Towards a generic physiologically based kinetic model to predict in vivo uterotrophic responses in rats by reverse dosimetry of in vitro estrogenicity data

Mengying Zhang,Ivonne M C M Rietjens,Bennard Van Ravenzwaay,Eric Fabian,Jochem Louisse

doi:10.1007/s00204-017-2140-5

Mengying Zhang, Ivonne M C M Rietjens + Show 3 more

Open Access

https://doi.org/10.1007/s00204-017-2140-5

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Abstract

Physiologically based kinetic (PBK) modelling-based reverse dosimetry is a promising tool for the prediction of in vivo developmental toxicity using in vitro concentration–response data. In the present study, the potential of this approach to predict the dose-dependent increase of uterus weight in rats upon exposure to estrogenic chemicals was assessed. In vitro concentration–response data of 17β-estradiol (E2) and bisphenol A (BPA) obtained in the MCF-7/BOS proliferation assay, the U2OS ER-CALUX assay and the yeast estrogen screen (YES) assay, were translated into in vivo dose–response data in rat, using a PBK model with a minimum number of in vitro and in silico determined parameter values. To evaluate the predictions made, benchmark dose (BMD) analysis was performed on the predicted dose–response data and the obtained BMDL10 values were compared with BMDL10 values derived from data on the effects of E2 and BPA in the uterotrophic assay reported in the literature. The results show that predicted dose–response data of E2 and BPA matched with the data from in vivo studies when predictions were made based on YES assay data. The YES assay-based predictions of the BMDL10 values differed 3.9-fold (E2) and 4.7- to 13.4-fold (BPA) from the BMDL10 values obtained from the in vivo data. The present study provides the proof-of-principle that PBK modelling-based reverse dosimetry of YES assay data using a minimum PBK model can predict dose-dependent in vivo uterus growth caused by estrogenic chemicals. In future studies, the approach should be extended to include other estrogens.

Highlights

The development, validation and application of reliable non-animal based approaches for the hazard and risk characterization of chemicals is urgently needed for modern twenty-first century toxicological risk assessment (Wetmore et al 2011)
Concentration–response data from in vitro assays need to be translated to predicted in vivo dose–response data to facilitate the use of in vitro toxicity data in toxicological risk assessment. This translation is feasible using so-called physiologically based kinetic (PBK) modelling-based reverse dosimetry (Coecke et al 2013; Louisse et al 2017; Wetmore et al 2011). We have shown this Physiologically based kinetic (PBK) modelling-based reverse dosimetry approach to adequately predict in vivo developmental toxicity for diverse chemicals using concentration–response data obtained in the embryonic stem cell test
The PBK modellingbased reverse dosimetry approach applied in the current study includes 5 steps: (1) development of PBK models that describe E2 and bisphenol A (BPA) kinetics in rats, (2) PBK model evaluation, (3) determination of in vitro effect concentrations of E2 and BPA in in vitro estrogenicity assays, (4) translation of in vitro concentration–response data into in vivo dose–response data using the PBK models developed, and (5) evaluation of the predicted dose-dependent estrogenic effects, including benchmark dose (BMD) analysis of predicted dose–response data and the in vivo dose–response data obtained from the literature

Summary

Introduction

The development, validation and application of reliable non-animal based approaches for the hazard and risk characterization of chemicals is urgently needed for modern twenty-first century toxicological risk assessment (Wetmore et al 2011). We have shown this PBK modelling-based reverse dosimetry approach to adequately predict in vivo developmental toxicity for diverse chemicals using concentration–response data obtained in the embryonic stem cell test We showed that in vivo dose-dependent nephrotoxicity of aristolochic acid could be adequately predicted using PBK modelling-based reverse dosimetry of in vitro toxicity data obtained in kidney cells, indicating that application of the approach for diverse toxicological endpoints seems feasible (Abdullah et al 2016). The in vitro and in vivo data were combined via the developed minimum PBK models for E2 and BPA to reveal whether PBK modelling-based reverse dosimetry of in vitro estrogenicity data can be used to predict in vivo uterotrophic growth, serving as a starting point to develop a generic PBK modelling-based reverse dosimetry approach that can be used for risk assessments of large groups of estrogenic chemicals

Materials and methods

Methods

Results

Discussion

Compliance with ethical standards