Treatment of Plutonium Poisoning with Zirconium Citrate and with Calcium Edta

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ZIRCONIUM CITRATE AND Fortunately neither Hanford nor other AEC installations have had the opportunity to treat an early serious case of Pu poisoning. treated three individuals having small measurable amounts of Pu deposits in the body as indicated by urinary excretion. zirconium citrate and one with calcium EDTA. reported along with another case of D r . Foreman.(l) Two were treated with The latter case was conium citrate was effective in greatly increasing excretion and concomitantly decreasing bone deposition of plutonium and radioyttrium in poisoned r a t s , it was felt desirable to see if zirconium would be effective in treating Studies with laboratory animals had indicated that zirconium w a s 1.5 grams/kg of zirconium citrate was repeatedly injected into the peritoneum of r a t s . (3) No chronic effects were observed. The L.D. 50 dose for acute to*c levels was 1700 mg/kg a s zirconium. Within 24 hours after the injection of zirconium, 80-90 per cent of the metal was excreted in the No deaths to laboratory animals occurred when The early work of Schubert and White(4' 5, seemed to indicate that the amount of Pu o r Y excreted in the urine was roughly proportional to the size of the dose of Z r . F r o m this work, they felt that the minimum amount of Z r which would lessen the skeletal deposition of P u in acute poisoning was between 5 . 1 and 1 2 . 3 m g per kilo. Z r injected 24 hours after P u and Y prevented further deposition of the radioelement in bone but had no other observable effect on their organ distribution.(6) Hence the need for treatment of poisoned individuals a s soon a s possible after exposure was stressed. By 1951 i t was postulated from animal work that the most effective dose in treating plutonium poisoning in man would be a t least 100 mg of Z r per kg of body weight. The preparation suggested by S ~ h u b e r t ( ~ )and the one which we still stock has the following makeup:

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Zirconyl chloride - 2.1 gram Single dose container . It m a y be seen that giving 7 grams of Z r would necessitate giving 2 9 grams of sodium citrate, a very large dose considering the evidence of citrate toxicity when multiple transfusions with citrated blood are given rapidly o r when there is liver disease o r there is obstruction to hepatic circulation.(8) The danger is in depression of the serum calcium level of the blood and the view is developing that citric acid intoxication can and does occur, frequently with a fatal outcome. Bunker suggests a possible relation between hypotension as well as difficulty in blood coagulation and an elevated citric acid blood level, Tetany is the usual sign of low serum calcium and calcium gluconate should be immediately available when there is the possibility of low serum calcium occurring as when zirconium citrate Cookson(?) states that citrated whole blood is not suitable f o r transfusions during operations on the heart a s intoxication and even death may ensue when the material is administered rapidly, massively o r intraarterially. Even in small doses, s o d i u m citrate is a heart depressant and since the citrate removes ionized calcium from the blood and tissues, cardiac a r r e s t in diastole. is a possibility. Burneau and Graham(l0) found that dogs bled repeatedly and continuously; given transfusions of citrated blood,survived a much shorter time than controls receiving heparinized blood. emphasizes that the train of toxic symptoms following the administration of citric acid and its sodium salts in toxic quantities appears to be identical with that of calcium ion deficiency consisting of increased general activity, hyperpnea, vasodilation of the peripheral vessels , salivation, muscle twitching, clonic and tonic convulsions, cyanosis, Cheyne-stokes respiration and some deaths. Sollman(l2) points out that the safe intravenous dose of sodium citrate varies with the r a t e of administration, but recommends that total dose should not exceed 5 grams. These studies would indicate that the sodium citrate is the limiting factor and not the zirconium in the intravenous administration of zirconium . , This has led to a search for a less toxic salt than sodium citrate

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Before giving intravenous zirconium citrate to an employee with relatively innocuous absorption of plutonium it w a s felt advisable to administer a small dose to an incurable patient. Therefore 50 mg of zirconium a s the citrate has been administered to such a patient. of zirconium in the 48-hour urine sample was 8170, and there w a s noevidence of toxic effect from this small dose. Early in 1951 an incident occurred a t the Hanford Works in which an employee received a very small fraction of the minimal allowable body deposit of plutonium by inhalation and ingestion. intravenous doses of 600 milligrams of zirconium a t 5 , 21, 98 and 118 hours after exposure. The rate of excretion of P u was increased by a factor of approximately three. The amount of sodium citrate administered along with each 600 mg of Zr was 2 . 5 grams which is one-half the dose suggested by over a period of about ten minutes. He was given repeated The 100 cc of solution containing the 600 mg of Z r was administered A second employee with a small fraction of the allowable body deposit of P u which he had received througha breakin the skin was given a repeated dose of 600 mg of zirconium intravenously a t 153 hours and 177 hours after the exposure. found in the urinary excretion r a t e of plutonium. Given this late after the exposure, no increase was No abnormal signs, symptoms o r laboratory findings occurred in Ten c c of 10% calcium gluconate were simultaneously given to preWe have had no suitable cases for treatment with zirconium since H a r r y Foreman has been the chief proponent of ethylenediaminetetraacetic acid (EDTA) in treatment of plutonium poisoning. lizes heavymetals from the body through i t s property of forming stable water - soluble chelates with these metals, which then a r e rapidly excreted via the kidney. the calcium chelate. otherwise might result through the combination of EDTA with the serum It is introduced intothe bodyfully combined with calcium a s This prevents the danger of hypocalcemic tetany which Calcium EDTA still functions in mobilizing plutonium because of i t s preferential avidity toward this element as compared with calcium. * Calcium is displaced from combination with EDTA by Pu and the material calcium and other metals, with regard to the improvement of EDTA

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is relatively nontoxic a s has been showr, by its increasing use in treating poisoning with lead and other metals. Dr. Foreman worked with us i n treating experimentally a young chemist whose exposure ata plant other than Hanford was presurned to have occurred seven years previously through inhalation of vapor spray during neutralization and oxidation of solutrons containing Pu. estimated from his urinary excretion that his body burden w a s 1.2 microtrial was carried out as a test for the effectiveness of calcium EDTA in increasing excretion rate in chronic Pu poisoning. of CaEDTA in saline by slow LK drip on the f i r s t day, 2.0 grams on the second day in two separate doses and 5 . 0 g r a m s on each of the three succeeding days. The 5.0 gram dose was divided into two doses of 2 - 5 0 grams each in 500 cc of saline and given over a period of about 80 to 90 minutes, with an interval of about five hours between the two daily treatments. all average urinary Pu excretion increased about tenfold over pretreatment levels during the five days of trial. There has never been any indication of injury from the Pu. The He was given 0.10 gram This case and other clinical cases described elsewhere by D r . Foreman verify animal experimentation, indicating that CaEDTA accelerates the excretion of Pu by humans particularly when given shortly after the ?eta1 tas entered the body. possible to analyze tissues, it has been found that skeleton as well as the soft tissues a r e depleted of Pu by the treatment. In animal experiments where i t is Dr. Thompson will discuss the experimental work with animals which has been done at Hanford to date to increase our knowledge as to the effectiveness of these agents in the treatment of plutonium poisoning. Based on this work, the work of Schubert and others, together with what clinical experience we have had, our treatment of an employee with acute plutonium poisoning would be a s follows: As soon as i t is reasonably established that a person has received an exposure which would probably result in a body burden closely approaching o r exceeding the presently acceptable maximum permissible amount ( 0 . 6 microgram) the following treatment would be given as rapidly as possible by a physician: calcium EDTA and zirconium citrate would be given successively as soon a s possible using the following doses and methods of *This material is discussed in m o r e detail in an article by W. D. Norwood, Ind. Med. & Surg., 25:135-139, 1956, (M.W.R.).

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If a physician is not immediately available, the registered nurse may on phone order from the physician s t a r t the infusion of CaEDTA pending the arrival of the physician. Route - intravenous drip only of solution not to exceed 3% Maximum dose per hour not to exceed 0 . 5 gm per 30 lbs. Maximum dose per day not to exceed 1 . 0 gm per 30 lbs. Maximum dose per week not to exceed 5.0 gm per 30 lbs. Maximum dose per course (with 7 days rest between courses) not to exceed 7.5 gm per 30 lbs. For the present, two such courses (with 7 days r e s t between courses) should not be exceeded. Method of Admini stration used. One cc from this ampule (0.2 gm CaEDTA) is to be diluted in 250 cc of 5 % glucose o r 0.9% sodium chloride solution suitable for intravenous administration. The 250 cc should be administered by vein over a oneTest Dose: Ampules containing 1 gram of CaEDTA in 5 cc should be interval of not l e s s than 4 hours, 1 gm (5 cc from an ampule) is to be diluted with 250 o r 500 cc of saline o r 5% glucose solution a s above and administered over a one-hour period by intravenous drip. twice daily f o r periods up to five days, preferably followed by two days r e s t and five more days therapy, if indicated. Therapeutic Regime: If no untoward signs a r e observed, and after an This dose should be administered Zirconium Citrate Administration Either before or after the initial dose of calcium EDTA, the patient This should beshould be hospitalized and zirconium citrate administered. within the first four hours following the accident. Zirconium citrate is stocked in 1 0 0 cc flasks and contains 2.1 grams of zirconium as well as the other constituentsindicated previously. slowly administered intravenously along witn ten cc of a 10% calcium gluconate solution. The zirconium citrate has a shelf life of 6 to 12 months and constitutes a very expensive standby drug. of zirconium citrate as quickly as possible. as dictated by further experimental and clinical knowledge. We plan to administer only one dose This regime will be modified

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Administration of Ethylenediaminetetraacetic Acid in Plutonium tional Medicine, 10:226-231, Sept. 1954. ment. Science 105, April 11 (1947). and Thorium -Salts in Rats. The Journal of Pharmacology and-Experimental Therapeutics 94, Sept. (1948). Zirconium on the Excretion and Distribution of Plutonium and Yttrium, The Journal of Biological Chemistry 184, M a y (1950). The Effect of Different Dose Levels of Schubert J. An Experimental Study of the Effect of Zirconium and Sodium Citrate Treatment on the Metabolism of Plutonium and Radioyttrium, The JOU$M~of Laboratory and Clinical Medicine 34, : *: White, M. R. and Schubert, J., The Action of Zirconium and otder Metals on Plutonium and Yttrium Distribution and Excretion. Personal commuziication from J. Schubert. Effects of Citrated Blood and the Search f o r a Suitable Substitute for Usein Cardiac Swgery. Ann. Surg. 139 430-438, (1954.). ...I Citrated Blood-k Transfusions. Archives of Surgery, 47 Oct. (1943). Marshall, G. L., Citrate Tolerance, California Medicine Vol. 73, Sollman, T. H., A Manual of Pharmacology Therapeutics and Toxicology, 6th Edition. and its Application to

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D r . Schubert: I would like to make a few comments about the toxicity of zirconium. think may be related to the fact that heat sterilization was used. not have complete proof of this. We had hoped that a pharmaceutical house could be interested in the manufacture and testing of zirconium The toxic properties that have been recorded I Secondly, the doses of zirconium given to the humans a r e not large enough to cause any appreciable increase in excretion, and none would be anticipated. D r . Rosenthal, the small doses of zirconium, say around 10 mg/kg, do not cause much change in urinary excretion, but minimize bone depositions as effectively as doses 1 0 times as large. In order t o observe a urinary excretion increase you would have to administer a t least 50 to very small dose of zirconium will minimize bone deposition w i t h many elements to an extent superior to EDTA alone. O n the basis of the animal work described by when combined with EDTA, i t would appear that a There is no point in giving repeated doses of zirconium. best thing is to give a single dose a s large as possible and no more, except in cases where the blood levels of Pu a r e continually replenished from tissue depots, a s for example, the lung. In such an event periodic administration of zirconium might be advisable. Repeated doses do not have much additional effect. That is not true, of c o u r s e , with EDTA where you can keep mobilizing the material. So the main use of zirconium is to minimize bone deposition to an extent which appears to be generally greater than that following EDTA alone. Question: What is the rationale behind D r . Norwood's use of a small, cautious test dose of EDTA ? D r . Norwood: We are just being extremely careful. Actually, the routine which we have was worked out with Charles Dunham. It probably represents m o r e care than is necessary, but I would rather be more caref u l than the other way around in treating people who really may not …