BIOLOGICAL MARKERS OF ACUTE ACRYLONITRILE INTOXICATION IN RATS AS A FUNCTION OF DOSE AND TIME

Three markers of acute acrylonitrile (AN) intoxication, namely, tissue glutathione (GSH), tissue cyanide (CN), and covalent binding to tissu e protein, were studied as a function of dose and time. Doses administ ered and responses expected were 20 mg/kg (LDO), 50 mg/kg (LD10), 80 m g/kg (LD50), and 115 mg/kg (LD90). Liver GSH was the most sensitive ma rker of AN exposure. At 80 mg/kg AN, virtually complete depletion of l iver GSH was observed within 30 min with no recovery through 120 min. Kidney GSH showed a similar, but less intense depletion; while blood a nd brain GSH were more refractory to AN. Whole blood and brain CN rose progressively during the first 60 min in a dose-dependent fashion. At the lowest dose, CN levels decreased thereafter, whereas, at the thre e higher doses, CN levels were maintained or continued to increase thr ough 120 min. At the highest dose, blood and brain CN remained at acut ely toxic levels through 240 min. Covalent binding increased rapidly i n all tissues during the first 30 min at all doses. At the lowest dose , little additional covalent binding was observed beyond 30 min, while at the three higher doses, covalent binding increased, although at a slower rate. The data indicate that these three biologic markers of ac ute AN intoxication respond dramatically in a time-dependent manner in the toxic dosage range. Furthermore, the data provide evidence that A N toxicity is gated by GSH depletion in liver with the resultant termi nation of AN detoxification. (C) 1997 Society of Toxicology.