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n I I c I SI;IE N"1'IE'I(: ADVISORY 1t(IARU to Thc Council for Tobacco Research - U.S.A., Inc as of Dccember 31, 1974 SHELDON C. SOMMERS, M.D.. Chairnwn Director of LaAorarorks, l.enots NiU No.pital Clinical Pnr/ruur of ParAolo[7 Collc~e of Physicians & Suraeona o( Columbia University New York, New York RICNARD M BING. M D. Director r,f Careiororr a.d rnrromural Medicine NuntinRton Memorial Ho.pital, Pasadena. California ProJrssor of MrAicint University of Southern California School of Medicine Lo. Angeles, California 1OSEPF1 D FF:LDMAN, M D. lhad, IhQartmcnt of Immunopalholo6y Scripps (linic and Research Foundation 1~ Jolla, Cdifnrnia WI[1tAM U GARDNER, PH 1) Scirnri/Gc 1)irrc(or, The Council for Tobacco Reacarch -1) S A, Inc. E. K. f/unr ProJrstor nl Anatomy (rmrriluw) Yale llnivcrsity School of Medicine New Havcn. Connecticut ROBERT 1. IIUEBNER, M.D. C.hir/, Viral Carcino6encsis Program National Cancer Institute Bethesda. Maryland LEON O. IACOBSON, M.D. Dran of the !)ivision of Bicrlotical Scicncrs RrCrmrrin Professor of Biological Scirncrs Univcrsily of Chicago Chicago. Illinois AVERII.L A t.tf:BOW, M.D. Pro/rssrrr and Chairn.an. Ikparimenl of Patholo" University of California SchcxA of Mcdicinc San 1)iego, Cali/ornia /Ii:NRY "1 I.YN('H, M t) f'rofrttnr rind (hoirmun 1k 1+.,jin rni ~,1 PirvrMivc titcdicine anJ Public /fcallh (icir) t„n lfmvrrvtv S h1.1l Od Mcdi(Inc ( h).hr. Nchr.i.l. IIANS MEtER, [) V.M., Dr. Mcd. Vd., M R S If. Srnior SraO ScirnriV The Jackson IaMoralory Bar Ilarbor, Maine 1OIiN P. WYATT, M.D. Director Tobacco and Flealth Research Institutc University of Kentucky LcRinaton, Kentucky gc1rat16e StaR.f The (;ounrll WILLIAM U. GARDNER, Pa.D. Scientific Director ROBERT C. FIOCKETT, PH.D. Research Director JOHN FI. KREISNER, PN D. FREDERIC W. NORDSIEK, PH.1 .t ssociare Research Director DAVID STONE, PH D. Associare Research Director A ssociare Resrarch Dirtcror VINCENT F. LISANTI, D M I) Research Assuciatr

Introduction CONTENTS Introduction Canccr-Rclatcd Studies . . . . 7 Abstracts of Reports . . . . . . . . . . . . . . . . 13 Cancer•Rclatcd Sludies . . . . . . . . . • • • • 13 The Respiratory System . . . . . . . . . . . . 20 Ficurt and Circulation . . . . . . . . 33 Neuropharmacology nd Psychophysiology . Pharmacology . . . . . . . . • Immunology and Adaptive Mcchanisms . Epidemiology . . 43 . 47 52 . 58 Miscellaneous . . . . . . . . . . . . . . . 69 Active Projccts . . . . . . . . . . . . . . . . . 72 Completed Projccts . . . . . . . . . . . . . . . . 79 Index of Senior Authors . . . . . . . . . . . . . . . 88 Inde: of Principal Authors . . 89 ( t The investigarioro supported by The Council for Tobacco Research - U.S A.. Inc. that were published during 1974 are summarized in Ihia Ar.r•.ual Report under their specific titles. These investi8ations relate largely to sludio of cigarette smoking and smoke derivatives and probkms of health. They have been grouped into categories that are oriented toward either specific diseases or o.g.ns, or that are d'ncipline-.ssocialed, i.c., epidemiological, immunological, or psycho- or neuropharm.cologic.l. The heallh-rclated disturbances associated with cigarette smoking are also .ge•associaled manifestations that often require prolonged periods of observalion in intact animals; therefore. In vitro cellular sludics and even sludies with microbial morkls have been undertaken. Man is the only animal that smokes for hn own satisfaction. Hcnu, stud- ks are continuing on why man smokes and those diseases to which he is .ub• ject and which may be associated with amoking behavior. Such ob.ervatio." supply inferences or associations but fail so demonstrale e.use% or mecha.i.rns. Animal models must be used for such experimentation. Animal models for the study of the problems relating to tobacco srnokiag and health are not easy to devise. Smoke e.posure is stressful for animals and presumably prolonged pcriods of smoke eaposure will be required. Extensive studies have been undertaken during 1974 to determine the most satisfactory animal model for smoke inhalation studies. Mice have been chosen beesuss .hey have been inbred and selected for differences in response to strer, rss- ceplibilities so diRerent disease:s, and differences in histocompa.bility and anligcnic characterislics. Mice of different inbred strains differ in the capacities of their liver microsomes so Incre.se the levels of enrymes that melabolir.e a carcinogenic hydrocarbon. )•methykholanthrene, following the injeclios of inducing aRents. These enzymes, aryl hydrocarbon hydroaylases (AIIHs), ar+c inducible in mice of aonre strains so that cancer may be e.pre+sed while .01 expressed in mice of other strains. These enzymes arc under genetic coulrol. The vailabiliry of mice of inbred strains provides much genelic control (or the animal model. The interaction of environmental variables on esantlaqy identical genotypes also can be studied. The human eounterparts to mice of inbred strains are provided by idcnti- ea) twins. The Swedish Twin Registry, which has provided data on the smoking histories and the incidence of pulmonary and vascular disease symp/onr in monozygotic and like-sesed twins born in Sweden between 1886 and 1925, has been eapanded to include similar rfaa on twins born between 1925 and 1959. This will provide additional data on a population that has a bng life eapect- .ncy and a very kw lung cancer incidence Arwrther twin regisuy has bee• started in Finland where the reported incidence of lung cancer is about Avc times greater than that in Sweden. lhis should ar.ssrnent greatly the numbcrs of i.kntical and non-identical hke scscd twins that are discord.nt for smoking esperience .nd other environmental e.posurn Furthcrmore, the twiru among those receiving multiphasre health checkups in the Northern ('aldornu K.ucr Perns.nente Mcnccal ('.re Program •re being survcycd as a potential wwucr of identical .nJ like scacd non idcnrrcal twins that havc rather c.rcnrnvc mcdr eat and health hnlories and .re fuxn diAerent racial rruu/» SraniA..n1 diAer- ences have already been reported in the pulmonary function tests of repre• S

I ! tentativcs of the different racial IrMrps. Not nnly is intormation hcmg uht:rineJ on snr.rling capencncc Mrt on a wide range of envuomncnt.l csp.tsures and ocaopational acuvrtres in rcl.ruon to morbidity and mortality Ihe twin rckis- nies should prnviJe a valujble source for many other shwlics that will inclnJe the effects of multiple environmental variables on individuals of identical scno- typcs and during the prncess of aging. Studies on lamdral predisposition to disease are also being done The tendency for canccrs to occur in swnt families is Ire+ler than in olhcrs 'This tendency may be restrrcled to cancers of certain sdcs or to two or nwre sucs. The prcdisposrtiun of persons with knowa genctrc conslitulions to acquire emphysema a/w has been demonstrated and nsay be caused by deficiency of a subsunce or substances that inhibit proleolytic en:ymes. Individuals with this genclic deflcrency, fortunately only a small percent of the populatan, are par- trcularly vulnerable in -'smog- environmeMs. Emphysema also occurs in indi- vidua(s without thn spccrflc gcnetic deficiency; a special risk im/rcr.ror rs pro- vrded by the family history, an indication that other umdcntUfkd ge.xnc deter- minants of prednpositiors may esisl. The epidemiological projccts o( interest to I he Council involve mostly prospective studies of selected populations that pro- vide special contrasts for genetic or enviromnental similarities or Jdferences. Basic research n also being funded on the chemical identification of pcoltascs and their inhibitors .nd how they intcract. The levels of proteases in different organs and in normal, embryonic and cancerous tissue-i are being studied Furthermore, estcnsive cfluru are being made to improve the A1111 assay, using human tissucs, to promote its application to human cpKlcmioloti- cal studies. Wrthrwt basic investigatron, the improvement and perfection of ndytkd techniques and the devclopment of new or modified concepts of disease prevention or control wJl be ItmitcJ. WILLIAM U. (;ARrsr+ee, PN D. Scientific t)ucctur I Caticcr-Rc9atccl Stuclics Among the diseases that have been associ.tcd .tatisucally winc cigarette smoking in population srrklics, c.rcuwma of tht lung has app.rently received the greatest auention. Neverthek,s, thn Jrsea.c occurs only rn a small minor- ity even of heavy smokers. lhis emphasr:es that research on its pathogencus nrust include consideration of possihle suAstamiul ddfererkes among tndrvKluals hrNh in their genetic characteristics and in the numerous conditsontng inllu. ences tn which they have been whjecteJ. Many anomalous and contradictory aspects of ,he epidcmiologrcal flndings have been JcscNhcJ, and the great dillicully of conducling human sludies with controls adcqualo (or resolution of Ihese anomalies has been recogni:ed. lhc reasons for this are both ethical and praclical. Nence, tht crucial questions °whelhcr, how, to what talent, under what condrtions, and in whom" rrrwking could contribute to pathogcnesis of the disease remain unanswcred An alternative approacb to the problem of descrnbrng the interactions of intrinsic and ealrinsic influences in Ihe process of carcinogenesis lies in rhe design of suitable nsodcl ayslems involving animals, animal lissues or cells or. in some inslancn, human Iissues or cells. Superficial eaperiments with inade• quately defined species or atrains, whether whole animals or their ti.wres or cells, will ral solve these problems. lhere is strong basis fow doubbing that mouse skin painting with stored coedensales of the particulate phase of smoke. altered in physical state and in chemical compositKSn and lacking moN com ponenls of the gas-vapor phase of "whok, fresh normal snwke;' can eslablish, define or quantitale the "carcinotenit hazard" of smoke inhalation by msn under life conditions. The design of such model systems is a most er<actin~ entcrprise, since the question of the applicability of the results from Ihese nsorkls to man in hn actual environments must be asked at every stage and eventually answcrcd The Council has, neverthekss, undertaken to develop a series of rrsodel sys /ems for the purposes mentioned and to caplore slrategies for relating the results to man. CarrinoReneais a. a M.al(i-Sta6e Process r I 6 Tlwugh the term "earcinogen" is often applied to Individual chemics compounds or mistures as rf "carcinoRcnicity" were a specific or unitary prop erty of matler, like a molecular wtight- an absorption spectrum or a dipob mramnl, it is well known that this is not the case Irxluced carcinolenesn - rathcr a ororeu presunscd to requue a series uf scyuentud changes in the bu, logical systenn of the host 7 htse, in turn. are presumeJ to Jeperw) both upu, the rnitial, genetically influenceJ characterntas of these systems rw1 also utw, a series <.f separate actions by the eaternal inciting agent or agents that requu quite spccifk physical or chemical propcncws arnJ condrtmons. Sur h agcntu ha• hahdually been grouped together as "caacinoCens- or "pincntial carcinogens Ncverthckss, it is wcll kn.rwn that "carcrnoten" fnr one apecies, strain 41 tissue under parlrcular circunsuanccs. may n.rt he a"carcinogen" (or anorhr species. strain or IisuK. nr rrnder othcr circumslanccs. Metabolic modificatnon may be necessary to crrnverl the eatern.l `poler 7

tial carcinnRcn" into a form that can directly attack sonse particular struclure in the cell ('ells rnay be more, or even esclusively. vulnerable to such attack durtng srrnse particular stage of drvisKrn Hcnce, influcncea that sunmulatc cell division or arrest the process at a particular stage may play a sigmfscant role in the process Factors that alter the normal DNA repair mcchanilms may be implicated in allowing abnormal combinations to survive. [krepresation of a viral tenome or n oncoscne may be implrcaled. When a normal cell has been transformed into a malignant one. the activities of the immune system in its many manifestations may determine whether the transfrxrtsed cell can survive, clone and prolderate. Undoubtedly these are only a few illustrative eaamples of the krnds of factors involved and wsa.y othen undoubledly awai/ discovery and description A strategic goal in the research program is to identify those animal atrains in which such individual lactors are combined in a way to produce ma.imal cancer susceprMhty, Another goal b to create such comhinations of traits by genetic manipulation. As a eorollary, the discovery or producturn of strarns with other combinations of such traita should help assess the relative roles of such pulative contributing factors to the overaM process of carcinojenesis. Sysfens. /or Chronic Smoke Expo.ure by the /nhafation Route For  long trnse the lung has been the organ of primary interest in The Councd's cancer research program Therefore, its program has been premised upon the concept that approprutt whole animal test systems shr„dd he based upon the chronic inhalauon of Iresh, whole cigarette smoke generated under defined conditions that simulate as nearly at posstbk those ecperienced by human snsokcrs, from ciSarcttcs o/ dcflned arsd constant compoutan, and administered in quantiutcd dosages to carefully selected and dcfined animal species and strains. [kvclopnsent of mechanical devices for accomplishing uch esposures of animab has been an eaacting, trmetomumint task even Iter the estabinhment of criteria for acceptable corwlilioru. Despite the seventeen-year his'tory of lhe ('ouncil's smoke inhalation esperience, recognition and definition of these cri- teria have developed only with time. TAese have been detailed clscwhere. Two devices that meet many or most of the crileria reasonably well for mice and other small animals have now been developed and a numher of uniu have been in use on a trial basis in Council proiccts. lhn eapcrience has led to modifications and improvements on both. With Mrth types of device, current emphasis is being placeJ upon the efuanhutron of dar+age to the respuatory Iract by use of separate traccr mgredi- ents for smokc paruculatcs and lor gas vapor phase. I hrwgh hununs smoke voluntarily, often probably for the rrlrtl of strns, the cnnddron+ of saxrke inhalatw.n by esperimcntal animals arc nrvedunury and stressful so that the contributions of tensions to the oveeall espcrimcntal results must t.e conuJcrrd caucfully Animal containers lor nse in smrrke urhalalion Jcvicrs havr had tu he JrsrRucd to minrmrre these eflecN Met1...1s Int uulrRat- urg Ihcrn, nce r Jc of hahrtuatron in reducing them and the usc of unccp-ed "mat hinc cr+ntrol ' an m..ls I rr estrmaUnt their m0uence have all had to be a rJrrd r.tenavrty i.r avurJ complrcatmg ol»ervauwms on snioke ellects per rt. Thoush smoke inhalation studies with animals have been spcrosorcd almost continuously by The Council since its organization, the progrevrve improve- ments in controlled and monitored systems are e.pected to jusufy beginning a new and more extensive series of esperinsents a1 a higher level of sophistication within the coming year. FssentuUy the same inhalation systems can obviously he used in atudies beatint on cancer, on cardiovascular diseases, on chronic pulmonary dneases, on pharmacology and on other questions. Selection of Animal Su6 ject. for Cancer Studie. Princpks underlying the aeketion of animal species and strains foc carci. noIenesis studies have been described and these re being used as a guide to aekction of animah for the forthcoming new snxrke inhalatnsrs eaperimenu. There appear to be more cogent reasons a this time lor use of the tnare than any other speeics, and this is our thoice for present major purposes. Aside from the obvious advantages of low cost, ease of handling, modest apace re- quirements, short life sp.n, eatensive e.isling information on their viral and bacterial fbra and methods of controlling Ihese, there arc others of even greater importance. Many inbred mouse straim eaist which show greatly contrasting degrets of wscepibitity or resistance to carcinogenesis as observed empirically over the years. lltese differences are now being related progressively to genetic factors and Interpreted to a significant degree in terms of biochemical mechan- isms. In such mouse slrains, moreover, the implicalions of competitive coo- cepts of the viral etio[o`y of cancer have been eap[ored much more eaten.ively than in any other species. 7heir immunological responses to eareinolgen{e events have also beeo investigated quite inlensively, though they are aill ia• completely understood. Despite the disadvantages of small lung size, meager volume of blood for tests, drfierences from humans in lung structure, and the fact that mic. sre tase breathers. the use of mice from strains that have sharply eonlr.a(ing susceptibilities to the process of carcirqgenesis presents a unique taperinxntal model. 11 a particular regimen produces carcinoma of the lung in one such strain but not in another, and of these strains have been deacriba( with respect to genetically influenced biochemical difierences, the results may provide valu- abk inferences regarding the roles of such biochemical factors in the procesa of carcinogenesis Such inferences should furnish leads toward the search (or analogous biochemical bases for cancer susceptibility or resistance in man. In a long series of preparatory studres, a number of biological and bio- chemical characteristics deemed likely to he related to cancer susceptrl.iluy have been studied in many inbred strains of mice. A number of papers have been published describing these studies and when are in preparation Among these prcliminary studies was an em{,irical survey to compare and quantitate the relative (and contrasting) overall susceptibilities of a numbcr of mouse strains, both inbred nd rarwlom-bred, to margrnal, suhautannws dosn of aeveral polycyclic hydrocarbuns known from eaensive e.perrrnce to be "carcnwrrcnic" to nsKe in 1he cornvtntional sense lbese hydru.vrlruu In eludcd 1-methylcholanthrene (M('A) and henro/..)pyrcne 7he sutauuneous route was used because doses crMdd he aJmmwereJ wnh precision, nd the 9 0 I

I i m tr B © m W Co (-n treatment zone kept undcr close scrutiny On the basis of a carefully dcviscd scoring system, very strrking differences in Iumor responses were /uunJ among these slrains. Strarns sekcrcd from the spectrum of varying subcutancous susceptihdities were then subjected to direct instdlatron of the aame polynoclear hydrocarhons intu the lungs, in varKxn media and by several technpues. Squamous cell lung carcusomas have arisen at different rNes among these animals, shovrns that some strains at kast are suxeptibk to Ihis disease. Continuing espcnrnenls are eapccted 1u reveal more fully the magnitude of these strain drflcrcncrs With- out the assurance that Ihe animals to be used in smoke inhalation eaticriments can develop the disease under inve+sip/ion. the interprelalion of ncgative re- whs from such esperiments would be impourbk. The Metabolic Actinotion ol Polycyclic Aromatic Hydrocarbona (PAH.) Some PA11., at knt, must be mNabolirrd to active lorms before they can tramform celh, induce turssors or produce mutations. This activation is accomplished by enzyrnes of the lamily sernKd "mised functan oadases" found in the mkrosomes of the cells of many tiasuca. The enzymes that pro- duce the change are designated uryl hydrocarbon hydroxylases (Alllls). These entymes occur in cells of many lissues of both mn and animals N' moderate kvels and are probably in some way .ecessary to life. In swne ani- mals, however, esposure to certain polycyclic aromatic hydrocarbons stimulates production of an increased kvel of the enzymes, while in others it does not. Those that respond to such esposure by production of more (and perhaps drAcrcat types of ) Atilt are said to be "A1111 inducible." In the eaperimenls cited. Atilt inducibility ranged widely in mice of ddlerent strains and was correlated with the susceptibility of the s/rain to M('A- induced subcutaneous carcrnogcnesis. Twis may well be one clue to the bio- chemical difference hetween more susceptible and less susceptible animals with respect to induced cancer as contrasted with spontaneous cancer. Many other subslances can stimulate Atilt production in "irsducible" animak. TAeae include internd agents such as eortkosterod hormones and bibrubin; esteraal ones including barbiturates; chlorinated hydrocarlxx» such as UDT and certain defoliatin= agents; and compounds that occur in several vegetabks. Exposure to such compounds in the environment may, therefore, increase sorne aspects of eaKer susceptibility in bolh animals and men who are Atilt inducible. InducihJrty of the Alll) system by M('A has been rcported to he geneli• cally based in mice. Susceptibility to induct«sn by methykholanthrene was rcpnrted to aegrciatc as a single auto.Ofnal dominant gene in crMxs between inducible and non inducrble strains. Puhhshed repurts of these mouse studies from The ('r„rncrl proeram stim- ulatcd uther invcsti`atoms (not ('ouncil ponsored) to study Atilt Icvels arsd irwlucibJrry In man, w Iest the concept that this function nught Le under gcnctK cun,rul iii man as well as in mice. fur several rrasuns such determrnations in man have been much more ddlicuh than in mKe Ihe ('ouncJ unJeruwk to ssist the research of the to invcstiCators alluded to. Also, looking to the practrralrtscs of extcndrng such stud,es to large human SrrNrps fur elucidation of the mrMk of mherrlance, lhe ('ouncd inau6ur.ted dduronal efforts to improve the Atilt assay systems woh respect to sen.itrvity, accuracy, replrcaMlity and specJ Populations of lung cancer patients as well as human lamrty ag`resrations (kindreds) character- ired respectively by unusually high and very low familial levels of cancer incr- dcnce, already under stutly (or other purposcs, are available lor survey as methcxloluCical developments permil. Other sludres relating to Atilt induction include more detarkd investitr lion nf the melahohc routes for henro(a)pytene, of the mtcrmedrates fornxd, the aclivnres of these in cell systems, the enzymes that produce and desuoy them, and of agents that may bloct their formation. Immrrnocom1.efence o/ Mouae Strain. Mice of all the contrasting strains that are candidates for use in chronk cigarette smoke inhalation studies are being given an ealcnsive battery of pre- liminary tests /o deteet any large differences in the basic competence of their immune systems. The tesls are then repeated during experimental regimcnt to delect any consistent changes in the hope of determining whether immunoloti- eal impairment may be a factor contributing to the end results of lung term experiments. MufaRrn..ia and Rryxrir Mec/rani.ma Metabolic activation of potential carcinogens and alteralioru in immuno- eompeterxe re two of the seyuential changes that may he involved in the multi-stase process of carcinotenesis in many cases It appears that both im clude 6enetic bases for susceptibility as well as foc the interventron of esternal gents in an interplay. There is a widespread belkf that the conversion of  normal cell into a potentially malignant one is closely related to the process of muutlon. Sensi• tive nsodel systems for appraisal of "nwtajenrc potential" of environmenul agenls suspected of a role in carcinogenesis have been developed by several investigators In The ('ouncit program. some of these are being assessed for their applicability to tobacco snwrke and its nujor Iractions as an adjunct to the inhalation c.pcrirsscnls When cellular componeN., esl.ecially those in the nucleus that are he. lieved to regulate the acuvnres of the cell, uncludrng drvisrun, have been changcd, perhaln by muraRcnesis. into a potentially maligrunt stale, it u widcly Lelieved that normal rcpjir mcchamsm may reverse these chantcs by cluninar ing the nsorhficd cell curuponcnts A deflciency or dcprrssron of uxh reparr pracntial nuy consnwte rn.Nhrr step in he overall prrKrn of carcrnogrne.i• MuJel syslems prulrrxJ fur j.x•ssiut the e/liY rcnc y of rrparr mri hanisms •re under study in the proRram is anudrer slcp in the rnvcsugatwrn of conuaabno suscepUhildhes in mouse atr.ms 1I

Srncrke hrlrnMtion in Relation to the ('arr•i rr trRrn gioai. 1'rores. The principlcs, concepts and developmental sludies that ha+c been de- xrihcd briefly are being incorporated into the design of the new serit. of lonc- tcrm chronic cigarette snxske inhalation esperrmcros. In these t.pcrrmtnn, mice will be used that have the combination of factors nsost conducive to cancer suscepliMliiy, on the basis of present knowledge For the rcasons out- lined. mice of other s,rairn with contrasting susceprrhihtrcs, nn the hacis of available bxx:hcmical rnformation, .rill be employed for compai i..rn If un- equivocal sqnarncsus cell carcinomas of the lung should develop rt a suhstmtial kvcl in some striins and rsnl In othen, useful kads into the study of human susceptibility nughl be suRycstcd. By "unequivocal" lung carcinoma Is meant a cancer anatr•Fous to the human disease not only in morphology but in hehavior, being aRRres.ively in- vasive, mclasutic and rapidly fatal. IKagnoses are to be made irxfcpen.kntly by several capericnccd palholotists. At the present stage. "pre carxerou." ksrons- rhouth they are to be described and recorded. •re not regarded as acceptable end points In one Council sponsored pro}ecl of several ycan' duration, a Sendai virus infection invaded a colony of mice that were under chronic smoke inhalation caposure I ung lesions were found that could easily have been mis- diagnosed morphokssrcally as early lung carcinoma, but which were ultimately shown to be atuihut.rhle to the virus. to regress rn many eases and to occur in controls not e.pnsed to smroke. This esperrenct recommendc R''eat vigilance with respect to prevention and deiection of infeclions in smoke inhalation slud- ics, as well as cauUnn ur J$aRn mn Obvioutly, resuln /runm su.h mou.c e.ptrimtnts coukl not he carapnlattd drrrrrly to hunrans, srnct the hsRhly susrtprihle mxc repit%tnt comhinau4ins of eharaetertthcs rhal may iacur never ur tarely in rnan I)cvclupmtru ul Ihc drs- ease in al/ suarns woulJ proviJe lesc Studance ut ihe kinJ mtntinneJ Its oc- currence in nonr of the strains would suggest that the trcaunew r. rncapable of bringing about the ncctssary sequtnual changes of the carcmoRtnk pnrccs% In any case, however, the model syslem should have other important uxs. Ilumans do not live under the rigidly controlled "hot house" envrrunrsscnts pro- vided for caperimenut mice. lhcy are generally eapoud to cunsidershk amounts of "potential carcinogenic agenti' in the contemporary environnsent. Tlse model can he used to espbre conditioning tRecta of small chronic doses of lhese agents The human situation can be simulated to some degree in mice by administering "primrng" doses of such "carcinoeens," trw small to produce cancer aMrse, and then suhjectm8 theu mice to chronic smoke inhalation ,o determine whether the latter shows some type of "prurrsoter" acuvrty SimJarly, the possuhk synerlInlrc toln of controlled haclenrl •nJ vrr.l in(eclxrns, e.- po.urc to agents that prorhrct inflammatron, mtchamcal danuRc. hcat Irauma, presence of lung inlarcrs, hormone and vit.min ckRcrencre+ or e.cescea. Jep.ni- Iwns of ashtstnt, immunosuppression or shmulalron. liver dy+fn(xnun, and many other factors common to human eaperience can be studied empuKally or on a ralxrnal basis s t j RunraT C lirx ar sr. Prt 1) Reseuch 1lircctur Abstracts of Rcports Following are abslracts, approved by the suthurs, of repsrts on new rc search acknowledging support from The Council that have appeared in sckn litk journals since publication of the 197) Report. The name of the recipicn n in italKS. TTse abstracas are grouped under these headin8l: 1. Canccr-Related Swdrer 11. The Respiratory Syslem, II1 Hear1 and Circulation, IV. Ncunpharmacobt• and Psychnphysioloty, V. PharmacoloRy, VI. Immunology and Adaptive Mccl. anisms, V11. Fpidemio{oty, V1I1. Miscellaneous. 1. Canrer-Refetecl St..rlie. TRACFIF.OBRONCHIAL EPITIIELIAL MUL.TINUCI EATION IN MAI IGNANT DISEASE During a continuing study (2,9fi) cases Ihua far) of tracheobroncbirl to folialed cytobBy in surgical patienls subjected to endouacheal annthnia, th authors nNed that individuals with krsown malignancies scemed to have ur usually numerous mullimrckated ciliated eells Further e.amrnation of smc., taken from 112 patients known to be suRerinB frons a wide variety cf malit nant tumon confirmed this observalion. Multinuckation was 2 08 limes nwi frequent in this population than in a supposedly malisnancy (rce control Sroo matched by sea, aBe in decades, and smoking habit It is hoped that recot nirion of this phenomenon may lead to the devclopnsent of a new kst (n the diagnosis of occult cancer, and may open new pathways /or inves/itauo of canccr-hosl relationships. The authors •re currently tackling the Rrsu ul jeclive by looking for occult cancer in eontrols who have high pcruntatn 4 tracheobronchial epithefial multinucleation. Chalon, l. er at. Science Iti):S2S-S26, 1974. Other arrpports National Cancer Inslilute From the Department of Anesthesiology, Albeit Liinslein Colkge of Medicine Yeshiva L)niversity, Brona, N. Y. 1FIF. ('I'1 t I11 AR IiV1iN1S ASC(X'LA11=r) WIllt RI'(:RFtiCIUN ANI) PR(XiRISSIUN OF MURINE IM(1L.UNI:Y) SAR( ()MAS Prcvicxn hislopathobgic claaifktions of Muloncy urcomas have diAar widcly, ran6inP from a benign, reparative -i nflammatory reaction to mt.r, chynul .arnxna Furthernxm, a compkre sequcntral analysis of the ctllul infiammatury evcnts accon+panymg Aoth tunwsr prugresuon and relrcisrrn still lackine Ihe awhors, there/ore, cMae tu inJuce Muluoey tiuco.n in r.r- nalal and adult mrce in orJer tu charactenre Ixith its hosarltosrc nature aI 12 I) I '

the course ul events that develops following the injcclion of its tr:rnsplantahlc cells. In nconales, intramuscular injcctions of either I(/r or 1(P' cclts Irom a cultured murine (MrAoney) sarcono line induced neoplasnn that prrrRrescJ In adults, only the larger dose prrduced Ihn eflecl; adult mice receiving tU' cells usually developed tumors that regressed. lhe Rrowlhs aere esarnrncJ by light mrcroscopy at 2-1 day inlervals throughout the course of therr Jev.lop- menl and suhsequent reArnsNSn or progression Initially, all tumors were in- filtrated with polymrrrphnnuclear leukocytes - mainly neutrophds - and edema was extensive. By the ersd of the second weck after inoculalion, this acute in- flammalory inRltrate had been repiaoed in adult mice by one consisting ot mononuckar cells; neonatal mice never drcveloped significant numbers of these inflammatory cells in their tumors. Of particular sigmfkance, since mrNxsnuckar inflammalory cells were associated intimately with tumors durrng the process of regression, was the disappearance of these cells 12-14 days after rnocula- /an from tumors destined to progress in adult mice. Ilyperplastic chan6es were lound in the cortrces and meduRae of regional lymph nodes drarnrng Ixs/h progressinR and regressing sarcomas The dcvelcspment of secondary neoplasms was common, and the distribution of these kuoru was relatcJ to the ages of mice at the tUnse of irwculalioc. Russcll, S W, and CorAranr, C. G. Inrrrnorlond Journal oJ Carsrrr 1)( 1):34 61, 1974. Other auppor/: l/. S Public Hedth Scr.ice. From the 1)cpartrnent of Esperimental Pathology. Scripps Clinic and Rcsearch Foundation. La 1o11a, (-.1 IIFRI'.L)ITARY I.l'MPIIOSARCOMA IN WII RABHITS ANL) HI'R1 1)11 ARY IIt M(1t Y I I(' AN1=.MIA ASS(K'IA 1 Fl) WI I 11 TFIYMOMA IN SIRAIN X RABHIIS Among their "partially inbred" rabbit Nraina, the authors searched lor those genes which produce susceptibility and resislance to certain types of tumors. lhcy (ound such a situation in the wirehair (WII) strain: lyml.hosar- coma occurs al a nscan age of eight monlhs; susceptibility is conferred by a aiogle aulosomal recessive gene designated b. There is tenlative evidence wMch points to the presence of a C-type RNA genorne coding lor the interspccles dc- /erminanl of the group specific antigen. Ilighly positive reactions were obtained with potent antiura produced in rats to the p-A(is of murine C type virus. Complete (infectious) C-type particks have nol been found by dcctron micro- scopy; thus, cell free transmission has been negative to far, and ssays for ••helper- activity have been inconclusive. Howevcr, cellular IransmrssK,n rs successful upon imxulatiors of lymphosarcoma lissue into felusts 1'resumably, the 1s gene confers susceptibility to virus induced tumoritenesis I be mvcsli- Ralors have also observed thymomas auoualed with hereditary hcmulyuc anemia in strain X rabbits In these rabbils, which are genetically related to ssrain W11, ancmia ~K'rurs at ahout (Sve monlhs; susceptibility is cunlcrrcd by ..rnKlc .u~.r~ r nal rrlrsirvr Rrr.e, aymtwdrrcJ ho I he J.ta fur ,hcu Iwo Jn -.h L..rh imxepl+ ul cCncl.c wxcplrh0hly .nJ Ihe ..Jv...... r .,f . .,r.l /rnunrc I Afrirr, ll. and Foa, R. R. Bibliorhrro llurrnorolooriru (No. 39: Unifyipg ('(incepts of I eukcmra):72.92, 1971. Otbrr auppr.rt: National Inslilutes of Ileahh and the National Cancer In- tlilule. From Tfie Jackson Laboratory. Bar flarbor, Me. INFLl1F.NCE OF PRFINFFCTION OF CS7R1 /6 MI('E WtIN (;RAFFI I I:.l/Kl?MIA VIRUS ON 1.MElHYLCIIOI.ANTHRENF-INDl/CFD Sl1H('UTANEOUS SARCOMA (b oncosenie agents which induce diflerent types of rscoplasms have an eflcct upon each other? lhis study on the combrned eflects of the (iratR leukemia virus and )-methykholanthrene (MCA) attempts to answer this queslion. It investigates the mutual infh,ences of virus-inJuced kukemia and chemKally-Indlsced sarccsrna in CS7B1./6 mice and eRamines turthcr the launcy period as a determining factor in Ihe comoccurrence of induced neopla.ms ddlering in cell type. Results from these experiments showed that when C37H1./6 mice were given both Graffi kukemia virus and M('A the deveMp- nsent of either leukemia and/or sarcoma was dependent on the dose ot each carcinogen given A high dose of virns reduced sarcoma rnJucruon because. due to the high incidence of leukcmia. /he survival Imre of the mice was kss than the average latency period required for tumor development A hiRh dose of MCA (3(1QrR) increased the incidence of knkensia rnJuclion by a low dose of vinis without fleclin` the incidence of sarcoma lhis occurred since the latency period for sarcoma and kukemia coincided and 'S% of the mice developed both leukemia and sarcoma The combination of a low dose of virus and a low dose of MCA dK1 not aiter the incidence of leukemia or sarcoma; however, with this combination of virus and chemical carcinoRcrn. the average latency period for the development of kukemia was delayed and the average latency period for sarcoma induction was accelerated Grafli virus faikd to increase the incidence of M('A-induced sarcoma under the conditions studied Whitmire, C. F.. and Salerno, R. A. (Aficrobiolotlrul Arsorlorr,) ProrrrJintr o/ the Soclrry /or Ea prrimrnrol Biolory and AfrJirinr 141( 2):674- 67t1, 1973. Other .upport: National Institulcs of Neaith. From the 1lepartment of Viral Chemical Oncoloty, Micrrd.ioloAical Associates. Hethesda, Md IIYL)R(>t'ARH()N MI'IAH(11171NG A("IIVIIIY (11' VARIUIIS MAMMAI IAN (-E1I_S IN ('tll.l(1RE Recent in viro studies strongly sugRes( a rrlatUomhrp between kvclr of hydrocarfr)n mrtaholirrnR enrymc activity and srn.rhvny to ju)lycyclic .ro- m.rtic hy.IrrKarl.r.n inJurrd chcmkal carcrnoRcnr+~s In the limilcd nun.lur of ln vu.a syster.n avaJahlc. the kvrl+ of Ihese enrymcs nuy wrrnRly udluence the sensitivity of cells lo tran.lurnutran uK1u.rJ by cerlarn /vdycycl,c aro- IS