The Use of In Vitro Toxicity Data and Physiologically Based Kinetic Modeling to Predict Dose-Response Curves for In Vivo Developmental Toxicity of Glycol Ethers in Rat and Man

Abstract

At present, regulatory assessment of systemic toxicity is almost solely carried out using animal models. The European Commission's REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for specific target cells, whereas in vivo dose-response curves are regularly used for human risk assessment. The present study shows an approach to predict in vivo dose-response curves for developmental toxicity by combining in vitro toxicity data and in silico kinetic modeling. A physiologically based kinetic (PBK) model was developed, describing the kinetics of four glycol ethers and their embryotoxic alkoxyacetic acid metabolites in rat and man. In vitro toxicity data of these metabolites derived in the embryonic stem cell test were used as input in the PBK model to extrapolate in vitro concentration-response curves to predicted in vivo dose-response curves for developmental toxicity of the parent glycol ethers in rat and man. The predicted dose-response curves for rat were found to be in concordance with the embryotoxic dose levels measured in reported in vivo rat studies. Therefore, predicted dose-response curves for rat could be used to set a point of departure for deriving safe exposure limits in human risk assessment. Combining the in vitro toxicity data with a human PBK model allows the prediction of dose-response curves for human developmental toxicity. This approach could therefore provide a means to reduce the need for animal testing in human risk assessment practices.

Prediction of in vivo developmental toxicity of all-trans-retinoic acid based on in vitro toxicity data and in silico physiologically based kinetic modeling

“…Finally, as we discussed before (Louisse et al 2010a(Louisse et al , 2012, the ES-D3 cell differentiation assay may not produce the right in vitro effect concentrations for specific in vivo developmental toxicity endpoints, indicating that research is needed as to whether specific in vitro tests would be required for specific in vivo developmental toxicity endpoints. The in vitro ES-D3 cell differentiation assay used in the present study should be regarded as a simplified first tier model of the developing embryo and cannot be used to predict specific in vivo developmental toxicity end points with the greatest possible accuracy.…”

“…The in vitro concentration-response data presented were taken from our earlier study , whereas the predicted in vitro dose-response data are hypothetical risk assessment, like a benchmark dose (BMD). Regarding developmental toxicity, this approach has been used to predict BMDs for a group of glycol ethers (Louisse et al 2010a) and of phenol (Strikwold et al 2013), based on the translation of in vitro concentration-response data on the inhibition of embryonic stem (ES-D3) cell differentiation into in vivo dose-response data. To further explore the potential applicability of the reverse dosimetry approach, examples with chemicals from other chemical categories, with different physico-chemical properties and/or specific mechanisms of action, are needed.…”

“…The translation of in vitro concentrations into in vivo doses can be achieved using physiologically based kinetic (PBK) modeling with a reverse dosimetry approach (DeJongh et al 1999;Forsby and Blaauboer 2007;Louisse et al 2010a;Paini et al 2010;Verwei et al 2006a;Rotroff et al 2010;Wetmore et al 2012;Strikwold et al 2013) (Fig. 1).…”

Expert opinion on toxicity profiling—report from a NORMAN expert group meeting

“…For most MoA other than dioxin-like activity and endocrine disruption, however, the expert group recognized that lack of toxicokinetic and toxicodynamic knowledge prevents such an extrapolation. Translation of bioassay derived toxicity profiles into risk profiles can be further facilitated by establishing in vitro-in vivo relationships using physiologically-based pharmacokinetic (PBPK) and pharmacodynamic (PBPD) modeling, as has been done in human risk assessment for decades (Clewell 1993;Louisse et al 2010). Compared to human risk assessment, however, additional challenges need to be overcome in ecological risk assessment when using results from short-term bioassays, such as extrapolation from the individual to the population level and from one (or few) to many species.…”

Zebrafish embryos as an alternative model for screening of drug-induced organ toxicity

“…In fish embryos, exposure is static and internal concentrations are established by partition equilibrium. Physiologically based kinetic models could provide a link between fish embryo and mammalian toxicity, but such models have not been developed for the fish embryo so far (Louisse et al 2010). Furthermore, support by chemical analytics for the time-course of internal concentration in fish embryos would be needed.…”