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Interpreting in vitro developmental toxicity test battery results: The consideration of toxicokinetics

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Author: Bosgra, S. · Westerhout, J.
Type:article
Date:2015
Source:Reproductive Toxicology, 55, 73-80
Identifier: 527797
doi: doi:10.1016/j.reprotox.2014.11.001
Keywords: Toxicology · In vitro test battery · In vitro-in vivo extrapolation · Protein binding · TK modeling · Toxicokinetics · 2 ethylhexanoic acid · Ammonium derivative · Cyclosporin A · Diethylstilbestrol · Endosulfan · Gluphosinate ammonium · Hexanoic acid derivative · Methoxyacetic acid · Methylhexanoic acid · Methylmercuric chloride · Phthalic acid 2 ethylhexyl monoester · Retinoic acid · Unclassified drug · Valproic acid · Animal experiment · Clinical observation · Controlled study · Developmental toxicity · In vitro study · In vivo study · Mouse · Mouse defense test battery · Nonhuman · Predictive value · Protein binding · Quantitative analysis · Rat · Reproductive toxicity · Risk assessment · Simulation · Toxicokinetics · Biomedical Innovation · Healthy Living · Life · RAPID - Risk Analysis for Products in Development · ELSS - Earth, Life and Social Sciences

Abstract

In the EU collaborative project ChemScreen an alternative, in vitro assay-based test strategy was developed to screen compounds for reproductive toxicity. A toxicokinetic modeling approach was used to allow quantitative comparison between effective concentrations in the in vitro test battery and observations of developmental toxicity in vivo. This modeling strategy is based on (1) the definition of relevant observations of toxicity in vivo, (2) simulation of the corresponding systemic concentrations in vivo by toxicokinetic modeling, and (3) correction for differences in protein binding and lipid partitioning between plasma and in vitro test media. The test results of a feasibility study with a number of known reproductive toxicants has been described previously (Piersma et al. [15]). In the present paper, we take a more detailed look at the toxicokinetics of these compounds, and add the analysis of some compounds from subsequent studies. We discuss how the consideration of toxicokinetics allowed comparison between test systems with differing test medium composition, has helped to interpret the in vitro findings in light of in vivo observations, and to gain confidence in the predictive value of the test battery outcomes. The same toxicokinetic modeling strategy, in reverse order, can now be used for risk assessment purposes to predict toxic doses in vivo from effective concentrations in vitro. © 2014 Elsevier Inc..