Medical and Health Sciences Division Research Report 1976-1977

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Oak Ridge h soci a ted Universities (ORAU) is a private, not for profit association of 45 collcges and universities. Establislied in l93G, it was o n e of the first univcrsity-based, science - dated, corpora te management groups. I t conducts programs of research, education, information, a n d training for a variety of private and governmental organizations. ORAU is noted for its cooperative prograins anti for its influence on the dcvclopinent of science in the Soutli. The Medical and Elcalth Sciences Divisioii conducts in terrclated researcli programs in immuno li ology, biochemistry, radiopliarninceuticals, cpidcniiology, and radiation biology that focus on chemical toxicants aiid radiation problems related to energy production and developiiieiit. Unique facilities include KEAC/'TS (Radiation Emcrgcncy Assistance Ccntcr/Training Site-the Department of Energy radiation accident trcatment ccn ter) anda marniosct research colony. I n addition to rcsearch, pre- and postdoctoral training is provided in lipid-incmbranc Liochemistry, i in mu noli ology, cellular and radiation biology, and nuclear medicine.

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‘rhis rcport dcscribcs rcsearch progress in the Medical and I-lea! t h Scienccs Lhvision for thc period October 1, 3 9 7 6 , t h r o u g h Scpteinbct 30, 1 9 7 7 . Tlie mnjor tinues to be focuscd o n six major program arcas: Iiuiiian radiation biology, epide~niologictecliniqucs to idcntify arid lcssen occupational dangcrs rclatcd to energy production and radiation, bioclicrnical studies to undcrstniitl the role of surfactant production in the prcvcntion of i)uImoiiary disc a x, biocheniical techniques for modifying cellular mciiibl-anes w i t h tIic aini of a! tcring ccllu!;?r responses to toxic aiid carcinogcriic coinpounds, iiiiinunological and cellular approachcs to undcrstandiiig cell sur~~ci!lanccsystems with the aiiii of achieving protection against cancer, and development of improved agents lor dctccti!ik various cnvironinental cancers and chronic lung diseases. The sckn tific research groups rcsponsiblc for dcveloping and carrying o u t tlicsc prograins are the h d i tion Emergency Assistance Centcr/TraininS Site (R.EAC/TS), Immunobiofo Biological Clieqistry, liadiopliarinacciitical Development, a n d Epideiniology. These units also participate in various bioincdical training progrnms, which include high school, undergraduate, predoctoral, a n d postdoctoral participants. ’The Division also assumes a major responsibility for DOE in maintaining a national radiation accident registry as part of t h e R.EAC/TS program and coliaboratcs with other DOE facilities in dcvcloping health and mortality studies for D9E. The reorganization of the Medical and Health Scicnces Division in 3.975 led to a redirection of o u r rcsearch efforts i n response to tlie broadened role of DOE’S responsihilitics for cnvironmental a n d biomedical problems rclatcd to thc developm e n t o f new energy supplics from fossil Eucls. Since 1 9 7 5 , iicwly identifiable service units have evolved; tliesc are nmv einphasizcd in tlic iicw organizational chart of employees (Scction 6). Newly idcntifiable research units and needs are also beginning to surf:icc. For instance, we expect cytogenetics, \vIiicIi in the past was principnlly concerned with radiation dosiinetry in the IIEAC/TS program, to eventually develop as an independcnt research unit, apart from the REAC/TS program, cinphasizing chcniical ratlicr tlian radiation tlamagc. LVC are forming tlie ccpcrimcntal patllology u n i t , which currently provides scnricc (incluJinS vcterinary, pathology, and clcctron microscopy scrviccs) and rcscarcli inpiit i n t o various Llivision rcscarcli prograins. Thc need for a toxicologist and a cell cuittirc biologist to bugincnt o u r research efforts has beconic incrcasingly urgcnt; we cnvision that this new manpower and tliesc areas of expertise will be assiinilated into thc administrative structure of the experimental pathology unit. During 1977, excellent ncw centralized quarters for expcriinental animals wcre completed. Major efforts arc now under way to complete the anci1l:iry facilities, such as specific rooms for surgcry and laboratory work. Coniplction of these arcas is cxpcctcd to be the last s t e p ir? rcceivins accreditation from the National science prograiii has planncd a liuslxiridry program and an csp and cd facility for nisrinosct brccding. Tlic facility will be uscd as an area rcsourcc for bionicdical research purposes. Funding for the proposed facility a t ORAU is currently being considered by N 11-1 iincl otlicr organizations. In addition to niotlcrriizing o u r anirn;iI facilities, a major rcnovation of rcscarcli laboratories for tlic I>ic~logical chemistry group is now almost coinplctc. Tliis 5280,000 prujtct will rc!ocntc the 1)ioIcigic~lclicinistry prop ii ~n t tlir: Vance iioad site. In conclusioii, we want to call :ittention to tlic divcrsificd funding sources (scc Scctiori 5) for tlic l-csc:ircli prosr:iiiis clcscribcd in tliis report. Lvlicrcar the prirescarcll projects ;ire fuiided by otlicr government a n d privatc iigencics.

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Iliis report was prepared as an account of work sponsorcd by an agcricy of tire United States Government. Neither the Unitcd States Govcrnnient nor any agency thereof. n o r any of tlicir einployees, niakcs any warranty, express or implied, nor assunics any legal liability or responsibility for any third party’s usc or thc rcsults ofsucli use of any inforniatioii, apparatus, product or process discloscd iri this report, nor rcprescrits t h a t its use by sucli third party would riot infringe privately I<cquests for additional iriforniation a n d for reprints of fuil-lcirgtli articles should bc dirrctcd to O a k Ridgc Associated Uiiiversitics Medical and I-lcnltli Scienccs Division

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cerned with tlie effects o f irradiacion and chcniical pollutants 011 i m ~ nuno - logical proces~csa t the ccllular Icvcl. I n vitro arid i n vivo stutlics are conprimary facet of o u r iiiodcls is the merism, a physiologic state that occiirs natcrally inthe iiiarinosct anti is induccd in tlie mouse by lctlial irr ~ d in tio ii followctl by bonc ~ ~ i a r r o wt rans pla n tat io 1 1 . The immu - nologic: tolorancc i r i cach of tlicse

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imniune system can bc measured. The allogcncic ratli;ition chiinera I i a proven to b c an csccllcnt animal motlcl for studying qucs ~ ion srclatibc c o rn ple tci 111~ i iu n ologi c to IC 1- mi c c c. scyte function can be, and most frcqucntly is, abnormal. A primary question ans\vered this year concerned the possible involvcmcnt of T cells in iniinunologic tolerance. A strong suppressor function was found fgr this cellular element suggesting, but not proving, that in this model tolerance maybe conveyed byT suppressor pression was nonspccific, inhibiting cells from nioLise strains unrelated to the chimera and also supprcssing iininune functions unrelatcd to the Studics in the marinosct continuc to demonstrate a diffcrcncc in immune niosct (S. firscicollis) and tlic cotton - tensivc in vitro studies o n the i-cspoiise capacities o f the T lymphocytes iridicatc tlic '1' cell coinpartnicnt of tlie iiiimunc systcni opcratcs in a n cquivalent fashion in both species. Isoiininunizations with wliitc blood cells in the white-lipped and cotton - topped ~ nar nio set sh v c now yiclded reagents capable of distinguishing among members of cach species. The markers currently providc a means of es tab1ishing leucocyte chi inc risni ingens dctectcd function as liistocoinpatibility antigens is n o t known and is currently bcing csplorcd in mise d - leucocyte culturc stuclics. The research prosr21n i n biological chciiiistry facuses primarily 011 iiit - iii - branc propertics and lipid mct;iLolism i n cancer and in rcspilatory rent projects inclurlc t h c follo\ving: from in od i fy irig biologicnl 117 cnibranes induced by fossil fucl pollutants and unnatural lipid analogs, (3) pulmonary surfactant rncta11c)lisni i n normal lungs and lungs csposcd t o nitrogen diosidc. ( 3 ) t h e rolc of cther linkagcs in lipids of cancer ccll menibranes, (4)penetration of membrane barriers with lipophilic chelating agents for intracellular rcnioval of plutonium, (5) biochemical mapping of intracellulnr membrancs witli respect to tlie location of erizymes and lipids associated with their inncr and outer surfaces, and (6) lipids and cules i n nuclcic acid arid protein Our studies on the man jp dati on of membrane propcrties Iiavc shown it is possible to cause drastic modification of nienibrane phospholipids by incorporating unnatural analogs of ethanolamine) or fatty acids (c.s., cliaulinoogric acid). Such alterations can modify SpcciCic biochcmical pro pcr t ie sof biological i n cinb rane s ; preliminary data indicate ccll division a n d die cell cycle can also be altered by lipid prccursor analogs. Toxicants (such as nitrogen dios i dc) derived from fossil fucls also modify niembrane lipid composition. O u r cxpcrimcnts are dcsigncd to pinpoint the qucnces of such modifications, particularly in relation to dcgcricrative ation. Wc h a w found that Nis0 p 1-0 p y ic t 11ari 01 ani ine, a17 a ria log o f cholinc, is a potent iiihibitor of c h 01 ine - inc tlia tc d p ro ccsses, some of which arc associatcd with cell cycle cvciits. 'I'hc lung studics have continuccl to concentrate on how a n d whcrc surfactant is synthesized o f nitrogen dios i dc011 the piilmonary surfactant system indicatcs that altercd surfactant nict;ibolism is a

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sensitive indicator of nitrogen diositlc exposurc. Results of studics on the role of eth cr lipids in canccr cells have revcalctl that tlic cnzynics responsible for the biosyntliesis of tlicsc unique lipids arc clistril~!ccd asymmetrically in mc in lr s ne vcsicles. A lic\v project initiatcd rcccntly is of lipid carricrs i n getting cliclating agents across menibranc barriers so that plutoniuni and other toxic metals can be rcinoved 1rom intrnccllular The objective of this program is to develop new radiopharmaceuticals for potentia: use in man. Most of these agents are intended for diagnostic purposes, b u t occasionally thcrapeutic agents are also studied. The identification of new radiopliarmaccutical agents is based on established inctaccsscs occurring in Iiealthy a n d discased states. Oncca potential apt is identified, it is syntlicsizcd in a radiolabclcti form and tested in animals for effectiveness and safety. When cffectivcncss a n d safety have been proven, thc compounds are tested in human beings after approval by tlie Food a n d Drug Adiiiinistration. Experiments are also performed to clarify t h e incclianisnis involved in disease proccsses. Collaborative research projecLs involvc Oak Ridgc Natioiial Laboratory a n d medical institutions affiliated with ORAU. A major addition to thc rcsourccs of t h e Division this ycar 113s bccn rlie purcliasc and installatiori o f a ncw instiunicnt for positron tomography, tlic Emission Coniputcrizcd Axial ORTEC Inc. When ~"'sitroii-cniittin:: radio p 11arm a ccu tic a 1s r~d i o pha rni a cc LI t ic '1 Is t I1e body, thc )I prod uc can ii ill il at ion p h 0.- tons that travel i n opposite directions. ternally by coincitlcricc counting. I)y viewing tlicsc ciiiissioiis from various anelcs in a coincidcncc iiiodc. it is possible to LISC coinpctcr tcchniqucs radiopliarrnaccuticals. The ECA'T has been successfully used i n patients wlio imaging tlie pancreas. Carbon-I 1 is a positron ernittcr Iiaving a half-life o f vc n t ional re c til in c ar scanning tech - niques has n o w been cxyandcd to a total of 41 patients. Even without thc advantages of the coincidence dctcction niode ( a d in spite of tlie handicaps involvcd with high energy 'C] ACPC has been shown to be a T h e most promising of other radionuclides under invcstigation is gallium68, which can be obtained froin a radionuclide generator. Ger in a niu ~ n - 6 8 , the radionuclide parcnt of gallium6 8 , has a long half-life (285 days), thereby affording a steady supply of gallium-68. Various chemical forms o f bcing considcrcd for positron tomography. Reccnt data obtained with the ECAT have demonstrated that the location of a brain hcinorrliagc Icnt visualiz;ition of a riuinbcr of tumors with [''Gd citrate. A colloid labclcd with gnlliuin-G8 is now bcing dcvclopcd for imaging the normal

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operational sincc its complction i n Junc 1976. 'I'liis past year a lead nntl stccl shiclded operating a n d autopsy tablc was fabricated and a hi$-/ in anu ~ nbc rof training courses and in-house accident drills arid excrciscs that cstablislicd confidcncc for actual gram activities arc now carricd out at tlic new facility. training \vas conducted cxclusivcly a t the ncw facility during tlic past year. Approsimately 1.00 persons including physiciaiis, hcaltli physicists, and emergency tcchnologists were trained REAC/TS radiation accidcnt readincss is now a reality through DOE'S Radiation Assista.ncc Programs. Specifically, REAC/TS has assigncd rcsponsibilitics lor sevcn private nuclear p o ~ v c ra1id reprocessing coiiipanics, sevcn installasitics, tlic Oak Ridge Union Carbidc plus four DOE-opcratcd naval reactor programs. Based o n these agrccmcnts and clircct requests by statcs and private institutions, RE AC/?'S gavc assistance in 18 radiation incidents involving 4 3 pcrsons this year. In addition to its scrvicc and training continued rcscarcli projccts in the cytogenetic methods of cvaluating radiation csp os urc and gcnctic risk cants. Studics of radiation-induccn~ vascular discnsc and gaiigrcnc in animal inodcls Iiavc con tinucd using sound techniqucs for early dctcction of r ;I d ici t io I 1 bu rns, in quality control and distribution of work is sup1mrtcd by. aniditional research projects coriccrning toxic and cliclnical propertics of DTPA a n d its modification for safer arid more effcctive use in humans. The Epidciniology program bccamc operational this year a n d assumed ERDA) liealtli and mortality studies perience of persons w h o have becii employcd in sclected installations associated with the nuclcar industry (Le., workers at Oak Ridgc; National Lead of Ohio; Mallinckrodt in Missouri; a n d Mound Laboratory in a y ear-scs-race-age-sl~ccif ic basis wi tli normal U.S. pop ~ il ation mortality. A spccial study of the inortality experience of workcrs with a history of csp os urc to mctallic niclicl is being conduct cd tliis year at the Oak Ridge Gaseous Diffusion Plant in cooperation, with Union Carbidc Corporation-Nuclear Division. The iiiortality in tlicsc workcrs is bcing comparcd t o that of other workcrs at Oak Ridge posure to nickcl or its compounds. T h c cpidcmiology prograin will concentrate o n cvaluating tlic effccts of occupational exposure t o hazards found incne rgy prod 11 ction F;ic il i t ics. Although tlic current progr;tin is limitcd to workcrs iri nuclear facilitics, plans arc bcing ~ ii adc to cvaluatc workers in coal convcrsion plants as thcse p1;ints conic iiito production.

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vicw articlcs, books, chapters, a t i d Joctornl dissertations b y Division pcrsonnci arc listed Iicrc. AI1 inaterid in press a t this tinic is includrd atid is so indicated. For abs tr xt s of ~ ~ d l - l c ~ igtl ~ casterti Ch:iptcr, Socicty of Nuclear hl c dic inc, Louisville, Kcntticky. Abstract.

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for two-way tablcs. I n Proceedings of the Statistical Computing Scctioii, Xmcrican Stntistical Association. Boston, hhssaihusetts, pp. 101-106. *Armstrong, R. D., a n d Frolnc, E. …