Research project An integrated in vitro and in silico test strategy for estimation of developmental neurotoxicity

The cells will be exposed during differentiation to compounds that induce neurodevelopmental adverse outcomes (AO) in humans. Attenuated neurite outgrowth and toxicogenomics will be used as hallmarks for DNT in vitro. The genomic expression profiles will be correlated to specific developmental AO endpoints by using multivariate data analysis to identify essential mRNA biomarkers for DNT. The concentrations that induce DNT in vitro, simulating the toxic levels at the target site in the developing nervous system, will be extrapolated to oral doses by using an in vivo-in vitro extrapolation approach including physiologically based pharmacokinetic modeling.A successful outcome of the project will give significant impact on the number of animals being needed for DNT testing (reduction). By using the integrated test strategy, toxic doses can be estimated and more precise doses can be administrated, i.e. less suffering for the animals (refinement). Ultimately, the project may contribute to the full replacement of animal-based tests.The project is a collaboration between Forsby’s research groups at Stockholm University and Swetox as well as computational modeling researchers at Swetox (KI).