Program of Research Medical Division Oak Ridge Institute of Nuclear Studies (Basic Plan)

Page 1

The BPsic Plan for the Medica.1 Division of the 0a.k Ridge In st it cte of Nuclear Studies developed by the Board of Medical Consultants and approved by the Atc-nic .%era Comuission directs the Medical Division t o conduct a program eEbodying ?our A . The directed research progrem. D . S2ecia.l projects in cooperation with the staffs of participating Ju ring the perlod 1949-30,t h e medicti1 program w8.s concerned primarily with the ckThe sentir2.l problem of the Medical Division of the Oak Ridge institute of FAdear St?;.dies isen investigztion of the value end uses of isotopes inthe therr-l=J at-ruct a hospital and its acconpanying laboratories; 'to bring together 3, research s-i,mctioTz and should be completed by a gro x imt ely mid-April of 1930. With tvo exbut due %o lack of phySZC8.l fec iii ties,their activities have been ro strict ed to p3.aming end perforning a few key experinents i n borrowed laboratorios. To inplement t h e program, it wa.s necessary t o design and conThese phjrsica.1 facilities are now under conClose relations have been developed with the twenty-two soEthern medical sr,%oo.', a d upon recomenda.tion of the Soerd of Medical Consultants, the pian allows mome s of tSe faculty of thase schools and residents reconmended fron these sch s rl s & joint her sd ical and research sta.ff of the Institute for work inthe gens:-2.1 is i n rssponse toa &m.nd from the Institute ' s meabcr institutions. The prog a a as developed so fa.r conforms with the ideals a.nd procedures of the Institute esa whole and is i n keeping with t h e Basic Medical Plan previously submitted end o.,?prove. It i s worth noting that this progosn By the be gh ning or' tho f3.scz.l year, 1950 - 1951, it i s znticipa,ted thet She 1. A thirty - bed hospital end lz bore tories shall have been constructed, accepted, and put into operation,

Page 2

2 . The nursing staff shell have received its necessary training in health physics and in the management of radioactive patients. The medical staff and technicians and the administrative staff shall have smoothed out the necessary procedures inpatient procurement and in ming the hospital unit. 4 . Complete lias on she.11 have been established with the member medical schools as t o types of patients, numbers, procedures, legal aspects of the program, etc. 5 . To test the general administrative procedures and for other re8.sons listed later,a small number of patients shall be accepted at first. h8.w neo lasms which can be studied with the e.lready standard usage of P3*, fill 1ou.d of thirty beds. 6. An animal colony with its.necessary equipment, yards, and adjacent experioratory s h a l l have boen completed in cooperation with the University of Tennessee Research Faro. 7 . Most of the items of equipment shall have been received and installed for use. These include special appa.ratus relating to detection end Nedical Division labora.tories, wards, and equipment w i l l be on display to visitors in much the seme sense that the Special Training equipment i s used t o demonstrate methods to visitors, It should be noted parenthetically that the All four of the programs of the Medical Division areto be orientated arollnd the use of isotopes i n t h e study of neoplastic diseases. ieen coordinated within one genera.1 p1a.n that will be discussed separately: A l l four progrems have A . The Directed Reeearch Program 1. Training- Beds: I n keeping with tne training program of the Medical Ds.vision, a small'number of beds t o the use of 1131, P32, Aul9i, ~ a.24. These beds will be used chiefly for tra:r.ing purposes as a service t o the reside'nts from the member schools, of the member schools feel that, i n addition t o having tmi nees raceive experienso i n working on m,ny of the newer and untried isotopes, they should return to the school with experience inthe use of me.terials already a veil z ble. gested by some of the member schools,that until their own facilities are completed f o r treatments with 1131; P32, Au198, a d Na24, that they be allowed t o send selecte: cases of thyroid diseese, polycythemia, chronic leukemias, ma certain circulc.tory diagnostic problems t o the Institute accompanied by sta.ff menbers of the inedict!?- approximately 5)will be reserved for cases a,da.$ed It has been sug2.Gallium Therapy: The treatment with gallium of osteoblastic-type bone neoUnder the prirra.ry direction of Commander E.R.KIu plasms, both primary and metastatic, psr tic ule rly the metasta.ses from prost st ic carcinoma, will be investiga.ted.

Page 3

t.he i4edica.l Division has already secured toxicity de.t8. using gallium citrate. sorption, retention,distribution, and excretion studies using~-Ga72.. mein progress fe rent i al concentration i n bone, especially in rep idly growing bone and ce.llus, but ed d it ional developmental work i s needed. Ga7* inthe rat. Similar studies will ex3,end t o dogs and a final more precise defin it ion of tho biological characteristics of gallium, excretion pattern, and probable gallium toxicity of radiation dosage will receive E. final test on the LcnCrace strain of pigs before requesting permission t o use it in hums. ree.sona.ble degree of selective localization in the bone is secured, end such 8.n 5,ss mp tion seems wasra.nted from the work already done on man atthe Naval Reseerch Ln st it ute 8.t Bethesda., a complete spectrum of bone neoplasms will be investigated. Since the gamma radiation of Ga72 p emits approxime.tion of localization in them - psu tic dosage from the surfs.ce of the body, a concornitcant investigation is proceed-. i.ng t o determine the best design of instrumentation to localize galli min the huCommander Dudley's work has indicated t h a t ge.llium shows preThis is now being done, using very pure Additional informetion i s necesse.ry to select the vmious salts for intravenThe gallium ion i s e.n e.ctivc protein pre c ip it mt and is insoluble exceptous use. i n strongly acid solution. The lethal dose values for the various routes of adminis t ration indicate that the chemical dosage allowable is far more than necessary t o attain therapeutic radiation dosage. However, the distribution of gdlium ion may depend largely upon the salt that is used and the route of a.dministra.tion. Hence, tho preparation of a form of gallium salt suits.ble for pile a,ctive.tion and subsequent conversion t o an a.ccepta.ble biological salt is being undertaken by Dr. Perkinson. I n order t o reduce the amount of inert c cr rie r gallium, a n arrangement has been made with t h e Y - 1 2 group t o obtain separation of Ga71, which on irradie.tioii becomes Ga72, without t h e presence of l - 1 / 2 times i t s weight of inactive Ga.71. Prive.te communication with Conmznder Dudley indicates that four patients hz.ve already received tracer anounts of Gp.72 without definite toxicity effects being noted. The procedures t o be followed by the Medical Division e r e as follows: I, A study of the toxicity of gd liu m. 1. Injection studies using gallium lax tate in distilled water a t 3, concentr8,tion of 3 mg. Ga./ml. Adult elbino rats end e d u l t m.Pbits used. InJections into large ta.il vein end subcuteneouslg 2. Control animals injected with biologically acceptable soluticr,s of gallium Li c tate conta.ining 10 mg/d. 3 . Results: Minimum lethal doses (LD-$0) Rabbits : Intravenous k 3 rng body weight

Page 4

B. Medical Division Project: 1. To repee.t the studies of the toxicity of ste ble gallium using tion has a pH of about 2.5. half with sterile physiological saline forming e. so lu tim of 3.7% and the pH adjusted t o 7.0-7.4. This solution was diluted oneAbove solution injected slowly into tho large tail vein of the rat, i n doses ranging from 30 mgm Ga/Kgm body weight t o Results (not complete): Groups of f i v o rats each were given doses of 3 0 , 40, 50, and 60 mgm &./Kgrn body weight, and 100 hours post injection were 011 alive and showing no ill o f - fects from the drug. groups f o r doses of 60, 70, 80, 90, and 100 LU@ Ga/Kgn body q pears to be much higher than that obtained by Dudley using Tho test is being repeated for fiver at The LD-50 of gallium citrate given by our techn-ician 11. Study of the Distribution of Gs.lli um in the Rat, 1. The tio sues of rats and rabbits used inthe ID-50 determination of gallium 1n.ctate were examined a t autopsy and anelyzed f o r galiium by photofluorographic method described by him. 2. Results: The distribution of gallium i n animls receiving gallium lactate varies with time. The kidneys initially contained the greatest omount, followed by bone, liver spleen, muscle, etc. The concentration of gallium falls off rapidly in e.11 tissues exceat bone, i n which the gallium is fixed, and is given up slowly from bone over 8 period of nonths. 1. To determine t h e distribution of gallium i n the form of labeled gallium citrate in the tissues of the rat during intervals of from one to four days. The predetermined Is-50 dose (in roferenco t o gallium toxicity) will be injected intravenously into a series of thirty rets. will be the same chemical solution e.s used in the toxicity studies but will be t8.gged with a small concentration of irradiated nB.tura,lly occurring gdlium. This is approximately. 6070 Ge70 and 4 6 Ga72. Tho forner he.s ahalf - life of 20 minutes, the latter lect ed will be at tracer levels. The ra diet ion dosage of the taggod Ballium se-

Page 5

These ani mls will be sacrificed 8.5 follows: five after two days, and five every other &.y thereafter until the tenth post-injection day. Studies will be made of the following organs t o determine the relative distribution of gallium i n each orgem correlated with the post-injection time: Brain, lungs, heart, GI tract,liver, thyroid, pancreas, spleen, kidneys, gonsds, muscle, end bone. Radioautographs will be prep red of one of the enter i or femurs of one of each group of rats. dose will be autopsied immediately if lysis of the tissues h,s not Five after one day, Rats that receive a lethal Studies of the seperate tissues and organs will be m de after mh - ing tho tissues at 5OOOC, and thereby determining the radiation in - tens it y of each sample. 111. A Study of the Pathological Changes i n Rats (caused by e. minimel lethal A . No previous studies of pathological changes invoked by gallium inte.ke tomical changes have been found in the kidneys of inJected animals. Dudley has m.de several comments to the effect that anaB. Medical Division Project: 1. To study the p,tho logical chmges in the tissues of the rat from The IB-50 of ste ble gallium citre,te will be injected in the same manner 8.8 previously described, and using the s m e concent ration of solution. A series of rats will be used, their nunber depending upon the results of the problem of distribution of gallium. The inter - val after which they will be sa,crificed will also depend qon the results of this problem, md will coincide with the longest time gallium i s found t o be retained in the specific tissue or The organs which appear t o be the most proba.ble sites of petho logical change are : Kidneys, liver, bone, and possibly the Specimens will be prepared and studied. IV. A Study of t h e Metabolism snd Excretion of Gnllium: A . Dudley h8.s performed similar studies using gallium lactate and citra%e on rats, rabbits, and dogs, and administering the drug by both intra - venous and subcutaneous route.His results for gallium citrate show th8.t both t h e bone a.nd kidneys receive large mounts of the element and other soft tissues receive no sign if i cent concentration. mary route of excretion is the kidney. between the biological actions of the v8.rious salts that en attempt must be made t o determine the most biologically acceptable salt. Sufficient difference exists

Page 6

do this, arrengenents ore i n process with the Y-12 Stable Isotopes group t o investigate the chemical methods of preparing various salts of gallium such 1.6 lactate, onnoniun citrate,cart rate, mlate, succinate, tartrete, and others, In vitro blood plasma experiments will attempt t o determine the mss action constant which determines for each of these mlts the relative rate of f om tion of the gs.llium proteino.te end the size of the proteinate particles, since t o e. certain oxtent the size o f the pr tic les determine its distribution. 1. To determine t h e netabollsm and mode of excretion of various gallium salts in the rat and the dog. 2. Project using rats: A group of 45 ro.ts will be given the toxicological LD-50 dose of go.llium salts by t h e same technique, i n same concentration, These mats areto be sec rif iced in groups of 5 every 8 hours for 72 hours. Those that die will be autopsied immedictely. Prior t o death urine and feces will be collected s cp amt ely and ashed. Counts on the residues will be made. On autopsy, the following tissues will be obtained and ashed: Kidneys, intestines, stomach, liver, spleen, pancreas, muscle, skin, and subcutaneous tissue, and bone, Counts will be m.de of their residues. Correlations will be made of the amounts .of gallium i n the excreta, and the examined tissues. 3 . Project involving dogs: Ga/- body weight) will be injected intravenously intoa group of 6 13,ree dogs. intensities will be used as i n the preceding ex2eriment. The urine and feces of the experimental cnim,ls will be col - lect ed sep m to ly. A cholecystotomy will be perforxed on 2 dogs, d lowing bile t o drein freely, and a fist u lo of thc p8ncrea.tic duct will bc; made upon two dogs with a cphheter i n place, collecting FS.;!- All dogs will be sacrificed et the same time, fron 24 t o 48 Sini1c.r studies will be made on excreta and tissues8s WPP performed upon the rats in the previous section of this ex-

Page 7

periment, and i n addition, studies will be made on the bile and pancreatic juice of t h e dog. f. The results of these studies will be correl8.ted and studied Dudley attempted these studies but was handicqped since the specific activity of his gallium was not high enough. known whether the chemical o r the radiation LD-50 is the limiting As a result, it i s not 1. If the ra.die.tion ID-50 i s near or loss than the toxicologic LD-50, gradient doses of high specificity gellium (obte.ined by the ele c …