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Laboratory begun i n summer o f fora program and things have since long-lived bone-seeking e radioactive elements i n animals. 1950 all information on biological effects of plutonium was obtained Concern regarding better information on the effects of from experiments on mice and rats and the short life span of such animals limited information on delayed biological effects. Decision made that a definitive experiment should be designed and set up using dogs as the test animal and it was agreed that we would endeavor t o run this experiment a t Utah. All information on human problems in relation to Pu goes back to poisoning of humans inthe l9ZOfs, industry used a paint that had components of %, RdTh and MsTh. People working i n watch dial Varying amounts of these things were added to the paint mixture. Varying degrees of illness were brought about by this. effects were a combination primarily of Ra but the others were indicated, There was great interest in the ratios of toxicity between Pu, Ra and MsTh, i n dogs more reliable figures can be devised for man. With the injection of these three elements that from this experiment will come sufficient biological data of an even more reliable figure of the toxicity in humans of Pu. Now have one year and four months of experimental work behind US. We have seen primarily hematological changes, Probably beginning to see beginning bone tumors. Our effort&Sh€NMbAll on this point -h&t h e kind of $hing w& from what' has been done previously.
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Detection of the3dio active Burden of Injected Beagles The decay schenes of t h e radiml and mesothorium series were reviewed, a d opport unities for I-i n viao assay were pointed out. These occur a t places inthe decay series :.rherc penetrating y-rays are emitted and ahere radon is produced. pli cations due t o possi3le daughter relocation were discussed, especially in the Inthe case of the rzdiun dogs, the --i n vivo assay is carried out by breath radon exhalation neasureinents (giving radon ex lal ation) and measurements of Y-ray emis SiOn from the body (giving radon retention). The e-haled radon i s rneasured by collecting the ed la led breath in a large plastic bag and sampling with a specially designed the dog (li,ghtly anesthetized) inside a large, 4~ liquid scintillation counter (K-3) Results t o d a t e on 3 dogs injsctect a year ago ( t = 1 y e a r ) and on 5 dogs (t = 1 month) month dogs shoved a higher fractional exhala tion(that decreased iqith time). The 7-ray en is sion from the bod j is determimed by placing The one year dogs d-~ooi~edaboiit 80$ radon exhalation, while the one Inthe case of dogs injected with mesothorium and/or radiothorium, thoron exhal ation is ver; likely nez lig i ble due to the short 54 second half - life involved (this Doint will be checked, hoxever). (16 3j$ i n excellent agreenent yi th the value obtained with a phantom. RdTh retention was about 8b$. at, the end of a month, K-9 measurements shoved a drop by a factor of tvoin the sane period. nx)r e tent ionis considera5l;r less efficient ; this is under investigation at present. Pleasurements on eight dogs amounted t o This shows that daughter products (probably
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Radioactive Content and E is tri but ion Studies Radiurn i s an all cal be earth an2 its c:?er.ical properties are similar t o those and is affected by factors xhich affect calcium metabolism. Thus, the metabolim. of radiwa is shi lar to that of calciuxJ Plutonium and ??1or im Tetravalent plutonium and ti ori uz have no 23hysiological analogs and thus ed a s such, re sQl ting in cornplex ion formationJ YartLal hydrolysist colloid f orz7ation, or pre c ip it at ton de>-?endent uTon the nature of the solution. hizh p9, the presence of citrate, proteins an4 meas of hizh negative charge deiisity of biological systeys are ver:T favorable for bonding FlutonPJ3 and thoriun. Both a r e found t o deposit on the endostem, perLosteLq, and trabecular surfaces o f the bonesJ and i n the liver. Age, an important factor in calcium netabolism, has a ?ronoulzced effect on made on a group o f 3 adult beagle dogs, 5 of xhich were 15’rnon-bhs o l d and the other 3 vere 2 1/2 to4 years at tine of injection. :;rere skeletal ly mature, the older dogs excreted a sig if i can tl J greater fraction of the radium. A 28-da;- excretion stuw was Even thou ~ ha l l Age $ Ra Excreted The age effect is nore ?renounced :.dien puppies are compared vith adults. No. Dogs Age 5 R a Excreted i n 2 4 hours Additional data for the older dogs are as fol lov s : Days after Inject ton Excretion Rate
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B. Flut oniun and Thorium T'ne excretion of plutonium durinz the first 22 days fol ln rh g 'intravenous icj est ion :?as been neasured fora group of 19 adult bearle dogs ranging i n are from 15 rionths toke3 gears. The average excretion is 125, and therec During the fk rst 3LL hrs. after injection radium i s renoved front he blood more rapidly in puppies than i n adults, indicating more rapid bone netabolism Thorium i s removed f r o n %he blood nore slarly than radium, but eventually reaches a lower level than radium. colloidal properties of thorium and the tenacious bonding of de?osited E. Plutonium and Thorium These facts are consistent vith the Iietained radium i s found alxost quantitatively in the skeleton, the tissue deposition being a host negligible after the first few days. after injection the skeleton of afive month old puppy contained 87% of the injected radium, ;r'nile the skeleton of a 15 month old dog contained 60$. Retained 2luton iw is found a host quantitative lJ in the skeleton and the liver. 70% of the injected dose deposits inthe skeleton and 205 i n the liver. As anticipated from the ~ O T Jexcretion rates, the gross distribution of plutoaium rernaim approximately constant during t h e first year. zonal analysis of 1032 bones shows that plutonium is redistributed within the skeleton. Tne importance of this observation is that,vh ile the total alpha particle energy dissipated per day inthe skeleton rem in s constant, thP amount of energy which a particular part of a bone receives varies 3. Plutoniun a-nd Thor iur
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B is to path o log and Dose 3ates The three questions :.rhizh ve are ~t aresent focusing o w .?ttention on are : deposited i n bone; (2)vh at cells are being irr232ted and the xa.znitade of .the ir ra diz tion lose; and (3) ;%ifiatare the local aEc! systexic Yesponses of the a nix al t o t'ne irrztdiation. Data presented i s limited t G two dous sacrificed at2bhowS and one year fol loving administration of3 microcuries/:iilopaic of Pu. Radioautographically Tu is Fr in ci pally deposited on the surface of trabecular The average dosage rate receivedbone strlclcturzs just beneath the endostal layer. by the tissue within the range or' the alpha particles in trabecular bone i s 50 rep/ day as calculated di rez t ly by .?ama track counting radio auto pa as aEd bjr calculation from geoinetrical distribution data blasts, osteoblasts, etc. of the enclost.ea1 layers. Osteoblasts are specifically ir ra diz ted by the intracellular incorporation of ph toni un. xam@:r cells are Trithin therage of the gxma particles in areas of trabecular bone. A nuch smller Zraction of the narro7s is irradiated in the shafts. The dram tic denression or" the circulating e ry thr cid and myeloid elements appears t o be Tne principal cells irradiated are the fi bro - About 1/5 o f the bone The histopatho1oZi.c changes ?resent inthe bone of the one year sacrificed 2. General abl ation of bone mrro:d in areas of trak ec ulm bone - ith islands of h cer plastic marrox. 3. Corqlete abserce o f osteo!:lastic ;n2 os teo clastic cells a:?r! act iv i ky since a dni nist ration 0.' Tu. he PU mobilization into rnarro:r ssaces i n !'dead xacrophages" containing aggregates of hernociderin. 5. Early resorption of bone :ritl?out the presence of osteoclasts. T!?e e:rtensive diffuse dzzage t o connective tissue elexents of bone 71hich i s present z t one year in this high dosage level of plutonium is thouEht t o clcud any more subtle changes sush a s those cl" a precarcorcat Study oZ animals receiving smaller adrninistered ?u'?g and Ra internal 0." tize should be more luc rz ti vein stu&jing the pathogenesis of gam irradiation induced bone tumcrs condit$3g, if present atall. doses mera seater
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The 5e:ntolo:ical chanzes i n dogs injected with plutoniuq or radi m for a ?erLoi of one ;rear a r e smnarized below. in an is als rec eiv bg the t?ro laxest ciose leyrels (0.014 or 0.96 uc&) of either radioproportional tothe anount of isotope achinistered. The one high level plutonlun dog vhich had clinical nanifestations of irradiation sickness had the zest Severe toho xonths folloving injection. heterophils; the other leukocytes were not altered vith the exception of as light drop i n absolute eosinophil count. returned t o normal values. 7 0 siLmlficant alterations in red cells,vh it e cells c)r platelets were observed 71ith higher doses the degree of depression of the various blood c e l l s vas Animals receiving %he internediate dose of e i t h e r isotope (0.27 uc/kg) denonThis leukopenia vas due xainly to a fallin Fp the third nonth the leukocyte count had heterophils, eosinophils and gonocy5es. in the above group 09 animals ; dth sxbnornal values persisting throu@out the year. The lymphocytes demonstrated as lc rer 'cut progressive decline with a borderline lynphopenia exist in = durin? the year, found inthe Dlutonium anknals at three r.reeks vith restoration of norm1 numbers by '.Kth this dose there is an absolute decrease i n heterophils, non-se,mented The leukocyte count rose more s10::ly than 9significant decrease i n blood platelets vas The radium .logs at this dose level have shoma more variable The animals given the highest rlose of plutonium o r radium (2.5 uc/kg) exhibited a depression of all fo med blood elemezts. SO$ mas found within 10 days totvo ..reeks : dth minimum values a t one month. the four level ani mls the depression in total white cell count i s due t o an absolute decrease inall types 09 leulcoclrtes. The irhite count began to rise slovly at three The lymphocytes fell more slovly; a significant lymphopenia developed a t one t o two months, and tkere vas no tendency tovard recovery durin? the first year. The blood platelets in a niz als receiving s it her radioisotope denonstrated an 30'3 t o 905 drop a t three wee!:s vith reco7rer;r t o normal numbers by the second or third month. a is tent depression or" erythrocjri;e values has been found inthe plutoniuq treated dogs. This anenia i s normocllronic an2 aoraocySic i n type and appears fran tvo tosix months after injection. The red cells regenerate rapidly and normal values xere found inall ani mls at one year. The red cell response is more variable inthe high level ra6i.m A decrease i n vhite count of approxin2tel.J Those ani mls :rhich develo2ed an anemia had only as light drop i n eryy%hrocyte
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l,!or?holosical alterations such a s have been described follo ? ~ i n gvarious other t:,Tes of irradiation have been noted in ani mls recei.rin2 the hizher dose levels. These cois F st ir, the appearence oZ sant hypersegxentec! and toxic heteronhils 9 vith indented nuclei. cells and ret icu lo cyte s &x-ing the period of anexia inthe high dose level dozs. Bone marr0r.T exaninations which have been limited to ilia c crest aspirations have been unsatisfactory on the vhole. Those preparations i?. >fi-ich the cells have been well presemed have shown a decrease inthe myeloid/erythroid ration after injection of There i s an increase i n number of circulating nucleated red I n summary, there is a significant depression of red cells,total vh it e cells, he t ero phil s, lymphocytes and platelets in the five level dogs; depression of white count, he t ero phil s, lymphocytes and platelets in four level dogs, depression of white count due t o heterophil and eosinophil decrease in three l e v e l dogs and no change i n dogs receiTring the two love st doses. Plutoniun and radium during the first year following injection have a sirnilar effect on granular leukocytes and monocytes and a slightly greater degree of lynphocyte depression i n radiun injected platelets. The significate of these early blood cell changes must be evaluated on the basis of the further life history of the anixals, and the mechanism causing these changes >rill be sought through study of the henatopoietic tissue on serially Plutonium a-wears t o have a greater toxic effect of ery-bhrocytes and
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Experirnaqtal Pninal Colony - Development and Xaintenance I. Xistory of Colony 3. Short hair coat a . One of the oldest pwe breeds i n U.S.A. 1. Decided t o breed our own dogs because: b. Better controlled eqeriment (1)Complete history on each individual knom (4) Can use sane sex of litter mate groups frequently C. Original Breeding Colony 1. Seven females and cpe male. Originated i n Vest TJirgMa and Indiana a. Tremendous shipping costs b. Poor nutritional state Fleas and lice. Took six months t o get then in condition t o reproduce. First pupTies born i n Xovenber and December of 1951 11. General F’rc‘clems in Z stab li she nt and Xaintenance of Bealthy Colony 1. Kennels and runs kept clean 2. Feed pans vashed and disinfected daily 3. Clean prater pans with fresh mter atall times h. I11 animals must be noticed early and treated immediately 5. Preventive medicine is watch word a. Immunization principles sound (1)Carres Virus of Distemper (3) Controls for internal parasites
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(b) Controls for external parasites (5) Controls of insect vectors - flies (5) Good nutrition for adult colony, pregnait fem les, gro:.Jing ( a ) Problern of overcrovding here (a) Tattoos and tags plus control boards (b) Segregation and watched closely for lO-lb dags (e) Heated xhelping boxes III. Toxicity Studies B. Selection and physical H. Elood serum for A/G ratio, Calcium, Phosphorus K. Tags stamped with research number €1. Blood disappearance if desired Q. Repeat liver functions yearly R. X-ray fourth and fifth levels every six months. S. Periodic return to metabolism cages & tire