ATTACHMENT 22 U.S. DOE ARCHIVES U.S. ATOMIC ENERGY COMMISSION Collection DBM Folder 3359 INTER-OFFICE MEMORANDUM Date: March 2, 1950 To: Dr. T.L. Shipman From: Wright H. Langham Subject: Large Animal Studies of Relative Chronic Toxicity of Plutonium and Radium REFERENCE: H-4 The recent discussions of an official maximum permissible body content of plutonium have focused attention on a rather drastic weakness in our knowledge of the toxicity of plutonium a applied to man. This weakness our knowledge is not confined to the toxicity of plutonium alone but rather to all radioactive isotopes that tend to deposit in bone because of their fixation by the original matrix. Among the materials of importance to the Atomic Energy Program, which deposit in bone according to this rather unusual pattern are isotopes of thorium, protoactinium, actinium, uranium (U233, U234, U235), neptunium, plutonium, americium, curium, and a number of the isotopes of the lanthanide rare earth series. The meetings on tolerances emphasized the necessity of establishing maximum permissible levels in man by comparing the toxicity of the various isotopes with radium. This comparison takes advantage of the experience gained from the human radium poisoning cases of the past thirty years. The most important question was one of deciding what factors to introduced in order to allow for the difference in mode of deposition between radium (which seeks the bone by incorporating into the mineralized portion) and plutonium and other substances which seek the bone as a result of fixation by the organic matrix. The above question was decided largely on the basis of Dr. Austin Brues' experiment son the relative chronic toxicity of plutonium and radium in six dogs, and several hundred rats and mice. These results showed that plutonium in equivalent microcurie amounts was more toxic than radium. The criteria of toxicity used were mean survival time, the incidence of bone sarcoma, the number of fractures and other bone abnormalities. Dr. Brues' work is excellent and is the best experimental evidence available. In order, however, to extend our knowledge to the point where extrapolation from laboratory animals to man is subject to less uncertainty, an experiment should be designed which would, insofar as possible, correct the following objections to our present experimental information.: (1) Rodents, unlike man, continue to grow throughout their life span and the union of the epiphyses does not occur at maturity. The highest concentration of plutonium and other osteoid seeking isotopes is found in the epiphyseal junction. It is quite possible that the deposition of plutonium in a mature animal whose bone development and structure more closely resembles man would give a different incidence of sarcoma than is observed in rats and mice. CLASSIFICATION CANCELLED BY AUTHORITY OF DOE/OC Jose Diaz 4-1-81 ______________ _______ Reviewed by Date Wilbur A. Strauser 4-2-81 By: Dick Koogle 6-4-87 5650.2, III-12 (Admin.) INTEROFFICE MEMORANDUM DATE March 2, 1950 TO: FROM: SUBJECT -2- (2) The life span of the rat or mouse is short as compared to the latent time required for the production of sarcoma by bone seeking radioactive isotopes. It is, therefore, a common practice to inject relatively large doses of the materials into these animals while they are still quite young in order to gain the maximum conditions for sarcoma development. It is doubtful that the deposition of the radioactive material is independent of the age of the animal at the time of injection. The detailed quantitative aspects of plutonium and radium deposition may be quite different in young rodents and in mature animals whose epiphyses are united. Bone fractures in plutonium injected rats, for example, seem to occur in an area corresponding to the position of the epiphyseal junction at the time the animal was injected. It is problematical, therefore, whether or not such an observation has any relation to the choice of a chronic tolerance dose for an adult man. (3) Pneumonia is endemic in the rat and almost invariably all animals die of a chronic pneumonia. Mean survival times of injected rats become more or less a measure of the effect of injection on the ability of the animals to resist pneumonia. This finding may have little correlation to the chronic tolerance dose of the material in humans. (4) Regardless of the size of the dose, treated rats tend to die of pneumonia at about the minimum time required for the production of tumors. Therefore, tumor incidence in such animals may be decidedly misleading. It is quite possible that the absolute relative tumor incidence from radium and plutonium is essentially in accord with the energy relationships of the radiations from the two substances. The time required to produce tumors with plutonium may be slightly shorter than for radium, therefore, more tumors from plutonium may be observed before the animals die. (5) Presently available experimental evidence is based on administered dose of radium and plutonium rather than on retained dose. The lack of chemical similarity between radium and plutonium and the lack of similarity between the excretion of these substances by rodents and by the human complicate the interpretation of present data in terms of a tolerance dose of plutonium for man. I would like to submit for your consideration the accompanying general protocol of an experiment to compare the relative chronic toxicology of plutonium and radium using dogs. This experiment would tend to alleviate DOE ARCHIVES INTEROFFICE MEMORANDUM DATE March 2, 1950 TO: FROM: SUBJECT -3- the above objections to the state of our present knowledge regarding the chronic toxicology of radioisotopes that are fixed by the osteoid matrix of bone. I have recommended experiments on dogs for the following reasons: a. The epiphyses unite at maturity. b. Their skeletal growth, bone structure and development more closely resemble the human that does the rodent. c. The fecal and urinary excretion of plutonium by the dog closely approximate that of man. d. The rodent excretes 85% of the radon as compared to 40-50% by man. Radon excretion by the dog should resemble that of man more closely than does the rodent. e. The dog is more resistant to pneumonia than is the rat. f. The life span of the dog is relatively long as compared to the latent period of tumor induction by radioactive materials. g. The ratio of skeletal weight to total body weight of the dog more closely approximates that of man than does the rodent. The experiment should be set up and financed to last for at least five years. I would like to suggest that the Division of Biology and Medicine of the AEC be approached about the possibility of financing the experiment on a subcontract basis through the Office of Santa Fe Directed Operations. I would like also to suggest that the experiment be supervised by the Health Division of the Los Alamos Scientific laboratory as this is the laboratory cost concerned with tolerances of plutonium and other bone seeking alpha emitters. As is known by Dr. Shields Warren's Office in Washington pure bred fox hounds are to be used in forthcoming Eniwetok operations. Breeding stocks are already being purchased and the Division of Biology and Medicine has financed the construction and maintenance of a kennel to be operated under contract by NRDL to supply animals for Eniwetok. I wish to suggest that the Division of Biology and Medicine be approached regarding the possibility of maintaining and increasing the dog breed- INTEROFFICE MEMORANDUM DATE March 2, 1950 TO: FROM: SUBJECT -4- ing stock, the kennels and the contract with NRDL for the purpose of performing studies of relative chronic toxicology of plutonium and radium in dogs. I would estimate the cost at about $50,000 per year or $250,000 for the five year period. This figure is probably less than the cost of a ventilating system designed to change the plutonium air level of a single major plutonium operation from 10-11 uc/cc to 10-13 uc/cc. If you feel that the accompanying experimental outline and the proposal set forth in this memorandum have merit, please take the matter up with Mr. Bradbury and, if he approves, with the Division of Biology and Medicine in Washington. Wright H. Langham