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.

Mechanisms of toxicity induced by SiO2 nanoparticles of in vitro human alveolar barrier: effects on cytokine production, oxidative stress induction, surfactant proteins A mRNA expression and nanoparticles uptake.

An in vitro human alveolar barrier established by the coculture of epithelial human cell line NCI-H441 with endothelial human cell line ISO-HAS1 was used to evaluate the effects of amorphous silicon dioxide nanoparticles (SiNPs), in the presence or absence of THP-1 cells (monocytes). SiNPs exposure induced production of proinflammatory cytokine and oxidative stress. A high release of TNF-α and IL-8 by epithelial/endothelial cells, potentiated in the presence of THP-1 cells could contribute to the observed downregulation of surfactant proteins A mRNA expression resulting in the damage of the alveolar barrier. The obtained results suggested that in vitro approach can be used to study pulmonary toxicity as long as the applied in vitro model mimics closely the complexity of in vivo situation.