Plutonium in vivo and drugs to remove it from man

Abstract

Plutonium-239, an important component of the nuclear fuel cycle, can enter the human body by ingestion, inhalation or by absorption through the skin or a wound. If sufficient quantities are deposited in the body the emitted alpha-particle radiation may induce serious toxic effects, including bone and other tumours. Gastrointestinal absorption is influenced by age, physiological and dietary factors, but in adults it appears unlikely to exceed 0.1% of the ingested amount. Absorption through the intact skin is probably less than 0.01%. However, depending on its chemical form, the absorption of inhaled material from the lungs may range from <5 to 100%. Following entry into the systematic circulation, plutonium deposits to more than 80% in the skeleton plus liver of all the species studied. Skeletal retention of plutonium is prolonged with half-times equal to, or longer, than the normal life span of the species; for man a half-time of 100 years is assumed. In liver both the uptake and the retention show marked species variations. Some species, e.g. dog and chinese hamster, show very prolonged, if not infinite, retention while in others, e.g. rat, tupaia, macaque and baboon, more than 90% of the liver plutonium is lost with half times ranging from a few days to a few months. Into which category man falls is uncertain. Complex formation with biological ligands plays an important role in plutonium metabolism. In blood, plutonium occurs as the complex with the ion-transport protein transferrin and this complex may also play a role in cellular uptake. Within the cells of liver and other tissues plutonium is largely deposited in lysosomal structures and within these structures the metal may be associated with ferritin [1]. Human exposure to plutonium comes principally from the metal which has been released into the atmosphere by nuclear weapon testing. Autopsy data suggest that for the general public the total body content of plutonium lies between about 15 and 50 picograms (35 to 110 milliBequerels). Exposure to higher levels of plutonium may occur amongst workers in the nuclear industries. During the past forty years several hundred workers have acquired body burdens of plutonium ranging from some tens of nanograms to about 4 mg and the health of these people is being carefully monitored. To date no late effects which can confidently be ascribed to plutonium toxicity have been observed [2]. During the past thirty years various treatment regimes designed to reduce the risk of late effects arising from internally deposited plutonium have been proposed; these are all based on the assumption that accelaration of the normally very slow excretion of the metal will lead to a proportionate reduction in the risk of late effects. This hypothesis is not yet fully proven. Many substances have been tested for their ability to remove plutonium but only the polyaminopolycarboxylic acids, especially diethylenetriaminepentaacetic acid (DTPA), have proven to be really effective. DTPA, as the Na 3Ca- or the less toxic Na 3Zn salts, has been used widely and successfully in man and this substance is the current agent of choice for the treatment of plutonium contamination in man. Toxicity presents little problem and the possibility of serious depletion of essential trace metals seems to be small, especially when the Zn salt of DTPA is used. The efficacy of DTPA treatment decreases with increasing time after exposure to plutonium and it has only limited ability to remove inhaled insoluble plutonium from the lungs. Removal of fixed bone deposits is also difficult [3]. Normally DTPA is administered by intravenous injection or infusion, but recently inhalation of an aerosol [4] or oral administration [5] have been shown to be effective in animal studies. The search for more effective agents than DTPA continues. Much interest was shown in a lipophilic derivative of DTPA — Puchel — which, unlike the ionized DTPA species, was able to enter cells. However, despite promising early results, this substance proved to be no more effective than DTPA and to be rather more toxic [6]. Recently new types of linear polycatechoylamino ligands (LICAM's) have been developed which are designed specifically to complex plutonium. Initial studies suggest that these may represent an interesting new approach to plutonium removal, but that their true therapeutic advantage over DTPA for human treatment remains to be assessed [7].