TOXICITY OF SUBACUTE INTRAVENOUS MANGANESE CHLORIDE ADMINISTRATION INBEAGLE DOGS

Manganese (Mn), a naturally occurring essential trace element, is curr ently being used as a metal complex for pharmaceutical and magnetic re sonance imaging agents. Despite its popularity in these practices, min imal attention has focused on possible toxicity of released free Mn io ns, which could occur if these agents decomplexed. There is especially limited information available regarding acute toxicity of Mn in dogs. In this study, we performed an in-depth evaluation of acute toxicolog ic potential of manganese chloride (MnCl2) when administered as a 4-hr /day intravenous infusion to male beagle dogs. The dose of MnCl2 used (16 mg/kg/day) was equivalent to approximately 3-5 times the daily dos e of Mn typically administered in some of the Mn-complexed agents. All routine toxicologic endpoints were evaluated, including cardiovascula r parameters. This dosing regimen resulted in the death or moribund sa crifice of all the animals within 4 days of initiation of treatment. C linical evidence of toxicity included loss of appetite, reduction in b lood pressure with reflex tachycardia, and a marked increase in liver enzymes, beginning with the first dose and increasing in severity with successive doses. Gross and histopathologic evaluations confirmed sev ere hepatotoxicity. which was characterized by massive hepatocellular necrosis, periportal hemorrhages, and mild biliary epithelial hyperpla sia. These results indicate that acute treatment of beagle dogs with M nCl2 causes severe hepatotoxicity and hypotension with reflex tachycar dia and suggest that dogs are very sensitive to toxic effects of Mn.