Developmental neurotoxicity testing in vitro: models for assessing chemical effects on neurite outgrowth

In vitro models may be useful for the rapid toxicological screening of large numbers of chemicals for their potential to produce toxicity. Such screening could facilitate prioritization of resources needed for in vivo toxicity testing towards those chemicals most likely to result in adverse health effects. Cell cultures derived from nervous system tissue have proven to be powerful tools for elucidating cellular and molecular mechanisms of nervous system development and function, and have been used to understand the mechanism of action of neurotoxic chemicals. Recently, it has been suggested that in vitro models could be used to screen for chemical effects on critical cellular events of neurodevelopment, including differentiation and neurite growth. This review examines the use of neuronal cell cultures as an in vitro model of neurite outgrowth. Examples of the cell culture systems that are commonly used to examine the effects of chemicals on neurite outgrowth are provided, along with a description of the methods used to quantify this neurodevelopmental process in vitro. Issues relating to the relevance of the methods and models currently used to assess neurite outgrowth are discussed in the context of hazard identification and chemical screening. To demonstrate the utility of in vitro models of neurite outgrowth for the evaluation of large numbers of chemicals, efforts should be made to: (1) develop a set of reference chemicals that can be used as positive and negative controls for comparing neurite outgrowth between model systems, (2) focus on cell cultures of human origin, with emphasis on the emerging area of neural progenitor cells, and (3) use high-throughput methods to quantify endpoints of neurite outgrowth.