Open AccessModelling human variability in toxicokinetic and toxicodynamic processes using Bayesian meta‐analysis, physiologically‐based modelling and in vitro systems
Author(s) -
Testai Emanuela,
Bechaux Camille,
Buratti Franca M.,
Darney Keyvin,
Di Consiglio Emma,
Kasteel Emma E.J.,
Kramer Nynke I.,
Lautz Leonie S.,
Santori Nicoletta,
Skaperda ZoiVasiliki,
Kouretas Dimitrios,
Turco Laura,
Vichi Susanna
Publication year - 2021
Publication title -
efsa supporting publications
Language(s) - English
Resource type - Journals
ISSN - 2397-8325
DOI - 10.2903/sp.efsa.2021.en-6504
Subject(s) - toxicodynamics , toxicokinetics , computational biology , chemistry , biochemical engineering , environmental chemistry , biology , biochemistry , engineering , metabolism
This external scientific report summarises the results from thearticle 36 grant GA/EFSA/SCER/2015/01″Modelling human variability in toxicokinetic and toxicodynamic processes using Bayesian meta‐analysis, physiologically‐based (PB) modelling and in vitro systems”. Extensive literature searches, data collection and modelling of human variability in toxicokinetics (TK) (phase I, Phase II enzymes and transporters) and toxicodynamics (TD) are summarised and further elaborated in supplementary material and EFSA knowledge junction, open source databases(MS Excel) and peer reviewed publications (objective 1 and 2). In addition, in vitro TK and TD information from laboratory studies and literature searches are summarised for a range of case studies relevant to EFSA including pesticides (i.e. triflumuron, chlorpyrifos, phosmet), natural toxins (e.g. microcystin variants, mycotoxins), food additives and polyphenols (i.e. resveratrol, tyrosol), food additives as well as drugs (i.e.amiodarone). These include isoform‐specific metabolism and kinetic parameters for single chemicals and inhibition constants for multiple chemicals (TK) and identification of molecular targets (TD). Finally, generic quantitative in vitro in vivo extrapolation (QIVIVE) models, PB‐kinetic (PBK) and PBK‐dynamic (PBKD) models were developed in the R freeware, calibrated and validated usingcase studies for single and multiple chemicals. Supplementary material and model codes are available on EFSA knowledge junction. The results are in line with EFSA priorities for the implementation of the use of new approach methodologies (NAMs) for human risk assessment (RA) of chemicals and the need to develop open source TK TD databases data and PB‐K and PB‐KD models have been identified as key steps of this process. Future perspectives are discussedincluding the integration of pathway‐related variability and generic human QIVIVE and PB‐K models and PB‐K‐D models into TKplate, a Toxicokinetic Modelling Platform under development in EFSA.