Modeling developmental processes in animals: applications in neurodevelopmental toxicology

Biologically based dose-response models can provide a framework for incorporating mechanistic information into our assessments of neurotoxicity considering both kinetic and dynamic processes. We have constructed models for normal midbrain and neocortex development and we have extended these models to evaluate the neurodevelopmental toxicity of ethanol and methyl mercury. Using such modeling approaches, we have been able to test hypothesized modes of action for these neurodevelopmental toxicants. Specifically, we have compared ethanol's effects on neocortical neurogenesis and exacerbation of apoptosis during the synaptogenesis period. We have used methylmercury as an example of how one can link toxicokinetic and toxicodynamic models and also as an example of how mechanistic data on gene expression can support model development. In summary, using examples from our research group, this paper illustrates the need for models that evaluate both qualitative and quantitative kinetic and dynamic factors in order to understand the potential impacts of neurodevelopmental toxicants.