Use of physiologically based kinetic modeling-facilitated reverse dosimetry of in vitro toxicity data for prediction of in vivo developmental toxicity of tebuconazole in rats

Abstract Development of novel testing strategies to detect adverse human health effects is of interest to replace in vivo-based drug and chemical safety testing. The aim of the present study was to investigate whether physiologically based kinetic (PBK) modeling-facilitated conversion of in vitro toxicity data is an adequate approach to predict in vivo cardiotoxicity in humans. To enable evaluation of predictions made, methadone was selected as the model compound, being a compound for which data on both kinetics and cardiotoxicity in humans are available. A PBK model for methadone in humans was developed and evaluated against available kinetic data presenting an adequate match. Use of the developed PBK model to convert concentration–response curves for the effect of methadone on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in the so-called multi electrode array (MEA) assay resulted in predictions for in vivo dose–response curves for methadone-induced cardiotoxicity that matched the available in vivo data. The results also revealed differences in protein plasma binding of methadone to be a potential factor underlying variation between individuals with respect to sensitivity towards the cardiotoxic effects of methadone. The present study provides a proof-of-principle of using PBK modeling-based reverse dosimetry of in vitro data for the prediction of cardiotoxicity in humans, providing a novel testing strategy in cardiac safety studies.

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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

Molecular Nutrition & Food Research ◽

10.1002/mnfr.201900880 ◽

2020 ◽

Vol 64 (2) ◽

pp. 1900880 ◽

Cited By ~ 3

Author(s):

Suparmi Suparmi ◽

Laura Haan ◽

Albertus Spenkelink ◽

Jochem Louisse ◽

Karsten Beekmann ◽

...

Keyword(s):

Kinetic Modeling ◽

Dose Response ◽

Response Curves ◽

Reverse Dosimetry ◽

Physiologically Based ◽

Dose Response Curves ◽

Vitro Data ◽

In Vitro Data

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Predicting the in vivo developmental toxicity of benzo[a]pyrene (BaP) in rats by an in vitro–in silico approach

Archives of Toxicology ◽

10.1007/s00204-021-03128-7 ◽

2021 ◽

Author(s):

Danlei Wang ◽

Maartje H. Rietdijk ◽

Lenny Kamelia ◽

Peter J. Boogaard ◽

Ivonne M. C. M. Rietjens

Keyword(s):

Dose Response ◽

In Silico ◽

Response Curve ◽

Developmental Toxicity ◽

Toxicity Testing ◽

Maximal Effect ◽

Blood Concentrations ◽

Reverse Dosimetry

AbstractDevelopmental toxicity testing is an animal-intensive endpoints in toxicity testing and calls for animal-free alternatives. Previous studies showed the applicability of an in vitro–in silico approach for predicting developmental toxicity of a range of compounds, based on data from the mouse embryonic stem cell test (EST) combined with physiologically based kinetic (PBK) modelling facilitated reverse dosimetry. In the current study, the use of this approach for predicting developmental toxicity of polycyclic aromatic hydrocarbons (PAHs) was evaluated, using benzo[a]pyrene (BaP) as a model compound. A rat PBK model of BaP was developed to simulate the kinetics of its main metabolite 3-hydroxybenzo[a]pyrene (3-OHBaP), shown previously to be responsible for the developmental toxicity of BaP. Comparison to in vivo kinetic data showed that the model adequately predicted BaP and 3-OHBaP blood concentrations in the rat. Using this PBK model and reverse dosimetry, a concentration–response curve for 3-OHBaP obtained in the EST was translated into an in vivo dose–response curve for developmental toxicity of BaP in rats upon single or repeated dose exposure. The predicted half maximal effect doses (ED50) amounted to 67 and 45 mg/kg bw being comparable to the ED50 derived from the in vivo dose–response data reported for BaP in the literature, of 29 mg/kg bw. The present study provides a proof of principle of applying this in vitro–in silico approach for evaluating developmental toxicity of BaP and may provide a promising strategy for predicting the developmental toxicity of related PAHs, without the need for extensive animal testing.

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