Developmental neurotoxicity evaluation of acrylamide in Sprague-Dawley rats.
Based on the literature to-date, the potential of acrylamide (ACRL) to cause developmental neurotoxicity in laboratory animals has not been assessed. We examined this potential in Sprague-Dawley rats using a study design similar to that proposed by the USEPA. Dosages of 0 (deionized water), 5, 10, 15, or 20 mg/kg/day were administered at 5 ml/kg by oral gavage from gestational day 6 to lactational day 10 to groups of 12 mated females each. Females were allowed to deliver and the offspring were evaluated for survival, growth, development, behavior, and histological changes to brain, spinal cord, and peripheral nerve. Behavioral assessments consisted of open-field motor activity, auditory startle habituation, and passive avoidance tests during both the preweaning and adult periods (1 animal/sex/litter). All F0 and F1 animals in the 20 mg/kg/day group were euthanized early in the lactation period due to high pup mortality. Significantly increased pup mortality was also present in the 15 mg/kg/day group. There were dose-related decreases in average F0 maternal body weight gains during the dosing period in the 10, 15, and 20 mg/kg/day groups, and characteristic hindlimb splaying was observed in dams of the two highest dosage groups. Pup body weight proved to be the most sensitive indicator of developmental toxicity. Dose-related decrease in preweaning average weights were observed at all dose levels, although only transiently in the 5 mg/kg/day group. Average weight gain during the postweaning period was significantly decreased only in males of the 15 mg/kg/day group. Significant decreases in average horizontal motor activity and auditory startle response were observed only in weanlings of the 15 mg/kg/day group. The only behavioral effect in F1 adult animals was a decrease in auditory startle response in females of the 15 mg/kg/day group. There were no effects in the passive avoidance test or in the histological examination of the nervous system of preweaning pup or adult animals. Based on these results, the NOAEL (No Observed Adverse Effect Level) for developmental toxicity is less than 5 mg/kg/day, the NOAEL for maternal toxicity is 5 mg/kg/day, and that for developmental neurotoxicity is 10 mg/kg/day. Thus behavioral changes in the offspring were observed only at a dose which was also maternally toxic. These results suggest that acrylamide may be a selective developmental toxicant but not a selective developmental neurotoxicant, because a conventional measure of offspring toxicity (i.e., pup body weight) was affected at a dosage lower than that which produced maternal effects or offspring behavioral effects.
Wise
L D
LD
Merck Research Laboratories, Department of Safety Assessment, West Point, PA 19486, USA.
Gordon
L R
LR
Soper
K A
KA
Duchai
D M
DM
Morrissey
R E
RE
D020106:Acrylamide; D000178:Acrylamides / Q000633:toxicity*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005069:Evaluation Studies as Topic; D005260:Female; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009420:Nervous System / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects
D000178:Acrylamides; D020106:Acrylamide