A Physiologically Based Dosimetry Description of Acrylonitrile and Cyanoethylene Oxide in the Rat

Abstract

The cytochrome P450-mediated oxidation of acrylonitrile (ACN) to the mutagen 2-cyanoethylene oxide (CEO) is thought to be important for the carcinogenic effects of ACN in rats, while glutathione (GSH) conjugation of ACN and CEO is regarded as detoxication. A physiologically based dosimetry description for ACN and CEO in the male F-344 rat has been developed from in vitro data and studies of the iv pharmacokinetics of ACN and CEO. The dosimetry description includes tissue partition coefficients and in vitro estimates of the rates of reaction of ACN and CEO with hemoglobin and blood macromolecules and the reaction of CEO with tissue GSH. Metabolic parameters for ACN and CEO were estimated from iv pharmacokinetic studies. Rats were given bolus doses of 3.4, 47, 55, or 84 mg ACN/kg via the femoral vein and blood samples were collected at selected time points. ACN and CEO blood concentrations were determined by gas chromatography. The iv pharmacokinetics of CEO were also determined using 0.6 or 5.3 mg CEO/kg. ACN elimination from blood was described by saturable P450 epoxidation ( V max of 6.5 mg/hr/kg and K m of 1.5 mg/liter) and first-order GSH conjugation (30 hr −1/kg). CEO elimination was described by first-order GSH conjugation (750 hr −1/kg). Calculation of hepatic clearance values shows first-pass hepatic extractions of 61 and 90% for ACN and CEO, respectively. The dosimetry description accurately simulated the dose-dependent urinary excretion of ACN metabolites derived from epoxidation to CEO and from direct GSH conjugation of ACN. The dose-dependent formation of hemoglobin adducts from ACN was also well simulated.