Acta pharmacol. et toxicol. 1960, 17, 151-156.

From the Division of Biological Chemistry Hahnemann Medical College Philadelphia, PA., U.S.A.

Some Effects of Cortisone on the Toxicity of Uranium BY

Julio Cardenas and Arthur W. Wase (Received February 25, 1960).

The toxicity of uranium and its distribution in animals and man have been well established and recorded (TANNENDAUM 1951 ; VOECTLIN & HODGE 1953; BERNARD 1958). Renewed and increased contact with uranium has been favoured by a world-wide acceleration of ore produc- tion and processing. Advanced uranium technology, necessary for reactor development programmes, has created on an increased scale chemical and radiological hygiene problems, of which industrial hygienists have as yet many to solve (EISENBUD & QUIGLEY 1956). Our interests were directed to the study of the influence, if any, of some commonly used therapeutic agents on uranium toxicity. One of the first drugs studied was cortisone. This was selected because of its wide-spread usage by the medical pro- fession in the treatment of many common ailments.

Methods. 5 g of reagent grade uranium acetate, U02(C~H302)2 . 2Hzo were dissolved in

distilled water, 200 mg of sodium hexametaphosphate were added to stabilize the solution, and the pH was adjusted to 7.0 with O.IM-NaHC03; the final volume of this stock solution was one litre. Serial dilutions were made daily to prepare solutions of the uranium equivalent to 50 pg per ml of the original salt or 28 ,ug U. Micro- crystalline suspensions of cortisone were prepared and diluted as required to give a conccntration of 10 mg per n-,I.

Male “Swiss” mice (25 & 3 g) were used i n groups of 36. Thosc in group A were given daily 0.1 ml of the uranyl solution (2.5 pg U) subcutaneously, for eight conse- cutive days: those in group B were given the same daily and total dose of uranium plus a daily dose of cortisone of 0.5 mg for eight days. Th? animals in group C received eight daily doses of 0.5 mg cortisone only. Group D was maintained as an environ- mental control without any treatment.

152 J . CARDENAS AND A. W. WASE

Fig. 1 . Kidney of animal treated with uranium. Lesions confined to proximal convoluted tubes and cyst

formation. 25 X .

Results. The animals of Group B (U plus cortisone) began to die on the twelfth

day of the experiment. All were dead on the 13th day. Animals in Groups A, C and D survived and exhibited good health up to 60 days, when they were all killed for histological examination.

Members of Group A (U only) showed the usual typical nephrosis of the proximal convoluted tubes, characterized by loss of nuclei, oedema and cast formation (fig. 1). The distal tubes were without damage. Histological examination of liver, heart, spleen, lungs, bone-marrow, brain, pancreas and genitalia revealed no abnormalities.

Menqbrrs of Group B (U plus cortisone) exhibited an extensive nephrosis not confined to the proximal tubes, but extending the whole length of the nephron (fig. 2). Extensive cast formation and dilation were observed. Erythrocyte infiltration into the glomeruli was noted. Besides this pan- nephritis, the liver showed extensive fatty metamorphosis and pleomor- phism of the nuclei (fig. 3). In the spleen, there was a marked shrinkage of the malpighian bodies, and the sinusoids were filled with large clumps of hemosiderin pigment, indicative of haemolysis. In the lungs, there were observed focal areas of haemorrhage and fibroblastic proliferation at the

TOXICITY OF U R A N I U M 153

Fig. 2 . Kidney of animal trc,il<tl wi!h iir:iui!.lni plus cortisonc. Extensive lesions in proxiinal and distal lubes, ~.)cdcm:i, haemorrtiage and

cast formation. Some glonicrular daiiiagc. -3.5 X .

Fig. 3. Liver after uranium-cortisone treatment. Fatty infiltration and nuclear pleomorphism. 25 x

Acta phannacologica. vol. 17, fasc. 2. 11

154 J . CARDENAS A N D A. W. WASE

Fig. 4. Cardiac tissue from uranium-cortisone treated mice. Notc early myocardial necrosis, disruption of myocardial fibres, lymphocytic

and potymorphonuclear infiltration. 175 X.

level of the alveolar walls. In the adrenals, moderate hyperplasia of the cortex was observed. In this group, all animals (100%) had myocardial lesions characterized by necrosis with polymorphonuclear and lymphocytic infiltration (fig. 4). Some animals exhibited extensive myocardial necrosis with calcification (fig. 5). The aorta was not involved. Histological examination of brain, bone-marrow, gastro-intestinal tract, pancreas and genitalia revealed nothing abnormal.

Members of Group C (cortisone only) exhibited involution of the lymphoid organs. Some of the animals showed widespread infections, with lymphocytic and polymorphonuclear infiltration of the organs. With the exception of myocardial necrosis and calcification, found in 20% of the animals, no notable histological changes were observed. Members of Group D (environmental control) showed no pathological changes or abberations in any way assembling those of the other groups.

Discussion. Physiopathologically, the potentiation of uranium toxicity by cortisone

can be explained on the basis of an early kidney lesion that impedes the excretion of uranium. This tentative explanation implies that the cortisone

TOXIClTY OF U R A N I U M 155

Fig. 5 . Advanced myocardial necrosis with extensive calcification after uranium - cortisone administration. 25 x .

increased tissue permeability, thereby permitting extended toxic effects by favoring greater metal-to-protein-binding in tissues other than the common target, i. e., the kidney. In reference to the heart pathology, it has been reported (SELYE 1959) that fatal myocardial lesions, similar to those observed in these experiments, can be produced by steroid-electrolyte interaction. In the experiments of Selye, NaH2P04 was administered orally, at 300 mg doses twice daily, with various amounts of steroid. Recently (CRAIG 1959) has indicated that phosphate loading alone will rapidly produce pathological changes in the Kidney. The low doses of uranyl ion and the fact that it is a cation indicate that the mechanism of action in these experiments is different and peculiar to uranium and cortisone. Repeated experiments, with twice the dose of cortisone meil- tioned above, gave precisely the same results. Hence it would appear that cortisone action was optimal at the 0.5 mg dose. Regardless of mode of action, these results indicate that cortisone markedly potentiates the toxicity of uranium ; consequently cautious use of corticoids on persons exposed to uranium is advised.

11 a

156 J. CARDENAS AND A. W. WASE

Summary. Cortisone-treated animals were found to be more sensitive to sub-acute

toxic doses of uranium than were non-treated animals receiving the same dose of uranium. The lesions extended beyond the target tissue, the kidney, and included the liver, the spleen and the heart.

R E F E R E N C E S Bernard, S. R.: Herilth Physics, 1958, Vol. 1, p. 288. Craig, J. M.: A.M.A. Arch. Pathology, 1959, Vol. 68, p. 306. Eiscnbud, M. & J. A. Quigley: Internotional Conference U I I the Peacefirf Uses

Seiye, H.: “The Chemical Prevention of Cardiac Necroses” 1958, pp. 64-81,

Tannenbaum, A. : “Toxicology of Urotiiicm” 1951. McGraw-Hill, New York. Voegtlin, C. & H. C. Hodge: “Pharmcrcology arid Toxicology of Urcinium

of Atonirc Energy, 1956, Vol. X111, United Nations, New York.

Ronald Press, New York.

Compoundb” 1953, McCraw-Hill, New York.