The Use of Toxicokinetic Information for Setting Concentrations of In Vitro Toxicity Tests and for Interpreting Their Results: A Proposed Workflow

Abstract

Background:In vitro assays are increasingly used in the toxicological testing of chemicals. These use high concentrations and the only criteria to set an upper concentration are related to solubility and cytotoxicity or by a predefined concentration as a default. However, the top concentrations in vitro should also consider the equivalent dose in vivo. A concentration causing an effect in vitro that exceeds the internal concentration at a maximum external dose in vivo may not be relevant for toxicological assessment since the cellular effect observed in vitro cannot occur in vivo. Materials and Methods:To avoid this, we propose the use of measured or modelled toxicokinetic data to extrapolate the top dose in vivo to an upper concentration in vitro. This in vivo to in vitro dose extrapolation (IVIVE) uses pharmacokinetic/toxicokinetic modelling to yield an in vitro concentration (cmaxIVIVE) which reflects the internal dose at the maximum external dose in vivo. Results:The cmaxIVIVE can be used to (1) define a relevant upper concentration for the in vitro testing (integrated approach) and (2) interpret the results of an in vitro test, even if the top concentration exceeds the cmaxIVIVE (post hoc approach). We describe a workflow which uses solubility and cytotoxicity data, as well as in vivo and in vitro toxicokinetic data, to derive cmaxvivo or cmaxIVIVE to optimize the setting of the top concentration of a test substance in an in vitro test system. Finally, we demonstrate the…