Modelling human variability in toxicokinetic and toxicodynamic processes using Bayesian meta‐analysis, physiologically‐based modelling and in vitro systems. Issue 4 (27th April 2021)

• Record Type: Journal Article
• Authors: 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, Zoi‐Vasiliki; Kouretas, Dimitrios; Turco, Laura; Vichi, Susanna
• Is Part Of: EFSA supporting publications. Volume 18:Issue 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-04-27
• Subjects: Food -- Europe -- Safety measures -- Periodicals; Food -- Safety measures; Europe; Periodicals; Periodicals; 363.192094
• DOI: 10.2903/sp.efsa.2021.EN-6504
• Languages: English
• ISSNs: 2397-8325

Abstract

Abstract : 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.