A NONLINEAR DOSIMETRIC MODEL FOR HEMOGLOBIN ADDUCT FORMATION BY THE NEUROTOXIC AGENT ACRYLAMIDE AND ITS GENOTOXIC METABOLITE GLYCIDAMIDE

Hemoglobin (Hb) adducts, formed by the neurotoxic agent acrylamide (AA ) and its genotoxic metabolite glycidamide (GA), were measured in the rat by means of a method for simultaneous determination of the adducts formed to cysteine. A novel, nonlinear dosimetric model was developed to describe Hb adduct formation. This model incorporates the saturabl e kinetics of the metabolic conversion in vivo of AA to GA. The pharma cokinetic parameters V(max) and K(m) and the first-order rates of elim ination, k1 and k2, for AA and GA from all processes except conversion of AA to GA, were estimated directly from Hb adduct data to 19 M hr-1 , 66 mM, 0.21 hr-1, and 0.48 hr-1, respectively. At low concentrations , approximately 60% of AA was metabolized to GA. The nonlinear dosimet ric model for adduct formation has potential general applicability in high-to-low-dose extrapolation of genotoxic effects.