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RATIONAL CANCER INSTITPSE: Table of contents &e% B. Clinical Medicine & Medical Resdarch- L.O. Jacobson, Section Chief 2. Employees Health Service - 3, Garm tt Allen 3, Clinical Laboratory Braminations - LOO, Jacobson 4. Clinical research - Sa Schwarte 6, chronic effects of ~ r 8 9 Report received: November 10, 1944; Figures received: Dee Human Subjects Project
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1. Single doses of X-radiation Po Paired doses of X-radiation - survival 40 Acute effects of irradiation on dogs 1. slug impurities - histology Therapeutic effects of high water output Do Medical Industrial Hazards - J,J. Nickson, Section Chief 42John Rose, Associate Section Chid ~ o logic a lAction of X and Gamma Rays 44 Ifo University of California - Radiation Laboratory - J.G. Hamilton 51 Technical Progress Report on Metaboli'? Studies of Fission Products
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Robert S. Stone, Disector . Leon 0. Jacobson, Assistant Director The effect of TO (NO ) on tissue metabolism has been studied by infecting Tinto rgts &%k ill ing them at intervals for study. Anaerobic g&ycolysls and the rate of oxidation of choline by the kidney were unaffected in T poisoning. were a l s o unaffected. However, the synthesis of glycogen, the synthesis o f urea and the oxidation of pyruvate by the liver were inhibited to some extent in T poisoned rats. The minimum mount of TO (N03)s necessary t o procuce a rise inthe blood N.P.N. values was dund t o be 0. 1 mg per Kg ' injected in a single dose. Potitto phosphorylase activity, pyruvate dismutbtion, and gym v tte condens ation(synthesis of acetoacetic acid) were Earkedly inhibited by T. Lactic dehyarogenase, polyphenol oxidase, trypsin, ribonuclease were activity of succinoxidase inhibited by T work on the combination of T and other metals allied to T with During the month of' September 15 t o October 15, 1944, 5,800 clinical laboratory examinations vrere made; t h i s included laboratory W o r k on 9 2 new personnel, 256 controls a n d 848 in the v~orkhazard count alone show Individuals with abnormalities i n these groups of found betileen the urine oataluse o f human control and T exposed groups in either the Chicago o r Ames laboratories. Biochemical studies of a 58 year old female who received, i n a period of 18 days, a total of 156 r total body x-ray thera2y for a metastasizing parotid tumor shovied the folloviing significant changes; a pomLJt sustained rise i n the adenosine- tri ? os p hate fra o tion of the white blood cells i mediate ly followinC the in st it u - tion of' thera?y and lasting beyond its comgletion; a fall. i n the white blood cell oount only after the e n t i r e dose had been delivered. Normal subjects stand this dose.) of T i n 1/10 cc semgles of urine. Copro?or?hyrin isomer studies in groject ? emo mel coritinue t o The ~ 0 2values of the liver Alpha hydroxyaspartic acid reactivated the enzyme vdhen used at a ratio of A sir;.ple ultra filtration method has been devised for our Abnormalities considered on t h e basis of the white blood The injection of Tinto rabbits is followed by a prompt increase No significant difference, however, has been A sinple procedu're has been devised for the micro-~.-uantitbtion The method is sensitive to less
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personnel as cornJared t o control indivic?uals. and other urine pignents show freh.uent elevated values i n !iroject personnel with various ty?es of exp sure. Studies of urorosein Little is known about the I n general beta and gamma surveys in the New Chemistry building indicate very little change inthe degree o f contamination. hazard present in D-1OA ( New Chemistry) has jrompted reconslendat on for installation of ventilation to diminish the hazard. Three rooms in the West Stands ( 8 , 9 ana 217) were returned to routine use a f t e r decontamination but widesareaa beta o r soft gamma contamination agdn Approximately five hundred film meters are developed each week; during the period 8/21 t o 10/8/44, 7 films of project personnel had readings greater than 0.6 rfor one week. for the p eriod 9/7 t o 10/11/44, 81 meters gave a daily reaaing O f the pocket rrieter readings Of' these 35 were felt to be valid readings. Rats exposed toI 13' va2or retained 10 percent of the inhaled material. The absorptfon from t h e lung was 95 Geroent comglete a t the end of a 30 minute exposure Vii th a 10 percent deposition i n the thyroid and 90 percent elimination in the uri min 24 hours. Half ' of the retained yttrium (57d) ahloride aerosol was eliminated from the lungs of rat in a day a t tracer level. lung retention of 26 Cper rat caused no detectable his to logical - damage i n one week forR lung exposure of 1500 r. 2rg3-Cbg3 injected into the heart or tail vein ofthe rat was An average initial deposited in lungs, 10 t o 20 percent, liver, 10 t o 20 gercent and ske leton, 15 percent With a urine excretion of 30 pei%ent a t 10 days. The 50 percent l e t h a l dose uas 5 c/gm for 15 day8 survival. The distribution of radiation intensity in $he femur of a rabbit injected with S99has been determined by 8 ,hotographic film reThe technis,ue develo2ed for assaying retained Sr89 i n chronic animals by external counting of live animals shows that4to5 percent of' betas escaEe through t h e dorsal surf,ce of the mouse. the recovery from an initial exgosure of 300 r is ex2onential upto three weeks witha half recovery time of one reek. The survival of rats after two exposures t o x-ray indicate that A more complete experiment does not show the change f a the growth Dogs showed gradual increases in 21a.ma histtmine a t a l l levc-.ls
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A dose of 57 n from the cyclotron was lethal to 50 percent of CFl female mice in 30 days. from Clinton. This is oonsiderably lower than the value It gives an X/n ratio of 8.1.
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The laboratory has been engaged during this month in further studies on the mechanisfli of T poisoning, on t h e prepkration of hydroylraspartic acid t o be used Tissue :.etcbolism on T ;io:soned-Rats,--It has been shown i n previous re; orts that the rnetcbolism of the Kidney i s profoundly and progressively inhibited after the injection into rats of 0.5 mgs TO (N03)2 per %E. days showed a contf .uous dii:linution 05 02 uptake inthe presence of succ in ~ te, ppv ate, and alanine a3 oxidizable substrates. is not inhibited atall. The metabolism of the liver of nod rats varics greatly unless tlie anint-ls 3re starved for at least 48 hours. In the eq i er bents re-srtd i n Table I both conThe zn Lis w re killed two md threc days after in Jsc tion of "02(N03)2 (0.5 r ~ s per Kg). The 02 uptzke of the live rms pr : x tic ally the sate as the c,ntrol; in tno out of tfiree animals there YJ&S as light inhibitioti of 02 uptake hthe presence of pyruvate as the oxidizable substr&te, inhibition ivhich vias also i.iinifest when the mount of pyruvote utilized aas measured. arginine and loctr?t;e. This synthesis was inhibited 31 percent in the liver of rats po2soned by To Rats killed on successive This inhibition is not agen wal deposited inthe kidneys, but som of i2 is found i n the bone arid i n the liver, The utilization of pyruvate in t h e - .hen rats a m stzrved for 48 hours the clycogen of the livcr is corxpletely depleted because liver ylycocen i s rcpidly used by the sn3nzi.l t o provide food for its enorFj roquirementa. by T Ilofsoninl:as can be seen in Table 111, stant - tion had lost 35.5 ;lorcent of the live ? glycogen. 2& hou, ~l ater lost 99 Zcrcent. starved rat:; Ydth no glycogen in the l i v c r can be used f o r the study of Glycogen synthesis in the liver by foedirq then concentrLtcd solutions of ,glucoss a d kill in ? the anirmls a t ap;ay.+riatetimst the glycogen found inthe liver rh3.l be synthesized glycogen. I n these expximents rats trest.dxith5qs T02(H03)2 were used three days after the injection, after the introduction of glucose into the stoidach there vms an inhibition of animals killed6 hours after introduction of glucose into the s tom ch (Table N). In conclusion T poison hg produces not only Mdney dayage but &so liver dzixrzge as shown in the slight inhibition of pyruvate metabolisaz, a d urea synthesis, and in the inhibition of glycogen synthesis. It aust be reczlled that Lan (1) eqeri : ento confirm kin's in vitro findings. The rate of Lais d e & letio nrias slightly nffected .hen food .tiis not irithdrcvJn, t h e loss a s 88 1;erccnt. These ..hen the animals were I ul lod4hows The inhibition 1'038 t o 44 pr cent in the
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t o 62 mg percsnt atthe end of the4th dsg. that Ma' inhibits sox enzyi;ie reactions irhile it has no arf ect in others. Further proof of this specificit;. is given i n Thble V I ukere the ei'fect of "02 on the various zh boli c reections of pyruvate has been tcbulsted. pigeon liver (washed and unmshed) IYLS used ki these eq cer he nts. Suspension PELS tre it cd ivith the ay:po::ristc auount of l'o,(i,iCg)s for 13 ninLtes; efter this the phosf..hste bultfcr v'mi added and the ofidation 0 :vays of p::ruvate utilization arc narc corqlex because thcre i s not only oxidiition, but also d is mt ation and condensation lezdinl; $o.synthusis of &ceboecctste, 4 keto glut a rate and citrate. 'i'he effect of T02(PI0 ) on the synthesis of acetoacet&te ;vzs therefore stud?iie in this system. nutation of pyruvate, as nsesurod by C02 fora. t i o n i n Ringer-bicarbonate i5ti.i Ti2: CO as grjs phase, wis co..;pletely inhibited A t h 0,OCU & TO2(i;03)2, and 75 perccrh on j > piva ted isn uk tion,rrd ' ben pyruvate utilization YJWmeasured, the inhibition v : a 45 percent, synthesis of acetoacetic acid w a ~i nh ibi ted 54 1;ercent ivith 0.001 & TO (PO ) Lhat i n Idgeon liver suspensions, the oxidetion of pb nva tc is only slightly glucose 1-phosp 2ate. Uizyrne activity cm he i:,eEsured c it her by the amount of ments were performed a t pi1 6.2 i n irnleate buffer (added 5di iu tess f ter the tddi - tfon of Toz(IIO )z to the enzyme solution). 0.301 & TO (I40 ) produced 32 percont inhibition (Table VIII), Tryr!sin.-$iie 2cf iv it y of c rp tal line try ps in iras udr ' ected by the aid it ion Gf Pol~~llmolSxia;ae.-T02(I;03)2 tit a concentrztion of 0.091 & h x l no r:ffect on Lactic Dehydrocenase.-This enzpe kctivk es 1,xti.c xido a c i d is oxidized t o pyruvnte by ciii.,hosl:ho;,yridine nacleotide (Li'i;) vdrich is reduced Xtcr 15 xi nuts s the enzpe ;rcis
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This reversible reaction, goos to the right in the ?resence of a subst ace xhich combines with p,vruvate end the rate of tho reaction can be measured spectrophotometrically at 3450 8 where the (I)PN)Hz shows an absorption band. This enzyme was practically uninhibited by To (1!")2 0,301 & (Figure 1). Dounce (2) hns rcDounce is more complicated th;n t h c t used by US. orthe second protein i n not known, ported sone inhibition. It must 2e pointed out hoyiever t h a t the system used by bounce h?-d lactic dehydrogenase .,hether the reported inhibition was due t o action on the firs's The Reactivation of Enzymes InhiLited by TOq(N0 r wort s thtit the rct c tion be he en r09" and-em .-It has been show in previocs is, under cert z in conditions, acids among which citric acid was found the most po ue rfd agent. that reLctivating cizents vfould be those cb leto form cyclic cor( ounds with T02Ls which were not easily dissociable. ports it :.ras predictcd that hydroqynsytartic acid, zn u ~ n oacid posa is s hg the CChand OH croups so situated as t o favor the f om tion of T32 cyclic co;.,-ound, .vould be a good reactivating agent. cent by citric acid mtf 47 percent by hydroxjas:x&.c Zcxd, organic acids were added a t 10 ti;.es t h e concentr;.tion of T02(N0-j)2. as part ic is the only udno acid xhich has been found t o be a good rcvcrsal ¢, Reactivation of the enz;ae was obtkined on cddition of cert.in orgL5.c It was post doted Ina list of coqoun~*g1ven i n one of OUT reI n both cxes the and its efficacy *dl1be co::,pred dth that of citrate ad carbonate, acid is not known. has not yet been found i n proteins. The Combination of TO9 bines with enzy;:res reversibkj, the next step is t o estLblioh the ni ture of t1.h cornbination and the groups inthe protein molecule Aich bind t o TO2 . These studies are going t o be undertaken with crystalline proteins 2nd in la qe scale developed. A rapid metkod for the ultr & filtration of protein solutions haJ also been devised. The solation t o be filtered is put intoa cellophane bag shich is suspended, inside a double-layer cheesecloth bag, in a 50 cc centrifuge tube. deatc but'for a t sevcral pH vslues uere ultra filtered eccording t o &.c tcchnicjce or below, 83 t o 93 per cent of T np;earcd i n the ultra-
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Liver X-etabolism of' Rats trczted i t h To2(N03)2 (0.5 q s Per Kg)* K i l l e d 2 days aftcr: JO -(O uptcke per ne per hr in Rin&el'-l'Ok buffer, pyruvate utilized in 0,- as zas -t:z.se; 3 *2 s cmm pyruvate utilized in the absence The synthesis of urea by tho liver of rats (slices) treated with TO2(N09)2 . (0.5 rigs per Kg) synthesis In the -nesence of arginine and lactate.
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Synthesis of g1.ycogc.n by the liver 2f rats after introduction of 8 cc of a seturat!.d solution 3f glucose tnto the stomach. I Clycwen, mg perg of liver pJucoce in jo c tim
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b) ground unwashed liver a) os rneasurcd by C 0 2 productioi 111. iicet oacetate Lynthcsis
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zffect of small m m n t s of TO2(N%l2 on 7pwvate okidatiQn by Digeon washed, u t ill zat ion
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System J3 Value a t p liberated ,730 mu in 40 min.
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i rect ly m - 3 ) Irtional t o enzyme activity under the k;ffcct of T02(N03) an the x it iv it ya f 'olyDheno1 oxidase.
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A c i d as heactivating tigents of Lnzyme 'InhibitimsocHydroxyospmtic dicid find Citric Troduced by …
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