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CTR HN 011536

i. • ! ('ORICItJAI, WO NOT I2EMOVE UNLESS Tp~; rAKE A PlIOTOCOP y .~ ~ . : ~. _ SCIENTIF.IC DIRECTOR.< aaRovcE ooor ,•,rrnt, ac.n. -4 m TIIE (:OIINCII. FOR T()OACCO RE_SEAR(:11-lI.S.A. ~. m ~ : m am 0 m ~•

4 t f . `.P ~. ~, lZatiO[1 '` . , ~'olicY~ - ' r. , ~. - •.. _ ~. . . . ir~~~,T1~ Caa;acr7 bor lbbipo~ l.p.rclhll•t.A• L T ~ 4 ^o+ e pr'oitr.. °S t+e..att! 1NO !pa'ti°om artobaco w0 a.d be.fti. It Me. -~i~I i~. r.{~~d V Mfl~ 1YS4.y Ir~.~tlM f!< IObaCOO erae4tKlY[tlt. •: ,;' ~~- ; ~po+ior~ !sd w~r.~r.qo, prb .rc~ r..eudt tbrpr~b . proa.m d ;, 1t t?t/p , , r ~ ~A 4 Zide.tl6S /1QTboR Do.rd /b Tb Carocil .d®ieisten tbis pIffints- :' b•+W prope,. Tb Boerd wrready oo..iMs d w. .cieeelsL ..d eo«ton .bo .+abe.L tbdr rapec!}ve L.titvtiaisel dlW.timr. A Wt of the Board oe.nber..pqcars an par ~. i TU Scie.tiAc AAri.or7 So.r'Q bas fw0 tc.pos.3bWty for reaeercb potky ••.ad prop.a+mkc Ai . Board II doea .ot directl2 e.tage le reseerch tor ': 7U0 Oo.uail. .oM dau T1e C',oeMr kacu opa.t4 .ar r"altlch facility. Unots•i.-aJd for re.ep.rcb are made by the Board to lodcpeadcot aci- ~'. ,_' , s~lael pbo ue raursd coeflpkte aicnri6c trttdom In conducting tlxir t~~ti rM..fcb. T1ey.ipee.re re.poeribk for rrportin4 or publithing their findings til/ woepted ltieatJlt e+aeeet-tMough medical and acientific Journalt ' f7,727,000. ' • - ,, . t ~ .r ~ ti,~. A Wt, pf rY.e.r~ prvjocU wpQoreoe !2 itre Council 4 included In Rspoet• ALo iocluWed .re abstr.cta o( 62 re.earch paper., .cknowrkdg- ~' C,oteed ivpport, th.t have .ppe.red in .cieaWlc Foueaala since the ~ 1p63-" Rcporl Md tlrorgh December 1964. A totel d 401 lvch papers !!SA S' ~. ,yry beew ribil#od bt Vrsat rccipienis. TMOT.T V. BafTMRT W. T. IIOiT ((Jl 1..: :. • . (]..Ir~..n '~ !•aeeMli..INr.e~er T11C (:()(RV(]L POR T)dA(:(:() REaF:AR(lt-I1.9.A. 633 T1IrJ A.e..., New Yerk, N. Y. 10017 ~pt}K !00 borQitab, aal.ettklatM yd fc.carcb in.titullon.. These Irant award. •~~(hesta by Ibs WKd t5rourb 1964 ha.e been made to 212 Kicotiat. In , a= ` ANN(IA1. HEI'ORT uJ the ti(;1!':N'1'1!''1(:. 1)ilt!•:(:7'()It (7.ARF,N(:B (aN1K 1.1f'TLF:, S4:.1). I I

SCIF:NTIF'1(: A1)Vlti/)RY 1){/Alt[) to 'lhe ('ouncrl l(or I uhacco Rescarch -U S A. KI NNF1II MI RRII I. 1 YN('lI, M I), St 1), l.l. h, ('hnrrnrun ('honrrllrn and l'rtr/rstnr o/ I'arhofogy Medical ('(rllesc of South ('arohna, Charleston, South Carolina IIUWARI) H ANI)IiRVONT, Sc D. Scirnnhc f-Jrarr, The Journal of the National Cancer Institute Bethesda, Maryland RI('l1ARD 1. HINO, M D. 1'ru/rrsor anJ Chairman, Department of Medicine Wayne State lJniversily ('ulkge of Medicinc, [ktroit, Michigan Mt K FI:.N ('A7'1Pit 1) , M 1) 1'rofrrtrw I ntrrNUt tn/ 1'l+urmat nLrfy ('runcll trnrvcrsity McdKal ( o11cRe, New York, N. Y. I EiON 0 lA('OHS)N, M 1) 1'rnfrttur and ('hunrnun. Ih•partmenl of Medicine llniversity of ( h+cagts llnrctrw. ArR(mnc ('anccr Research Ilospital, ('hica6t+, Illinnis PA111. KO11N, M 1) A nrrI rnrr 1)rrrr ror lrn f rrJd SruJrrt National ('nucr InslUtutc, Itcthc.d.r, Maryland ('I ARFN( ri ('(1OK 1 I111 F, S( 1), I 1 1), I ttt I). .Sr irmr6r 11rrr+ nrr, Ihe Cr+unul (ra I tthacco Rcscarch - l I S A. 4 F llrrrr rnr F rnrrtrut, Ruscoc 11 )rikson Mcnwrial I ahuratrny Hat llartKjr, Maine STANI NY P RI IMANN, M I), St n ~ (hrrfrrN Ernrrirur, The Insutulc for Canccr Research Philadclphia, Pennsylvania .w7. WIt L1AM F RII:N11OI-F, 1ot , M 1) .~:~.. !'rn/rjtnr I-.mr.irur rr/ .Surxrry ~ lohns Ilupkins llnivcnity Srhomd of Mcdiirnc. Italtimurc, Maryland m Ptt 1) 1 MtsRRICON f11tAt1Y, M 1) ~. R 1(' II(x'KI?1-1' RO1t1: tn , . A r na urrr .1r irnrr/Sr I Lrrr hw A t r,H rarr 1, rrnlrn~ l rnrr r,rr 0 7 Lv'S CJ G u r (7, P ~ (<1 N n I t Edwin B. Wilson. Ph.D.. LLD. 1879-1964 Ur. Edwin Bidwell Wilson, whose career spanned the fiekls of authematics, physics, aeronaulics, sulitlics, epidemiology and sociology died on Decearbcr 28. 1964. hr. Wilson had servcd as a member of the Scientific Advisory Buard to The ('ouncil lor I tobacco Research-U.S.A. since 1954. lie was a professor enserilus of vital statis- tics of the Ilarvard University Schad o! Public ttcalth. Dr. Wilson had been a vice president of the National Academy of Sci- ersccs and edited its Proctedints from 1915 until his death. lie taught mathematics at lwth Yale and llarvard and was chairman of the Department of Physics at the Massa- chusctts Institute of Technology. Dr. Wilson served as a consultant lo the O/6ce of Naval Research for many years and was a recipient of the Navy's Distinguished Civilian Service Award. Ile was a past president ol the Amcrican Statistical Associaticsn, the Sucial Science Rcsearch Council and the American Academy of Arts and Sciences.

TA/t1.F: OF (:()N"TF:N'Tti lhe PrrIrcss of Research 5 Abstracts rrr Rcrmxts . . 26 Psychn PhysH'hr8ical Studies . 26 I ( arJNrvax'ul.r Ihscasr 1(/ ('arcinoRcncsis 9tudies 41 ()thcr (-anccr Studies 47 Pulnu.nsry Physirrlrrgy Studies ('hcmwry & llitthcmittry Studies 48 SI f'harmsc(Ji>Ry & PsyiMr Pharrnai"d"Ky Studies 55 Other Studies 56 R ccipicnts ul Grants 58 i 1'he Progress of Research The Council for Tobacco Research is committed to a oontinuing and etpaodin` progrsm of experimental and clinical studies of human diuases. The Council's pro6ram, therefore, is primarily one of medical research, which spreads over into the various related branches of science that can be brought to bear upon problems of disease. Withid the broad field of tnedi- cine, emphasis is placed upon etiology, that is, upon the facton, influences and agenls, both internal and esternal, thal may have something to do with the causation of disesse, rather than upon methods of treatment or cure. 7 his emphasis upon disesse genesis is due to conviction that prcvenrlvc mes- wres will probably do most eventually to reduce the toll of those diseases that are now our greatest kiUen. The selection of diseases for study is based on the relative present inci- dence of the disease as well as its importalsce as a cause of mortalily, and the degree to which it has been reputed to be auoeiated ststislically with lobacco use. The various diseases which have been selected for study ats belong to the broad category of constitutional diseases. These include, amons others. the cardiovascular diseases, lung cancer, ukers and the various chronic respiratory ailments. In such diseases external agents are difficult to identify, often compks or multipk and of minor importance or even impMent unkss and until lis- sues of the host organism respond by reactions characteristic of their basic and predetermined biological and biochemical makeup. llris situation is in marked contrast with that found in the infectious diseases where one or more specific external agents are involved Thcse in- fcctiuus disease agents invade the cells and tissues as enemy aliens snJ they rrmain su, mrpauinR, killint, destroying the cells and tissues wluch they inv.rk "I hc invrsnRator can devckhs techniques to isrrlrle thrm and tn rnutivate ur rkstruy thcnr In turn without harm lu the hv.ty cells In the trwrstituuunal discaus. Ihe situaurrn is ddlrrenl ('rnrcr crlls arc a part of the NKty nJ arc naf slicn to it 'lhry •rc mrKhlicd hut arc very much st hrnne Sinularly, the aging cclls of the circulatory system are still hjK1y cclls, impaired and wcakrncJ in function Irul still not strangers P 5 s v r 9 m

4 3 ~ 70 ...~. .i:.. 0 1 ~ In cooslitulional diseases the prncess is inrrRrarrd with the rflccted cells In infcctious disease it is a competitive and dual process and the agent is nor inrrtrartd with the cell, but is an antagonist The research program of Thc Council received impetus from the pub- lication of several epidcmioloRical studies that reported morulity from a score of diverse diseases to be hither among cigarette smokera than among rson-srrxrken; repcsrls which havt been and still re the subject of much debate among statisticians on tcchnical grounds. Ifowever, such epidemiok>(ic studies are helpful since they contribute hints and kads for clinical and esperimental investiRators. The Council seeks to utilitt such hints and kads to a masimum degree in ordcr to pursue the shortcat and most realistic roules toward the "l of practical preventicsn or control This coursc, howcver, requires some cautkxs. The mathematical association of one variable with anothcr typically raius a numbcr of alternative esplanatnrr hypcsthcscs T1sis is particularly truc when the clala used have been Rathcrcd from nature by observation, without the intcrvcnlitm of esperirrsenlal planning nd controls to minimite the cRects of disturbing variabks The cstablishmcnt of any one prnsibie csplanatcxy hyf,tsrhrsu requires e.clusic,n of all other reasonable altcrna- tivcs This is c>ftcn a difficult task When an auc><-iatKxs bttwccn the incidence of some discase and cita- rrtte smokina is rcpttrttd, thrrc qucsttnns ursc 1. Is ciRarcttc srntAtnR a c au%c 4,( the tIIKa%c, / t J.rs it omtnhutc in some way tn rts cuwIt,Ry, whcthcr wc.ktV, trr~~nKly, lrrct tly ter indtrcctly7 2 Is cr6arcttc smwkcnR an tnth.attrr m twn.ntmr.nt trf c,rngcrutal char- actcristics that prcdrsf.Crse It, rhr tlncast crr rhat cnRcnJcr a pattern of living habrts, mnc or more of whMh may cause, ur prcdrtlxxe to the disease? 3 Is the asscxiation fortuitous of an artifact due to technical operations? We wJl kave Ihis third question tu Ihe statisticians. If either of the first two questions could be answered definitely, the answer would probably su"est measures for prevention or control of the disease A positive answer to the first might lead us eventually to some change in tobacco or tobacco ameke that would have protective value On the othcr hand, a positive answer to the second question wuuld suggtsl atscntitrn to the smoker rathcr Ihan to the smoke f?ach qucstrttn suKgests certain lines uf rrsearch, quitc drllcrtrN ttncs rn each case 1/ we knew (ur certain whtch hy{MoIhcsts wa srnrctt, we cuuld pl.rs antl guuk rruarth mucli mtuc cRrurnlly antl ctttnnmrcally Sutcr we do nut kntrw, rrs ncc catc t,f ny tlr+casc, we havc little chuic'e buI to putsue studtcs 1uyFc.trJ by each possibility 'this has been lhe (-nuncil's fNtlicy. P u P I I I In annual reports over the past I I ycan, 71se Council has provided es- tensive reviews of its work in the fiefds of lung cancer and cardiovascular disease. New developments regarding these topics will also be discusscd bat. Tl+o ('ouncil's ulcer studies are of special interest because they i0us- trate the natural history of a research effort in the field of coautitutional disease etiolM. Beginning with repoAs of an ssocialion bttweto smoking and uker, The Council over a period of yeart has suppostcd reseiuch de- si6rsed to esplore and evaluate various esplanatory hypotheses. These Council-supported ulcer studies illustrate both the difT'iculties of research into constitutional disease and the many by-products of such rc- search which often have an independent scientific value of their own. I'eplic Ulcer and Smokirg Tlsc term pcptic ulcer really includes two diseases: ulcer of the stomach and ulcer of the duodenum. These are generally believed by physicians to dif(cr in their etiokw<y, but they do have some common features. No one seems to have studied the relative iruidence of these diseases in ci6aretle smokers and non-smokcn, either separately or lumped together simply as "uker." One survey rtported, however, that dearhr from uker. though not very numerous, were about four tirsxa as frequent among cigarette smokers as amona non-,mokers. Another similar study found a ratio of 2.e). Mortalily figures are really not very satisfactory in this case because scores of people who get ukers are able to keep these under control or have them cured so that eventually they die from something else allo- sethcr. We need to know what proportions of people contract ukers among the groups with different smoking behavior. Neverthekss, these studies were interpreted as showing a strong asusci- lion between ciEarette smoking and uker mortality. As mentioned before, we can ask three basic questions about this association: I. fkses cigarette smoking cause uker, or contribute somchow to its causa- licsn, whether dircclly, indirectly, strongly or weakly? 2 f).rcs heavy cigarette smoking show the eaistcnce uf conslilutitrnal quali- Iica that ntake a person susceptibk tn uker n. that make hirn adrspt a palltns of life /sabits that tend ta hriut on the disease? 3 Is Ilse asstK'iation accidental ur dtte to a technical artifact (etua ins prupcr sarrsphnR ur s.rect other cause? It can hardly he said that when lhe ('ouncil's ulcer studies were begun, 7

hyptithcsis hat receivcd no support from this work anJ these investigations have not yrclded any practical suRgestiuns lur ulcer prevention Ilurrugh mrxfificalions ol lobacco use tx alteratUrm tit tobacco products Whrk, from the stantlpcYinl of pure logic, the first working hyfwithesis has not been disproved, it has been weakened by lack of suplxxt from ex- temive perlinent atudy. llence, it hecanx reasonable to consider the second hyprNhesis~ 1hKr heavy cigarrttr tmrrkint show tht atistrrxt o/ cunrtuurinnul quolrnrr that maAr a prrrrrn tuttrptyMr to ukrr trr that ma4e him udupt a pattern nf h/r haf+us that trnd to bring un the dirrasr? It is widely bclicvcd that peplic ulcer is to some cnnsitkrabk degree a "psychostrmalic" disease in which a genetically dctermincd predisprnitirrn makes certain kinds t>( pcrstsns respond to certain degrees or kinds of stresses by rkvek,pinR ultcr r'r Presumably slrtss would nM induce ulrer with•rut snnre degree rr/ prtdisfwisilwxt and 1ht pctdlsposllNrn al,rne would not pro duce the disease w,tMrul some degree of stresa ahovc the threshold of the indrviAual's tultrarsce Onc would espcct a reciprocal rtlatiunship: the higher the prcdispcailkrn, the less the atrtts reyuircd for precipitation or ovcrt discasc T?icse mnccpls, which have been drvclry.cd to yuile a snphivicated Itvclr'r atc in harmony with the «trrnJ wrnkmR hylwrlhcsis and pruviJ; a ptnsihk hasis lur it It has alsn hren suggcsled many timts Ihr1 sonrc cll;arcltc snurkcrs may pursue this practice as a resf+rontc Irr strrss nIJ fru.ttatnrn, tit in the scarch hor relief from such In this cvtnt, their genetic tit crrnurlulinn:rl ahilhlics to handle stress tsr frvsuawm might hc cspccted to dctcrmine ur inllucncc their need or desire to sm(Ae Combining these two conccpts, it appears entirely reasonable to porttu- late that pcrst)on who are so constituted as to he likely candidates ftx ulcer mi6?II also be of a type especially inclined to seek stress-relkf through ciR- arellc smr.kinR Such a silualiun would be cspcclcd to prcxluce a statistical association between smoking and ulcer murtality. Yet, in Ihis case an asso- clall(M would MN imply that smoking nude any conlrihutirm to causation of the discasc On the crrnlrary, it would suggetl that if smoking is truly elfrctivc in reducing slress, it might tn that rrtrnr ai lually hrlp thrne predisrWascd tn ulcer to defend thrmulves against slrctt influcrscct nd r)wt tscrcitr srnnrr prcvtnlivc rllrclt Ilrit it a crwnllary uf Ihe tetrrnd hylwrthrs/t hu1 n nra nrcctsary Ir, tit vcrilrcaurwl 'thc stcond hyl+4rthesn Jryrnds only ulw.n tlrr Irr^Irr.nJt., !/1.a,.n, l •nd ttrtY. 11 /1 IAr /n/1nrn.r .•l I'n.A..l.rrr. lu.r.rrr (Ip.n l.u .nrrrrrn,J Ihrrr.bemrr A Strnt..rru.n tht P.Ychrrin.lY/ra 1)u.rirrlY, r ~ul, ,01~ potlulale that ulcer susceplihks sa,A slress relief IhrouRh smokin6, whether tx not they achieve if If they achieved complete relkf, presumably the asso- ciation between ulccr and smoking would disappear altogether. The yuestiun whether smoking affords some degree of relief may be susceptible to investi- Ralion through a suilably designed study of uker-prone persons divided a1 random into smoking nd non-smoking groups for comparison. Several Council studies hcar upon the question of perstxulily in relation to smok- ing, and uprm its possible "Iranyuilizin6' efletas, at the kvel of psycho- pharmacolo6y. Test of the second hypMhcsis. that ulcer susceptibles as a group may restxl to relatively heavy cigarette smoking as an escape from slress, has hc6un, but presents some difficullks. Stress is not easy to define or measure and, msloritwsly, "one man's stress may be another's pleasure." It appears necessary lo arrive at a method of describing or identifying the ulcer prone person in tcrms of some group of physiukstkal, hitKhenlical and/M psycho- logical characteristics that can be measured. An idcal profile should make possible Ihe reliable itknlihcatitm of the individual who is ralher highly susceplibk to uker under rclatively "normal" environmental condiliuns. 1 Presumahly any person, evch a highly resistant one, could develop ulcer under eslremc conditions l Short of the idcal, which may not be attained for a long time, is the development of a profile capable at least of separating a Rrrtup of the rela- lively susceptible from agrrwp of the relatively unsusceptibk with a mini- mum degree of overlap If the susceptible Srtwp then contained more or heavier cigarette smokcrs, whether or not they had ever had uker, the hypt>thcsis would receive support (though hardly proof). [kvelopment of this type of profile appears to lie within the realm of attainability in a not- Icxt-dislanl future. There are many other diseases, notably cardiovascular conditions, for which similar crileria ftx idenlifscalicxs of the highly susceptible would be very tksirable, and many efforts to establish such profiles are underway under various auspices Studies of this kind are slill in their infancy. None has yet been highly successful hut slow, steady progress is being made. Tlris type of research nlust certainly become a major efltsrl in the fulure since it appcars to offer the best hrq.c rd reducing Ihe loll of Ihose slowly-developinR cunJi- Iirrns that are preunlly Ihe IeadinR causes ol sickness antl tkalh A vast utd al,nnst uneapbhed nplrnlunily Iks here within Ifsc realrn u/ hluthemlttry 1 he rtlatrvc levels and actrvrlks tsf the varirws cuzymrs and enryme systcros as revealed fry eaaminatirrn of urine, hlt>,rd, saliva and freshly csci.cd tissues secm likely to bccomc the basis for descrifYlivc profilcs that will revcal Icndi ncics and prcdisprnilirms to imhat.nce even hrng hefurc I

rn ~ 9 actual disease tkvch+ps Such birrchcmic3l prnfilcs prr,mise to become an eventual vrong diagnostic resource anrl a rnajrrr guide to cnnslitulional disease prevention In the case of ukcr, one new arluoach toward the tkvclapmcnt of means for identifying the prcdrspined has been x+ught Ihrnugh studies of the taste sense It has been shown that genetic factors predominale in determining taste sensitivity to 6 n prr.pylthrtwracil (PROP) and evidence adduced that this measurabk characteristic sorsxhow refkcts the basic hiochemical makeup of the human hrrdy It had been postulated also that these differences in sensilivity to bittcr taste might conelatc with the incidence of certain gc- nctic dise•ses, nd some confirmatory evicknce had been collected A('ouncil study investigated 1•ste sensitivity to PROP in duodenal and gastric uker patient• in comparison with naxm•1s Significant drfferences were fuund hctwccn the ducxfen•I uker and the gastric ulcer subjects ??se former were more sensitive t•sters Subjects having htah ulcers rescmbkd the duodenal grrwp (iastric ulcer patients tended to Ise significanlty less sensitive to PROP whik duwKlenal uker patients and thrne with Iwrlh ulcers showed a greater t•ste unsruvny Ira I'R( )P than normal suhjccb 1 he data therchac supfwnt thc concept that durr.knal and gastric uker arc drftcrcnt dise•ses, nd suggest • crtnsutuurrnal haus at least fnr the lat)cr 1 hr y also tuggest that mr•surcments nf taste scnsnrvily to I'ROP might con.rihule to a prurik for scgrrgatnrn nl thrrsc prrdr+ptned tu gastric ulcer (rrrm the "normal" prrpulatiun hut Ihal thrs rs prrrh.hly nrH the case for dwKlcnal ulcer candidates Subjccts without ulcer bul who smrrke at least nnc pack of crRrrNtes per day were alut tested for PROP scnsithvity, lhrse relatively heavy smokers showed a significantly higher prrtpr+rtirm ul insensrtive tasvers in comparyson 1u non smokers. 1hus, this Iimilcd approach to a complcx probkm does pruvitk snntc eviikncc of one cunstrlulirmal Jdfcrcncr cunt- mcm to gastric ulcer patients and lo relatively hcavy cigarcttc smrdus to that cslcnt, it tends to supporl the hyl.rrlhcsis under considcration An obvious question is whelher Irrng term smrrking ilaclf mrtihfics taste scnsitivity A study rif yrnrng pcrstrns, snntc n1 whrtrn are jusl IxRinninK to smrtke, has been unrkrrskcn in sn eHorl to dcterurrnc whethcr Rrnctically hased taste acuity rhxs indced att as a dclermur.urt rrf Acvcl,yrrnr, snurkmg practices 11 has f.rrn shown alrrarly 111,01 « nvlivny Irr I'R/11' is stnul:rr in hrHh sescs up tn Ihe age ro( (h 1t/ yr•rs, hut rhrr-rlh•r t/rtrrssrs m mnlrs at the ratr rd III1t1 Ihtcshuld (Kr yrar anJ to Irnrrlrs it Ihr rar u/ Illllh lhresh4rld prr year In sumrnary, it r an iv %Inlcd that /ac~rnt cvirlcnt c frrun Crrunr rl sludics 12 r fails to suppnt the Iryp,slhc.is that cigarette snu+king cuntrihutes to the genesis of pcptic ulcer, and is better in accord wilh Ihe concept that genetic characteristres which predispuse to uker also tend to encourage smoking It cannot be said that Ihe matter is finally or conclusively seltlcd Many gaps in knowledge have been indicated in the discussion above. Among the needed additional studies are the following: I. lipidcrniolagical studies to esplore any possible statistical correla- lion between cigarette smoking and incidcnce of peptic ulcer, with separate consideration of duodenal ulcer and gastric ulcer s sep- arale clinical and etiological entities. 2. Carefully controlled clinical studies of uker healing under defined regimens, with random division into smoking and non-smoking suhgrrrups for crtmparisoo. 3 Ilcuer utethtrls of defininR and classifying stresses and of ineasur- ing the reactions of suAjects to them. 4. f=.aploration of other psychological, bic.chemical or physiological characlcrislics of Juudcnal and gastric ulcer patients with a view to irnpruving the reliability of differentiation between high-suscepti- hks and low-susceplibks. 5. Within a group of highly susceplibk persons, preferably without overt uker, observaticsn of the relative incidence of overt disease anrnng randomly selected subgroups who smuke or refrain from • smoking. 6. Psychnlrrgical and psycho-pharmacok+sical studies to assess nico- tirx or smoking as a"Ir•nyuiliter'• or reducer of stress effects. 7 he study of peptic ulcer deserves considerahk attention in its own right, nut so much as a majtx cause of mtxlalily but as the source of much disctrnrlurt and sullering in our modern stressful society. Ifuwevcr, ulcer has been discussed at snme kngth in the present in- stance more particularly tn illustrate the nature ol Ihe problems that are faccd in the study of cnnstilutitmal diseases and Ilse kinds rd •rpproaches that 'Ihe Council is makmg to their invesligalion, In fact, these same prtrhlctns and apprusches have duminaled 'Tlx Council's more eatensive invcstiga- tiuns o/ twth lung canter and Ihe cardiovascular diseases llefutc Ihe sulblrcl is IcII, it rhoulJ Ire Iwtmlcd rwl also that lung canccr patbcnts shuw a mut hgrrater hislnry rrr Isrptrc ulcer than the gcnrral fwqrula lurn Iltis facl suy,grsts thr thought tha whatever faclun preJnlrusc to ulccr may prove to ht• releterl lu thusr rhat also predislwse to carcinurru of this site. 13

..v~ ~ ~ S~~.'~$ ~4"a (t• ~ Uri ~ Q. ( irrrsIi/rilioifvl I,vcfors ift ( urrliorascular l)iscnse 1 he general ccxrsitkrations that h.vc hccn applied in approaching The study nf pcptic ukcr re equally valyd in rclatitm lu scveral of thc leading cardiovascular discases such as atherosckrosis, hypertcnsion and stroke. Numcnws studks have been carried out rcgarding the effects of nico- tine or of snrnking upon the physiological or buncemical factors that are considercd to h.ve some possibte relation to the etirtlugy of the cardiovas- cular discases Many of these were enumerated in the Council's 1963-64 Annual Report So far no ckar picture has emerged of their etiulogy, and the fxnsible relations of tobacco use to the suspected factors in etiology are still kss ckar A vast body of informaticsn on the acute pharmacobgy of nicotine has been built up, both by Council sludies and othcrs, but concepts as to how such effects could contribute chronically to genesis of cardiovas- cular discascs remain highly conjectural A number of working hyputhcses have, rd cnursc, been set up and are under test. f erhaps thc studies most relevant to The question are those in which human or aninul subjects have been c.posed chronically to nicotine or smoking for kin6 pcricxls Rabbits or hens kept on rather rtificial types of athcrugcnic drers dtd nrH ahtrw any convrnctng differences in Ihc condition of their arteries if given nrculmc rrgul.rrly with the dict. A human autopsy study, nnl sprrnst+rcd by lhe ( oumd, %huwcd Ih:rt any association csisting hclwccn smoking Pracuccs and the devrlt.rmcnt of arlcriosclcrosis or Icsions resulting thcrcfr,nn is tcnuous anJ mctmtlumvc A sinnlar autopsy study has b<ch sMmstucd uvcr a Ittng f.crurJ by "1 he Cuuncil but results are nul yet available l hc well known prospective stuJy of the )'ublic Flealth Service in Franringham. Massachusctts rcp+rlcd, arnong numcruus other findrngs, that cigarette smttkcrs have no greater incidence of angina pecloris than non- smokers Sincr this syndrome is regarded as most often being a chronic mani- fcstation of coronary artery sclcrusis. this finding suggests that smuling drres not cause or accelerate such sclcrosis Still furthrr, as evidence of The non-involvement of smoling in the chronic development of sckrutic cliseaus crf thc vascular system are thc statistical indications that cigar and pipe anwkcrs have very nearly the same incidence rrf thrse diuascs as non smttlers. cven thuugh they prtthahly absnrb as much nicntirx as cigarrltc srnnlcn At thc prrscnt linrr rhrrclorr, tlic wcrRhr rit rvulrntr is aKa-t thr cnnccpt that ctthrr rnctNtnr ra smtrlmg in/lurntrs thc rthrrm. krtrut prtKrss 1 hc prrsvhtlity rrmains, howcvcr, thal smoking may ctrnlrthutc in s-trnc way lu prrcipit.tuwm t,f an acute cflistKlc in pcrsons whtr have r prctli.lutsing 14 P • t basic sclerotic condition. Since the factors bringing al>,rut acule cardiac ischemia or 1hn+htbosis are sbll quite obscure, several Crruncil-sponxxed studies have been inaugurated with emphasis upon clotting mcchanisms and the possible acute influences of smoking or nicotine upon Ihcse. On the whotc, therefore, it may be said that whik there is little evi- dence at present to support the first hypdhesis, which attempts to rclate cigarette smoking to causation of major cardiovascular diseascs, yet this hypothesis cannot yet be considerLd as finally rukd out. Mcanwhik investigations wggested by the second hypothesis have been underway. The Council has contributed for many years to a study of the precursors of hypertension and coronary disease, which aims t identi- lying characteristics that may form the basis for profiks capable of scparat- ing highly susceplibk persons from those of telalively low susceptibility. Such factors may include 6enetic; physiologiul, metabolic, psychoksgical and environmental ones. When human subjects are classifsed by a single taclrx, the overlap between groups is so large that relative risks of dcvehK+- ing disease cannot be estimated with any cerlainty for the individual. When, however, the differcnliation is based upon the presence or absence rr/ several faclots. the degree of differentiation is improved and overlap diminished. 71se people presently under study do rstA as yet shuw any evidence of cardiovascular disease themselves but have been divided into groups of presumably high, medium or tow susceptibility on the basis of a nuntber of factors with special emphasis on family history, since these diseases have been found to show familial trends which are considered 1u have a genetic basis. f)iscriminant function analysis has been useful in the investigation since it masinsirts differences between populations. In one such study, nine vari- ables were used. The somatic variables used were heiRht, weight, systolic pressure, diastolic pressure, pulse rate and serum cholesterol level. I sycho• logical variabks were scores for dcpression, anaiety and arsgcr. Subjecls grouped according to the history of hypertension among their parenls (ho/h, father, nsnther, ncilhcr) showed significant nsean ddfcrcnccs in syslulic presurc, diastulic pressure and serum chulestcrol, but no signifi• cant ditlcrcnccs in psychukssic:al factors. A similarly condtKlcd study of pcrsons in relation to parental coronary Ji.case (fancer, rntNher, neither) shuwcd mcan significanl chtlrrcnccs in ansrrty and tkprrwrns, hul nrwsc (r-r any 44 the tiR sumatir varirblcs WfKn Itrur gnrups of wh)ccls were crrnstruclyd ras Ihe hasis rrf prr+cncr in their parrnn (nruhrr, father, mulhrr. Iwr1h) u/ either hyltcrtrnutrn ur coronary di.case or Mrth, aignificanl mcan dilltrcnccs hclwecn thc.c grtHrps were luund wirh rcclxct lu an ttrty, systtrlic pressure and dia.tulrc prcuurc . 15

Mean diflcrcnccs in serum chtdcstcrul and pul%c rate only aflprnachcd signific ance. ('umulativc frequency distrihutittm nf the lunctit+n scores of the four grnups rcvcal in detail the clcar separation nf three uf the four groups 1?u wldcst scparation Iies between (iroup 1, with Iwn negative parents and (:roup 1 V, with two positive parenls, with no crossing over; (irrlulr 11, the father yx,sitrve, mother negative group, takes an intermediate Mlstlirln while Group I11, Ihc father ncgalive, mcs(hcr positive grnup shuwcd little dillcr- cnce frrlm Gr<lup I The subjectf were all males and this finding suggests a scx dtllcrence in the ,nnsmissksn of characterislics A relalinn between smoking practices of subjecls and the cardiovascular disease historics uf their parents was shown previously by the same irivcsti- gators 1 his suggesled not only that constitutional characteristics play a role in determining smoking behavior but that these charactcristics may also be linked lo those that predispose to discases of this kind 'I hc invcstrgat us have now analyred the smt+king practices rlf the same people in rclaUnn Itl the same nine snrnalic and psychological variables lhe men wcrc first dtvukd inlrl three groups ftlr comparisrrn: ( 1) non stnokcrs and (tccas/11naI smwkers, (1 ) heavy ctRuettc smokers and ( J l intermediate smtlkcrs (Itght and mrakratc ctR.rctlc smttkcrs plus combined snurkers of cigarctres anti n,hcr furms of Inhatcnl A highly signdicant dd/crence was found hclwcrn Rr luln ( I 1 and ( 71, a.iu.rllcr vl•nilir.int mne bt'Iween ( I 1 and ( 1 ), hut ntr vRntht an1 tliflcrt n, t h, t..t rrl (? 1mnil f 1) I.ilrrI a divivtto was nlJde Illlll rlrfll g/oall,• 1 I 1 li/t h m/, 1/••11 •n.i. t~ r% . (i 1 thn%t' whtr smtlked less than oncc a dry, ( I ) .-•4, r. ~•I I r.- I11 trl.trtttct de11V, (<1 smukcrs of I I Itt 1V cigarcttcs ds Iy. 1% /"I ~mt I+et k mr mwc drdy, (6) pqsc snulkcrs- (7) smttkcrs trt aIl ,hrcc /t~trus n1 t.-hacco, and /M) cr snrokers 7hcre were loo few snlnkers ttl ugars unly tu of pqses plus cigars to form a group Analysts of these eight gnlups shtrwcd significanl di/fcrcnces It appeued that n<ln smokers, occasional smokers and pipe smokers formed a conslcllaticxt of similar perscros, whilc former smokers and nrixcd smokers appeared lo be quite a bit alike, falling about half-way Ixtwcen non smukers and heavy smokers. In both Ihree-group and eiRhl-grnup ennlparistms, the rnean discrim- inant function score of ntln-smokcrs was al one ewlreme and that of heavy cigarette snurkrrs a the other In the Ihree Errnrp crml/larisnn, pulsr rate and an>ttely ctNruthuted mint Its the dtllerentulu.n In Ihr rtyhl gtr.rtl+ anolysis. Lulsc tatr tuntrtl+ulyd the nlusl, wrth t h,d.llctul, drJlrt0it Iltrsvurr anti anRrr tttntrlt.utulg trs a/essrr rrlenl Whtk it mirhl Ilc argued Ihal suth stnnatic (:uttrrs as pulse ratc, diastolic pressure, w th.dc,trrol level nnght Ihcm.elves tre allcrcd hy recent trr ctm I i tinued smtrking, it seems ralher unlikely that anxicty or anger scores would be altected by smokrng, and such psychological characlcristics sccm more likely to he a part t>< the congcnilal makeup which may influence the kinds crf smoking behavior adapled. On the whole, it appears that rather substantial support has been atkiuced for the hypothesis that common or related constitutional factors may influence both susceptibility to cardiovascular diseases and also smok- ing behavior. Despite these sludies, there is still no assurance that the best somatic or psychological factors for differentiation have as yet been found. Thuse employed were selected somewhat arbitrarily on the basis of suggestive studies by others, ease and reproducibility of ineasurcments, etc. There is every reason to suppose that other illuminating ones can Ix fuund by con- tinuing investigations of this type, and the relative success heretofore at- lained should encourage inlensificaticxs of the search. Reference has already been made lo the opptxlunilies that may fit in the use rd biochemical measuremcnls Glydiocxlscular Disease arrJ Stress One Council-sponsored investigator has looked into rclations between stressful occupation and incicknce of cardiovascular diseases Since stress cannot easily be measured by objeclive rrxlhods, an indirect melhcKl has been used. Among lawycrs, physicians, and other professional groups. there are specialties that by common agreement are particularly stressful while others are relativcly low in stress Assuming that a large group within a high-sUess specially must contain more persons subjecled to stress than a corresponding group in a low slress specialty within the sadse professicsn, comparisons were ntade of the iclative incidence of heart and arsery diseases. A significant difference was found. There was also a correlation with the amount of cit- arelte smoking Ilowever, persons who slopped smoking showed signifi- camly lesr cardiovascular disease incidence than Ihrtse who had never snwkcd at all This finding is not in accord with Ihe conception that ahcre could be a cumulalive chronic effect of smoking or of nicotine upon the cardiovascular system II has been interpreted s indicating that voluntary '•shtphers•' are  selected group containing an eac•ess of persrrns whu can handle and resrdve stress relatively easily Such sludies are continuing (It/rrr ( ardi0fYlu•ulur .S'Irulrrs A long series of ('uuncil assistcd studies has culminated in dcvelup- nlenl of an trnl)ruved rnclhrxl using rubidium a14 clearance for measuring Ih : I7 0