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

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.Electronic supplementary materialThe online version of this article (10.1007/s00204-017-2140-5) contains supplementary material, which is available to authorized users.

Quantitative in vitro-to-in vivo extrapolation (QIVIVE) of estrogenic and anti-androgenic potencies of BPA and BADGE analogues

“…Starting point in the extrapolation are the EC 50 /IC 50 values obtained with yeast-based bioassays. Recently, Zhang et al (2018) and Fabian et al (2019) revealed that results obtained with a yeast estrogen screen (YES) provide a good prediction of the in vivo potency of BPA, after conversion of the in vitro effective concentration of this compound to equivalent oral doses in rats using PBK-based reverse dosimetry. Zhang et al (2018) even reported a better predictive value using data from the yeast bioassay than using the MCF-7/BOS proliferation or the U2OS ER-CALUX bioassays.…”

“…Recently, Zhang et al (2018) and Fabian et al (2019) revealed that results obtained with a yeast estrogen screen (YES) provide a good prediction of the in vivo potency of BPA, after conversion of the in vitro effective concentration of this compound to equivalent oral doses in rats using PBK-based reverse dosimetry. Zhang et al (2018) even reported a better predictive value using data from the yeast bioassay than using the MCF-7/BOS proliferation or the U2OS ER-CALUX bioassays. Though these results suggest that relevant absolute potency estimates can be made with in vitro assays like the yeast-based bioassay used in the present study, the goal of the present work was mainly to determine the in vivo relative potencies of different bisphenol analogues compared to BPA.…”

Novel strategies for risk assessment of pyrrolizidine alkaloids

“…shown that data on in vivo toxicity can be adequately predicted by translation of in vitro concentration-response curves to in vivo dose-response curves for toxicity using this in vitro-in silico approach Louisse et al, 2010;Zhang et al, 2018). In this way in vivo dose effect levels and PoDs have been defined, for example for developmental toxicity Louisse et al, 2010;, kidney toxicity , and estrogenicity (Zhang et al, 2018).…”

“…Chemical research in toxicology 14, 101-109. Zhang, M., van Ravenzwaay, B., Fabian, E., Rietjens, I.M., Louisse, J., 2018. Towards a generic physiologically based kinetic model to predict in vivo uterotrophic responses in rats by reverse dosimetry of in vitro estrogenicity data.…”

“…For example, the sensitivity analysis showed that permeability coefficients (Papp) had a large influence on model prediction (Chapter 3). Use of experimental Caco-2 transport studies to derive the Papp values in PBK models has been reported Zhang et al, 2018). To build a generic PBK model for a large number of chemicals, such parameters could be obtained from in silico methods.…”