smoung Lper. Baul Gas:nc Secretror.s rn Mar Patholottc-Anatom': S:ud cf Ce:::,u Cltan, s tn Hur•':^ The Isolatron and IdennAca:lor. of Crrain LoWer-Borltng Corhpone.^.ts Of C:pre:tc Smoae Patholopc-noatom c 5tud• o! Cc:ic:ac Changes tn Human Bron:n: Patholopc-Anatomic Stud, Of Ce:laiau Changes in Human Bronc`.: En:.maric Tncstormauocs of Ntcounc Q_an:itative Anal.sns of \u:ieocrotc,es T111Ue1 Fror' 1^..Ta.i 5.: e:':: - Tooacco Smote D• !1.:resx:co;'.c+o me:ry and Inrerfere.n.cc N.crosco:• Co- reia:ed .M Cytaop:a, and Huto:e;, ca. Studies D~~1DE M„v 1s.PH D .tf,cca:r E'cc: of Tobacco Smote ard Tona::o P-o•rjlo•r•Pno-aro,cr Tr-: r Rcs dues on .Me:nvlchoiat t`.rerr Ln..c-sn, Srnoow c! P-)ar^'a:, dc.p"..: J:. Pcnns)tvan,a P- . L~:uceC S.:r Caranotenesn tr M::c 'C , CHARLES CMcARTHL'R. P-. U r•,o,oeir r~ rnr L n•• r•l,r•. ti ro o: 5•.. Soc:a' and Personal Determtnar.u o! Smottng Behaaor /C i rrr) HanarC L'n-ers", 78 Mass.unuuits tSee Fa-s.o' • a~: Hca:• KELLY T McKEE M D. .r,ror., . o•,,o rrNO• o• Mra,rnr ktf: : ~„ flc c. Soc:r. Caro-r.a C,vr,es:cr So_ •_ i O'. M S,ud, of Luog Function m Smotm and hon-Smoters LJ T i"+ i i i j 0 .i, .S, 3ti.1r 9

GItOTEE A%D INSTITLTION HUGH MO!•TGO1stERY• M D.. Aasoc+• arr trornaor of Mra,crnr. Umvenfrv of Penns>r.nansa Medsul School. PhdaCcl• Pn;a 4. PcnnsYtsanu GEbRGE E 1•fOORE. Pss D. M D. D,• .rcro• Rot.•cll Parc Memortat Instr• tuse. Buftaso 3. New York t5ee Bock ) HURLEY LEE MOTLEY. %f D, Profrs• ro, 01 Mra.n-r onC D"rrro+ Co•a,o• Laooraro~. l.'n,•ersstv of So.,iee^s Caiifornu Schoot of Med,• e r• Lot Angces 1', Caldorn,a w-ILLUNi 5 SfL'RRAY. SC D. Rrrrorrh AriOC:Crr on: AO-,nU7rOftOry D-IfCror. Roscce B Jacison Mcmonai Laoora• tory. Bau Harbor. Masne C M PO\tER1T- PssD. P•orrrtor o+ C,+o of, k,nntnr, of Texas McCrca! Brance. Gar•eston, Tesas H R PR s,^•THOMAS \f D. Pro,rrror o' P-n,o,or McdtU' Colictt of Soutn Caro.,r.a CMricston. Soucn Carouna VICTOR R:CHARDS kf D. P•orrrrc• o' rrr:~r.lr Hra: Drea-1r-, c' S••r.• 5 s^!or. ! m.e+su• Scr.oa. ot sfrc.: r.e Sar. Francisco 1'. Ca" (O'r.: R H RlCJC,: V D. Prorrrro• c' PJ- n,o'or . zD,•rrrc• Lo^oraro^ o' P.r.c.oi• Ln~e• c! Teus ~le.: al Brar,cn. Galvutor.'Teaas SYD',EY C Rf: , ENBERG PN D. Pls,- frrro• o' boc,r•,o,or, Un,.crslrv of Soutnern Caitfornra. Los nnjeles. Cai,. /orn'a K'ILLIASf 0 RUSSE! L. M D. Parno/o ltu,- re.e' M D Anderson Hosc:ea) anC Tur^c• )nsu:ute (-'r-e-v:. or 7cras Slc:.u. Ccnter. Houstor :. Tca1 s PHOJECT TITLE Inlluence of Tobacco Smokrng on trc Blood F1oW of Skin anC of Musc es of Eitremss,cs m Svmeatne:tomtuC ant UnsymDasnectomtaeC Subtecss An invt3upuon of the Pnsuo,opea! V (ecss of Dtrect fnnalauon of Tooacco Smoke b) L.Uborasory Ansmais anC tnt Study of the B,o:opcsl Resoonse o! Laoorasorv Ansma!s to Contsr.uous In. Mnon of D et•Tooacco Proaue: Mu- rures lC-Pt A Studs of the E'!ec:s of S^ea:r:: or Putmonar~ Funcuo~ The Product,or of Genvca:1s ConrrNie: Anrmals and Tumors for Usc sn Es:er.• mentai Researcr on Tooacco t- Rca• tson to Heattn by fa, the Esoans- of Knowm InbreC Ssocas and Sou-:es o.` Tumor SupoiY. tb. the Procucaor o! Suct•. Htbrsds or Hctcroatous T,xs as Become .'.ectssarya and I c, the Rc::- tuon of tnss Materai to Stxctsc Eeper.. mental work at the L.Aborator. Fel1o+'shsps for Studvsnj the C::fturc ef Human Lung Tissue and the E1cc:s of KnoWn and Poss,bie Carc+noges,c Agenu Upon Such Tissue ADDLdnnn of a `e+ B,o-/sssa. Tccnn,c:r rn Eaamtnatton o!CtEaretre Smote Cor- densates for Poss,bte Carctnofc-,s Pa!noto;,c•Anstormc Study of CcCu a~ Changes in Human Bronc-i A Comparlu,e Stud, of sre E"e:n c' µ-o.c anC Fra:i,onatez! E.:+a::s . CGjarene Smoa ane Tnosc o! Carc;notre^s o.n. . . ee C•to ct, rr_ 1~uctear D%A Ccrten: of E:,aerna ' tarious S'raint of MiCc anC Cr The Ctito,ots anC Luc ca• D'-1, C. ten, of Lunl an3 E:ntne,,ur• of the Broncn,a! Tree of u,ce and Hamsrc•s SiuC. of tre E^cc: o! Mt n.icnoia.^.trrrr: or tr.c Trssuet of :^.c Duct .' E- pr.as,s or. r^e Reac: cr :n t r'ira:"n QT.en Comoued wr.~ the Sc,r e! v.r boC~ ano the weo of ire Foo. tP. Su+d-es on sne Mecnan,sm of Bacurui Mctaer+l,sm of A,eot,ne and Rt,ate: Compounds Patnolotnc•Anatom,: Stuo• o! Ce::ulas Cnan(tes in Human Bronc.:: Ci R i ii i 011310

GHANTEE A.D I.STITiTION PAL'L D SALTMAN, Px.D., Auuronr Prore»or of Brocnrmerrn. Unt.enrry of Sousnern California School of Medr• etne. Los Aniteies 7, Calslornu ISA AC SCHOUR. D.D.S.. Px D. D-Sc.. Prorraaor of Huroroi% ano Emorsolop ' ano Dron Unrversrsy of lllrnots Col- lesc of Denustry, Chicago l:. Blltoots MAURICE S SEGAL. M.D.. Chnrcal P•orraao• or Mrornnr Tufts Unrrtrsity Scnoo o! Medicine. Boston. Massacnu- seas D••ec:or Dreorrrnrnr or Inno/o- no" T.rna: ~ Boston Cuj Hospital. Boston. J.1 assacnusetts E SHERUOOD. M D. .1r- rrr.a~r P•orrrso• o, Roa-oior Lnrser- s::s c.' Ro:nesirc Scnool of Mcd.anc an~ De-us rt• Qocnesser.'.e% lort D.A,N'rD L SIstON. MD. Inrr.ucror In Mretc:~r o.- Frlio• rn Cararovatr.rlar Reara•c° L'nr.enny of Cincinnati Col- lejc of Med,cine and C-ardrac Labora- tor) Ctne nnati General Hospital. Ctncinnaa :9, Onio SAM SOROF PN D. Rrlrorch Auocrarr Tnr lns::tu:e fr. Canccr Reseu:' and Lancrnau Hosp:3t Researct lnsa:ute. PM~ade,;nra 11. Penr.s)icanra FREDERICY: 1 STARE. PtiD P•orrr- rc• c• Hanarc S:-.oc. ct rut!:: Boston 1`. Massacnu- se:;s MAR1'J',; B S; L2BERGER. MD. P•o- ns: • . _ Cncr•rnan Dr~o'rn"nr o' Dr•~:e~c'oro~C S~pr:rioro(he~ 1or: Ln..enon Posi-Graduate Medical Scnoo. Drrrro• ir. y'o" S:" an1 Lni.e•u!s. Cancr• C>7 : he- York Be::e•:e Nea.c:: Centcr 1e~ lon It Ae- 1 cr. CAROLI`'E BEDELL THOMAS. M D. Afaocrarr P•orrrso• o' .Nrarn"r )onr.s Hopeins Lnivenn. Scnoot of Medicine Baltimore !. Marvland TISSL'E CL'L'. L'RE ASSOCIkTIO` (P•rrrar,: D• Margaret R Murras. Arroc-arr P•c1rrno• o' Anoro-1 Co- IumDU Ln-ers,:, Colielc of P-ivs,c:ans and Suraneons. he,. Yor. N Y r ?6 PRO1k:CT TITl•E The Enzymatic Mechantsm for the Darl Fsaauon of CO. Dy Towuo (P) Histologic Chances In tne Oral. Pharyn- rca1 and Nasa1 Tsssues of Espenmenul Animals Sue/cctcd to Tobacco Smosc (P) EAects of Cigarette Smoking on Lung Funcrson m hormal Sueict:s an0 Pa- tients W'nn Certain Respmtory Dscax Condruons IC-P; Invesuga!ron Into the Satura' Hrs:or. e' Carcinoma of tne Lung W rt~ Part,cu,ar Reference to tne Radrolrapn cApoear- nce of Such Processes tne Eaniesi Mantfesutron of Cancer on Chest X- Ray PnotopapAs and tne Taoulatror. of she Resauonshtp of Smoiing Haet:s and Occupation Wtth the lnctdence of Lung Cancer (C) The E,lects of Cne-tng Tobacco on :nr Cardtovascular System of Man IC-P t Chemieal and Pnysreal Studies of e-e Trs- sue Prote ns Invoived in Cnemical Car• cinorenrrs Eaoarimental Studies of Ca^,cr a',ev. Tecnn-pue to See if %unous Tars Esirac!ed From Too.cco Mas lrcue t^c Formauon of Lung Tumots •,C, Invesu(zauon of the Eftects of Tooacco or tnr Human 'vascular S.sum rr. L , "oiun!eers. and in Pan:cular o(tne Possi1b,lnv tnat Certain Tooa:co Elte::s are Based on Peculiar Allergic Suscea- b,l,t, of Spectflc Indiv duais Ra:.".er Tnan Lpon Ooi.catoruy Toaic Proaucu rn Tobacco Smo.e The 5rsniflunce of DrRerent Indivrdual Panerns of Circulator) Response to Cigarette Smoking To Ass st in esublrsnment of Summer Training Course !n Ttssare Cuiture Tecnnros,es ar Lnlve•srr) of Coioraic Medtcal School. Denver. Colorado IC r l.r TRt t N 011311

Glt 1NTEE A%D 1NST1TLTION JANET TRAVELL. M.D.. Auoetarr Pro- Irraoc of Cltntroi Pna.rnoco/oc,. Cor- nedl Lint4cnrly Medtcal College. Fe. lort :1. Ne. lork E. D WARNER. M.D.. Pro/ruo, of Pa- rnotot% State Untverutr of Iov,a Co;- lerc of Medsctne. 10.3 City. 1o-a RICHARD L WECHSLER. M D. C6ni• cc/ Pnrsjo/oltn. Monunore Hospttal Ins(stute of Resarcr.. Pittsburgh 13. Pcnnsytvanta RLSSELL k%,k 'ELLER M D. Potholo- fn)! \lemort]: Hospital. Kcst Cnesler. Penns,,.:n:: Por.,oaoe:V - Communi'l Hospita.. Epnrata. Pennsst%anta. Ajro- nctr P•o'rs~o• o' Pctnoio(, Hanne- mann Medical College. PhtudeipMa :. Penns>t•anu SISIO',; H w'E'l!DER. PssD. Rrsrorrti P.o'r.ro• o' Citr~,rr- Lnr.•enity of Osiano-a Researcn Instttute. !vorman. OJanoma 1 EDu"ll,; WOOD. M D . Inn•,+cro• in Mra,n.r Boston Un+ventt) Stnool of S1t::;me and Robert Da-son Elans N1er^..or:ai Deparmen! of C ni;a, Rc- searv. and Pre•cntt•c Medi. nc Massa- cnus;tts Mcmor:a: Hospt:a,s bosion I8. Massa;nusetts PNO)ECT TITLE EJccsrocarOtolprapAic Eftecu of Ntconne in tne Rabbit with EspKnmcnul Coro eury wsneroaclerosss Patnolopc-Anatomic Study of Celluiar Cnan;cs sn Human Bron;ai Elfecl of Cipretsc Smoktng em Ctrebnl Blood Flov. Cerebral Metabotssrr.. Btood Gases. Biood DH. Arterial Pulse Prrssurc Curties. Etectrourcto"ms, a.nd Eicctrotnctprnato(rams tC i Palnolopc-Anatomtc Studl of Cxa,.:ar Cnanges in Human brorcn: A Oualsuuve and Ouantttanve Srjd> of the lndtvsdual Potypneno: Con;cn: o: Lt{arettc Tobacco and cf '-'le Smoce and 'Tan' Resutttng fror.. C,larecc Smoking. and Also Study of sne Fa!e of These Compounds tn tnc Aaursai Resptratory System The Efltc1 of Prolon;cd InAalas on of To bacco Smote and of Prolonged Absun- ence from tne Lu of Tobacco or• V~e Pcripneral lvasCular Rcspoosc to Acute Innaiatton of Tobacco Smote tn Man (C-P) i..r TR t i N •.+r .B. .S. .+t .L 2

Abstracts of Reports Eaca recipient of a Tobacco lndustn• Research Committee grant is responsible for the initial publtcatton or presentation of tne results of hss research in appropriate scientific publications or sctentif;c meettn¢s. Follow,nc are abstracts. approved b% the authors. of reporns that ha-.c appeared in the indicated publtcatlons. with acknowledeement of suppc- from ;h: T.1 R C. The name of the scientist to whom the T.1.R C. pan: %%as mace :s gsven in paren:hesis at the end of each opening parazsa;^ "AL'~TILATION IN CHRONIC PL'LMONARY EMPHYSEMA 1. Pres- sure•\ o;u:^e and Pressure•Fiou Relauonships. 11 Correiauon of Cer.i- piiance and Mechanical Resls:ance %ktth Routine Pulmonarn Funcuon Tests " B% ER``ST 0 ATTI'GER, MERRILt M. GOLDSTEtS. and MACR.LE S St:GaL. Department of Sfedlcine. Tufts Untvenrt} School of Medtc:r.:. and L::ng Station (Tufts ) and Department of Inhalation Therap). Bos:c^. Ctt\ Hosp:ta'.. Boston. Massachusetts TAe Americen Re~rrw of Tube•- crdosrs ona Pui.nonor' % Distosrs. \bl. 7:. No 2. pages 210-.19 and =:C- '__S. Aurist 1956 (T.I.R.C. arantee: Se¢al) Purpoir of arudits: 1. There are still larPe ¢aps in our knowledge of :hc ph~sica: properues of the human lune whrc5 remain to be soived. The stud~ is tn:ended to dernonstvate the imponince of pressurr-volumc anC pressure•:'.ew r::ationships in the evaluatton of patients with c.".ron:c pui- monar\em.ph%sema 11 The purpose is to scpnr; the resufts in 12 paticn:<• wi•^ :^rcr::c~^,..:~-ncrar\ ernon%s:rna in Ahorn the me:ha-ics c° '^•eat.^.,-: , . - were c.,.e:~tec wl;^ the cor.ventiona: pulmonan funcaon tests Experiments: I The stud:es e!earl% demonstrate wh% patients %L::` c^ro^;: brer.ca:~i asthm:i or chron c puimonary empn.%sema can be (u:!,• despite ver. Ittt!: X•ra~ or pathotc¢ic evidencc of e;s- aciLt•. a arec part of the;r energ} and ozvgen uptake is spent on the proc:ss o` treatnir,e aione. 11 Pa; ents wuh caronlc puimenan e.^ pn.~se : in renera: show a decrease tc tne e:asc;: properties of the lun2s Iccrr- ;... i anC an increase in mrc"anica! reswance (whicn expresses pressure n:cessas% for a elven air now ) Findinr.: 1. Patients with chronic pulmonar-Y emphysema produce lower Cow, rrates. reoulre greater pressure gradients to move air in and out e` thc iungs. anc ne:_ prepeniena:ci% more time for expiration tnan norrna: sublects 11 T:^.e %LorK of breathinc has a stenlncant InAuence on the In- eapant% of these patients anc is an impenan; (a: er tn determustnE Lhc degree of dtsaouit) r.F TR \  . 4 • 011A" 113"

"EFFECT OF.CIGARETTE SMOKING ON CORONARY BLOOD FLOW AND MYOCARDIAL METABOLISM." By L. M. BARCExo%. 1ta., M.D.. D. EHMKE, M.D.. F. GonLV.oL, M.D., A. CwSTELLANos. M.D., A. SIEGEI, M.D., and R. 1. Btnc, M.D.. Department of Exper;- mental Med,ctne. the Medical College of Alabama. Btrmsngharn. Circuto- non, Vol. 15. No. 2, paces :51-257. February 1957. (T.I.R.C. grantee- Btr.g, Purpose oJ studies: Despite the ¢enenllv accepted actions of nicoGne on specific ttssue. t,^,c eflect ot smoking on the heart has been a controve:s:a'. sublec:. anC :ne literature has been contradtcton. The purpose o' t;,;s tnvestteatton aas to measure bv catheterization the chanaes caused b~ etearetie smok;nc on eoronan biood flow, eoronary vascutar tts;star.:e, cardiac heart rate. and myocard;al extiactton of lactate. gwcoset p~ruvate. and ketones. Erparimenri: A statistically stentficant rise in blood AoW occurred a`.trv smoking a etgare:te in 11 pattents. from a mean of 69.8 ml per mtrr per 100 gm of heart muscle to 82.8 ml Coronary vascular resistance te:l st2ntncantly from 1.30 mm. to 1.05 mm. Hc per 100 gm. per mtn. k1vo- cardtal oxygen extraction declined from a mean of 1:.7 voiumes per ce^: to 11.2 vo;umes per cent since tt s+as proporttonal to the nse tn bioed flou, the oxvgen usage was not s;cntF;an:l% changed The heart nte in- creased from an averiec of 87 to 9? Extra::ion of glucose fell strntficanti%, of pyruvate fe:+. but not strntficantl%. and extraction of ketones rose, but not stgntficar.:h findinF,: These results tndtcate :,careae smoking in normal sublec:s ,does no: res:;:: tn constr;ctton o' :.,. ceronarN biood vesse!s Other Rrantor,: U S Publ,; H:z':^. Ser.ice. Life Insurance Med:cai Research F;;nlt. 3nd Arnertcar Hcir: Asscl;,anon. DIaG~'OS' ~%-kLL'E O- A:'. .`• 0- MALIC DEY.~ On~ GENASE A',:D PHOSPHOHEXOSE ISOVERASE Pre;;m;nan Rc:cr: of Ftndtntts in Patients wtth S1~oc:ircu' l^`3rcaor, and Liver Disease " B% ' R1cMkR:) : Bt%G. %I.D . ALBER7:~ I:.S'E'-.A.os. M.D.. and AeuAN•%t StEGE_. St S. Deoanment of the tiledtcal Coi;e:e of A,a^ac,a. B:-:-:m_.^a::: Pc_.:s'c_ . -r /cc,.;oi o' tnr ATn:ca^ 1frdicc: .frsc::o:;on. Vol 16=. ',, c,3:!S 6."-650. June 8. 195" (T.I.R.C. grantee: B;nt, Purpo.e o/.turif~: Rnowledx c' ... :c%e. el activity in human oiasma of maltc deh%ercecnase a ca:a~%<.• c .....r. acid cvcle. and of V^es- phohexese uc:c,e:ase a~i~:o caalc2es the reve-,s:`:c reactions bet~een gtucose-6-pnes:^a'c anc irjctose-6•phosphate. is ;m tden::`.tr.: portant in sn:e••;rng t.^.e proere%s 3 :r,arct;on and in liver dtsease De:cr-nrna:;e^ c` ~. :_r:-^•ra:;on of these and a thcd entNme-amtne:~nerasc-tn con:ras• ,•.:7% c:rcr hear, and blood data was therefore undenaren CTRt i N 011314

E:perimenn: Concentrations of the three enz_vmes were determined ir the oiooe pi3sma of 18 pauents with m%oeardial tnfarctron and me figures were compared with electrocardtoeraphic findin¢s, blood pressure• sedi- mentatton rate, and leukoc*•te count. The same enzvmes were determined in plasma from 14 patients wtth liver disease. and the fieures were com- pared with the quanutinve results of other ehemical tests for liver function FindinFi: There was marked elevation in the activity of these ennr,:es in the biood plasma of patients with myocardial infarcuon. the peak of enzyme acuvtq occurtne 24 hours after the onset of pain. At that time. atquefacuon necrosis is at its hetght, accompanied by infiltration wtth poly- morphonuclear leulocvtes It is thus hkel% that the increased aca%t:.~ ej the enzvmes is the result of dissolution of the heart rrtuscle cea. The le%e; of 3ct:vit% of malic dehydroeenase and phosphohexose tsornerase was simiiari, eiesated ~r the plasma in ltve: dtsease, the hte•^.es: uve,s fer ~ .,!I enz~mes uc:nc found in pauents with tnfecttous hepat:t,s Orl,er rrnnro.,l• S P,:b'.i: Heal:h Sernce. Ltfe Insurance `fed:ca' II/Researc"• F::ne. and American Hear, Association I i "EVAL[.'AT;ON OF SUBSTANCES CAUSING LOSS OF SEBACEOt'S GLANDS FROM MOUSE SkIN " Bs FAtD G. Bocs:. Sl.S.. and RHCC, I Muvo B S.. Rosuell Park Memonal Instttute. Buftalo. New York. Ti,e Journal or lnretrrgan, e Dt.marology, Vol. :6, No. 6, pages s79-t8", June 1956 (T.I.R.C trrantee: Moore ) ~ Purpo,e ol rrud.: D sappearance of sebacerws glands from mouse skin ~ durtn_tr the first dass after exoosure to certain earctnoeens has beer known since 19.30 In 195= %V E Smith r: al (Proceeain¢s• Amer:can As- I soctauon for Cancer Research i re:)orted that this e'tect could be used tc predr;: the ;arcrnoeen,; properties et certitn pr.roleum fractions W1thh th;s ~: in mrnd. the autaors undertook to detcrmrne what factors mtgh: aQe;: the ! des:ru;;;on c` seDaceous elands bs sanous materials y Erperimenrf: Tne ha r uas shasrd from large sections of the backs e! ~ S,iss ^•• ;e ated Sc-65 da%s anc tcs: solutions app:,ed to the arcas tw:;c Ca:i% fer tnr-- dass The n-.ice Kere sacn;red ene week aft., , ar.:t s...es s:aine'. to perrna m croscopic ooser.auor, Sebaceous a:anc sup-,ress on resuitcd frorrm aportcauon of seven test sciu- ticns ~ T•n•e su,^oress on ndes uas 10.000 for meth0c'solanthrene and di met^a•- ~ ber,zantnrace^c 3 000 for dibc^zanthr:icene and berr;.}rene. and sma::er fer me other :rrec ;ornpounds Fcrt%- wc other cornpounds v`ere feunc : ha%e nc ae:nonstranie se^acee:< c:ar;d superess en e~ec: Tne meths % caoiantcrene e*7ects wr.e not a"ec:ed ot ti^:e of das of painting or bs Ine oxs8en concenuauon of the air to LLh ch tne animals were exposed. Findinrs: Amonc tne compounds stud ed. the sebaceous ttland sup-.res- slon e9ec: is l:mtted to h%,'~.rocarbons and is t)aral!ei to the reportee car;:necen ; or co-:)e;:r.ds of this eroup There is nearc% addu %e sumr:a::en of tr,c elccts o` several suppressor eompounas Khen combined in cne so,u: er. ClV EtE"4 0t 1311c~--$

-'CHANGES OF BODY WEIGHT IN NORMAL MEN WHO STOP SMOKING CIGARETTES." By J. BROZEK and A. KErs. Laboratory of Physiological H-,gtenc, Scnool of Public Hcalth, Unrventt,v of Mianesou. Mtnneapolis.*Publtshed in Science, Vol. 125, :~o. 3259, Page 1203. June 14. 1957. (T.1.R.C. grantee: Brozek ) Purposr of iturf% : The role of overweight and obesny in the development of the so-ealled deeeneranve d:seases and. consequently, the factors that affect bodv wei¢ht continue to be of interest. Amon¢ these facton• the occasional large gains in weight among men who stop smoking are famsLar but hitherto the phenomenon has not been studied systemaucally. Erperiments: Out of a group of approximately 300 business and pro- fess:enai men. 21 tnd:v dwis who voluntaril. stopped smoktng. and on whom we:¢^; oata are avauabie for two years before and two vears atter the year :n wh:c^ the% stopped smoking. w•e-.e scudLed :n companson %:tn a cen:ro: croup obtained b% seiecun¢ men whc+ did not step smoking and wno were matcned in age. re:auve bod% weight (expressed as a percentarc of "s;andard•' we:t?ht for sex. aee and height). and actual bod% weight. Both eroups were essenttall% "normal" men; excluded were these who stepeed smoking because ot tntercurrent eoronarv heart disease or in whorn a r:g„rous reducing diet together with stopping smoking on med:cal orders was a part of therap~. Findintr: Longitudinal oeservat:ons on smoking and body weight. using the average ra:es for veors I and 2. and for years 4 and 5. revealed a subgtanual (8.2 lb l statisticall% ht¢hlv stentficant rise in the wueht of the men wno stopped smok:ng. and'a small (171 lb.) stausucallv non-stgntncan: decrement in the control groue On companns the mean difterence between the chan¢es. there was a net d:P.erence of 9 3 Ib. between the stopped- s:nok:ne and smok:ne groups. wh:ch is also statistically h:¢hlv stenincan: The ouesuon of pern:anence of thr gain in the stopped-smok:nc croup be%or~.~ tuo vears re^ia:ns open Experimental observat:ons or. te tn- hi~,.rer: o.` gas:nc hunecr cenrta:::ens b~ smok:nc and the :ncrease :.n .,,ns:r-,nucn amcc; mC I .•.itc3a wFo are maintained on red.:cet caior:e !n:a.:e suc_ ccst t.`.a: s^noK,ne :ends to depress t^e fei: ne-_d fer feo-' ~Othrr grontor: L' S Pu:l:c Heaith Service '•CHE\11CAL CH-NNGES 1,~ T}:E LUNGS OF TUMOR-BEARING RATS - B% LEOPpLD R CERECEDO. ED\%.kRD BRESI~ICK. HkRRY HoCh- STA,kSSER, HELE~ L RoDRiGCEZ. ED-AAD T. SCHI,'lEAT• and EDwA1lD J Sr.GER. Department of B:ochem:str., Fordham University. New York. with the cooperation of Vt%CE%T S PkuADt.o. Depanment of Patholon• Meadoworoor Hoso:ral He^es:ead. Long Isiand. tieu York. Biocnrmrcc er B.epn•.rrc,: Ac:.: \o: :=. No 1. Pages SB-61• April 195'.. lT.1 R C Va ntee: Cere:ede) I C TR M N

Purpose oJ irudr: It was previousiy shown in this laboratory that stg- ngncant changes occur in the nucleic acid conccntrauon sn acrum tusues of tumor•bearsssg rats. and that the presence of the Walker 256 tu©or caused an sncruse in the concentration of desoxyriboaucletc acid (DtiA ) in the host lung. It was of interest to study this eflect in some detail. as svell as the nbonucletc acid (RNA ). protein nitrogen (P': ). cholestrol. and pousstum in the IunF. and similar relauonships for the Murphy-Sturm lvmphosarcoma. E:penmewt.:• Male rats were implanted with either of the tumors at a to 6 weeks of age. The host antmals were killed in groups cont:utreatly wtth comparable groups of control animals. It was shovm that during the growth of either rumor the dry weight t:oneentr3uon of host lung DNA tor.eases markedly; that the RNA eoncentrauon remained fairly constant for the Murpnv-Srurm Ivmphosareoma hosts; and the RNA. PN. ehoiesterol anC pouss:um concentrations remained constant for the walker :So hoss Finrfine.: If a constant amount of DNA per normal somatic dlpio!d nuc:e.s is assumeC, the decreasing rauos to DNA of each of the other eonsntuents occasioned bv the rise in D",'A concentrauon could be tn- terDreted to mean that the host lung cell is being depicted of the four other substances during the progressive erowth of the tumors. A posstbiltry to be considered is that nutritional demands of the tumor mav be responstble. but this is considered unlikely. since no over.ll losses occur when the data are expressed as total amounts per organ. normalized for bodv weug:::. Work is in proeress to determine whether the ef!ects observed are due to an increase in cell numbers Whatever is the nature of the lung resoonse to the tumors. it mav be assumed that it is mediated by an agent produced bs the tumor and transmitted to the lung via the circulation. Expcnments to investigate this posslbiltty also are now in prog?ess. "NL'CLEIC ACID PAT7ERNS DURING GRO%%TN AND REGRES- SIO\ OF T}iE M1,'RPHY-STZ•:RM LYMPHOSARCOMA I*.%* TNL RAT" By LEOroc:) R. CEraECEDo and EowxRD Br•Es.lcK. Depar.r.:en: of Biecccrnts:n. Fordham Univers:t~. Neu York B ocnimrca er Btoanvnca Ar:.. I ... Ne 1 pacc __6. lanuar 195". (TI.RC grantee Cere- cedo) Purpoir ol erud v: It was observed ir, this laberatorv that the Prow-0 of tumors ,•nn rats is accompanied by chan¢es in the nucinc acid eoncentntter. o' ~ar ous ussues of the host, and that cortisone treatment of Ivrnpnosar- eoma•!+ear:ng ra:s results in a retardatton of tumor erowzh. It was of tnteres: to deter-nine whet.^.er re¢ression of an impianted tumor would be accom- pan ed b~ a eomDlete reversal of the nucleic acid pattern to normal E:perimener: Growth of the lvmphosarcoma results in an tncrease in the desoxyrtbonucletc acid (DNA ) content. Reeresston of the tumor is ac- companied by a practtcall% compietc reversat of the increased DNA con- te^t te ncr.na; On the other hanc. tne rioonucietc acid (RNA ) eoncent:a- tion is no: aftected by either sttmu'us 4? C1'R_ HN 01131. *7

Findine,: It has also been found that protrresstve Irrowtn of t.hc Iymo':o- s?r rra results in an increase in the DNA concentration of the lungs. ar.c t t regression of the tumor results in a return of the lung DNA to nornai ,Iues. ~ Orhtr Frnnror: National Cancer Institute "EFFECT OF CIGARETTE SMOKING ON' EXCRETION OF I;RO- PEPSIN AND CONCENTRATION OF PLASNIA PEPSIN'OGEN." B% PHILIP CoorER. 's1.D.•. Associate Professor of Clinical Suraer%. Boston Lnncrs:t% School of Medtctne, and Chief. Surgical Service. %e:erans Adm;n:s:rauon Hospttal. Providence. Rhode IsunC. wtth HAROLD L S'E1\. \!.D., GOLO1 • F. M00RE. B.S.. and HeROLD 'A' HOLROw Erl. N', ;i Ti:r R•r.1r ltin!! .1frd!co! Journol. Voi aC•. No . D3c_es ::5-.16 i. .5:. Atr.: :9'" tT, R.C. grantce Coope:) •DCxn• .r ~o. Cn1r! e! Sarpui Senrrr .r 1.1 ftro... ~r~rr.n~ .aw.N.urr.~. Noa,~rr~a nlr NtR JDODNrrO r~ I C~rnta~ rrortu0. ol )..r~fr~ ~~ t~< En1.r• MrC.L~. x_ Purpo.e oJ,rurf.: Having found in previous research that no s:cnt.^-.:an: cr.:rces Merc produced in ¢astnc secretions by smoktnc. the aut!:ors under- toor. to measure the excretion of uropepstn and the concentration o. :e;+- s!no_er. in plasma in a croup of habitual smokers during and after a pertod of aosnnencc. The concentration of ptasma pepsrnogen in tnd!vtduai suD- te;:s is fatrt~ constant from das to das. is not altered st¢ntFcaeus "s usual %3r:anons in d;et and aca%m. and its laboraton determination is reiubie. f,aP.ram.nr,: Twents male cigarette smokers aged ?2 to 65 (average -; In nospiul for a vanets of eeneral conditions and free of an% s% T.D:onss or sicns of castro!ntesttnal. cardiac or urolo¢tcal cond:tions. and 11er. ncrmal unnalsses and blood urea nttro¢en values. werc ooser.eC fer !: Ca%s Thc p.:!ents stopped smoking on the first da% and rtsumed on :r: s;vtn d.i% No cflor Mas made to re¢ulate d;et or fluid in:ake dur:r.; :es:s and none o! the pattents received drugc wh:ch could a3ec: pe:n: a:I :...r rrnai ex;re:ien Th: aNerzce datl% nur^Cer of Ct_:are::es snoceC e src:nC per oC ~as _: 3 Th: rr.:an d,°erence tn tn: ez::e:;er. c' urececs.r. oetwecn t. c tv.c c.::oCS was no: stausuca!is ,.,i s:a:ts:.cail% s!cn; ,c3n: d:-rease ec..:rted in ..., pe:~sinoee., te%e. C.... ., c s-:orm_c Dcr;oC comoared ~tth the non-smoktn¢ period Finrfincs: Lropeps n cxcreuon determtnaaons in thts stud\ oe tee saT.e crc.,c o~ vat!en:s %ar ed so -idei% that no conclusions rciauve to tn: e^ec: cr .a:r c' e"e;: o•` ci_earet:e smoK:nr couiC be drawn 1nCc:~. in s:^e ;a:....:s Cv. to da\ var a::ons in ,ne•ez:._aon of urepe;s:.. C.... .••••- t:s: ~er:oC exceedeC the rncan dtP.errnce for the entire grou: be:wce.. .... t~o txriocs Ci,zret;e smok n¢ after a pertod of absttnence precuc:d a sta- tisttca: s!cni^can: decrease in the concentration of a plasma pe:srnogen OF CIGARF r F SM.O}:ING ON GASTRIC SECRETIONS OF PAT:EXTS %k I-,r? D~ODF~AL L'LCER " B~ PH::t. CoorEta. C TR MN 0 1 1_31 e

M.D '. Assoetate Professor of Clinical Surgery. Boston Untverstt} Schoel of Mcdtane: chief. Surgical Servtce. and director. Surgical Research Labor- ator%. Veterans Administration Hospital. Providence, Rhode ]sland. anc 1aNtt:s E. K%iteHT. 1tt . M.D.. Resident in SurEcn, Veterans Aommtstra- uon Hospttal• Providence and Stassachusctts Memorial Hospitals. Boston. \tass.chusctts. The nnt Enc/onA Journal of Medicine. Vol. No. =-:. p3ces 1'-? 1. 1ul% 5. 1956. (T.1.R.C. grantee: Cooper ) w-~e••a s•c 'OCMen n rM. C~r~ M S•: Sr•.c: n< It-. ~rn- •aT-.nn1- Purpot. of arurr, : Res:e%% of the literature fails to re%ea! ans s::;o:es sutc;en;k deatied or adeouateh controlled to substanuate tne mzm cuntcai opinions on tne eBect oi smoi.in^ on eistrtc secreuer.s Erprrimrnr.: T%%o stud:es %%ere coneucteC in an attemp.: to de:c:-tne the f-c;s The litrst concerned !_u patients Ktth duoacnai uice:ss na:` o' whom smoi.ed and half of whom did not smoke durinc test ^,eneds in wh ch e2stnc measurements ~ere taken The second was l mt:ed to measur- tn; pH c`zn¢es of ¢astnc tuice after smoktn¢ and broth sttmuiatter. and tnsuun sttmulonon. in 16 patients befcre and in 11 patients af:e: castrectems for duodenal ul;er F:rs: stud~ µithtn tnc -'smoke:" ¢rcu: and %snhrn the -'control" croup there v.ere stc^thcan: aiterat:ons in .otun: peptic concentration or peptic output in one or more pertods. but com- pansons bets`een the "smokers'' and "controls- resealed no stgn:^can: d:'e:er,ces between the \oiun;e. pH. ' free actd." peptic eoncentratien. er pepn: output Second studN It w3s foun~ in both groups that the pH ~as eie~ a:eC durtn: the smokin: ^ertcc Findincs: Under the ccnd:ucrs c" :'•.e tnsesricoucr. the s^ck:n: c` et^are:tes b\ patients s%:th d ccec did not produce chans!es :n gastric secreticr.s "CONTRAC7ILE PROPFR';cS OF -\CTO\ilOSIN THREADS 4N: B-\NDS PREPARED FRO\1 DOGS HFARTS " B% L DrTnt. Nt D. and R J Bt\e. \1.D . !,-ledtctne. The Med:._. Co;:er c`. A!abar,a. B:rmi-_--.2- T-. 4mr•,ca,: lournci o' P-so-7q~ \ o: 1S". h o I paees 1-",-: `: O:'c-;r 19`6 (T.I.R C. prantee B:r:; Purpoir o/ irull.: Prc~te.;s rese3r:^rrs ha%e been unable to es:abl:s^. a rclat:onshto between the snr r:cr,r: oi ac;omsos:n threads from antmal hearts and the Ke:eh: Itfu-.: ciric results from appticatton cf ATP /acenos;ne t: ..ose .. _ a::a !: data be: z at..,_..ed •c teChn:cal difficulties tn haro..^- DreakTbie and sttCKs threaCs The purrosc of the prescr, .., .s : in,est:cate the depenCrncc oi ..•. ATP-tnduced contraction u;e- ^. ...e ioad and the Drotetn content o` such threads. Four sertes of cs:r.:ne^•:s %kere performed Mtth tmprosed apparatus. CT R f` IN 0 113":tc.3

E:perimrntr: Series 1(36 tesu): These duplicated the work of previous workers and were attended by similar scattering of results. hente are not reported Series lI (25 tests ) : The leneth of the threads was held corutint at 21 mm. Their thickness was varied by depostttng different amounts of actomvostn in the solution. and nitrogen content of the tnreads was de- termtned followtne cdntracuon ScattertnF of results perststed Series 1I1 (30 tests): Ezactl% 1.5 mtlltitters of a.54'b aetomyostn sotuuon was de- posited. and the films were compressed to bands exactly 15 millimeters wtde. TAe iength of threads -as constant at 21 millimeters. and the wtdth varied to obtain different protein contents per unit length. There was a dehntte trr.erse linear relationship between shonentng and load up to about 4 5 mtiitnrams. above whicri the bands did not shorte.nn at all and broke wt:h:- a'.ew minutes Series IV: Isometric contractions tn resung len¢th wtrre studied tn a larcc number of bands. No relationship was found betKeen te^s:orn de%e!oved and sper_:f~c nttro¢e^, content The banCs de- veioped tens;ens up to 60 mtlltcrams but then tore. as did the overioaded bands in Se::cs 111. The resuits therefore are not presented in detail Findinrs: Tne performance of the actomvostn bands described is limtted b% the speed of ATS ttansport into the protein. Therefore, thts preparation is no: suited for quantitative ktneuc studies. However. since the error tntroduced Cv d;.°.us;on ts constant. the bands are a useful tooi in compa:a- tve experimental studies Other Ernntor.: National Hear. Institute (H-1129). the American Heart Assoctauon- thc Alabama Heart Association. The Life Insurance tiled:cal Researc6, Fund. and the Swtss-Amertcan Foundation for Sctenttfic Ex- ehanee. "CONiRACT1LITY A"~D EXTRACTABILITY OF HEART AC'TO- ,!YOSIN AFTFR DEATH " B~ L DETTLI. ti!.D., and R. J. Bt.c. %S.D . Depan:r:en: c.` cxper;men:a! Me^ictne. the Medical College of Alabama. B;r:^tng^am CrNCu;Glto, Resrcr:r.. Voi 14 No 5, pages 519-'::. Sep- tc:r,ber .;1c 'T I R C cran:.. B;r- Purpoi. or atu'f• • Benson (C:r; R:s ?:_.. 195 5 b~ productnC ez- per;mer:a. c-ror.:; heart fa;iure in dees Kas abie to show• that actom~os;r, from fa:::a: nea^s d:flereC frem t.^,a: of nerma! hearts These stuotes were based on :r.e prem;se tnat characteristic ero,^er.tes of actomvostn do not chance !Cr a b^e` period after dea:". Accordtnaiv. an tnvesuca:tcn was be;un u"~.... ,.ca:s w;:' a c...,,:artsen er tnc prc:~ert;es of actomvos:n L•ctr. dccs hea::s t^. ,:~;atr. af:'-. „ea:.n ant one nc~. i:-. Findinea L;::,c C;t'crrnceKas seer ae:ucen fresh hearts and hear:s ex- tra: eC one hour a'.trr death in the vteld of total and soluble protein and actomvestr: per 100 em hean wetrht This finding is not surpnstng. since postmer:c-, sranit:•. o' tne centrac:re eie:^ents in the isolated muscle in tir•e nas beer •t:• bas,s for ~A;ce'• used pnannacoioetcai tests T'.c tnsult to tee ~ a d.:r:n; its e:tracuor, is probabi}, more severe than the denaturat;c^ t.ia: o:c rs Cor,nr t^.e first hour after death Desz:tte the vtgorous treatments tn tne ezper;ments. the contractile prope:ves of t}:e . • ~... ~-•_ ~..E C TR t !N 011 „~2.

protein are preserved to a peat extent. These studies may open the w.% for an tnvestlttatlon of the properties of actomvosln obumed from faiiin; 4uman heans. /Orlrer `ronrorr,: U. S. Public Health Servtce. the Amencan Heart Assocla- \\/// uon. the Alabama Heart Assocutton. and the Life Insurance Medlcai Researcl Fund. "COMPARATIVE VASOCONSTRICTOR EFFECTS OF INHALING TOBACCO SMOKE IN WARM AND COOL ENVIRONMENTS AND BEFORE AND AFTER ABSTINENCE FROM TOBACCO." Bv JoM, W ECUSrtIN, M.D., J EowN WooD, M.D., and RoeERt W. µtLWs. !s1.D, Cardiovascular Dlslslon, Evans Memorial & Massachusetts General Hospitals. ar.d t".c De;,_r:rnent of Medicine, Boston t,'nlven(tv Scioa: of Medlc:ne Tnr Anrr•rcon Hrarr lournol. Vol. 53. No. 3, pages 35S--t6=. !slarch 1957 (T.I R C Ftantee: wood) Purposr oJ.rud~: It is generall} a¢reed that ulhaling tobacco smoke causes vasoconstrnctlon in the foot, but comparative data on the relatl~e Intenslt% of the vasoconstncuon are not available These experiments uere desl_ned to compare foot blood P,ou responses to smoking under dlftercn: control eondluons of vasomotor actlvlt}, to compare the vasoconstnctor response to smoklne-AIth that produced by a eool envlronment. and to determine wne:ner or not a period of abstinence from tobacco produces a more profound vasoconstnctor response to smoking. Erprrim.nu: A decrease in averagc foot blood flow occurred on smok- rnc under a!1 conditions of the studs except in 3 of 31 experiments. in the ? ezceptlor.s Anere no chan:e in blood flow occurred. smoklnc %Las associated i as in al: tests I Klth Increaees in blood pressure and pulse rate and reducuon :n the sarta:lor.s of biood f1ou The range of response in the wa,^ anC cee' roe.^.is etoressed as per c.n: reducllons from centrol vacccs ~ere re.^:arKaoiN slr^u.ir and the dls:r;butlon of variations of coe' anc war- roo-. smo.mc resoonses LLas a::-os: svmme:r;cal T-ne ranecs C' s^..oAIP% e5^_'ses ~e'..- J.^.~ af:.. . .. _...,..rs o! s:SloAln_i aostlnen.. wYre Ver'• st.^.71;ar. as 4ere I.^.c troCD a%e:ae=s Findrnpe: Tne slmuarns of responsr uncer the eond:tlons of this swd, su:.cs:s tna: :.., e.:'.eren: control leve':s ot vasomotor activity do not actcr slenl^can:n t^e sasoconstrlctor e^ec:s of smoKtnc e:aa:ettes Under t^- cond,tlens e` :^:s scud. smoi.,ne as a iess Ir•,:e^se vasoconstrlctor sum.u::s .na^ :oo;;rc tr•c e^~!rcn:-:e': F to 6; ' F "N11TOTIC RATE OF G1NGl% AL EPlTNELII;>1 IN TIWO AGE GROUPS " B•. JLL1, \1EYER. B S. A`.7ARJIT S MAR.vAH. B.D.S.. and JosEPrt P V D . Dl%lslon c! Ora! Patholov%. L'nlversl:-. of Illinois. Coiie¢e o.` Den:ls(r.. Tnr lournc; o! Invrtrrgarrve Dermaroaog). Vol .', No a paees 2? :' . Oc:eoe: !956 fT 1.R C. grantee: Schourl Purpo.r ot ,ru.fi.f - Tne hndlnes b, B,:Lc.;ch (J Exp Biol 26 26; . 1949) that eei; dl~Islon I m(tosls I In mouse eplde^nls htquently is eon- ;F C 1 m~ HIN 0 11341

siderabi% higher in middle-aged Nan in young animals contndlcts the common concept of aging accordmg to which the bodily proeesses slow down. AccordtnFl}•, it wAs decided to investigate whether human ussue in which maintenance depends on the perpetual proliferation of cells also shows h,ener regenerative rates in older sndtvtduals. E:p.rimenu: A stud%. of biopsy spccuments of epithelium of the gums (attacned gingtva) of 30 men atted 25 to 34 and of 30 aged 50 to 78 was made and cell stze and density computed. The average mttottc index for the voung men was 0.98 cells per 1000 and for the oldcr 1.56 per 1000, the 50rc increase in average frequency being stausucally stgnlficant. findine.: Epithelium of human gums benaves like epidermal eplthe!ium in mice and men. sugeesttne tnat current concepts of age as slowing doAn he tissue maintenance processes may require revlslon in the case of ep- Nella, tlssue OrhrrFrentor: \:uer,a: lnsututes of Heai:h iC-:'v5i. l: S Puci:c Heait6. Serslce "TRAI'%SA AND CANCER. AN EXPERIMENTAL STUDY IN THE WHITE PEKIN DL;CK." By R. H. R.tcoon, M.D.. Laboratory of Ex- pertmental Patholog). University of Texas Medical Branch. Galveston A.tif.1 Arcnrver of Parholog), Vol. 61. No. 6. pages da3-sa9. June 1956 "TUMORS INDUCED IN SKIN WITHOUT FOLLICLES AN EX- PERUlENTAL STUDY IN THE DL'CK." By R. H. RteDO•. Cance, Rriecrcn. Vol. 16. No 8, pages 80a-80', September 1956 "LYNiPHO1D HYPERPLASIA PRODUCED IN THE SKIN OF CHICK- F.NS BY NlET}-iYLCHOLANTHRENE " Bs R. H RtcDOn. RES Bulican (Puciuned bs Soc r.y lo• Resso.cn on rne Rer,c4io•Endoiner,a: S trrm 1 \'oi 11 No =. pages aG-:6. FaIS 1956 IO\14S A\ EXPERISlENT?,L STL'DY ll~ THE Di:CK Bt R H R:GDO~, )kCK 1kALKER, and A H TEDD'.E. Cancer, \'Cl 9. No 6. paet:s 1 10?-1115. tios -Dec !956. "CARC:~'OG~~ESIS IN THE u Hl; c PEKIN Dl-'C): " B~ R. H Rlc- Do%. Trsas Rreorts on Brolog> ond .tifcdic ne \'ol 14. \e a. paees 505- 5:'. µ:nter 1956 (T.1 R C erantee RlecOn i Purpo.e of .ruillfJ: \ arlous asDects o.`'carc-uno¢enesls need clarl.^.caUon and proo!_ suc^ as the role of the lymphatic system, tne hair foNlcies. t;.e blood suppiv of cancer eells. and the tnf!uence of trauma. The absence of lymph glands in the duck and the availablltts of skin areas wlthout feathers maKe it a useful laboratorv animal to studs these factors under van;nc conditlons Experiments: Tne strone carcir.o¢en methpicholanthrene was >tpolied in varlous s.•ass. at Varvl.^.c t:mes and m%ar\ing quantities to the Uen, bi,l. skin or lmplanted succutaneousis ln white Pekln ducks and young chickens C 14, Z H N 0 1132 2

Vanous ;ypes of tumors developed, mostJy benten. including among others paptliomas. jangltoneuromas. hemangiomas. Pacsnsan eorpuscles. and a tumor with the morpholoetcal characteristics of a squamous cell carcinoma that ngresses spontaneously. as did numbers of the other tumors. Findings: 1. While tumors may occur without trauma, the pluckinc of feathers in the duck does have a eoearctnogenu effect when a carcinogen is applied to the plucked are:; also, lymphocytes occurred in some ehtckens following incision by scalpel. 2. No metastatic tumors were found in the duck. indicating that a lymphatic system may be stgntncant in the spread of tumors in mammals. 3. Tumors may result from application of a carcinogen in epithelul areas not associated with feather folltcles. hence i: would be unwise to consider that all sksn cancers in man arsse from hair follictes and to support this opinion by experimental observanon in t^t mouse = De%eiopment of blood vesseis in tumors which unite with the vaecular svste^s of the host animal sueeest that a hisaocsu rr,as ':e :.._ cei. sumu,a:ed os the carcinogen. leading to a proliferation of aneiob:asts assec:ated ktth some enzymatic actton. 5. Diminished blood suppi% to hemangtemas and the absence of a lymphatic system are sugeested as related to spontaneous regression of tumors in fowls A sig.nifscant fincing to be treated more fully in a later paper is the variety of mechanisms in- vol.ed in spontaneous reeression of tumors in ducks and chtckens Orher Erontor: \auonal Cancer Instttute, l:. S. Public Health Service "THE DARK FIXATIO, OF CO_ BY SUCCULENT LEAVES MET- ABOLIC CHANGES SUBSEQUENT TO INITIAL FIXATION" Bs PAL'L SALTMA-,. VICTORIA H LY.-~CH, GEORGE M. Kh,ITAKE. CLYDE ST:TT anC HERIiERT SPOLTER. Department of Biochemistry and \utrltton. School of Medicine. Un %ers t% of Southern California. Los Ange:es. Pianu Pn.%s1oioq . Vol 32. \o. 3. pages 19'-20Q. May 1957. (T.I.R.C grantee Sa!c^:a,-l , Purpo,e oi studies: Succulent piantscre charactenzed bv a diurnal rhst~.rr e` darc utth !oss of sto.red ;_rbowdraec. and lieh: deacnd:;,ca- tien. uher: ercanic acids are converted to earbohs•drat: These exper:,^;en:, were uneer,ai,en to rain further tnsteht into the Dathwavs of C"O. dur:n_c dari: r-;ea=oi:srt pertocs from I minute to : hours. £iptrimtntr: A specialls constructed apparatus permitted excised leases c.` crenarusn to be exposed to C"O: in total darkness Rac;e- auto_rraor.s e! the resultan: compounds were uken and various fract:ons uere te;^::ieC bti other procedures and calibrated by the respecave ex- pesure times of the leaves FinrlinEi: The compounds. which sncorponte C"O. during the dark fixation of the leaves. tdenufied by rwo dtmensional paper chromatopaph% . were maiate, c:crate. tso-c::ra:e. succtna:c. fumarate, asp3nate. aspara_etnc. glutamate. g:utamine. alanine. givctne and senne. The ktnetics of the sncorporati0n were studied. and the pattern observed in the oreanic and amrno ac:es sugges:ed the operanon of the Krebs tricarboxylic acid e~cle 48 C TR H N 0 11342,..~

in its ennret%. Amino acids were s)•nthestted from their respenrve aivna- keto actd analogues b% tratisammauon or by reductive amtnauon. Labelltng Mas observed in serine before it could be detected in eiyctne during the dark fizatton b% succut¢nts. (Dr. Saltman reports tnat essennally the same system rs operative in tobacco leaves. and that further work cosers uuiw- uon of the dark-fiaed CO. durine ensutnc Itaht pcrtods. ) _- Otlter frontor: Nation3l Science Foundation. "IMMED1ATE EFFECT OF CHEWING TOBACCO ON CIRCZiA- TION OF HABITUAL CHEWERS " B} DAVID L. S:ao., M.D.. ARSDLD IGLACE1l. `1.D.. 10H% R. BRAUVSTEIN• M.D.. and ROBERT E . RAKEL. Ca:d:a: "bcrater). Department of Interna, Medre;ne. Ctncrnnau Gene:al Hcsptta: anc Kettcrtne Laborator~. L'ntversr,s of Ctnannaa. Ohio. Tnc /orrrna! or rhr Amrricon Mcarcol Arroctarion. Februars :. 195'. pages 35=•356- (T.I.R.C. grantee: Simon) Purpose o/ itudirs: Althoueh 81.000.000 pounds of chcwtne tobacco are consumed annuails in the United States. vtrtualh no information is avat;• able about its ph%stoioeical ef?ect or specifically about its eEect on tne hear: and circulation Erp.rine.nti: -Pu1se rate. blood pressure, skin temperature and eiectro- car~loeraph and balltstocardtoeraph readines were taken of 24 male volun- teers aeed 34 to 'I who were habitual chewers of tobacco. Each sub,ecc chewed. on alternate dass. a IoM•ntcottne chewtne tobacco (.31 rc to .a'Cr ntcottnei. or a cheMtn4 aum ptacebo. and a regular commercial brand of tooacco ( 1.53rr nicotine i Twents•tnree of 24 subtects showed detenora- uon of tne balitsttc wase pa:tcrn on averaee 15 minutes after chewrng com:nerc:al tooac;o. and the ccteerns t^adualls returned to norma".. No er•.anges Aere ooser%ed 15 r: nu:es aiter creu tnc the placebo eurn Pulse rate o` one rerna ned ccns:an: ar-' e! I a mcre :sed marked!s aiter c;rew:^; cc^......:a. tecac.,,. u::~ to ,,zac.... th.c rare uas constant ... ....-caset tr er.c. anc in nine subiects: with eurr.. one sut,•e;: shoued a sitc^• rac ac-' one a sitgh: falL Blood pressure measureme.n.ts in 16 sue:ec:s a-c, c.._~:ne commercial tobacco shov.ed ste^:~:an: rtse of ali sss;oir ~ress res and !5 out of 16 showed sienificant rise e' dtasteitc pressures In c..c s:.:!•e;: wnose blood pre%sure rose s:e- n;ccan:r% af:er ene,sire co-Te•;:_. te;a;;c no rise Aas recorded a':cr cr.c~k:ne ;... The skin te^ .era:_re ;car2es were those usuallv associated sr,ectne as previous Findints: The cnewtnc ef toeaccc :n a croup of older men who habttua!l} eneNed tobacco produced an increase ,n pulse rate and blood pressure. a decrease in skin tem:~eraeurc arf a deterioration of the baiitstu- ear"ioera-. 1: :s bel:e%eC :-esc :-r.cs are attributable to the nicotine abscrbee durnne !ne c~eu n; c: tcpa;;: CiYR t1N

CTR HN 01 1325