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 long term low level exposure in humans based on annual data involving short-term high-level exposures. Uncertainties in extrapolation can be, in part, based on potentially different mechanism associated with different exposure scenarios. This study evaluated the adequacy of short-term exposures to acrylamide for predicting neurotoxicity produced by long-term exposures. The neurotoxic effects of acrylamide (ip) were assessed in 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. Histological examination of sciatic nerve and spinal cord was also performed. 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. Behavioral endpoints showed both qualitative and quantitative changes as a function 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 acrylamide in the target tissue. The less than strict cumulative toxicity of acrylamide may result from an interaction between administered dose, tissue damage, and repair processes.
Crofton
K M
KM
Neurotoxicology Division, National Health Effects and Environmental Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27709, USA.
Padilla
S
S
Tilson
H A
HA
Anthony
D C
DC
Raymer
J H
JH
MacPhail
R C
RC
D020106:Acrylamide; D000178:Acrylamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D001299:Audiometry; D001303:Auditory Cortex / Q000187:drug effects; D001309:Auditory Threshold / Q000187:drug effects; D001369:Axons / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D018737:Hand Strength / Q000502:physiology; D006454:Hemoglobins / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009498:Neurotoxins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D013216:Reflex, Startle / Q000187:drug effects; D012584:Sciatic Nerve / Q000187:drug effects* / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology; D014018:Tissue Distribution
D000178:Acrylamides; D006454:Hemoglobins; D009498:Neurotoxins; D020106:Acrylamide