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ENHANCED NEUROTOXICITY OF 3,3-IMINODIPROPIONITRILE FOLLOWING PRETREATMENT WITH CARBON TETRACHLORIDE IN THE RAT
Citation:
Llorens, J. AND K. Crofton. ENHANCED NEUROTOXICITY OF 3,3-IMINODIPROPIONITRILE FOLLOWING PRETREATMENT WITH CARBON TETRACHLORIDE IN THE RAT. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-91/270 (NTIS PB92113323).
Description:
The present work tested the hypothesis that IDPN must be metabolized by the liver to an active metabolite to neurotoxic. Thus a reduction in IDPN neurotoxicity would be expected when liver function is compromised. ale rats were given ip injections of saline, 100 (IDPN1) or 200 (IDPN2) mg/kg of IDPN for three days. Half of the animals in each IDPN dose group received corn oil po and the other half 1 g/kg of the hepatoxicant carbon tetrachloride (CC14) for three days, starting one day before IDPN administration Motor activity and acoustic startle response (ASR) were monitored prior to, and 1,3,9 and 16 weeks after IDPN exposure. n observational rating score was obtained at 1,3 and 9 weeks. Auditory thresholds for 5-and 40-kHz tones were estimated by reflex modification procedures at 10 weeks. nimals receiving IDPN2 alone displayed the overt behavioral signs characteristic of IDPN intoxication (postural disturbances, head dyskinesias, backward walking, circling, increased motor activity, and decreased ASR.) They also showed weight loss, hyperactivity, a transient rearing deficit, decreased ASR amplitudes and elevated auditory thresholds for low- and high-frequency tones. one of these symptoms were observed in the animals treated with CCl4 alone, and only a mild transient ffect on the observational rating score was shown by the IDPN2 alone animals. n contrast, IDPN1/CCl4 resulted in the same or higher toxicity than the IDPN2 treatment. DPN2/CCl4 resulted in severe toxicity (38% mortality over a two-week period) and enhanced body weight and behavioral effects compared to IDPN2 alone group. mpairment of xenobiotic biotransformation was confirmed by elevated pentobarbital sleeping time in animals under the same CCl4 dosing regimen. n conclusion, pretreatment with hepatotoxic dosages of CCl4 leads to increased toxicity of IDPN. his suggests that hepatic transformation of the chemical is not required for the manifestation of IDPN induced neurotoxicity, but instead may be involved in the detoxification of this compound.