Modeling Developmental Neurotoxicity and Mechanism Based Dose Response Models. T. A. Lewandowski, J. M. Hoeft, S. M. Bartell, E. Y. Wong, W. C. Griffith, and E. M. Faustman, University of Washington
Biologically based dose response (BBDR) models have been developed for developmental toxicity based on an underlying mode of action hypothesis that rapidly proliferating and subsequently differentiating cells represent sensitive cell populations for environmental impacts. These mechanisms are proposed to apply across a variety of toxicants: ethanol, methylmercury, and some pesticides. Critical parameters such as cell cycle lengths, rounds of replication, and contributions to the postmitotic population during each round of replication have been elucidated for normal neurodevelopment and for specific brain regions. For example, in central mouse cerebral cortex, cell cycle lengthenings and percentage of new cells leaving the proliferative population to migrate to the cortical plate increases as neurogenesis proceeds. Using a model to predict outcomes from detailed in vivo ethanol toxicity studies, ethanol appears to lengthen the cell cycle prematurely and delay the onset of migration. In this example ethanol induced changes in proliferation can be hypothesized to quantitatively account for a significant fraction of its neocortical impacts. Similar approaches have been undertaken for MeHg. Application of this methodology for evaluation of a variety of pesticides is explored. These models provide testable frameworks to evaluate hypotheses on the mechanisms of developmental neurotoxicants.
Supported by EPA grants R826886, R825358, CR825173, NIEHS 1PO1ES09601 and NIEHS ES07033, ES07032.
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