Application of in vitro data in physiologically-based kinetic models for quantitative in vitro-in vivo extrapolation: A case-study for baclofen.

Physiologically-based kinetic (PBK) models can simulate concentrations of chemicals in tissues over time without animal experiments. Nevertheless, in vivo data are often used to parameterise PBK models. This study aims to illustrate that a combination of kinetic and dynamic readouts from in vitro assays can be used to parameterise PBK models simulating neurologically-active concentrations of xenobiotics.

Refining and neurotoxicity approaches by accounting for interspecies and interindividual differences in toxicodynamics.

Introduction: The process of chemical risk assessment traditionally relies on animal experiments and associated default uncertainty factors to account for interspecies and interindividual differences. To work toward a more precise and personalized risk assessment, these uncertainty factors should be refined and replaced by chemical-specific adjustment factors (CSAFs).

Areas Covered: This concise review discusses alternative (/) approaches that can be used to assess interspecies and interindividual differences in toxicodynamics, ranging from targeted to more integrated approaches.

Acetylcholinesterase inhibition in electric eel and human donor blood: an in vitro approach to investigate interspecies differences and human variability in toxicodynamics.

In chemical risk assessment, default uncertainty factors are used to account for interspecies and interindividual differences, and differences in toxicokinetics and toxicodynamics herein. However, these default factors come with little scientific support. Therefore, our aim was to develop an in vitro method, using acetylcholinesterase (AChE) inhibition as a proof of principle, to assess both interspecies and interindividual differences in toxicodynamics.

Human variability in isoform-specific UDP-glucuronosyltransferases: markers of acute and chronic exposure, polymorphisms and uncertainty factors.

UDP-glucuronosyltransferases (UGTs) are involved in phase II conjugation reactions of xenobiotics and differences in their isoform activities result in interindividual kinetic differences of UGT probe substrates. Here, extensive literature searches were performed to identify probe substrates (14) for various UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7 and UGT2B15) and frequencies of human polymorphisms. Chemical-specific pharmacokinetic data were collected in a database to quantify interindividual differences in markers of acute (Cmax) and chronic (area under the curve, clearance) exposure.

Bayesian meta-analysis of inter-phenotypic differences in human serum paraoxonase-1 activity for chemical risk assessment.

Human variability in paraoxonase-1 (PON1) activities is driven by genetic polymorphisms that affect the internal dose of active oxons of organophosphorus (OP) insecticides. Here, an extensive literature search has been performed to collect human genotypic frequencies (i.e.