ESNATS aims at developing a novel toxicity test platform based on embryonic stem cells, especially human ESC (hESC), to accelerate drug development, reduce R&D costs and propose a powerful alternative to animal tests (3 Rs). ESNATS will develop toxicity tests using hESC lines subjected to standardised culture protocols. Tests will cover embryoid bodies in different developmental stages and differentiated derivatives including gamete and neuronal lineages, complemented with test systems for hepatic metabolism. Predictive toxicogenomics and proteomics markers will be identified. The tests will be integrated into an "all-in-one" test system. To enable future industrial use ESNATS will prepare automating and scaling up of hESC culture. Leading European researchers in alternative testing, toxicology, ESC research, genomics, modelling, and automation will collaborate in ESNATS together with representatives from regulatory bodies, the pharmaceutical industry and ethical advisors to ensure rapid applicability of the developed test systems.

TNO's Task

• To compare in vitro with in vivo metabolism of representative compounds of interest both qualitatively as quantitatively and describe a model (as part of PBPK/PD model) to extrapolate in vitro data to the in vivo situation
• To build PBPK models to describe ADME processes in rats/mice and humans based on in vivo data from literature or in vitro ADME data of compounds tested in the in vitro repro and/or CNS tests
• To link kinetic data, as described in PBPK models, with dynamic data from in vitro toxicity test to extrapolate in vitro effect levels to in vivo effect levels
• To compare predicted in vivo effect levels in rats with measured in vivo effect levels to evaluate the validity of the integrated approach of in vitro testing (with or without metabolic system) and PBPK modelling
• To predict human effect levels for reproductive and/or CNS toxic effects based on in vitro testing and PBPK modelling