Arthur Lindenbaum

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 ...

A Survey of Naturally Occurring Chelating Ligands

It can be no great exaggeration to describe chelation as a seminal concept in modern biochemical theory and practice. Beginning with the work of Werner (A. Werner (1893), Anorg. u. Allgem. Chem., 3, 267; (1901), Ber., 34, 2584), and extending through the illuminating organic, physical-chemical, and pharmacological studies of such pioneers as Schwarzenbach, Martell, and Albert, the idea of molecular rearrangements, alterations in charge, conformational changes, etc., undergone by both metal and organic ligands as a result of their interaction to form complexes and chelate structures could not help but evoke visions of biological control, especially with respect to the action of enzymes and drugs. By now, several thousand papers dealing with chelation phenomena in living systems have appeared in the literature, and no modern textbook of biochemistry or pharmacology is without numerous examples of chelation reactions between metals such as calcium, magnesium, iron, zinc, copper, manganese, molybdenum, cobalt, or chromium, and organic metabolites ranging in complexity from glycine to coenzyme-mediated enzymes.

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.

Marrow Deposition and Distribution of Monomeric and Polymeric 239pu in the Mouse, Estimated by Use of 59fe

Abstract Iron-59 has been used in mice as a tracer for bone marrow to extrapolate from the plutonium measured in a standard sample of tibial marrow to the plutonium in total marrow 5–6 days after intravenous injection of different physical-chemical forms of plutonium. A factor of 44 was obtained for conversion of the radioactivity measured in the tibial sample to total body marrow. Using this factor, and calculating the total skeletal plutonium burden as the amount measured in two femurs times 13, one can calculate the proportion of skeletal plutonium located in the marrow. For monomeric, mid-range polymeric and highly polymeric plutonium, values of 2, 7, 5 and 62 %, respectively, were obtained. Similarly, for monomeric americium and a highly polymeric americium, 1 and 20 % of the total skeletal burden was calculated to be in the marrow. In two experiments, in which monomeric plutonium had been found to be about twice as carcinogenic in bone as the mid-range polymeric plutonium, the amount ofplutonium in all the bones and spinal segments was measured at 15 days. Using these data and the 59Fe measurements, we have calculated and tabulated the marrow content of these two forms of plutonium throughout the skeleton. The total marrow burdens, calculated from the tibial samples, were 0.796 % of the injected monomeric vs 3.66 % of the mid-range polymeric plutonium. These amounts were 2.35 vs 14.3 % of the amount of plutonium measured in the total skeleton, respectively.

Studies on the mechanism of protection by aurintricarboxylic acid in beryllium poisoning. III. Correlation of molecular structure with reversal of biologic effects of beryllium.

Abstract More than seventy different substances have been tested to ascertain the relations between the number, kind, and position of functional groups, and the ability of an organic molecule to reverse two biologic effects of Be—the inhibition of plasma alkaline phosphatase and death in acutely poisoned mice. All compounds that failed to reverse the Be-induced inhibition of the enzyme also lacked antidotal activity. On the other hand, a compound that reversed the enzymatic inhibition did not necessarily protect mice from Be poisoning. The effectiveness of a molecule in reversing the biologic effects of Be is dependent upon a number of chemical and biologic factors, including the ability to form a stable five- or six-membered chelate ring with Be, molecular size, presence of hydrophilic groups, proton affinity of chelating groups, metabolism, and toxicity.

Alpha counting by liquid scintillation spectrometry: plutonium-239 in animal tissues.

A liquid scintillation method has been developed for the determination of microcurie and picocurie levels of plutonium-239 and other alpha-emitting radionuclides in animal tissues. A commercially available liquid scintillation spectrometer is used, and nearly 100% counting efficiency is achieved. Transfer losses and dilution of activity are avoided by preparation of the entire tissue sample, rather than an aliquot, in the counting vial to be used for the analysis. Organic matter is removed by alternating acid digestion with heating in a mufflle furnace. Optimal ashing conditions and instrumental parameters were determined for the analysis of plutonium in bone, liver, spleen, feces, and urine. In several comparisons of analytical results by liquid scintillation and by proportional counting, close agreement between the two methods was obtained. However, the liquid scintillation method is less laborious and time-consuming, yields closer replication of analytical values, and permits more analyses per experime...

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.

Toward an optimal DTPA therapy for decorporation of actinides: time-dose relationships for plutonium in the dog. I.

Studies have been performed to provide data needed for the development of an optimal protocol for the clinical application of DTPA (diethylenetriaminepentaacetic acid) for treatment of humans accidentally exposed to certain actinide radioelements such as plutonium (Pu). Groups of two or three beagle dogs previously injected intravenously with 0.3 μCi/kg monomeric

HEPARINIC ACIDS: DETERMINATION OF EQUIVALENT WEIGHTS AND SULFATE TO CARBOXYL RATIOS.

{}^{239}{\rm Pu}\text{-citrate}