An Integrated Approach to Testing and Assessment for Developmental Neurotoxicity: Fluoxetine as a Case Study

An in vitro battery (IVB) of 17 assays has been developed to screen chemicals for potential developmental neurotoxicity (DNT). This battery leverages new approach methods (NAMs) targeting key neurodevelopmental processes such as neuronal differentiation, migration, synaptogenesis, and myelination. In this presentation, multiple data streams will be combined for a case study compound, fluoxetine, in an Integrated Approach to Testing and Assessment (IATA). The IATA is designed to provide 
additional context to DNT IVB data by including QSAR modeling, physiologically based kinetic (PBK) modeling (with in vitro-to-in vivo extrapolation) and an in vivo alternative DNT model using planaria. The integration of PBK modeling is especially important for fluoxetine, which forms an active metabolite (norfluoxetine) that should be considered when estimating fetal exposures. In vivo animal and human epidemiology studies from the scientific literature will be reviewed in an effort to better understand the relationship between DNT NAMs and in vivo outcomes. This presentation will highlight both the opportunities and challenges of integrating diverse data streams in the application of DNT IVB.