Toxicokinetic and toxicodynamic studies of xenobiotics provide a useful contribution to the process of risk assessment 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 dose-response studies. This generalization permits prediction of toxic response 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 at current dose levels but may be at higher doses. The kinetics of oxazepam (OXAZ) has been studied in rats and is being studied in mice. The effect of prefeeding with OXAZ (2500 ppm) on its own elimination was investigated in the F344 rat. Results suggest that multiple or continuous exposure to oxazepam in the diet will only have transient effects on oxazepam kinetics. A physiologically-based pharmacokinetic model is being developed to describe the kinetics of OXAZ in the B6C3F1 mouse. This model will be used to help evaluate risks associated with human exposure to OXAZ.
