Toxicokinetic and toxicodynamic studies of xenobiotics are a useful extension of traditional chemical disposition studies in a number of ways. These studies provide a method by which quantitative predictions of systemic exposure to chemicals may be made. They also increase generalization of information obtained from toxicity studies. This generalization permits prediction of toxicity in species other than those tested, including man. The toxicokinetics of two chemicals, methacrylonitrile (MAN) and oxazepam (OXAZ) are currently being investigated in this laboratory. The toxicokinetics of MAN was compared in male Fischer 344 and Sprague-Dawley rats. This comparison was made to determine if differences in toxicity between strains was related to different levels of exposure to MAN or MAN-derived cyanide. The data suggest that the differences in toxicity between strains are not wholly related to exposure to either MAN or cyanide and is more likely attributable to acetone cyanohydrin. The kinetics of oxazepam (OXAZ) is being studied in rats and mice. The effect of prefeeding with OXAZ (2500 ppm) on its own elimination was investigated in the F344 rat. Results show that its elimination is increased relative to controls following 14 days of prefeeding. In contrast, following 28 days of prefeeding, OXAZ elimination is comparable to control values. The increase in elimination at 14 days was not correlated with changes in cytochrome P450 or cytochrome b5. It is speculated that biliary elimination is increased following 14 days of feeding. A physiologically-based pharmacokinetic model is being developed to describe the kinetics of OXAZ in the B6C3F1 mouse. This model will be used to extrapolate results of toxicity and carcinogenicity studies in mice to predict risks associated with human exposure to OXAZ.
