Development of a Generic Physiologically Based Kinetic Model to Predict In Vivo Uterotrophic Responses Induced by Estrogenic Chemicals in Rats Based on In Vitro Bioassays

Abstract

The present study assessed the potential of a generic physiologically based kinetic (PBK) model to convert in vitro data for estrogenicity to predict the in vivo uterotrophic response in rats for diethylstibestrol (DES), ethinylestradiol (EE2), genistein (GEN), coumestrol (COU), and methoxychlor (MXC). PBK models were developed using a generic approach and in vitro concentration-response data from the MCF-7 proliferation assay and the yeast estrogen screening assay were translated into in vivo dose-response data. Benchmark dose analysis was performed on the predicted data and available in vivo uterotrophic data to evaluate the model predictions. The results reveal that the developed generic PBK model adequate defines the in vivo kinetics of the estrogens. The predicted dose-response data of DES, EE2, GEN, COU, and MXC matched the reported in vivo uterus weight response in a qualitative way, whereas the quantitative comparison was somewhat hampered by the variability in both in vitro and in vivo data. From a safety perspective, the predictions based on the MCF-7 proliferation assay would best guarantee a safe point of departure for further risk assessment although it may be conservative. The current study indicates the feasibility of using a combination of in vitro toxicity data and a generic PBK model to predict the relative in vivo uterotrophic response for estrogenic chemicals.

Derivation of a Human In Vivo Benchmark Dose for Bisphenol A from ToxCast In Vitro Concentration Response Data Using a Computational Workflow for Probabilistic Quantitative In Vitro to In Vivo Extrapolation

“…This activity is known as quantitative in vitro to in vivo extrapolation (QIVIVE) (Yoon et al, 2012;Bale et al, 2014;Yoon et al, 2015). Examples of QIVIVE increasingly involve the application of physiologicallybased kinetic (PBK) modelling-based reverse dosimetry for the translation of in vitro to in vivo responses and the derivation of in vivo BMDs (Louisse et al, 2010;Louisse et al, 2012;Strikwold et al, 2013;Louisse et al, 2016;Boonpawa et al, 2017aBoonpawa et al, , 2017bLi et al, 2017;Punt et al, 2017;Strikwold et al, 2017;Adam et al, 2019;Zhao et al, 2019;Shi et al, 2020;Zhang et al, 2020). In these studies, all parameters, other than input dose or exposure, are held fixed at central values.…”

Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to PredictIn VivoAcute Toxicity of Tetrodotoxin in Rodents

“…PBK modeling-based reverse dosimetry has proven to be a promising NAM to derive quantitative data, which can potentially be used in risk assessment to estimate in vivo toxicity in rodents and human ( Chen et al , 2018 ; Li et al , 2017a ; Louisse et al , 2015 ; Ning et al , 2019 ; Shi et al , 2020 ; Strikwold et al , 2017 ; Zhang et al , 2018 , 2020 ). This study aimed to assess the potential of using the PBK modeling-based reverse dosimetry approach as a NAM to predict the neurotoxicity of TTX in rodents, based on in vitro toxicity data obtained in the MEA assay using primary rat neonatal cortical cells or data obtained using the mouse neuro-2a assay.…”

“…The generic PBK model developed in our previous study ( Zhang et al , 2020 ) was used with minor modifications, defining a PBK model for TTX in both rat and mouse. To allow model evaluation based on the 3 available in vivo kinetic data sets, all with different administration routes, the PBK model was built for oral, intravenous (IV), and IM administration ( Hong et al , 2017 , 2018 ).…”

Towards best use and regulatory acceptance of generic physiologically based kinetic (PBK) models for in vitro-to-in vivo extrapolation (IVIVE) in chemical risk assessment

“…Each of these relevant processes are simulated based on in vitro and in silico input data. On the other hand, generic PBK models generally apply only limited number of input parameters, particularly liver metabolism and distribution parameters like tissue:partition coefficients, to obtain first estimates of the kinetics of multiple chemicals (Jongeneelen and Berge 2011;Peters 2008;Zhang et al 2019). Different platforms are available that provide a userfriendly interface around bottom-up PBK model approaches, including commercial and open-source/freeware, such as GastroPlus®, Simcyp™, PK-Sim®, MEGEN/RVIS, and IndusChemFate.…”