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
Zhang, Mengying ; Ravenzwaay, Bennard van; Rietjens, Ivonne M.C.M. - \ 2020
Toxicological sciences 173 (2020)1. - ISSN 1096-6080 - p. 19 - 31.
generic physiologically based kinetic modeling - quantitative in vitro–in vivo extrapolation - reverse dosimetry - uterotrophic assay
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.
Combining In Vitro Data and Physiologically Based Kinetic Modeling Facilitates Reverse Dosimetry to Define In Vivo Dose–Response Curves for Bixin- and Crocetin-Induced Activation of PPARγ in Humans
Suparmi, Suparmi ; Haan, Laura de; Spenkelink, Albertus ; Louisse, Jochem ; Beekmann, Karsten ; Rietjens, Ivonne M.C.M. - \ 2020
Molecular Nutrition & Food Research 64 (2020)2. - ISSN 1613-4125
bixin - crocetin - peroxisome proliferator-activated receptor γ - physiologically based kinetic modeling - reverse dosimetry
Scope: It is investigated whether at realistic dietary intake bixin and crocetin could induce peroxisome proliferator-activated receptor γ (PPARγ)-mediated gene expression in humans using a combined in vitro–in silico approach. Methods and results: Concentration–response curves obtained from in vitro PPARγ-reporter gene assays are converted to in vivo dose–response curves using physiologically based kinetic modeling-facilitated reverse dosimetry, from which the benchmark dose levels resulting in a 50% effect above background level (BMD50) are predicted and subsequently compared to dietary exposure levels. Bixin and crocetin activated PPARγ-mediated gene transcription in a concentration-dependent manner with similar potencies. Due to differences in kinetics, the predicted BMD50 values for in vivo PPARγ activation are about 30-fold different, amounting to 115 and 3505 mg kg bw−1 for crocetin and bixin, respectively. Human dietary and/or supplemental estimated daily intakes may reach these BMD50 values for crocetin but not for bixin, pointing at better possibilities for in vivo PPARγ activation by crocetin. Conclusion: Based on a combined in vitro–in silico approach, it is estimated whether at realistic dietary intakes plasma concentrations of bixin and crocetin are likely to reach concentrations that activate PPARγ-mediated gene expression, without the need for a human intervention study.