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|Title:||PBTK modelling platforms and parameter estimation tools to enable animal-free risk assessment: Recommendations from a joint EPAA – EURL ECVAM ADME workshop|
|Authors:||BESSEMS Jos; LOIZOU George; KRISHNAN Kannan; CLEWELL III Harvey; BERNASCONI Camilla; BOIS Frederic Yves; COECKE Sandra; COLLNOT Eva-Maria; DIEMBECK Walter; FARCAL Lucian Romeo; GERAETS Liesbeth; GUNDERT-REMY Ursula; KRAMER Nynke; KÜSTERS Gabriele; LEITE Sofia Batista; PELKONEN Olavi; SCHRÖDER Klaus; TESTAI Emanuela; WILK-ZASADNA Iwona; ZALDÍVAR-COMENGES José-Manuel|
|Citation:||REGULATORY TOXICOLOGY AND PHARMACOLOGY vol. 68 p. 119-139|
|Publisher:||ACADEMIC PRESS INC ELSEVIER SCIENCE|
|Type:||Articles in periodicals and books|
|Abstract:||Absorption, distribution, metabolism and excretion (ADME) determine target tissue doses upon human exposure to chemicals. In this respect, ADME is a critical piece of information in the framework of chemical risk assessment. This is especially true in an era where risk assessment must increasingly be based on in vitro toxicity experiments. 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). Much of the information needed can be generated at tissue/cell or sub-cellular level using in vitro and/or in silico (data-based such as QSAR - Quantitative Structure Activity Relationship) tools. Finally, (computer) modelling serves to integrate disparate in silico and in vitro findings in order to simulate whole body processes. However, there are few freely-available computational modelling platforms currently available in the public domain. Also, the absence of a complete toolbox of in silico and in vitro prediction tools to provide estimates for kinetic parameters is currently a problem. Although some ADME processes can be reasonably estimated in vitro or in silico, important gaps withhold physiologically-based toxicokinetic (PBTK) modelling from wider use for in vitro to in vivo dose extrapolation. Examples of gaps include unknown applicability domains and lack of high-throughput models to measure the following: (1) penetration of barriers, (2) partitioning between blood and tissues and (3) metabolic clearance. This paper is based on a joint EPAA - EURL ECVAM expert meeting and provides a summary of the state of art of in silico and in vitro ADME models used to deliver parameter values for basic (Tier 1) PBTK modelling. Furthermore insights and concrete recommendations are provided to in silico QSAR and in vitro test developers, toxicologists, safety assessors and regulators on priorities to further progress towards a new integrated in silico / in vitro risk assessment paradigm for systemic toxicity without or with significantly fewer animals. The paper, (1) describes a set of critical in vitro and in silico methods providing credible input data for Tier 1 PBTK modelling; (2) defines recommendations for public availability of PBTK modelling tools; (3) provides concrete suggestions where to address the scientific issues to foster progress with a new integrated risk assessment framework; (4) identifies gaps and lists a set of recommendations for initiating PBTK assessment in R&D and standardization and optimization efforts.|
|JRC Directorate:||Institute for Health and Consumer Protection Historical Collection|
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