Multivariate time of peak effects assessment for use in selecting time of testing in acute neurotoxicity studies

One of the aims of conducting observational assessments shortly following administration of a test compound is to provide information regarding the profile of acute neurotoxic effects. By limiting the time of peak effects (TOPE) determination to a time range-finding study using only gait and arousal as the end-points for determining time of peak effects, as was proposed in the IPCS/WHO Collaborative Study on Neurobehavioral Screening Methods protocol, it is possible that the time of testing selected for the acute study proper may underestimate other neurotoxic effects which show a different time course. We explored the feasibility of including measures of autonomic activity as well as clonic/tonic movements in the TOPE determination in two experiments using chlorpyrifos and carbaryl as test compounds. A scoring system based on the original operational definitions provided in the IPCS/WHO protocol was devised. Results indicated that there were considerable differences in the time course for autonomic effects and convulsive behavior in comparison to effects on gait and arousal. It is concluded that the use of a multivariate approach for TOPE determination may provide a more comprehensive empirical basis for selecting a testing time for studies designed to profile acute neurotoxic effects.