Disposition and toxicity after oral and intravenous administration of cobalt naphthenate and cobalt chloride in rats

Abstract

The objective of this study was to determine the absorption and disposition in rats of two cobalt compounds: cobalt chloride, an aqueous-soluble compound, and cobalt naphthenate, an aqueous-insoluble compound. Their in vitro dissolution rates were investigated to determine whether they correlate with their toxicity. Dissolution of cobalt naphthenate was strongly media and pH dependent and showed increased dissolution in the presence of protein and at low pH. Cobalt oxide, an aqueous-insoluble cobalt compound, was unaffected by solution conditions. The in vitro alveolar macrophage results indicated that compounds added as particulates were more cytotoxic than those added in solution. Cobalt chloride was the most cytotoxic and cobalt oxide the least. These results suggest that the order of in vitro cytotoxicity to alveolar macrophages may be predicted from their in vitro dissolution behavior. When the in vitro dissolution of the cobalt compounds was tested at a pH of 2 to model the environment inside the stomach, the dissolution of cobalt naphthenate and cobalt chloride was identical. This indicated that oral exposure to cobalt naphthenate could result in essentially complete dissociation of cobalt at gastric pH. The distribution and elimination of cobalt naphthenate was identical to that of an equivalent Co(II) dose of cobalt chloride. The oral blood cobalt concentration curves were triphasic and exhibited similar pharmacokinetic parameters. Following intravenous administration, approximately 10% of the dose was found in the feces, indicating that cobalt can be secreted in the bile. The intravenous cobalt concentration curve was also triphasic with a terminal elimination half-life of 19.0 hr. Intestinal ring incubation experiments indicated that cobalt transport has both active and passive components. The finding that uptake was saturable may explain the small degree of absorption following oral dosing. The results of the heme oxygenase assays indicated that subcutaneous and intravenous administration resulted in increased activity over controls at an equivalent hepatic Co(II) content. Thus, these results demonstrated that the extent of cobalt absorption across the gastrointestinal tract is incomplete and that concentration and route of exposure may determine its systemic toxicity.