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 covalentbinding to tissue protein, were studied as a function of doseand time. Doses administered and responses expected were 20mg/kg (LD0), 50 mg/kg (LD10), 80 mg/kg (LD50), and 115 mg/kg(LD90). Liver GSH was the most sensitive marker of AN exposure.At 80 mg/kg AN, virtually complete depletion of liver GSH wasobserved within 30 min with no recovery through 120 mm. KidneyGSH showed a similar, but less intense depletion; while bloodand brain GSH were more refractory to AN. Whole blood and brainCN rose progressively during the first 60 mm in a dose-dependentfashion. At the lowest dose, CN levels decreased thereafter,whereas, at the three higher doses, CN levels were maintainedor continued to increase through 120 min. At the highest dose,blood and brain CN remained at acutely toxic levels through240 mm. Covalent binding increased rapidly in all tissues duringthe first 30 mm at all doses. At the lowest dose, little additionalcovalent binding was observed beyond 30 mm, while at the threehigher doses, covalent binding increased, although at a slowerrate. The data indicate that these three biologic markers ofacute AN intoxication respond dramatically in a time-dependentmanner in the toxic dosage range. Furthermore, the data provideevidence that AN toxicity is gated by GSH depletion in liverwith the resultant termination of AN detoxification.