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S(:I7:f+17•IFIc AnVISaPRY IN/ACt0/ In I he ('ouncil for Tobacco Research - U S A KIiNNI:I II MI•.RRII.1. I,YNC'lI, M U., Sc.l)., 1.1..1)., ('huummn ( bunr rflur und l'ru/rssnr 6mrritus of Pathology Mcdical ('rrllcge of South Carolina, Charleslon, Siwth ('arulina •IIOWARI) It. ANUI:RVONT, Sc.U. Scirnri/ic Ldra.r, 7he Journal of the Natiunal Canccr Institule Bclhcsda, Maryland RICI IARI) M[)tN(:, M I). I)rrn t.r u/ ('ardirrlugy and I ntrunrural Alydir inr IluntinKton Mcmurial Itospital, Pasadena, California I'.n/rssrw n/ Mrdreint lJniversily of Southern C.lifornia School of Medicine l.os Angcles, California McKI:E:N ('AT11?l.l., Pu.[)., M.l). I'rrr/rssrM Lmrrilus u/ l'Iw.ma ulrrRy C'ornetl linivcrsily Mcdical College. Ncw York, New Yurk RO©E:R 1' J. I IUl=BN1:R, M.1). ('hir/, Vital ('arcinogencsis Branch National Cancer Institute Bethesda, Maryland LEON O. )AC'ODSON, M.D. I)ron of the l)ivision o/ Biuingical Sciences Rrgrnslrin Pro/rssur of Uinlogiinl Sciences University of Chicago. Illinois CLAY"1ON G. I.(>USIJ,. Pn.[)., M.1). llasrings I'ru/rssur of Mrdicinr and Pathuingv l)niversily of Southern California SclKxsl of Medicine Lrn Angclcs, California C'LARFN(•E: C'(K)K LI'ITLI:, Sc.U., LL.I)., Lttt.l). Scirnti/ir I)irrclrn, The Council for Tobacco Rcscarch - 11.S A. lhrrctur l:rnrritus. Roscoe 8. Jacksun Memorial I.aiNUatury Bar IlarMrr, Maine WILLIAM F. RIL:NtIOFF, 1R., M.D. !'ro/rssor Emeritus of Surtrry Johns I lopkins Univeraily School of Medicine, [taltimure, Maryland SIIfLIX)N C. SOMMERS. M.1). Rrsrarrh I)irrctur,'I he ('ouncil for'Tubacco Rescarch - ll S A l)irrclrrr u/ 1 nAorararirs, Lenua I till I luspilnl IYrr/r~~~rr of PurlprLoRy ('ulumhia I lnrve(sily ('trllcgc uf 1'hysirians :rnd Sury,euns Ncw Ynrk, Nrw YrNk RUFII'.R7' (' II(K'K1: .'I"f, I'n 1) AffIM IOIY Sr irnnJu lhrn /-,r 1. MORRISON 1IRA11Y, M I). JOIIN 11, KRI ISIII lt• I'ir 1) AssrK ialr Jr irnlrfir I hrrr lur Assrr iulr.1( irnrrfa l)nr•r ror VIN('IiNt' F I tSANt1• I)M I). .1r irnhfir Ass,H wtr •Relired

(:ONTt:NT4 Introduction . . . . . . . . . . . . . . . . . . . 5 Status of Current Rescuch . . , , . , , . . . . . 6 Multivariate Analysis , , , , , , , , , , , , , 6 ('ancer . . 8 Cardiuvascular F)iscascs . . . . . , . . . . . . 12 NiccNine: Psychn PharmacoloRical and Fkhavioral ERects . . 14 Chronic Respiratory Diseases . . 15 Abstracts of Repxxts . . . . . . . . . . . . . . . . 18 Psycho-Physiotr+Rical Studies CarcinoRcncsis Sludics . ('ardiovascular System . Rcspiratory Systcm . Neurophysiology . 18 22 32 45 55 Studics at the ('cllular Level . . . . . . . . , . . 58 ('cll and Tissue Culture . . . . . . . . . . . . . 62 Fpirkmiok>Ry . . . . . . . . . . . . . . . . 67 F'harmacolo8y and PsychmPharmacolo6y . . . . . . . 69 Metabolic Studies . . . . . . . . . . . . . . 77 Chcnristry and Iliochemistry . . . . . . . . , . . 81 ( )Ihcr Studies . . . . . . . . . . . . . . . 84 Reviews . . . . . . . . . . . . . . . . . 86 Rccipicnts of n(livc 1'rujccts . . . . . . . . . . . . 94 Rccihicnts uf ('umpIrtcJ Projccts . . . . . . . . . 106 I Ilt COd11Ca011 The Council for Tobacco Research-U.S.A. was established in 1954 for the purpose of providing financial support for research by independent scientists Into all phases of tobacco use and health. From the bc6innin8, full authority and responsibility for policy, dc- velopment and direction nF the research efFort were given to a Scicnlific Advisory Board to lbe Council. This FFoard currently consists of 10 physicfans nd scicntists who retain their afTilialiuns with their respcctive Institutions. With their combined experience and knowkd8e, and with the advice or other experts from the scientific community, the members of the Advisory Board have worked toward one goal-to develop a research program to provide significant data about lung cancer, heart disease, chronic respiratory ailments, and other diseases. Through thc years The Council has provided the funding to enable the Scientific Advisory Board to develop and expand the research program. From 1954 through June 1969, the Board awarded over 4(M/ uriRinal Brants, and many more renew.ls, to 239 scientists in 186 hospitals, medical schools and research institutions. In the same period, these research workers published 728 scientific papers on their sludies, supported in whole or in part by The Council, in the profeuional literature. Studies from the Advisory Board's prcgram and from other prosrams have produced much valuable data In the past 15 years. They show, however, that we are not dealing with simple discascs and that we cannot expect simple answers. But the members of the Ifuard and of other scientific or6anizations re optimistic that answers will tic found. Investigators are constantly reporting results that will some day he pieced to8ethcr to help solve the puruk of these complex diseases. It is apparent from the great amount of research reportcJ so /ar that a variety of genetic and environmental factors may be inwrlvc.l I hc ('rwncJ for 1uhacco Research will c'ontinuc to wp/M.rt xknlffic invc.rUKa tirm and to work loward a beller undcrslanilin8 44 Ihe uuny unanswcrcJ questions that remain. 'Ihe response from physicians nd scientisla in IeadinR instirutions tu The Council's oRer d research support is most gratifying and cncrruraRcs The Council to adhere to the demands of a realistic and scientific aphruarh 5

Stattis of Current Research (-ertain epidkmicAugical studies have associated cigarette snruking with total mortality and morbidity rales and with mortality frcxn lung cancer, c.rdiovascular diseases, chronic pulmonary ailmenls, and various cNher diseases. 'Ihcsc ass.xiations have been widely interprclcd as siRnifting a causal role for smoking Ilowevcr, it is an accepted fact that a sta•istical associalirxr is not necessarily one of causation. The information obtained from cpidcmiolugical studies may be helpful to investigators in framing necessary c><pcrimental studies. tlndctlying most present intcrprctaticros of these epidemioiugical studies is n assumplir.n that cigarette smokers and rnmsmukeis are sufficiently similar in other respects so that it is Icgilimale to compare their murhiJity and rnrxtality espcriencc and to attribule obscrvcd differ- ences tu  sole faclur, smuking. lhe restricted momdactrxial intcrl+retatirrn of smoking as a causal factrx in total nxsrlalily or in relation lu tcrlain discascs ignrucs thc validily uf  vast anxwnt of research tclaling lu Ihe pussihlc inllucncc of many uthcr factors cx crmtbination of lacturs. Multivuriate. Analysis lhrce questions about epidcmiuluFical studies reported un tobacco are: ( I) Is cigarette smoking really a cause of increased mortality, either in general or from certain diseases? (2) 1 low and to what c><ICnt do smokers and nvnsmokers differ in gcnctic traits or Rcnctically inlluenccd hahits and patterns of living? (3) Are Ihcse gcnctic traits ra Rcnctically- inllucnced habits and patterns of living Ihcrosclvcs, singly rrr in gruups, influcntial with regard to dcalh rates'? tit ~tislicians gcncrally agree that it is imlwntant Irr wcight all known nr prnsihlc facturs, individually and in grrrups, as rn:rlhcmatical Incihchors of any cvcnl (suih as mortality) prcliminary tir sclccling Ihose wrlrlhy n( rclativc Irriinity Ihis is a very lal.onious Ia%k Ixcau.c numcnrus faclras atc I , I invr>Ived, and most of the large data collections that might hear rrn dte prcdicturs for longer or shorter life have nol been so ana(yzcd. Any mcaningful ana(ysis, of ccsurse, requires that adequate and accurate data on such factors have been gathered initially. Of equal im- purtarxe is the need for developing ncw, reliable and (aster computcr methods capable of handling these complc dala. Aware of this problem, The Council for Tobacco Research is engaged in the study of the development of such methods. Pilrrt Studr u/ /.on6evity A pilot study of longevity has been done in a gfuup of S(M) recently d•ccased velcrans in the [3rsston nea. A large budy af informaliun has (KCn collected on Urese subjects as part of a Council-supportcd pruject. 'I lie new mclhtxls of multivariate analysis were applied to see which factors would have served s the best predictors of lunger or shorter life, if they had been so employed at the outset. Many lactors, it was fuund, tcndcd to "cluster" with cigarette smoking statistically so that grwal predictions of longevity (in these data) could be made by use of a"prufile" of such other factors with smoking ilscl/ omitted as a predictor. 11x result was substantially the same as when snroking alone was used. In other wurds, the finding showed that smoking (and also alcohol use) appeared to "tummarize" and to be associated with other groups of characteristics. There was a significant by-product of this new approach. 11 was found that certain statistical associations between cigarette smoking and length o( life can he eap(aincd by the sccularity effecl-that is, the general change in prevalence and kvel of cigarette snwking with time. Secularily is dc- scribed in the words of the investigators: a consequence of rapid s,><ial change and the prolonged human life span. Thus, the yuunger deccdcn,s were part of a"selccted" population having, pcrhaps incidcntally, a dilfcrcnt cigarette smuking pattern than did the pupulatiun rcpresrntcd by Ibc oldcr dccerknts. It is e.pcctcd that these preliminary arplicalirrns uf multivaroatc analysis will Ise carried out on data collected in several rrdicr llrunril s(Krnarrcd prujccts on subjects not ncccssartly rclalcd to Ir1nl;vvuy but tu melhrKls of diuFnusis, etc. 1)i/Jrrenr•e. If#-trorrn Smokrra arul Nnrumr.k~r. Othcr (•ounk il suplwntcd prrryccts h:we stn-wn st:rthslii.rlly sit-mhi.int dJfcrcnccs Ix•Iwccn sim,kcrs and mmsnrokcrs I hcsc arr indii,Nuins /ur lw% sible use in ahc multivariatc rc analysis uf existinK data trdicolr,nc It 11.1% 7 6

been shown, for esampie, that there is a prevailing diflerencc in the dis- tribution of body build types. tnvcstiRatcxs have found personality diflcr- ences. One researcher has reported observations on a number of factors that differ in smokers and nonsmokcrs and may he predictrxs of early heart and artery disease Still another researcher has found a siRni,icant difference in basic brain wave patterns o/ smokcrs and oonsmokers. Cancer Lung Cancer Snsoke /n/ra/atJon E:ptrlmerrt. Previous Annual Reports have specified the etacting criteria for con- ducting realistic eaperimenls involvinR smoke inhalalion. It is impe.rtant to restate these criteria which have been derived from the resulls of er<ten- sive research and from consultaticxn with esperts in many disciplines. First and foremost, meaningful data can be obtained only i' the whole smoke delivered to the varitws parts of the respiratory tract of the animal Is in the same physical nd chemical state as that which re rches similar anatomical areas of the human durinR nrarnal cigarette smukinR To aeaxnplish this, it is ncress.ry tar heve a mcthanital devite--a smoking machine-that simulales hrnnan smwkrnR as thouly ss prnvble. This device should be able to dcl,ver putscd arni+unFs rd smtikc in a quan- titative and reproducible manner 1 he nu.hine shuuid hc so dcsiRncd and constructed that it will be ppnsible to measure accuratcly the lime between two successive puRs, the time of the pull, the volume of the puff, the estent of dilution with .ir, and the number of puRs per cigarette. C'are must be taken so that the temperature ts( the burning tip does not exceed that reached when a human smokes a cigarette, nor should the cigarette be "smoked" beyond a minimum butt length. The machine should have a port to permit sampling of the smoke stream for chemical or gas ehromatoRraphic antlysis, if desired. For frac- tionating the whole smoke and to permit the biu.uay of the Rascous phase, the smoking machine should be designed so that a('ambridRe fittcr can t.e attached. For comparison hetween labtxalorks, It Is desirable that  rcler- ence type cigarette be used. (lhe llniversily of KenhK4y is now p(Yrducing a rclerence cigarette ) lhe animal receiving the smoke should be placed sco that only its breathing apparatus is in the nrainslreanr of the smuke and no farthcr than the distance of the human nose to the main branching rd dre airways in human IunRs. '1 he animal used should be fully descrilxd as la aRc. Rciutic background, weiRht, nutritional state, physical conditiun, virus cumprmcnts, cxtcnl of surgical trauma, and the degree of stress to which it is subjccted Appropriate numbers of bo:h sham-smoked and cage-held animals should servc as conlrrtls. '1 hc end points sought should include more than mcxphological oItera- tions .nd the presence or absence of tumors. For proper interpretatiun they also should include appropriate biochemical measurements and their analy- sis. Multivariate analysis should then be applied to the data obtained (rom the systematic observations of the controlled paramctcrs relative tu the smoking machine. Ihc animal mcxfel, and the biological sud bicrchcmical measurements. Hy these mcans, it nuy be possible to develup bioassay techniques related to cigarette smoke. Past e><periments, where the sole objective was the attempt to induce tunan, must be carefully and cautiously intcrpretcd in light of tuday's knowledge. Sra(a61e Animal Mo.i./a NeMLd '/bere is a Rreat need for suitable animal models (or inhalation studies related both lu lung cancer and chronic respiratory ailments. Pending dev-h+pment td such models, tests have been designed under ('uuncil supprxt to provide a careful, quantilative, descriptive picture uf any and all observable morphological changes in the lungs of mice exposed to whole cigarette smoke rx the gas-vapor phase. 7hese eapcrimenls will be analo6- ous in design to those now being completed with oxides of nirrugen, ozone, and carbon mrmoside. As regards lung cancer, it would be very help/ul lu havc a positive animal model of the human disease. If squamous cell lung canccr thc type reported to tx most common in humans - could he produced by sume sinrpk and acceptable procedure and at a reprtKlucible level, it could be possible to plan systematic eaperinxnts to determinc what addkd facturs might induce it earlier or delay its appearance. Any such /aclurs found to contribute to susccptibilily or resistance in the animal mIMIcI cuu1J then be checked in humans I tre 6ua) is to trldain clues lu Ihe Ixrssrhle, tunlyd+urury Influence of nuny inacrnal and eattrnil fat:krrs in Ilu aninul m«Icl and then see if lhcsc arc related to the huruan es(xricnce in any way In addition tir snrakinR, a Rrca1 many ulher laclurs necd to hc cvalu ted in Ihis way One is the effect rrl vitamin defic'rencics, cs/+c.ially vdanun A. Another is liver danuge, which has already hcen shown by ('uuntil 8 9

sulqarrtcd studics to predisprne Ilr cantcr uf lite ur.d cavity. An-llhcr is dislurbancc of Ihe hoamt.nc balancc. Another is air pldlulil/n. I here arc nuny more. Ih-u.lopment oJ 11rINrratut nnd Tet•hniques lhe ('twncil has long supported research to develop apparatus and control methods for smoke inhalation esperiments and also to find salis- faclory lechniques of measuring lung surface tknagcs, especially of lite particulate phase of the smoke. Ctxniderablc progress has been made in dcvelupnlcnl of ilnprovcd mechanical cyuipmcnt for such studies, and several new dcvices are nuw undergoing esacling tests. Feasibility studies have been c/mducled and it is espccled that there shtxtly will be initiation of ncw, long Icrm inhalation wt.rk combining the use of improved eQuipment and also of hcller stand- ardircd aninral substrates. Certain animals, /or eRanrple, have long been considered inappropriate for mcaningful inhalation cxpcrimcnls. With the use of presently available and partially improved smoke esposure devices, scientists working untler a grant front 7he ('ouncil have exposed guinca pigs to short-Icrm, chronic inhalation of whole smoke in order to obscrve whether changes w/luld develop in the osidalivc cnryn/c activity of isdaled lung mtlxM,ndna Ihe stress effecls of handling and machine eRprnure without smlrlc inhalalH/n have Ix-cn asscsscd in cunlrl4 animals 1 hesc sludies arc nrlw hring eRlcnJcd tt/ Ionyt•r Icrw cRlHisures and to inhalation of gas vaplor phase wlthuut partUtulatc nlallcr or nit(-llnc lllou.eSkin PainfinR anti LrrnR (:anr-er l he induction of skin cancer on micc painted wilh cigarctlc unnke condensate ("lat") has bccn, and still is in some circles, accepted as evidence that smoking can contribute to human lung cancer. Ill/wcver, smuke condensate is rwst whole smuke. lite skin is not like the lung, and studics supplutcd by 7he Council have shown that various tissues ir, the same animal respond very differently lu a sing)c chclnical carcinogen. 'I Ix oral cavity lissucs of mice, fur exanlple, are nluth more resistart to IKntll(a)pyrene than their skins. It nlust he emphasired that there is no rcliahlc evitlcntc thsl thc cundensale fraction t'an pnKluce tu/nurs in the lungs uf eRIH'r1114'l1IJI aninlals Many eRpcriments wp/wrrlcd hy 'Ihc ('ountd and hy uthrrs have failcd tnnlldclcly Irr prtKluce lung tununs whcn sulutiuns ur c/nulv,,ns Id tigarrllc tmrlkc clrndcnsale were ilntillcd dirctlly intl/ Ihc lunls of Jutks. h.lnl./cra an l nnic Inlrttilm /t( snlulc t/lndcnc.lle rnwl.ilms inln lite I hhwKlctrcam of rni.c and ol lung-damaged rals ladcd tll prrKlutc lung lumurs, though IK•nro( a)pyrene emulsiuns did so undcr Ihc samc tcth- niyucs. Ihcrefure. there is no reliable evidcncc that the "lar" Ilat1i1N1 uf cigarette smukc atls as a lung carcinogen even in eslxriutcrd:tl animals VIrUSCS ll/fd G(f11fCr A growing field of research is concerned with the role of viral fattlrrs in human cancer. It has been known fur a long limc that viruses are dirc.tly involved in a numlrcr of animal cancers. 1 bc Council has sprmstxcd a nundxr of studies which lout hcd in tluc way or anolhcr uptMr 111e possible rtAc of various virus infections in lite gcncsis td cancer. Recent tkvclrqxnenls in the study ut virus cancer intcr- rclatinnships, spunsured by olher agcncics, have produccd nwch evidcnce to support a unifying hypothesis which combincs genetic concepls with con- tcmpurary knowkdge of the nature and action of viruses. '1 hcsc developments corxerning viruses lentl lu place new and in- creaud emphasis on the condition of the host in carcinogencsis cRl><rimtvrls and intnxfucc new dimensions and controls into animal test mtKlcls. -lhe ('ouncil has untkrlaken lo supptxt research ctNmcclcd wilh the testing and development of stxne phases trf this virus-canccr dlcory. At Ilk same limc, it is helping to develop new and beltcr-conutrllcd ccll cullure and whole animal nNUkls flx measuring lite inlcractiun uf wsccplihilily faclurs wilh eRlrrnal slimuli in lumur protluction. Su.h nrtKlcls, it is ho/.cd, will be uscful as assay systcros for Icsting lite effctls uf whulc, fresh, nurm:d cigarcllc slnukc or its fractions (particularly the g:IS.v:yK,r pllasc) or cnmptmcnls murc realistically than is possibk with crudcr rnclhods. IllcuGlcr Cunccr I)ata relating to bladtkr canccr in hunrans arc sparsc Ilthcr Ih:ln Ihllsc concerned wilh IKCupaliunal factors, where there is a nluth clrarer piclure. '111n,rgh several epiderniulugical studies have reputtcd a staualicul ass/Kia liun IK•Iwccn ciparelte snKlking and eancer rrf Ihe bladdrr in huluan nlalrs, lite qucsliun Id whclhcr thcre is a causal rclaliunanp rcmains IIIK•n I hc finJmf;c Iur fcm:dcs wrrc tvlnlruhclory, and thcrc wcrc intl.nantrnt rrsults Id aninlal cRpcrinlcnts wilh tigarclle snu/le clrndcnti:ltc V/lel ttetl~u.s fivl lite p.lst 1 t yr:us du n/rt sh.lw a fll,'llltlt arll ritc in rrliv-rrctl t.l. ..d btedLh 1 cantcr. Ilcntc. lite rcpwrrtcd Statlstll'JI :ISSIKIallull h.l. Lltkt l I.Itn n.J I R planallun I11 11

In 1965, a h,vlxtthcsis was advanccJ to Ihe cflcct that nicotrnc miRht so Jisturb the mctahidism of Irypluhhan as to result in ahm+rmal accumula- tir.n of certain rn.rmal intcrmediatcs rclalcJ chtmicilly it, suhslaucs whirh, when implanted as pellets in the hladdcrs of mice, were fuund its prr,Juce cancers in that spccies. A basic postulate of this theory was that h1aJJcr cancer palicnts Rcncrally show a Jisturbance of tryptuphan rnetalxthsm akin to that claimeJ to occur in smokers. '1 his hypnthcsis has been investi6ated in three JiRcrcnl cenlcrs as part of ^ broad b1aJJcr cancer study that included clinical, pathuh.Kical, bio- chemical ^nd espcrinsental aspects. Contrary to the hyF%Nhcsis, four out of five bladdcr cancer patients were found to escrete tryptuphan -nelab- oliles in a nornral pattern even ^fler tryptuphan loading tests In mict, the lihcral feeding of vitamin C prevcntcd pr«luction of bladder c^nccrs by implanted pellets of J-hydrosyanthranilic aciJ, a normal Iryplnlshan metahulite. 1 he coroparative excrelion patterns of nine tryptrrphan ntclatx+litcs by snrukinR ^nd rxxtsnKrkin6 subjects have also been under investigation and reprxts are scheduled for early publication. As part of its spunsorship of sludies in this field, 'I he ('uuncil ctrn- tribuled to the supfxrrl of a symf..nium nn "Iht I:pidcrniuluRy and I'IiuloRy of Iluman BladJcr ('anccr " jrdnlly afMmsorcJ by the ('anccr Itescarch Institute of the New UnRland Ikac.ntcss Ihralrital, and Ihc Ikpartmcnl of Pathoh+Ry, &.stun (lniversity Srhr>,d of Mcdismc the symp+sium was held June 6 and 7, 19611, in Huslnn, and mmt of the papers prescnteJ were published in Ihe /nurnol ol l lrr Nor.nrmf ( unrrr /nirrrurr, 41, 217 (1969). Cardiovascular 1)itieascs C'ardiovascular diseases accuunt for more dcalhs among I1 S males than any other disease category. 1 he cardiovascular system itsclf is subjcct to a variety of disorders. The most cummon of these is arleri.nclennis, the result of unknown pa11xr1oRical pnKCsses that lead to pruRressive Inas of resiliency of the arterial vessel wall accumpanicJ by incrrasrJ ripdily and narrowing of the luntrn A conurnm uyucl is ahrupt rx'iluv..n by Ihruml>,rsis, and the effectf includc a faulty supply of hhwKl to a lirwc or rwRan, inadequate to meet its nccds I rryuent c.uncyucnccs are to mna,n furnrs rrf hc:nt attaaks, brain sttoke. Rangrcne of a Irg, rulrture of thc aurla, and certain kinds of high bkKKl pressure. Ihcrc are a nurnt.rr of su"cucJ factras in arlcri.rscecrulic diccascs I includrng lipid nrclalxdism, vascular connective liswc d.rm:r);c, cnJrKnne dvsfunctinn, and fihrin deposits on the vessel wcJls. I)ict, hypcrlcnsrnn, rrhxsily, lack of crcrcist, psychological factors (stresc anJ Icn+wn), and smukinR have been rnentioneJ as possible csrntributnrs Some aulnpty studies have reported no association cclwccn suurkiug and arteriosclerusis Others have reported Ihat hcavy ciRarcllc sm44rrs have more cxlcnsive lesions of the coronary arteries than do IiKhl or nuncmukers 1 hese data are limited in quantity. 'I ht lesions repr.rtcJ also require further study to determine if they Jifler in quality or palhuKcncsis between smokers and nonsmokers, since smoking has not been dcmun- strated to have an etiologic significance. 1lietary chulcsterol has been cited by many as perhaps the majrrr factor in heart drxase. Ilypcrlension appears lu run sccund in inqx,rtanic, according to somc investigators. There have been reports claiminR a rcla tionship between smokin6 and hypcrtcnsion but, paradoxically, it has been found that men who are heavy cigarette sruokcrs generally have lower blood pressures than nonsmokers. It is obvious that the siluation, in 6cneral, is cunsylcR and ubccurc Trcin Slurlipa in Ilrarf INall-oae Twin studies cr>twlucted both in this country and ahrr.aJ undcr uthcr auspices have casl Joubt on smoking as a cause of heart disease. "1 hete studies help to cmphasize (by their control of factors which would ulhcr- wise vary between smokers and nonsmokers) the impurlance of not only continued work with twins bul of mullivariate analysis. If srnrrkrnR twins have no higher mortality than mmsmokinR twins (as indicatcd by pre- liminary rep+trls), such a finding emphasizes the need for caution in evaluating uncontrolled statistical studies. With support from 'fhe Council for Tubaccu Rcscarch, two scicntists undcrlrw+k a study of the el-ecU of environmental fpclurs un the develop ntcnl of athcnnrlerusis as revealed by aulrMny of acri.knt victinrs 1 hrir work, with sul+p.ut from other snurces, was later eslenJeJ to lie iniluJcJ in the Intcrnati.mal Atherosclerosis Project. lhcse invrsliRalurs found fatty streaks in alm.nl all rhe anrtas of IM.ys anJ Rirls aKcd 14) 14 and sinrJar strcaka in the cononmy :utrnc.. of most hrrsuns aged 21) 29 lhe slreaks are clinically IWrnllrft :1nJ Iwdrll lially reversif.le, they noted Ilowcver. they said alhcrus.lrr..uc Ic+wns may ^)pcar in Ihc curunary arlcrres 1hcfure the age of 2t- :rrul rh..t rlrc eunversiun of fatty strcaks to lilrruus playrics rKCurs at an a-arlrcr :.t-c m pupulaliuns with high curunary hcarl drsc:rsc murhidity and nuurahry I) 12

Nicot hic: I'sycho-I'ha rrnacologica I and Bchavioral I;f fccts Some oC the bases for human use of tobacco are certainly to tx founJ in social or psycholoRical needs. However, on the ssumption that others might also be fnunJ in the realm of psycho-pharnmacrdogy. Ihat is, in the eRects of smoking and/or nicoline on the central netvous system. 'The Council has suppcxtcJ a number of studies in this ficld, several tit which have been summarizcd in previous Reports. lhe volume of this work reached a level decnrcd to justify a public symposium on "'Ihc f=Recb of Nknline and Smrrking on the ('enlral Ner- vcws System" which was sponsoded Krinlly by 7 he C'ouncil and lhe New York Academy tit Scicnces on April 7-9, 1966, and published by the Academy in March 1967. Grantees of The Council participated in the session as did a considerable number of other independent investigators from the l)nited States and abroad Work reptxled at the symposium established that nicotine docs dcfi- nitely pass Ihe blood brain barrier and aRccb brain activity as shown by electroenccphalographic tracinga two1h in animals anJ in man. Ilccausc of the rapidity (if these brain wave chanRcs, it was postulalcd that smokc may also s/imulate nerve endings in Ihc IunRs tit send signals In the brain. 7he cflects ts/ nicotine on the brain are not always the same. I)cpend- ing on the slate of the nervous syatcm and on the Jrrsagc, an "aruusal" or "wake-up" effect may occur which is reflected both in brain waves and in behavior. 71tis effect is accomplished by a dilation of the pupils and a slight rise in blood pressure. Confirmatitm that this was due to nicotine came from esperiments involving direct instillalion of the alkaloid inlo the brains of animals. In larger doses or in a diflerenl stale of Ihe nervous syslem, a peculiar steady state of hroger duration is pnKluced which may be described as Intermediate between krlness and slccp. 7 his has been JcscrihcJ as a "tranquilizer effect." 'Ihese finding.s confirm Ihe suhjctlivc rcprxts of ciAarcltc smokers (islcnskrn of the clectroenccphahl.raphic stadics Irr hum:rn suhjctls has pnxluceJ umre ntnervalions that appear rclcvant tu the yucsuun wlry urnx persrrns nced rx want lo mnke while tNhcrs do ruN 11 was fuunJ that the prevailing encephahrgraphic palterns of nunsmokers JJler mark- edly from those u/ smOkers or fxrsons who haJ never tx•cn snuokcrs, even lung aftcr Jiccrrnlinuance of the habil A markeJ ddfcrcnte in thc ability tu produce Ihe "alpha" pattern by conscious effort also csistcd between these groups. Sincc long discontinuance of smoking by (ormer heavy smukcrs did not alter these relatinnships, it was postulated that the difference in prevailing brain wave patterns has a congenital basis and may csplain Ihe function of smoking to nnxlify or "nurmalize" central nervous system activity. It this finding is camfirmed, it will indicate that smokers and non- smokers may have imptxlznl basic constitutional d4ferences which also may produce differences in their prcdisprnititm to the development of cer- tain Jiseases, especially those of a"psychosomalic- nature. Since prcdis- pcnitivn to cardiovascular disca%e has been attributed to Jillcrcnces in psycht>fogical or personality lype, il becomes impcxtant lo investigate pcnsible correlations between types as defined by a psychtdugical Icsl and as distinguished by encephahsgraphy. Besides these eflccts, it was repuMed at the symposium that small doses of nicotine have a favorable eQect on the learning pruccss in txrth rals and uxne other animals when they are made to perform certain aclirrns to receive a reward cx to avoid a disatmforling eaperience such as electric shock. Several ramifications of this basic finding have been pursued further and certain pharmaculogical mechanisms were elucidated in sunic cases. Chronic I1cshiratory I)iscuscs llte Scienlilic Advisory Bwrd has long been aware of lhe need fur research into chronic respiratory diseases and has awarJcJ many grants in this field. 'I here is a teporlcd increase in such Jiscates as causes ol illness and death but whether there has been any curnparahle Irue increase remains questionable. 'I here is reason to believe, in any event, on Ihc hasis rrf rescarch findings. that one important factor in any reported incrcasc is Ihc res.ue, particularly with Ihc use tit antibiotics, of many pcrsons hum dcalh duc lu severe lung infctlirMn lhey then live rm wilh d:unagcJ lungs trr Jcvchqr chnmic respiratrny ailmenls later in life. ') he IKnsihlc inflwrnce td ciRucttc suruking rm Ihc caus:rti4,n or cx accrhatiun uf thrunic respiralury Jiscascs is Jrllicrdt tit a.scss (/uc rrl thc di/hcuilies is Ihe inabi6ty lu JrstinKuish adcquatcly Irlwcen (hrunic hrnn chitis anJ cmphyscma. Ifulh conJiliuns are uflcn fuunJ lu ccu cent in inany patients. 'Ihe accurate classi/icatiom and recugnitiun uf ernphysciua by the 14 15

medical prnfession have really not dvanccd very far For example, de- compensaticxr in chronic pulmonary discasc nd cardiac abnormalities are not yet accuralely distinguishable. Standarrlised Techniquta Ntedrd Further, standardized techniques are nceded lo compare the prevaience of emphysema in different societies or different ccwntries, an apptoach that is IonR overdue. Suilable morpholo`ic criteria frx properly classii yins, quantitating nd evaluating emphysema have barely begun to ernerae in the past five years. The necessary techniques are now used only in n few Institutions. Even fisalion of lunp in the expanded statt, the essentia' first step in establishing the presence, type and degree of emphysema, is rarely practiced. l?eath reported from emphysema cannot presently he defined with any accuracy as to what actual pathologic conditions may be presen.. No uniformly applied, scienlific.lly sound clinical methods are now in general use whereby emphysema can be identified and quantitated. The basic kn<+wkdRe and even the definition of chronic bronchitis are still IackinR dcspite some recent notable cunlribulions fkynnd the need to standardize, and even mrxe to find better clinical and patholoRic diaRr.enlie criteria for chronic brnnihilia. there are also problems of its possible rela- tion to repeated viral and bacterial infectiuns over a lifelime, particulate and nonparticulate irritants, ginR, changes in the bronchial mucusa, and hypersensitivity diseases. 'The Council has supported pioneering studies to describe anatomic emphysema more quantitatively and to ddferentiate amons the several dis- lin6uishsble types. It has also sponsored a number of clinical studies of pulmonary funcliim, for description of short-term effects of inhaled agents, including tobacco smoke, in subjecls of various ages nd in various condi- tions. lhcse have been dcscribed from time to time in earlier Annual Reports. More recently. The Council provided support for a sludy of The siblinss e>t chronic respiratory patients 1 he siblings and the patients were the test group and their spouses served as a control Rruup 'Ihis invesliRa. lion revealed the esistence of a familial tendency to funcliomal impsirmcnl of the lungs. (hher investigations have contributed to the present impressive evi- dence that certain genetic enzyme deficiencies (alpha, antilrypsin) slronRiy predislwne to enrphysema in homnryRutes carrying this gene and Ihat even hcterozyRotes may shuw an enhanced degree of prcdisl>•rsitiun. InJlept6 Cfiniea/ Studit. Undtr R'.y The Council has recently provided support for major lung lerm, in- depth clinical studies nf chronic respiratory disease enlilies in two Eeo- Rraphically separated urban centers. A third clinic that spccializes in iunR function measurements of young children has morc recently been added to the project. The hope is that Icm6-term repetitive examinations of patients can provide ccxnprehensive information on pcrsonaf characteristics, family his- tory, manner ot life, environmental espasures (including tobacco smokinR), conlributory infeclions, response to treatment and course of the disease. The extensive clinical and '.abrxalory dala compiled by the investigators may prrxluce better de6nilions of the various clinical emities and more reliable methods of differential diagrKxis. It seems obvious that such definitions and diagnosis arc absolute prerequisites to any real progress in the study of the etiology of chronic pulmonary diseases in terms of the interplay of intrinsic and estrinsic facton. 17 1fi