DOSE DEPENDENCE OF COVALENT BINDING OF ACRYLONITRILE TO TISSUE PROTEIN AND GLOBIN IN RATS

The dose dependence of acrylonitrile (AN) covalent binding to tissue p rotein, following a single acute exposure over a 100-fold range in dos e, was measured. Covalent binding was a linear function of AN dose in the lower dose range (0.02-0.95 mmol AN/ kg). The slopes of the dose-r esponse curves indicated that tissues varied by nearly 10-fold in thei r reactivity with AN. The relative order of covalent binding was as fo llows: blood much greater than kidney = liver > forestomach = brain > glandular stomach much greater than muscle. Similar dose-response beha vior was observed for globin total covalent binding and for globin N-( 2-cyanoethyl)valine (CEValine) adduct formation. The latter adduct was found to represent only 0.2% of the total AN adduction to globin. Reg ression of tissue protein binding versus globin total covalent binding or globin CEValine adduct indicated that both globin biomarkers could be used as surrogates to estimate the amount of AN bound to tissue pr otein. At higher AN doses, above approximately 1 mmol/kg, a sharp brea k in the covalent binding dose-response curve was observed. This knot value is explained by the nearly complete depletion of liver glutathio ne and the resultant termination of AN detoxification. The toxicity of AN is known to increase sharply above this dose, The data suggest tha t a comparison of specific tissue proteins labeled by AN above and bel ow this threshold dose may provide some insight into the mechanism of AN-induced toxicity. (C) 1997 Society of Toxicology.