Abstract:
In order to more accurately understand the potential for chemicals to impact early neurodevelopment, there is a need for risk assessment models that can incorporate mechanistic information. Towards that aim we have been developing and evaluating biologically based dose response (BBDR) models for developmental toxicity that are based on an underlying hypothesis that rapidly dividing, proliferating and subsequently differentiating neuronal cells represent a cell population potentially sensitive to environmental impacts. To test the effectiveness of the model, ethanol-induced CNS developmental toxicity data were evaluated. Extensive research in this area provides a rich data set for application and subsequent assessment of the model. Numerous human and rat behavioral, morphological, and cellular studies suggest the cerebral cortex may be sensitive to prenatal ethanol exposure. A number of critical parameters such as cell cycle lengths, rounds of replication, and contributions to the postmitotic population during each round of replication have been elucidated (Takahashi et al. 1997). In controls the cell cycle lengthens and the percentage of newly generated cells leaving the proliferative population to migrate to the cortical plate increases as neurogenesis proceeds. However, ethanol appears to lengthen the cell cycle prematurely and delay the onset of maturation (Miller 1995). We have developed BBDR models using this information from detailed histological analysis and have evaluated model predictions with detailed in vivo ethanol toxicity studies. At human blood alcohol concentrations that occur after 3-5 drinks (~150/mg/dl), our model predicts at 25-30% neocortical cellular deficit by the end of neurogenesis in the rat model. Independent stereological studies on ethanol-induced cellular loss in the rat neocortex support our predictions.