THE IMPACT OF DOSE-RATE ON THE NEUROTOXICITY OF ACRYLAMIDE - THE INTERACTION OF ADMINISTERED DOSE, TARGET TISSUE CONCENTRATIONS, TISSUE-DAMAGE, AND FUNCTIONAL-EFFECTS

Health agencies are often required to predict the effects of longterm low-level exposure in humans based on animal data involving short-term high-level exposures. Uncertainties in extrapolation can be, in part, based on potentially different mechanisms associated with different e xposure scenarios. This study evaluated the adequacy of short-term exp osures to acrylamide for predicting neurotoxicity produced by long-ter m exposures. The neurotoxic effects of acrylamide (ip) were assessed i n rats after acute (0-150 mg/kg), 10-day (0-30 mg/kg) 30-day (0-20 mg/ kg), and 90-day (0-10 mg/kg) exposures. Behavioral endpoints included motor activity, grip strength, and the acoustic startle response. Hist ological examination of sciatic nerve and spinal cord was also perform ed. Internal and target tissue doses were estimated by measurement of the concentration of acrylamide in serum and sciatic nerve. Functional and pathological results demonstrated that the effects of acrylamide depended on the dose rate and that the neurotoxicity of acrylamide was less than that predicted by a strict dose x time relationship. Behavi oral endpoints showed both qualitative and quantitative changes as a f unction of dose rate. Recovery of behavioral function in these studies was independent of the duration of dosing. Because duration of dosing had no impact on the kinetics of acrylamide, these data indicate that the toxicity of acrylamide is not due to an accumulation of acrylamid e in the target tissue. The less than strict cumulative toxicity of ac rylamide may result from an interaction between administered dose, tis sue damage, and repair processes. (C) 1996 Academic Press, Inc.