Marcia W. Rosenthal

Intracellular plutonium: removal by liposome-encapsulated chelating agent.

Chelating agents, such as ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA) were successfully encapsulated within lipid spherules (that is, liposomes). Encapsutlated [14C]EDTA, given intravenously to mice, was retained longer in tissues that nonencapsulated [14C]EDTA. Encapsulated DTPA, given to mice 3 days after pluttonium injection, removed an additional fraction of plutonium in the liver, presumably intracellular, not available to nonencapslulated DTPA. It also further increased urinary excretion of plutonium. Introduction of chelating agents into cells by liposomal encapsulation is a promising new approach to the treatment of metal poisoning

Influence of DTPA therapy on long-term effects of retained monomeric plutonium: comparison with polymeric plutonium.

In mice given a single intravenous injection of 2.6 μCi of monomeric239 Pu (IV) per kilogram, 30% was in the bone from 6 to 90 days, and 21% at 300 days; 82% of the mice had at least one malignant bone tumor at death. In a second group receiving the calcium form of diethylenetriaminepentaacetic acid (DTPA) daily for 12 days, beginning 3 days after plutonium, the skeletal plutonium was reduced to 14% of the injected amount, and the final tumor incidence was 75%. In a third group, in which DTPA treatment was initiated 1 hour after plutonium, the skeletal burden was reduced to 7% of the injected amount, and the final tumor incidence was 60%. Only 1% of DTPA-control mice had a bone tumor. Average survival times after injection in these four groups were 361, 450, 556, and 650 days. The death rate of mice with bone tumors increased both with age and with time elapsed after plutonium; it decreased with decreasing plutonium concentration in bone after DTPA. DTPA removed approximately equal fractions of plutonium ...

Tissue distribution of monomeric and polymeric plutonium as modified by a chelating agent.

Mice injected with a polymeric (colloidal) solution of plutonium retained more of the radioelement in the liver and spleen and less in the bone than did mice injected with a monomeric plutonium solution. After daily diethylenetriaminepentaacetic acid therapy was initiated three days later, the bone levels of the radioelement were reduced about one-half in each case. The liver burden of mice injected with the monomeric form of plutonium was nearly completely removed after a few days of treatment, but that of mice injected with the polymeric form was reduced slowly and by only about one-third. In the case of the monomeric form of plutonium all the fecal plutonium was derived from the liver in both control and treated mice, while the urine contained plutonium from the other soft tissues and also from the bone of the treated animals. (auth)

Deposition patterns and toxicity of plutonium and americium in liver.

The deposition and retention of plutonium and americium in the mammalian liver after administration of about 5 pCi/kg or less are briefly reviewed. Inferences are drawn regarding physiological mechanisms and radiotoxic consequences. The initial deposition patterns, but not the retention patterns, of plutonium and americium in the liver are generally similar in a variety of species. The major biological process responsible for the variable and non-uniform hepatic deposition appears to be phagocytosis. The amount of radionuclide phagocytized is dependent upon the extent of hydrolysis and polymerization of the administered actinide. The different biological half-times of plutonium and americium in the liver of different species suggest that there may be species differences in phagocytic function, protein binding, etc. The main route of elimination of plutonium (and probably americium) is via the bile and feces. There is a gradual aggregation of radionuclide by Kupffer cells and, at least in the mouse, also by parenchymal cells. This aggregation is believed to result from a repeated sequence of phagocytosis, irradiation death of the phagocyte, and rephagocytosis. In the mouse and dog, 20 nCi of 239Pu or =lAm per gram of liver appears to be the threshold concentration that results in sufficient radiation-induced tissue damage to produce accelerated radionuclide loss into the blood, and translocation to the skeleton. In man it is postulated that progressive aggregation of low levels of actinide in the liver could also lead to radiation damage and subsequent translocation to critical osteogenic bone surfaces.

DISTRIBUTION AND REMOVAL OF MONOMERIC AND POLYMERIC PLUTONIUM IN RATS AND MICE

SummaryMice and rats were injected intravenously with monomeric or polymeric 239Pu (IV). Both species deposited about three-quarters of the injected polymeric Pu and about one-third of the monomeric Pu in the liver. In bone, rats deposited approximately twice as much Pu as mice, 12 per cent versus 6 per cent of injected polymeric and about 60 per cent versus 24 per cent of monomeric Pu. By 12 days untreated rats had lost no Pu from bone, but about one-half of the monomeric Pu from liver. By 90 days the rat liver had lost one-half and the mouse liver one-quarter of the deposited polymeric Pu. DTPA-therapy in rats, from the third to the eleventh day, removed about one-half of both forms of Pu deposited in bone. From liver, DTPA removed all but 1·5 per cent of injected monomeric Pu, but none of the polymeric Pu. In rats which received the same experimental regimen, femurs and tibias had the same specific activity.

Removal of Polymeric Plutonium by DTPA Directed into Cells by Liposome Encapsulation

DTPA (diethylenetriaminepentaacetic acid) encapsulated within lipid spherules (liposomes) removes more plutonium (Pu) from the liver and femurs of mice injected with polymeric Pu than conventional nonencapsulated DTPA. A single intravenous injection, 3 days after Pu injection, of 100 mg/kg of the calcium trisodium salt of DTPA encapsulated in liposomes made with phosphatidylcholine and cholesterol (3:1) reduced the Pu in liver to 43-51% of the control level at 10 days, compared to 60% after injection of nonencapsulated DTPA. It reduced the Pu in the femurs to 60.4-62.5% of the control level, compared to 83-113%. Liposomal DTPA was equally effective when given intraperitoneally, or when stored for 3 days before use. Liposomal DTPA at doses as low as 25 mg/kg was not significantly less effective than a higher dose of 100 mg/kg. Four once-weekly injections of liposomal DTPA continued to give improved removal of Pu compared to conventional DTPA. When given 24 days after Pu, liposomal DTPA had a greater advant...

INFLUENCE OF DTPA THERAPY ON LONG-TERM EFFECTS OF RETAINED PLUTONIUM

Daily injections of diethylenetriaminepentaacetic acid (DTPA), begun 3 days after administration of Pu/sup 239/ to mice, were continued for 1 to 12 days. Significant increase in survival followed 8 or 12 days of DTPA. Twelve days of therapy removed 43.2% of the Pu from the bone by the end of the treatment period and reduced the fraction of mice with bone tumors by 42.5% at the time the last control had died. Two days of therapy had less effect on removal and tumor incidence. Bone tumor expectancy increased with time after the administration of Pu. (C.H.)

Induced accumulation of citrate in therapy of experimental lead poisoning.

Summary The concept of interference in a metabolic cycle as a means of modifying metal toxicity has been tested. The accumulation of citric acid in certain soft tissues of the rat has been induced by administration of small, non-lethal doses of sodium fluoroacetate. This has been found to give partial protection to rats acutely poisoned with lead nitrate. Of rats given the LD90 of lead nitrate, 53% survived when treated with sodium fluoroacetate. The LD50 of lead nitrate was increased from 58.2 mg/kg (as Pb) in saline controls to 67.7 mg/kg in fluoroacetate-treated rats.

Comparison of antipyretic activity of salicylic and aurintricarboxylic acids.

Summary The antipyretic effects of salicylic acid and of a structurally related compound, the dye aurintricarboxylic acid (ATA), were compared in rats with fevers induced by subcutaneous injection of yeast. The two compounds had comparable effects on fever and, when injected together, their effects were additive. ATA had a more transient effect, reduced the temperature of rats without fevers, and reduced fevers by a specific amount rather than to a specific temperature as did salicylate. These differences led to the postu-lation of a direct peripheral action of ATA.

EFFECT OF DESFERRIOXAMINE B-METHANE SULFONATE (DFOM) ON REMOVAL OF PLUTONIUM IN VITRO AND IN VIVO.

Summary An ultrafiltration screening technique was used to determine the effectiveness of desferrioxamine B-methane sulfonate (DFOM), a therapeutic agent that forms complexes with ferrous and ferric iron, in binding plutonium under physiological conditions. Although DFOM increased the fraction of plutonium ultrafilterable from blood plasma, the only effects when given intra-peritoneally to plutonium-poisoned mice were the prevention of further uptake of plutonium in the bone after initiation of therapy and a small rise in urinary plutonium.