Refinement and verification of the physiologically based dosimetry description for acrylonitrile in rats

The physiologically based dosimetry description for acrylonitrile (ACN) and its mutagenic epoxide metabolite 2-cyanoethylene oxide (CEO) in F-344 rats (M. L. Gargas, M. E. Anderson, S.K.O. Teo, R. Batra, T. R. Fennell, and G. L. Kedderis, 1995, Toxicol. Appl. Pharmacol. 134, 185-194) has been refined to include a physiological stomach compartment and the reactions of ACN with tissue glutathione (GSH). The second-order rate constant for reaction of ACN and GSH at pH 7.3 was measured and included in the dosimetry description. Metabolic parameters for ACN and CEO were estimated from oral bolus pharmacokinetic studies and previously obtained iv bolus data (3.4, 47, 55, or 84 mg ACN/kg). Rats were given bolus oral doses of 3, 10, or 30 mg ACN/kg in water, and blood samples were collected at selected time points. ACN and CEO blood concentrations were determined by gas chromatography. The brain and liver concentrations of ACN and CEO were also measured after 10 mg ACN/kg po. ACN elimination from blood was described by saturable P450 epoxidation (Vmax of 5.0 mg/hr/kg and K(M) of 1.5 mg/liter) and first-order GSH conjugation (73 hr(-1)/kg). CEO elimination was described by first-order GSH conjugation (500 hr(-1)/kg). The pharmacokinetic data were well simulated, although CEO blood concentrations after bolus oral dosing were somewhat overestimated. Sensitivity analysis of the dosimetry description indicated that the inhalation exposure route was much more sensitive to changes in metabolic and physiological parameters than either the iv or oral bolus routes. Therefore, inhalation pharmacokinetic data were obtained and compared to simulations of the dosimetry description. Rats were exposed to 186, 254, or 291 ppm ACN for 3 hr. ACN and CEO concentrations were measured in blood, brain, and liver at selected postexposure time points. The dosimetry description accurately simulated the ACN inhalation pharmacokinetic data, providing verification of the parameter estimates. The verified rat dosimetry description for ACN and CEO will be used as the basis for development of a dosimetry description for ACN in people.