The research goal of this laboratory is to apply toxicokinetic and toxicodynamic principles to methods of data acquisition and interpretation for chemical disposition studies. Two major advantages in the use of kinetic/dynamic principles is the accurate assessment of in vivo exposure to chemical and the potential for extrapolation outside of the conditions tested. Ideally, these studies will permit extrapolation to different dose levels, different routes of administration, and from animal data to human data. This latter factor will be important in the prediction of health risks to humans. The toxicokinetics of methacrylonitrile is being investigated as a first step in establishing aliphatic nitrile kinetic/dynamic structure-activity relationships. The right jugular vein of male F344 rats were cannulated and methacrylonitrile (58 mg/kg, normal saline) was administered via the cannula. Serial blood samples were withdrawn following methacrylonitrile administration. Serum was separated from blood and stored at -8O C until a capillary gas chromatographic assay was used to quantitate methacrylonitrile. Pharmacokinetic parameters were determined by nonlinear regression analysis using a two-compartment model. The clearance of methacrylonitrile is low (7.37 ml/min), which indicates that its kinetics are subject to change with the capacity of liver enzymes to metabolize the chemical. That is, enzyme inducers and inhibitors, and factors such as gender and age may significantly affect methacrylonitrile clearance. In the animals studied, a mean beta half-life of 35 minutes indicates that 99% of an administered dose of methacrylonitrile should be eliminated in less than 5 hours. The volume of distribution at steady-state is about two times that of body water (374 ml), indicating either distribution into more fatty tissues or binding in the tissues.
