TY - JOUR
T1 - PBTK modelling platforms and parameter estimation tools to enable animal-free risk assessment. Recommendations from a joint EPAA - EURL ECVAM ADME workshop.
AU - Bessems, Jos G.
AU - Loizou, George
AU - Krishnan, Kannan
AU - Clewell, Harvey J.
AU - Bernasconi, Camilla
AU - Bois, Frederic
AU - Coecke, Sandra
AU - Collnot, Eva Maria
AU - Diembeck, Walter
AU - Farcal, Lucian Romeo
AU - Geraets, Liesbeth
AU - Gundert-Remy, Ursula
AU - Kramer, Nynke
AU - Küsters, Gabriele
AU - Leite, Sofia Margarida Baptista
AU - Pelkonen, Olavi R.
AU - Schröder, Klaus
AU - Testai, Emanuela
AU - Wilk-Zasadna, Iwona
AU - Zaldívar-Comenges, José Manuel
PY - 2014/2
Y1 - 2014/2
N2 - 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.
AB - 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.
KW - Development stage
KW - In silico (QSAR) tools
KW - In vitro methods
KW - PBTK
KW - Tier 1 model
UR - http://www.scopus.com/inward/record.url?scp=84890838199&partnerID=8YFLogxK
U2 - 10.1016/j.yrtph.2013.11.008
DO - 10.1016/j.yrtph.2013.11.008
M3 - Article
C2 - 24287156
AN - SCOPUS:84890838199
SN - 0273-2300
VL - 68
SP - 119
EP - 139
JO - Regulatory Toxicology And Pharmacology
JF - Regulatory Toxicology And Pharmacology
IS - 1
ER -