Preliminary Evaluation of Toxicologic and Carcinogenic Risks of Copper Gluconate in Rats Given Multiple Carcinogens

The present study was conducted as a preliminary evaluation of toxicologic and carcinogenic risks of copper gluconate and to determine its optimal dose for use in an upcoming study utilizing the medium-term multi-organ carcinogenesis protocol. Male BrlHan:WIST@Jcl (GALAS) rats were initially treated with N-nitrosodiethylamine, N-methylnitrosourea, 1,2-dimethylhydrazine, N-butyl-N-(4-hydroxybutyl)-nitrosamine and 2,2'-dihydroxy-di-n-propylnitrosamine for a total multiple initiation period of 4 weeks. In addition, rats were fed a diet containing copper gluconate at 0, 1000, 3000, 4800, 6000, or 12000 ppm from the commencement for 13 weeks. While no systemic toxicity was detected, hepatic granulomas were observed at copper gluconate doses of 6000 ppm, or greater. Hepatic copper accumulation and metallothionein induction were demonstrated at doses of 3000 ppm and 1000 ppm, respectively, or greater. Putative preneoplastic lesions in the liver appeared to increase at a dose of 12000 ppm, and 8-hydroxydeoxyguanosine formation was enhanced at doses of 6000 ppm, or greater. These results suggest that copper gluconate exerts effects on the liver at the relatively low dietary dose of 1000 ppm and causes hepatic injury at 6000 ppm. The hepatotoxicity and possible hepatocarcinogenicity of copper gluconate may be attributable to oxidative stress due to the impairment of hepatic copper metabolism.