Cobalt metabolism and toxicology—A brief update

Cobalt metabolism and toxicology are summarized. The biological functions of cobalt are updated in the light of recent understanding of cobalt interference with the sensing in almost all animal cells of oxygen deficiency (hypoxia). Cobalt (Co2+) stabilizes the transcriptional activator hypoxia-inducible factor (HIF) and thus mimics hypoxia and stimulates erythropoietin (Epo) production, but probably also by the same mechanism induces a coordinated up-regulation of a number of adaptive responses to hypoxia, many with potential carcinogenic effects. This means on the other hand that cobalt (Co2+) also may have beneficial effects under conditions of tissue hypoxia, and possibly can represent an alternative to hypoxic preconditioning. Cobalt is acutely toxic in larger doses, and in mammalian in vitro test systems cobalt ions and cobalt metal are cytotoxic and induce apoptosis and at higher concentrations necrosis with inflammatory response. Cobalt metal and salts are also genotoxic, mainly caused by oxidative DNA damage by reactive oxygen species, perhaps combined with inhibition of DNA repair. Of note, the evidence for carcinogenicity of cobalt metal and cobalt sulfate is considered sufficient in experimental animals, but is as yet considered inadequate in humans. Interestingly, some of the toxic effects of cobalt (Co2+) have recently been proposed to be due to putative inhibition of Ca2+ entry and Ca2+-signaling and competition with Ca2+ for intracellular Ca2+-binding proteins. The tissue partitioning of cobalt (Co2+) and its time-dependence after administration of a single dose have been studied in man, but mainly in laboratory animals. Cobalt is accumulated primarily in liver, kidney, pancreas, and heart, with the relative content in skeleton and skeletal muscle increasing with time after cobalt administration. In man the renal excretion is initially rapid but decreasing over the first days, followed by a second, slow phase lasting several weeks, and with a significant long-term retention in tissues for several years. In serum cobalt (Co2+) binds to albumin, and the concentration of free, ionized Co2+ is estimated at 5–12% of the total cobalt concentration. In human red cells the membrane transport pathway for cobalt (Co2+) uptake appears to be shared with calcium (Ca2+), but with the uptake being essentially irreversible as cobalt is effectively bound in the cytosol and is not itself extruded by the Ca-pump. It is tempting to speculate that this could per