Relevance of in vitro neurotoxicity testing for regulatory requirements: challenges to be considered.
The current testing requirements for both adult and developmental neurotoxicity evaluation are based on in vivo animal models and the neurotoxic potency of compounds is mainly determined by neurobehavioural and neuropathological effects. In vitro studies are considered complementary to animal tests because they provide an understanding of the molecular/cellular mechanisms involved in neurotoxicity. However, the selection of relevant in vitro neuronal/glial specific endpoints applied to various neuronal cellular models should be done in a careful way to build reliable and feasible testing strategies since usually these endpoints have to be tested in various complementary in vitro systems. The requirements for applying a more complex test strategy where toxicokinetic aspects are included together with different tools to compensate for the lack of in vitro metabolic competence are discussed. Taking into consideration the recent European Commission chemical legislation concerning registration, evaluation and authorisation of chemicals (REACH) it has become a priority to develop new intelligent testing strategies integrating computational models and in vitro assays based on cell culture models and endpoints that are amenable for adaptation to high throughput screening to be able to test a large number of chemicals.