Fw. Benz et al., DOSE DEPENDENCE OF COVALENT BINDING OF ACRYLONITRILE TO TISSUE PROTEIN AND GLOBIN IN RATS, Fundamental and applied toxicology, 36(2), 1997, pp. 149-156
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.