Observational Batteries in Neurotoxicity Testing

Abstract

Behavioral evaluations are emerging as a key component in neurotoxicity testing. A neurobehavioral screening battery that is most often used for hazard identification consists of a functional observational battery (FOB) and motor activity. The FOB was developed as an improvement over routine cageside observations: major differences include the specification of observations, operational definitions of the behaviors to be observed, grading the severity of effect, and location of observations (open arena vs. home cage). A typical FOB protocol consists of approximately 20 to 30 end points, allowing for the detection and description of a range of neurobehavioral changes. We have focused on assessing critical characteristics (i.e., sensitivity, specificity, validity, and reproducibility) of these tests. Concerns have been raised as to the validity and reliability of observational methods for neurotoxicity screening. These tests were therefore the focus of an international collaborative study, sponsored by the International Programme on Chemical Safety (IPCS). The purpose of the IPCS study was to assess the general utility and reliability of neurobehavioral screening procedures in a diversity of testing situations. The test protocol was essentially that described in current United States Environmental Protection Agency (US EPA) guidelines. The resultant data indicated that all participants could detect and characterize the effects of known neurotoxicants, and the divergent profiles of effect obtained for different chemicals demonstrated the specificity of the methods. One conclusion, therefore, was that behavior can be a useful tool for assessing neurotoxicity. In addition, the study also provided a wealth of control data, examination of which provides evidence for the consistency and baseline values of behavioral measures. Reliability estimates were statistically established, providing a measure of the usefulness of individual end points for detecting chemical-induced toxicity. Another conclusion of the IPCS collaborative study was that the application of these methods requires careful attention to details of experimental design, observer training, and experience; these capabilities should be adequately documented by the use of proficiency studies. Recently, modifications of the standard FOB have been introduced, including expanded clinical observations (ECO) for standard toxicity studies. Although there are end points common between the FOB and ECO, it is not known if the latter is sufficient for neurotoxicity screening. Appropriate validation studies have not been conducted on these expanded observations. With the increasing dependency on these methods for neurotoxicity testing, and the number of studies that will be incorporating these methods, issues of test validity as well as data interpretation are becoming more critical.