Understanding Receptor-Mediated Effects in Rainbow Trout:In Vitro–in VivoExtrapolation Using Physiologically Based Toxicokinetic Models

Abstract

The European REACH regulation requires the use of animal experimentation to assess the risk of industrial chemicals. However, the 3R principle (reduction, replacement, refinement) demands the use of suitable alternative test methods. Many dossiers submitted for the authorization of chemicals have attempted to provide the required data without performing new experiments, relying heavily on in silico methods; in vitro assays were scarcely used. We propose a methodology that uses physiologically based toxicokinetic (PBTK) models to extrapolate in vitro data to the in vivo level. We collected experimental results for in vitro and in vivo ethoxyresorufin-O-deethylase and vitellogenin induction following chemical exposure and compared those results with model predictions. We found that the predictive power of aqueous chemical concentrations was limited; median effect concentrations (EC50s) based on internal concentrations in fish correlated better with in vitro EC50s. Our data show that in vitro assays could offer a substitute for fish studies when combined with PBTK models.

A comparative study of 3 alternative avian toxicity testing methods: Effects on hepatic gene expression in the chicken embryo

“…Often in ecotoxicological research, we tend to not determine actual concentrations of chemicals in the target tissue, but rather report exposures based on nominal concentrations in the medium or dosing solutions. Some studies in mammalian and fish species have investigated the toxicokinetics of chemicals through computational modeling approaches to be able to extrapolate from in vitro to in vivo methods (Brinkmann et al 2014(Brinkmann et al , 2016Kroese et al 2015). However, further research is needed to understand the differences in uptake of chemicals in the biological systems in alternative methods (Basketter et al 2012;Coecke et al 2013).…”

Dioxin in the Elbe river basin: policy and science under the water framework directive 2000–2015 and toward 2021

“…Currently, it is sought for practical implementations of these findings at least for the assessment of dredged materials. In addition to the experimental work conducted within the project, computational models were developed, which will be highly valuable to derive scientifically sound sediment quality standards (Brinkmann et al [ 174 , 175 ]).…”

A physiologically based toxicokinetic (PBTK) model for moderately hydrophobic organic chemicals in the European eel ( Anguilla anguilla )

“…In order to realise the full potential of the proposed methodology, the European eel PBTK model can be extended by the inclusion of toxicodynamic (TD) models, resulting in a PBTK/TD model. PBTK models have been used successfully to link results of in vitro bioassays with in vivo effects (Brinkmann et al, 2014a;Stadnicka-Michalak et al, 2014). With the present model, toxicological data from European eels can thus be retrospectively linked to internal concentrations at the target site.…”

“…PBTK models are capable of predicting the concentration of neutral organic pollutants in the whole fish and in different tissues at any time during exposure (Louisse et al, 2012;Yoon et al, 2012). Furthermore, they facilitate application of the results of in vitro bioassays, which have a higher throughput and reduce the requirement for experimental animals, to predict the effects in vivo; these models thus have the potential to make a valuable contribution to predictive toxicology (Brinkmann et al, 2014a;Stadnicka-Michalak et al, 2014).…”