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In order to better explain, predict, or extrapolate to humans the developmental toxicity effects of chemicals to zebrafish (Danio rerio) embryos, we developed a physiologically-based pharmacokinetic (PBPK) model designed to predict organ concentrations of neutral or ionizable chemicals, up to 120 hours post-fertilization. Chemicals' distribution is modeled in the cells, lysosomes, and mitochondria of ten organs of the embryo. The model's partition coefficients are calculated with sub-models using physicochemical properties of the chemicals of interest. The model accounts for organ growth and changes in metabolic clearance with time. We compared ab initio model predictions to data obtained on culture medium and embryo concentrations of valproic acid (VPA) and nine analogs during continuous dosing under the OECD test guideline 236. We further improved the predictions by estimating metabolic clearance and partition coefficients from the data by Bayesian calibration. We also assessed the performance of the model at reproducing data published by Brox et al. (2016) on VPA and 16 other chemicals. We finally compared dose-response relationships calculated for mortality and malformations on the basis of predicted whole embryo concentrations versus those based on nominal water concentrations. The use of target organ concentrations substantially shifted the magnitude of doseresponse parameters and the relative toxicity ranking of chemicals studied.

For the determination of acute toxicity of chemicals in zebrafish (Danio rerio) embryos, the OECD test guideline 236 stipulates a dose-response analysis of four lethal core endpoints and a quantitative characterization of abnormalities including their time-dependency. Routinely, the data are analysed at the different observation times separately. However, observations at a given time strongly depend on the previous effects and should be analysed jointly with them. To solve that problem, we developed multistate models for occurrence of developmental malformations and live events in zebrafish embryos exposed to eight concentrations of valproic acid (VPA) the first five days of life. Observations were recorded daily per embryo. We statistically infer on model structure and parameters using a numerical Bayesian framework. Hatching probability rate changed with time and we compared three forms of its time-dependence. A piecewise constant function of time adequately described the hatching data. The other transition rates were conditioned on the embryo body concentration of VAP, obtained using a physiologically-based pharmacokinetic model. VPA impacted mostly the malformation probability rate in hatched and non-hatched embryos. Malformation reversion probability rates were lowered by VPA.Direct mortality was low at the concentrations tested, but increased linearly with internal concentration.The model makes full use of data and gives a finer grain analysis of the teratogenic effects of VPA in zebrafish than the OECD-prescribed approach. We discuss the use the model for obtaining toxicological reference values suitable for inter-species extrapolation. A general result is that complex multistate models can be efficiently evaluated numerically.

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