PBTK modelling platforms and parameter estimation tools to enable animal-free risk assessment: recommendations from a joint EPAA--EURL ECVAM ADME workshop.

Information on toxicokinetics is critical for animal-free human risk assessment. Human external exposure must be translated into human tissue doses and compared with in vitro actual cell exposure associated to effects (in vitro-in vivo comparison). Data on absorption, distribution, metabolism and excretion in humans (ADME) could be generated using in vitro and QSAR tools. Physiologically-based toxicokinetic (PBTK) computer modelling could serve to integrate disparate in vitro and in silico findings. However, there are only few freely-available PBTK platforms currently available. And although some ADME parameters can be reasonably estimated in vitro or in silico, important gaps exist. Examples include unknown or limited applicability domains and lack of (high-throughput) tools to measure penetration of barriers, partitioning between blood and tissues and metabolic clearance. This paper is based on a joint EPAA--EURL ECVAM expert meeting. It provides a state-of-the-art overview of the availability of PBTK platforms as well as the in vitro and in silico methods to parameterise basic (Tier 1) PBTK models. Five high-priority issues are presented that provide the prerequisites for wider use of non-animal based PBTK modelling for animal-free chemical risk assessment.

Computational toxicology at the European Commission's Joint Research Centre.

The methods and tools of computational toxicology form an essential and integrating pillar in the new paradigm of predictive toxicology, which seeks to develop more efficient and effective means of assessing chemical toxicity, while also reducing animal testing. The increasingly prominent role of computational toxicology in the implementation of European chemicals' legislation is described, along with initiatives by the European Commission's Joint Research Centre to promote the acceptance and use of computational methods. Outstanding needs and scientific challenges are also outlined. In recent years, there have been impressive scientific and technological advances in computational toxicology. However, considerable progress is still needed to increase the acceptance of computational methods, and in particular to develop a deeper and common understanding of how to apply computational toxicology in regulatory decision making.