Cross-Species Extrapolation of Uptake and Disposition of Neutral Organic Chemicals in Fish Using a Multispecies Physiologically-Based Toxicokinetic Model Framework

Abstract

The potential to bioconcentrate is generally considered to be an unwanted property of a substance. Consequently, chemical legislation, including the European REACH regulations, requires the chemical industry to provide bioconcentration data for chemicals that are produced or imported at volumes exceeding 100 tons per annum or if there is a concern that a substance is persistent, bioaccumulative, and toxic. For the filling of the existing data gap for chemicals produced or imported at levels that are below this stipulated volume, without the need for additional animal experiments, physiologically-based toxicokinetic (PBTK) models can be used to predict whole-body and tissue concentrations of neutral organic chemicals in fish. PBTK models have been developed for many different fish species with promising results. In this study, we developed PBTK models for zebrafish (Danio rerio) and roach (Rutilus rutilus) and combined them with existing models for rainbow trout (Onchorhynchus mykiss), lake trout (Salvelinus namaycush), and fathead minnow (Pimephales promelas). The resulting multispecies model framework allows for cross-species extrapolation of the bioaccumulative potential of neutral organic compounds. Predictions were compared with experimental data and were accurate for most substances. Our model can be used for probabilistic risk assessment of chemical bioaccumulation, with particular emphasis on cross-species evaluations.

Development of a generic zebrafish embryo PBPK model and application to the developmental toxicity assessment of valproic acid analogs

“…PBPK models have been published for adult zebrafish, mostly for ecotoxicological risk assessment [18][19][20]. Recently, Brox et al [21] used a one-compartment two-parameter model developed by Gobas and Zhang [22] to explore the impact of physicochemical properties of polar compounds and of biological processes on embryo concentrations.…”

Importance of Toxicokinetics to Assess the Utility of Zebrafish Larvae as Model for Psychoactive Drug Screening Using Meta-Chlorophenylpiperazine (mCPP) as Example

“…This difference cannot be explained by the simplicity of the applied model. While increasing the model complexity generally improves model performance ( Rowland et al, 2017 ), and more sophisticated Physiologically Based Toxicokinetic (PBTK) models have already been developed for adult stages of zebrafish ( Péry et al, 2014 ; Brinkmann et al, 2016 ), no approach has, as of yet, been proposed for fish larval stages, for which chemical internal distribution differs. It has, however, been shown that the one-compartment model applied here is in agreement with the PBTK models regarding the prediction of chemical concentrations in whole fish ( Stadnicka et al, 2012 ).…”

In vitro or not in vitro: a short journey through a long history

“…A number of such models have been developed over the last decade in human toxicology (e.g. [ 13 , 154 ]), but corresponding approaches are now emerging in fish toxicology as well [ 25 , 136 ].…”