Toxicity of subacute intravenous manganese chloride administration in beagle dogs.
Manganese (Mn), a naturally occurring essential trace element, is currently being used as a metal complex for pharmaceutical and magnetic resonance imaging agents. Despite its popularity in these practices, minimal attention has focused on possible toxicity of released free Mn ions, 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 toxicologic 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 dose of Mn typically administered in some of the Mn-complexed agents. All routine toxicologic endpoints were evaluated, including cardiovascular parameters. This dosing regimen resulted in the death or moribund sacrifice of all the animals within 4 days of initiation of treatment. Clinical evidence of toxicity included loss of appetite, reduction in blood 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 severe hepatotoxicity, which was characterized by massive hepatocellular necrosis, periportal hemorrhages, and mild biliary epithelial hyperplasia. These results indicate that acute treatment of beagle dogs with MnCl2 causes severe hepatotoxicity and hypotension with reflex tachycardia and suggest that dogs are very sensitive to toxic effects of Mn.
Khan
K N
KN
Regulatory Drug Safety, Searle R&D, Skokie, Illinois 60077, USA. nkkhan@searle.monsanto.com
Andress
J M
JM
Smith
P F
PF
D000818:Animals; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D002712:Chlorides / Q000008:administration & dosage* / Q000633:toxicity*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D007262:Infusions, Intravenous; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D017895:Manganese Compounds / Q000008:administration & dosage*; D020149:Manganese Poisoning; D013534:Survival
D002712:Chlorides; D017895:Manganese Compounds; C025340:manganese chloride