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

Jos G. Bessems, George Loizou, Kannan Krishnan, Harvey J. Clewell, Camilla Bernasconi, Frederic Bois, Sandra Coecke, Eva Maria Collnot, Walter Diembeck, Lucian Romeo Farcal, Liesbeth Geraets, Ursula Gundert-Remy, Nynke Kramer, Gabriele Küsters, Sofia Margarida Baptista Leite, Olavi R. Pelkonen, Klaus Schröder, Emanuela Testai, Iwona Wilk-Zasadna, José Manuel Zaldívar-Comenges

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)119-139
Number of pages21
JournalRegulatory Toxicology And Pharmacology
Volume68
Issue number1
DOIs
Publication statusPublished - Feb 2014

Keywords

  • Development stage
  • In silico (QSAR) tools
  • In vitro methods
  • PBTK
  • Tier 1 model

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