title: PBTK modelling platforms and parameter estimation tools to enable animal-free risk assessment: recommendations from a joint EPAA--EURL ECVAM ADME workshop.
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.
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands. Electronic address: jos.bessems@ec.europa.eu.
authors.forename: Jos G
authors.initials: JG
authors.lastname: Bessems
authors.affiliation: Health and Safety Laboratories, Mathematical Sciences Unit, Buxton, UK.
authors.forename: George
authors.initials: G
authors.lastname: Loizou
authors.affiliation: Département de Santé Environnementale et Santé au Travail, Faculté de Médecine, Université de Montréal, Montréal, Canada.
authors.forename: Kannan
authors.initials: K
authors.lastname: Krishnan
authors.affiliation: The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
authors.affiliation: Systems Toxicology Unit/EURL ECVAM, Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra (VA), Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Bernasconi
authors.affiliation: Compiegne University of Technology, Chair of Mathematical Modelling for Systems Toxicology, Compiegne & INERIS, DRC/VIVA/METO, Verneuil en Halatte, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Bois
authors.affiliation: Systems Toxicology Unit/EURL ECVAM, Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra (VA), Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Coecke
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland, Saarbrücken, Germany.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Collnot
authors.affiliation: Beiersdorf AG, Unnastr. 48, D-20245 Hamburg, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Diembeck
authors.affiliation: Systems Toxicology Unit/EURL ECVAM, Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra (VA), Italy.
authors.forename: Lucian Romeo
authors.initials: LR
authors.lastname: Farcal
authors.affiliation: National Institute for Public Health and the Environment (RIVM), Bilthoven, Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Geraets
authors.affiliation: Department Clinical Pharmacology and Toxicology, Medical School (Charité), Berlin, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Gundert-Remy
authors.affiliation: Institute for Risk Assessment Sciences, Utrecht University, Netherlands.
authors.forename: Nynke
authors.initials: N
authors.lastname: Kramer
authors.affiliation: European Partnership for Alternative Approaches to Animal Testing (EPAA), 15b Avenue Herrmann Debroux, 1160 Bruxelles, Belgium.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Küsters
authors.affiliation: Systems Toxicology Unit/EURL ECVAM, Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra (VA), Italy; Instituto de Biologia Experimental e Tecnológica (IBET)/Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa (ITQB-UNL), Oeiras, Portugal.
authors.forename: Sofia B
authors.initials: SB
authors.lastname: Leite
authors.affiliation: Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: Olavi R
authors.initials: OR
authors.lastname: Pelkonen
authors.affiliation: BioMed-zet Life Science GmbH/Centre for Alternative and Complementary Methods to Animal Testing (ZET), Linz, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schröder
authors.affiliation: Istituto Superiore di Sanità, Viale Regina Elena, 299, Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Testai
authors.affiliation: Systems Toxicology Unit/EURL ECVAM, Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra (VA), Italy.
authors.forename: Iwona
authors.initials: I
authors.lastname: Wilk-Zasadna
authors.affiliation: Systems Toxicology Unit/EURL ECVAM, Institute for Health and Consumer Protection, European Commission Joint Research Centre, Ispra (VA), Italy.
authors.forename: José-Manuel
authors.initials: JM
authors.lastname: Zaldívar-Comenges
mesh_terms: D000826:Animal Testing Alternatives; D064420:Drug-Related Side Effects and Adverse Reactions; D004781:Environmental Exposure / Q000009:adverse effects; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics; D018570:Risk Assessment
chemical_list: D004785:Environmental Pollutants
keywords: AD; Development stage; In silico (QSAR) tools; In vitro methods; PBTK; SPME; Tier 1 model; applicability domain; physiologically-based toxicokinetic; solid phase microextraction