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CTR HN 011616

I EXTRA COPY REPORT / TI-IE COUNCEL FOR TOBACCO RESEARCH - U.S.A., Inc. 1972

1972 REPORT , 01 ~ lll~ m 41D m TIIE COUNCIL FOR TOBACCO Ri"r.SEARCIC-U.S.A., iue. TIIF: COUNCIL FOR T()1{A(:(:I/ RF:YF:AR/'ll-ILS.A., Ine. 110 E..! 59tV Sired, Ne.+ Yoh, N. Y. 10022

ti1:1FNTlF'll: AI1V1S(N1Y IL//AR1/ to 'Ihc Council for Tobacco Rescarch-l1 S A. Inc as of Ikccmber 31. 1972 SIIFl.l7nN C SOMMERS. M l),C'hairman Rrsrarch l)irrnor, The Corr.cil foc Tobacco Rcsearch-l. S.A., Inc. Uirrctr>w of I.aAuratorws, Lcaot Nill Floapital ('linira! Pro/rssor rr/ Potholoty Columbia Universily Co1kAe of Physicians and SurAcons New York, New York IIOWARD B ANL)I:RVONT, Sc.D. Scirnri/ic l:drror (rnbrd). T1se Journal of thc National Cancer lnstitute Bethesda, Maryland RICIIARD M BIN(;, M D. l)irrcror of Cordiology and Inaan+wal Alydicinr f luntinstnn Merrxxial Itcxpital, Pasadena, C'alifornia Pro/rssnr n/ Mrdrrinr l Iniversity of Southern California School of Medicine Los Antclcs, California McKFE_N CAT-1 Fl.l., Pit D, M D. Pro/rssor Fmrritut u/ Pharmoroloty Corncll llniversity Medical ('ollc6e, New York, New York WILLIAM I). (;AR!)NER, Prt D. F K. Ilunr Pro/rssor of Anatomy Yak University School o/ Medicine. New Havcn, Connecticut ROBERT J. IIUEBNFR, M D. Chief. Viral Carcino6encsis Brarxh National Cancer Institute Bethesda. Maryland LFON O. JACOBSON, M l). I)ron of the I)it•islon of Biolotiraf Scirncrs Regenstein Pro/rrtw of Biokrtiraf S4 irnr rs llniversity o( ('hica6is, Illinois CLAYTON (i 1.(X)SI.1, Pit 1). M I). llastrnRS Pro/rssw uf Mg,di(inr and PurhophoXy I Iniversity rrf Sr+uthcrn Calilurnia School of Mcdicinc l.r.s AnRclrs, ( aldnrnra KIiNNETIi MFRRILL LYNCH, M D., Sc.D., l.L.l). Chnnrr/Lrr and Pru/rssur F.mrrirus u/ Potlwluty Mcdical C'ulle`e of South C'anslina, Charkston, Stsulh (•arohna IIANS MEIEiR, D V.M., Dn. MED. VeT., M.R.S.lI. Srniew Soog Srirntist The Jackson l.aboralory, Bar 11arbow, Maine J()i1N P. WYATI', M.l) Pru/rssur and ifrad, 11,p artnxnt of Pathology l)nivcrsity of Manituba Faculty of Medicine Winnipc6, Canada WIl•LIAM F. RILiNFIOFF, Jrt., M.1). Board Mrrnhrr Emeritus ProrfrsfOr f nKrlptl of SYrgrry Johns Ilrtpkins University School of Mcdicinc, BallinNUe, Maryland ~Srirntifir tilafi o( Tlser (:ounril ROBI:RI' C. 11OCKI:Tf, I'tr l). AcringSr irrnrifir I)irrctw J. MORRISON HRAI)Y, M l). JOIIN 1I KRIiISIIER, Pit D. A ssrN iurr Sr irnN/ir I)irrrfur A+srh iurr SrrrnNhr I)irrr arr I-R1'l)I RI(' W. N(1RIISII K. 1'n 1). V1N('I N I F. I 1SAN7I, 1) M 1). A stur rurr' Sr rrnu/ir I)irrrrur , Xr rrnri/ir Asrrr. rru.•

i CONTENTS 1 etroductic>,+ . . . . . . . . . . . . . . . . . . 5 Curreot Slatus of the Research Propam . . . . . . . . . . 6 Cancer Studies . 7 Cardiovascular Diseasa . . . . . . . . . . . . . . . 8 ('bronic Respiratory [)iseases . . . . . . . . . . . . . 10 Other Studies . . 11 Abstracts of Reporu . . . . . . . . . . . . . . . . 13 Behaviorai EAecb o( Nieoline . Studies Related to Carcinotenes» Cardiovascular System . . . . 15 . . . . . . . . . 33 Rctpiratory System . . . . . . . 52 Pharmacr>Josy and Psychopharmacr4o8Y . . . . . . . 66 tNctaWic StudieS . . . . . . . . . . . . . 70 Chemistry and Biochemistry . . . . . . . . . . 71 Epidcmiolocy . . . . . . . . . . . . . . • . 78 Immunob6y . . . . . . . . . . . . . . . . 81 (knetics . . . . . . . . . . . . . . . . . 86 Active Projects . . . • . • • • • • • . . • . . . 89 Complctcd Projects Author Indca . . . . . . . . . . 13 . . . 96 Iniroduction Tfie Council for Tobacco Reaeamb-Q1.S.l.., Inc. is the spotuorleg a~o.cy of a program of research into queationa of tobacco uae and health. It is the outgrowth of an organization formed early is 1954 by representatives of tobacco manufacturen, growen and warehousernen. Research wpport has beew mainly through a program of tr.nts-in-aid suppkmeated by contracts for rexarch with institutions and (abwaloriea. The Council does awt iuelf operate a.y research racllitr. The Scientifle Adviwry Board meet- regularly 1o evaluate applications /ot aranuin-aid and contracts for research, using scientiAc merit and relevance n the sole criteria. Research grants art made by 7he Council to independent scientists who are aeured complete scientilk freedom iw conducting their studies. ()ranrar a/one arc responsible for reporting or publishing their /lndinp iw the accepted scienti/ie manner - throuA medical and acientilk journals and societies. TArough December 7972, research projecta have been approved foe 22) investigators In 199 hoapilab, universities and research instuutioru, 7Ue.e award" totaled more tha• $23,000,000. Thr reporl includea a brief summary of the present research propum of 7Ae Council as well as lists of the curreot and previous researcApr~ u sup- ported by The Council. Also included are abstracts of 127 reararch Papen, acknowledging Council support, that have appeared in scientific jouroals durt.y the period covered by this Report. A total of 1,012 .uch papers hu been pub- hshed by project recipienu. 11, N. RAMM Chairman and Presiiknt S

I Current Status of the Research Program The rexarch progrsm of The Council for Tobacco Research-U S A., Inc. hu progressed further during the lasl 11 momhs with a conhrued mapr emphuis upon cancer, chronic puh.o.ary disorden, eardiovaaculnr drseasea, and the "ptychopharmacology" of uwoki.g, is approaimately that order. The actual aumber of formally separasa proiecta is at present aomewht,t ku than Ihe historicJ murimum, refleetiwd a Iedrea of aggrekation into cerrain untera for the advantapes of Interaction among e.riwr different skills and mNhods. Seventeen of The Cou.ed's cvrnM projcets involve the espoaure of animals to the inhalation of Iobacoo nnote. Several others have been under• takea with the obtect of 'w.ch.diy srwoke exposure as soon as the necessary preliminary b.dot,cal work Aas beew suflkknly, developed. Iw all these inhalatio. .rudiee the aiwr Is to so control cord;tions as to insurt exposure to "fresh, whok, normal" tobacco smoke or ils pau-vapor phase in nu+rwlo.ed dose., In defined an:nah of several atrains and apecies, usually pathogen (rce and virus proHled, foc lirwe perioda determined by the aims of the eaperiment In several casea this is a lo.a-krm or normal lifeume c.posure. Cigarettes or oaher tobacco products of defined character.tics are employed. Concentration upon amole inhalatiot, eaperrments reflects the conviction that rcalntic studres murt be based upo. and evaluated by eapo.ures aimulating as nearly au possible those e.perrenced by human amokt:n. Sn.oAre Esposure Devire. fkvelopment of mechanical devices for accomplishing such eRposures with anirrula hu been an eaacunk, timc<onsuming task, even after ccubl6shment of criteria (or satisfactory conditions. Tlwugh The ('ouncd has been sponsoring smoke inhalation research (oe 17 years, the recognition of Ihese criteria has developed only with eaperiesct. The preaent proliferation of smoke inhalation atudies i• many Quarun ernphrizea 1!w neod for recognized standards to which all such studies muu conform, it a great con(usion of contradictory flnd- inp iN the scientiflc literature is to be avaided. Two devices that appear to meet many or most of the necessary criteria reasonably well an now a1 hand. Ur ie a relatively ineaperrivc and simple machine which should, hopefuly, be adequate foe use with intelligent care where relatively modest numbers of amalt animah are to be empbyed by in- veslfgaton who are rliNod aa biobgina but not necessarily as mechanics. TAe other device is more costly but should eoreserve manpower when larr numben of small anim.h are to be e.poced or when the use of large animals requires a greater amoke generating capaeity. A number of the srnaM rwachinss have now been diuributed to Council- rporrored iave.taptors .nd are in u.e. Conserauendy, a coosdcrahk increase in the flow of research results from direct sn.oke inhalation studres is to be e.poctcd llcrp,te these devctopmcnu, there are still many t>trks to be carried out 6 I to describe mexe fully and to measure mon aceurale!y the performance charac. Ieristics of these devices, especially as applied to animals of diflcrerM size aad different respiratory mechanicY and behavior. Especially important is devek+p- ment of better methods (or measuring the actual amounts of arnoke paniculatea deposited in the lunp of Ihese several species and strains of animala under actual operating conditans. Such measurements are necessary for reliable deter- minalion of dose-responar: relationships. Means for carrying out these studiea are being sought as a support foe the eaisting and growing program of inhalatios studies sponsored by TAe Council and, inereasingly, by other agencies. Fssentfally the same smoke exposure devicea eaw be used in studies targeted toward cancer probfems, pulmonary duease probiems, cardiovascular probkms, metabolic probkms, pharmacological probkms, and o/hen. In maay cases, paralkl eaperimenla are being conducted of planned 1o c.o.npare uy effecta of whole smoke inhda/ioa with those of the flas-vapot phaae (roe from parliculares. 1n all amoke inhalation taperirnenta invofving animals, the factor of atreaa ia being conaidered because, unlike man, mou anunats inhale snwke Involu.- larily while uationed in Gevices that impoae restrainl, noi.e, handlrng, and other disturbing influences. Tlria requires the use of `machine toMrols" eapo.ed to all conditions tacept the actual presenluion of amoke, for cornpariaon with unhandkd cage contro4 as well as with eapoted animals. Nabiwalion prcwrw- ably reducea stress and is a consideraliow in esperirnental design. fiiochemical monitors of streso, are also being eaplored. Thia problem has generated two mapr projccts in its oww right. Pethosene.i. Sttrdie. The Council p.oRr.ie inchrdn a sekction of promising k.ds inso an understanding of (acton that nuy be significant in the pathogenesia of dr several proup. of akin111-auocialed conNitutio.ul dirasea which are cw.esdy major causes of human motbidily awd wwrtdity, and also those reputed 1o ba linked statistically with tobacco use. Topia selected foe study are those deaned nwst likely to reveal important ueps in the pathogenesis of these diseases that may be tested is human ep4 dcmiological studies or developed into new and more meaningful bioassay lests, either in smoke inhalalion studies with whole animals or in organ or tissue culture systems of several kinda. By pathoseneais we meaa the progrca- sive succession of changes from no.mal, whether hntoiogical, biochemical, imnNnwlogical, uructural, or oaher, that lead to or are cor.comitant with d.eaae corditions. Caticer Studies Tlrus, in the cancer fkld, there are presently su Council aupposed nudlaa aimed at a betrer undcrstanding of how genetic faclors control wneeptrbiliry or resistance, and how the w called ('-type vrral genon.e may operare in eo.- tribwink to or.cueenedr Such knowledge is not only neoessary foc .ekctiy appropriate animal strains (or srnoke inhalatiou work but al.o (or defining isdrealors of susceptibility that can be applied to man. 7

lwo other cancer studies that do not presently involve smoke !spc.sure are in the fieW of immunulogy nJ are simcJ at learning how the hoddy mechanisms that bring ahcsut the rejectron of grafted tissues and o:gans as "foreign" material also operate in relectrng newly formed cancer cr IIs The work includes the ohjcctrve ol karning why thn rejcction system rlocs not always succeed in dettuoymg cancer celh and whether it can he stimulated without undesirable side effects It has been shown that Ihis part of the immune system is depressed by several of the "carcinornic" hydrocarhons and, if suitable new and scnsnive indicators of this depressive effect can be dr vebped, studies are contemplated for deserw.iwir.g whether chronrc tobacco su nu\e inn halatrors produces any such depressbw. (An e.tensrve completed tudy of immunosuppressinn by another rnedsor) iievdving stin transplsnlstion failed to show any effect by tobacco smoke eowdensates.) One relatively frequent type of human lung cancer is squamwis cell car- cinoma. which is seldom (ound (w nwinuls. Seeause squamdn eclls are not nwmally presenr in the lung, /hert nws( at ro.we time be • mNaplastrc con• verswn of other cclt types into squan.orr celb. It is not known whether this conversion occurs before or after the trawsfotmation of normaA cells into cancer cells. A new project has bee. desiped to determine whnher e.posure of living human cancer celis of other ryp;s b tobacco smoke w dl evoke squaman rnetaplaaia. Anin.d Modelt for Squan.osa Cell Lrn` (:.nter In medical ricnce, discovery of rncthods for producing a good duplicate of a human disease in an espcrvnen/al a.unul has often provided a basis fot rapid protreu in dcscribrnt the patho.*enesis of the disease and in finding methods of prcvention, delay or cure It has been more drfficull to develop such models /or the constitutional diseases than for the rnfectrous and deficiency diseases because of the strong tenetic aspects of susceptibility in the first. Several rnethods, however, arrived at by luck or necrdenl, have been reported for producing squamous cell carcinonu of the lung in animals. lwo Council propcta include mexhfic.tion of such animal models in the hope of producing the disease predictably and reliably and at a kvel adequate to permit syslematic studies of the influences of age, aea, urain, horrnone kvels, nutri- tasnd state, efficiency of the rnmune system, infectrorr, and other factors on the incideece of the disease. Such ierormalion dsould provide guidelines for the design of better oriented human studies. Cardiovascular Diseases As with cancer, curdiovascular diseaw are of compks eliology that in- cludn many contnMitory factors. among which hereditary prcdnpositurns may play an important rok. lhe predominant influence of genetic factors ha been further emphasized in recent years by sludks of identrcal twins with drscord.nt snw.\int hsbitu 1h -uth Ihe ('rwncil drd not participate in the spon.urnhip ol Ihc sho.hts .arrrtA iwi *on a C+rtJoh twin registry ur Ilvt original carcnsKrn of thrse sao-lits rar a i-in i4J,t0wm an tl.e IlnoteJ titslts• it u.upporlmt tsplnls. lions into the prnuhclitin of enlarging the sampks through international co. opcration. Ihe go.l is to obt.m more estensivt and cuncluuve data without waiting for the slow accumulation of morbidity and mortality figures from the original sampks. Meanwhik, the multivariale n.lysis of large e.isting human data collec- tinns is producing new perspectives concerning the rcpotleJ statnlical associa- tiom between smoking and the incidence of thest diseasn. The position uken by thc ('ommdlee that reported to the Surgeon General of the U S. Public lle .1th tiervice in 1964 was: "Male cigarette smokers have a higher death rate from artery disease Ihan nonsmoking maks, but It is not clear that the suoci- alion has causal signifkanct.- lAn statement is supported by increasing evidence that self-sckction of populations into those who "Irlie, need or wish (o arttOke` and those who do not, produces a non-random division into groups that ate not comparable with respect to nxxbiduy or life e.peetancy. Nenee, attribution of eaperiential diflcrcnces to the samc factor (smolling) that served as the basis for separation is ncocsaarily inconclusive. AlrrKSt hdi the current ('ouncil program in the cardiovascular (kld, aparl from the epidemiolntlical work already mentioned, is concentrated upon the study of atherosckr(><is or srtetiosckrosis. Qoes smoking have any effect upon the initiation or progrenion of these conditions that lead to incapacitation or death± One current project includes smoke inhalalion. Most of the uudies involve or include research on the eBects of nicotine. In several investigations, the initial nicotine research is to be followed by whole smoke inhalation. Induced hypertension is also being studied as ae additional factor in the totd design. 1 hree of Ihe asheroac~!rosia studies involve whok animal subjecu, two are irn vitro eaperiments using both animal •nd human lisaues for species wm- parisons, and one is a biochemical study of reactions in human blood. One of the animal studies, using chiefly p.imates, is eoncenlrated especially upon the (ong lerm cfiecu of chronic slresa in producing persistent hypertcnsion with consequential cardiovascular chanjes, when other influences are well conlroikd. Invesligation of potential nicotine effects In this contest is includrd. Carbon Monoxide Strdie. Another feature of the program is the incluslon of carbon rrrseosidg studies. Chronic inhalation of this gas by prirnates is being underlakeu to kyt a hypothesis that such espowre cas, hasten alherosckrosis. One sludy, at the cellular level in virro, is attempting to show whether the processing of falty materials (akin to those that eoat the arteriat walls in atherosclerosis) is dTtcttd by nicotine or carbon rnonoade eNher separately or in combination. All the malur human epidemiological sludiei have shown that cigu and pipe smolecrs drflcr very little in their cardiovascular disease e.perieoce from nonsmokers despite the fact that the smokes of these tobaccos have a relatrvely high nicotine content in a relatively alkaline environment conducive to rapid absorption in the oral cavity even without inhalatiwr Ilencc, the ('ouncd has been strening 101 many yesrs Ihe neeJ for precise quantitative and kinetic mcasurcmcnts of the relative naoUne absrNptiurs during the mumal smoking of cipreNtes, citan .rd pipes Analylical meth.n)s adcquue for du purpusc have been lacking A('ouncrl prolect is erdeavoring to develup n rmrnurxxhenucsl 9

assay method for this purpose 11 is gratifying that the government agencies have now recotnrted this need arnd have sobcitcd proposals for the develop- ment ol such mcihixls 11 the nicotine recerved frum these thrce forms of smokmg (and Irom chewing tobacco) should be closely simdar, thc cprdcmro- kKaal differences in disease rncrdencc among the users of these severaf producls could nrw be attrrhuted to nicotine (.l, rl»lic Respirotory 1)iseoses Ilistorically, several of The Council's Nudies of short- or lons ter n tobacco smoke inhalation by animals and rwan have included an eAort to dc.cnbe any obaer.ahk changes in pulmonary mechania or alterahons in the cells or tissues. lhs inlerpreutron of such observatior is relation to pulmonary dru.sea has hcrclofore been handicapped by the orneral lack of knowledge concrining the uap in pathogcnrus of these d.serun It wa., thcrefore, been conaidered neces- sary not only to sponsoe studin aimed at a better clinical dutrnclas between the several human chronic pulmonary diwrden but also to seek rnd follow clues to the prednpoulrorss and alseruio.m that determine the count of their paihoefcncss. Apart from lung canur, "chronic bronchite" aed "emphysem t" are the pulmonary diseases of special interest to Tlte Council Neither is really a single drsease and, therclcre, subdivisions into distinguishable clinical ent tics occur at research progresses ifu Council has contributed to the deveLspmenl of clinically diurngunhabtc suAgroups through subsidy of human paticnf studres in depth Both these diseases or group. of diseases are very incornpletely under• stood with respect to etrolo9y, which may well difler in the different subgroup.. FprdemsotoRrcat suudres in the past have been confused by poor chmcal da- cnmrnairon among acveral entrtres. lleredif.ry Prndupo.i/iow ro Ee.phy.ew.. Neither bronclutis not emphysema oecura commonly in animals in a form knowa to be clearly analogous to that encountered in man, so there is still uncertainty with respect to ths suitability of any propoaod animal model for studies directly rekvant to the human problem. However, uveral promising approaches have developed. One is the discovery that certain human individuals have a hereditary predrspoeilioe 1o emphysema due to a congenital defkiency of a cuculalrng antitrypsin which funclions as a protector of the lung pinst proteolytic attack by esollenosa oc endogenwn agents. The implicatwns of this fSnding are being pursued by aludy, oof a large human population. Estensive health and empbyment hislories are available for rnembers of this population who are also accessrbk for blood uaays of anti prdeasn. In the light of very recently developed information ow rnelics of the deflckncy, this study will attemp4 to relate the several genotypes 1o diAerences in respo.se to enviroer- mcntal rnflucwccs Animal wo.%, including sn.oke iohalalion study, is capilaliting on this discovery by obecr.auor to deuimi.e wt.ether changes tn anti prutease kveb may correlate with development of esperimental cmphysema or may be affected by cigarette smoke inhalation 1 here rs also recent evidence that emphysema rray be an au/oimmuno disease, caused or aggravated by chemical changes in the lung that cause lung lissue to be recognized by the immune system as foreign material and, lhcrefore, subjected to destructive attack. lhis concept also provides possible approachn to detection of those individuals who are especially susceptible to cmphy.ema and to ways of testing whe7her esposure to tutwke makes any conlributiuo to chances in the anutenicily of lung tissues. While the etiology of "chronic bronchitrs' in humans is still quite obacure, it is.considered very probable that an impaired capacity to clear bacteria from the lower regions of the lung is an irnpo.fant aspect of the disease. lhe Council long ago undertook support of studies to measure the rates of disappearance of viable bacteria lrom the lunde of mice after quantilated implantation, as affectod by I number of factor@ inclArnR whole smoke and ps-vapor phase inhalatio.. lhcse studies were folbwed by others concerned more particutarly with she pulmonary macrophates ao the probable major eflectors of the ckarance proceau. Both in vlro and in vitro smoke e.posures have been made, ard are conlinuing, to assess the toasA functional rnodrficaion of this protective system while avoiding the artifaclual ailuatio.n easily created by esclusively !w vlrro e ape r iments. Research findings about the protective function of the pulmonary macro- phages have led to other Council-aupporsed research on the operation of tAe.e and related defensive systems. At the end of November 1972, an infonnal roundtabk conference was arranged by Nafl at the requcu of the Scieaifk Advisory Board to lhe Council- Memben of the Board and stafl, investigators conducting studres on pulmonary defense meehanisrns, and several psesl .cicw- trsls mel to evaluate progrcu, eachange information and generate new ideas. 01her Studies P,yehopharwe.colo`y The Council is currently supporting Ilve studies in the beld of psycho- pharmacology that are directed toward further elucidating the paradoaical arousal and tranquifizing effects of nicotine and its facilitation of the learning process in animah. Chronic eRects of nicotine esposure have now been recognized in the sense that a shift has been reported to occur with time in the relative .ensitrvity of particular areas of the brain to nicotine as well as to other substances II was predicted that this thift in the brain area of major nimularion should have behavioral cornequcn4s in the promotion of "purposeful," u op- posed to random, activity in habituated rate receiving nicotine, 1 his prediction appeared to be upheld in tcsl e.perimcnis. Because human amoicrs ordinarily receive nicwine ch.onicslly, it can be reasoned that pharmacological e.pKrimen/s wuh naive anrmals may produce rewlts that aue not wholly relevant to the usual human situatrun flence, a new emphasis has developed concerning habituation effects on the psychopharma- eobgical responscs Io mcoline. 10 II

i Epiderrsioto6ica/ Studie• Four ep«kmiol•ugical studies are in progress which involve the analysis of large bodies o/ dau already collected by other agencies One es a continurng inveuigation inlo which it ia possible to introduce new tests upon the same subjects about whom a great deal r already known Fmphasin is upon the basic diflerencn, al many kveh, between those persons who have chosen to smoke cigarettes and continue srtsoking, thoae who chose to smoke but later ducon- tinued, and those who never adopted the praetice. Comparisons are also being m.de of the constitutional characteri.tio of cig.r, pipe and cigarN;e smoker.. One study provKks cornp.ri.or between men and women, whrles, black., (kicnuls, and Spanish Arneric.wa. trk differences that distrn6uish these several groups in rel.tion to a.wofti.s practices are relevant to 1(re question whether sell sekctron invalidates or rNulilka the causal interpretatioe.s that have been placed on statistical corretatioru belween smoking and disease. If smokers and noounokers are drqereM klwda of people, there may be basic cenatitutional dJferences in drease naaceptibility wnla/ed Io smoking prscticer. fhe data collected also contain rnaterial (or wsawy other multifactorial srudres Metabolie shu/ie. Two studies on mctabo4uw rue lookinR wNo relation. betwavn smoking and protein metabolism and Into the poraibke i.fluence of nicotine a.d smoking on the metabolism of various druK Y weM Y the possible effects o' drugs and medreinals on nicotine rneubdiam In the body. lAe current program represents a eoncescd effort by the Scientil(c Ad- virory Board and the scienti/k w.fl of The Council to achieve a new and higher degree of integration arnong Its eksne.u and a sharper focus upai key prob- kms in the area o/ tobacco and health rexarch. Robert C. Iloekett, Pit D. Acting SckntifSc Directur m (n O O m co cn 12 Abstracts of Reports I:ollowing are abstracls, approved by Ihe authors, of report. on new re- sc.rch acknowkditing support from lIK ('ouncd that have appeared in.ckMi6c jcwrnals since publication of the Report lor the year endrng June 30. 1971. lhc name of the recipient a in ItaIK.. lhe abstracts are grouped under these headings: 1. Behavioral Effects of Nicotine. I1. Studies Related to Carcinotienesn, 111. Cardiovascular Systerrs, IV. Respiratory Systcm, V- Pharmacology and Psychopharmacology, VI Metabolic Studies, VII. Chemistry and BioAsemistry, V111. Epidemioloty, IX. Immus- olo[y, and X. Genetics. 1. BehaoioraJ Egecta of Nicotine SIl1D1IS ON 111E MECHANISM OF AVOIDANCE FACIL_ITATION BY NICOTINE Does nieotine facilitate avoidanoe acquisition by enhancing memory eow- solidatqn or rnerely by atinwlating performance? To answer the queatio., a series of etperimenb waa run on 229 femak SpraRue-Dawky rats. AninuY were divided Into groups cnd trained (o. 15 one-hour seasiona in a diariwi- nated kverpreas avoidance situation with buzzer as a conditioned stimulw. More rats receiving wkotine, 0.1 n.g/kg, I p. irwnsedia(ely before each onoAotw daily session (presession) (eachcd a preaN karwing criterion than did aali.e conuoh, and rats receiving 0.1 mg/kg of nicotine performed better tham cow- trol. but not as well as those receiving the higher wicarne dose. Rau Rives similar doaes of qu.rlernary nicotine bismethiodide In an identical pre.ea.io, esperiment did not learn more profkientty thata controls. Other groups of rats were given four doses of aicoline in photocell activity cars and the dow of niaNine which facilitated avoidance acquiailion depressed sponlanean snotor activity. LAler uudies in which rats were given 0.1 and 0.4 mg/kit aicotine or saline i.p. immediately afrer each session (postsesaion) showed that the drug also facilitates avoidance acquisition by this method. hinally, rats were again trained with prerssion nicotine, but .aline was substituted for nicotine begin- ning on session 16. No drug dissociation effect was seen. lhus the resulu of these studies suggest strongly that small doses of nicotine permanently facilitate the consolidating neural mernoay trace and do not enhance avoidance merely by stimulating performance. t,ir4,on-C. K. r,yrhovhurmacorotiu (errr ) 22:)S7-)6e, 1971. From the (kpartmenl of Pharmacolory and lo.iculo=y, University of Kansas School of Ph.rmacy. I awrence. ('1/O1 INFRGI(- ME3('IIANISMS AND AVOIDAN('U BE'FIAVIUR A(Y)(IISIIIUN. I:1/ Y('1S OF NI('OIINN. IN MI(-li 1wo groupr of IS male ('F I strain mice were given rnu.perrtonc.l ro- jeclions of nicotine sulfate (I 0 rng/kg) or an equivalent vulunme of 0976 salro. I)

This treatment wat followed, 45 minutes later, by giving each animal a single training trial in an apparatus designcd to provide for the acquisition of a passive avoidance respnnu, consisting of loot shock given when a mixne stepped through a hok connecting a small vestibule to a large darkened chamber. Response latency linterval between placement and entry) was always undcr 15 aecondt A/esung trial was Riven 60 minutes after training lhcreaflcr, active voidanct training was initiated. Mice trealed with nicotine sulfate showed, as compared with the sahne-Irealed conlrols, a decreased incidence of active avoidance conditioning without effects upon either passive avoidance acquisition or escape behavior. The dlecy of nicotine was to reduce titnificantly the ratio of bound free acetyklwliwrt in the cerebral corles. This change was accounted lor by a decreased coMCM of slored mine, particularly in the synaptic vesicks, without any ehanW itn the turnover of the "free" storate pool A difference in the ratio of braia aeetykholine storage pools accounting foe different modes of avoida.ce is wnesled. E unwn, W. 1, and F-sisman. S. 0. prycholorkd Rrporh 29()).9ta7-11), 1971. (Irl:er a.ppsrt: Nalronal Instituses of Health. From the Department of PsycAolo", Queem College of the City University of New York, FknhinL N Y. (-HANOFS IN ('HOLINFRGIC A(-TIVITY AND AVOII)ANCE Bf?FIAVIOR BY NI('OIINE IN DIFFERENTIAILY ItOUSF.D MICE lhe brhavuxal and cholincrgie effects of the drug, nico/ine, appear to be dependent upon endogenow changes conferred by differential housing In Ihis eaperinstntal study, mice housed either in isolation or in groups of five for 165 days were treated acutely with erther nicotine sulfate (I 0 m`/kg) or saline prior 19 being trained to acquire a passive avoidance recponu Isolated mice showed markedly reduced passtve avoidance karning, but with nno/nse veat- ment their avoidance acquesuru.n was comparable with that of troup housed animals. In the case of the laner, nicotine did not affect woKlance acquisition rate. Active avoidance training, given following passive avoidance testing, indicated significantly impaired learning of the avoidance among nolated mke, without any effect upon escape from footshock. Nicotine-trcated, isolated animals showed  significamly greater incidence of active avoidance behavior, but group houscd, nicotine-treated mice showed appreciably reduced active avoidance responding Parallel studies of acetykhohne porrls in +he cerebral eortes of differcntully housed, drug lrealed mice indicated that ~xdatKon kd to a significant decrease in the ratio of 'hound':'Iree' acetykholine; nicoline treatment led to n ekvation of this ratio among isolated mice, but truup- hrwud animals given nicotine showed a significantly decreased rimn Ihe in- teraclion of differcntial housing with drug Ireatmcnt may serve a+ a model from which cholinerkic mechanisms related /o avoidance behavior may Iu viewed. Eun+an, W D fnrrrn.rlana! Irrurnal of Nrrrourrncr 2:199.206, 1971. (1tArr .upporr: Nalninal Instdutes of Heallh From the 1)cp.itmcnt of Psycl.oiogy, (hseens College of (he City Univcrsity of New York, I lu+hing, N Y. NI('OlINE ('HANUFS IN EEG AND BENAVIOR AFII?R INIRAVF.NOUS INFUSION IN AWAKE UNRFSIRAINI:1) CAIS This investigation was undertaken in order to determine whether IMra- verwws (t v) infusion of small doses of nicotine would induce in the awake, unrestrained cat, a similar phase of inactivity and FI:() hypenynchrony as has been reported for sleeping cals. lhc awhors showed tkat, sn the awake anirnals, i v, infusion of 10 pg/kg o$ nicotine usually led to an initial behavioral arousal and EIYi desynchronizalion in the ccutea and subcorlea. 1 hc hippocanpug eshibited theta rhylhm, and the amygdala an increase in rhythmic burst activity Protracted immobility wilh hypersynchrony in corte and lhalamus, and high voltage slow wave activity in hippocampus and amykdaia fd{owcd. Fpiwdca of slow wave and REM skcp were often noted. A 10-SO rg/kg dose of nicotine produced similar behavioral changes with increased ckctrocorrrcollram (F;('o()) dcsynchroniration or Ilaltening. A 100 pg/kg dose elicited marked changcs is behavior and so.nctimes temporary FCn(3 silence lhus, they conclude, nrcoture infuyon kd to an initial pJsasc of bchavwsral'and FF(i arousal, followed by a phase of prolracted immobrlny and FF(1 hypcriynchronitation indicating seda- tion. According to these investitators, the period of hippocampal theta rhylhm and increased amygClala bunt activity appears to be characteristic (ot the i.itial action of nicotine. Sl.dnicki, S. W. and StAarlPl, U. H. ArcAives fnfr.narionalrr dr 1'horwwcodrw.mir rr dr TArraoir 197(I):72-lS, 1972. From the Mason Research Inatilule, Woreesler, Mass. 11. Studiei Related to CorcinoRrnprti. HISTOL(K;Y AND UI-TRASTRUCIURE OF CU1.lURF1) IIUMAN TUMOR CEI IS EXPOSED 10 ANTISERA lU TFIE NI[RVE OROW7H FACTOR Various cell chankes described in this paper appear to represent a speeiRc type of antigen antibody injury. In the work reported here, several dilutions o( anti-nerve growth factor serum from rabbits or horses rmmunrred with punfkd nerve growth factor were added to rapidly growing, 48 hr monolayer cultures of  human gIk.hlastonu (C)S6) and of an H. Fp 2 cell line ('ytotosic effects. beginning two hours later and usually progressing to complete cell death at :7 hewrs, were sludred In vitro in stained covershp prtparalrons and by electron rnicroscopy Anuscrum made in lhe horse had N.ut one fifth the cytotosK acuvily shown try nliscrum made in the rabbit It I-p 2 celh were aMwt flve tmws as reuslant as (')S6 eells In fKNh cell Irnts, nrany n( the cells survrvrng the anliscrurh showed nuckr with generally intact memhranes, containing '0 lo 50 or niore reMrakd chronMnoNnc like Mrdres, uiitcsting pruphase mu.N6c activity ('onUol nw.nirlayers receiving normal rahhd or hor.e serum were eomparahle to the untreatcd contrrds Ihe cyloto.ic and cyrocidsi etlects are probably of thc antigen antibody type IS 14