Predicting Dose-Response Relationships of Acute Cadmium Hepatoxicity and Metallothionein Regulation in the Rat Via In Vitro to In Vivo Extrapolation

The purpose of this effort was to utilize cadmium, a known toxicant of environmental and occupational concern, to develop an understanding of the relationships between chemical kinetics (rates of chemical movement into the body) and cellular dynamics (cellular response to chemical entering the cells) in order to predict early target organ toxicity and refine/validate a biologically-based kinetic model. This effort involved three studies. The first measured cadmium kinetics over 24 hours in male Fischer 344 rats dosed intravenously with 0.0, 0.5, 1.0, 2.0 or 3.0 mg/kg Cd. Serum liver enzymes and histology were also monitored to determine the extent of hepatic damage. The second evaluated metallothionein (MT) mRNA regulation in these rats in response to the Cd toxicity. MT isoforms I and II were found to be separately regulated. In the third, male F344 rat hepatocytes were isolated and exposed to Cd in vitro at doses of 0 microM, 5 microM, 10 microM and 15 microM. MT mRNA expression in these hepatocytes was not similar to the in vivo response.