A Web‐based open source tool for Toxicokinetic and Toxicodynamic modelling

Abstract

This report presents the implementation of a web tool for the extension of exposure-and toxicokinetictoxicodynamic analysis that has been developed under a specific EFSA request to Open Analytics under the framework agreement (OC/EFSA/AMU/2015/02). An open source software has been developed in R as a WEB-based tool including different components for the modelling of toxicokinetic (TK) and toxicodynamic (TD) processes within a structured workflow. The workflow provides the steps to perform such TK-TD modelling for single chemicals in the human health, animal health and ecological risk assessment. The web-based tool results in the implementation of four modules: (1) Chemical specific modules, (2) Physiological and life cycle trait modules, (3) Toxicokinetic module, and (4) Toxicodynamic module.

Development of a Web-Based Toolbox to Support Quantitative In-Vitro-to-In-Vivo Extrapolations (QIVIVE) within Nonanimal Testing Strategies

“…20 It can be expected that the in vitro observed inhibition of TPO by propyl gallate relates to its antioxidant activity. 53 Inhibition of TPO is for example also observed for many flavonoids. 62 To what extent the inhibition of TPO by propyl gallate actually translates into adverse effects needs to be further elucidated.…”

“…An extended one-generation reproductive/developmental toxicity study, in which such markers are measured, is not available for propyl gallate . It can be expected that the in vitro observed inhibition of TPO by propyl gallate relates to its antioxidant activity . Inhibition of TPO is for example also observed for many flavonoids .…”

“…Although various freely available tools are available for PBKmodel development, including for example PK-SIM (http:// www.open-systems-pharmacology.org), PLETHEM, 51 Httk, 52 and TK Plate, 53 the key goal of the present study was to develop a toolbox that can be used without PBK-modeling software and without basic understanding of and experience with PBK modeling or R programming. In order to make the toolbox as simple as possible, the PBK models for rats and humans that are included were built based on minimal input, being the logP and pK a of the chemical (required for the calculations on tissue binding and for the calculation of the free fraction in plasma and in vitro hepatocyte/liver tissue incubations), a value for hepatic clearance, and passive intestinal uptake (which can be estimated based on the TPSA of the chemical) using a multiple compartment uptake model.…”

“…Although various freely available tools are available for PBK-model development, including for example PK-SIM (), PLETHEM, Httk, and TK Plate, the key goal of the present study was to develop a toolbox that can be used without PBK-modeling software and without basic understanding of and experience with PBK modeling or R programming. In order to make the toolbox as simple as possible, the PBK models for rats and humans that are included were built based on minimal input, being the logP and p K a of the chemical (required for the calculations on tissue binding and for the calculation of the free fraction in plasma and in vitro hepatocyte/liver tissue incubations), a value for hepatic clearance, and passive intestinal uptake (which can be estimated based on the TPSA of the chemical) using a multiple compartment uptake model. , In contrast to other PBK-modeling tools, the in silico calculations for the partition coefficients, ,, fraction unbound plasma, and free fraction in in vitro incubations with microsomes, S9 (assumed in this study to be similar as for microsomal incubations), or hepatocytes can be carried out independently of the PBK-model simulations, providing an easy and user-friendly tool for quick in silico calculations of chemical-specific PBK-model parameters, that can also be used as input for the user’s own PBK models.…”

Modelling human variability in toxicokinetic and toxicodynamic processes using Bayesian meta‐analysis, physiologically‐based modelling and in vitro systems

“…-Integration of pathway-related variability as statistical distributions and generic human QIVIVE and PB-K models and PB-K-D models in TKplate, a Toxicokinetic Modelling Platform under development in EFSA. This would have the potential to allow for testing the prediction power of the generic models using isoform-specific prediction, variability in TD processes and chemical information using a range of chemicals of relevance to food safety and to reduce animal testing (Bossier et al, 2020). iii)…”