ACUTE TOXICITY OF TOLUENE IN MALE AND FEMALE RATS:A SINGLE ORAL DOSE EXPOSURE 2-WEEK STUDY

Abstract

The Agency for Toxic Substances and Disease Registry (ATSDR) has identified the oral route as the primary route of exposure, and neurotoxicity as the endpoint of concern, in the priority data needs for toluene. The acute oral neurotoxicity of toluene was investigated in male and female Sprague-Dawley rats. Dose selection was made relative to a benchmark dose (BD). The BD was defined as the maximum nonlethal neurotoxic dose and was examined by range-finding studies. The 3 oral (gavage) doses were 3.0 ml/kg (50% BD), 4.5 ml/kg (75% BD), and 6.0 ml/kg (100% BD). To characterize its neurotoxicity, a functional observational battery (FOB) and spontaneous motor activity (SMA) were measured on d 1 (2-3 h and 4-7 h postexposure times for FOB and SMA, respectively), 7, and 14 following toluene administration. The data indicate that on d 1, when compared with the saline controls, toluene-exposed rats (males at 4.5- and 6.0-ml/kg doses and females at 6.0-ml/kg dose) exhibited significantly ( p <.05) greater horizontal (HZ) and stereotype (ST) motor activities. However, vertical (VT) activity was significantly ( p < .01) depressed in both sexes at all doses. FOB data indicated that on d 1, toluene-treated male rats exhibited dose-dependent increases in abnormal gait (1/10 rats at 3-ml/kg, 2/ 10 rats at 4.5-ml/kg, and 7/10 rats at 6-ml/kg toluene doses). Abnormal gait was present in 5/10 females at 3 ml/kg and 6/10 females at both 4.5- and 6-ml/ kg toluene doses. The open-field rearing scores were lower than controls in all toluenetreated groups on d 1, and this was perhaps due to abnormal gait manifested by the rats. On d 7, toluene-treated males at 3- and 4.5-ml/kg doses exhibited significantly ( p <.05) greater HZ and VT motor activities when compared with saline controls. Females rats showed HZ and ST activities very similar to controls, but there was a significant decrease ( p <.05) in VT activity in all toluenetreated females on d 7 compared to saline controls. FOB data indicated that rearing scores were higher than control in all toluene-treated rats;however, gait was normal in all animals on d 7. By d 14, there were no significant differences, except VT activity in the female rats was still significantly depressed at 3- and 4.5-ml/kg doses. FOB results on d 14 were similar in toluene-treated rats to those of controls. The d 1 data show the acute immediate effects after administration of the solvent, whereas postexposure d 7 and 14 data depicted delayed or persistent toxic effects after a single exposure.