scholarly journals The Use of In Vitro Toxicity Data and Physiologically Based Kinetic Modeling to Predict Dose-Response Curves for In Vivo Developmental Toxicity of Glycol Ethers in Rat and Man

2010 ◽  
Vol 118 (2) ◽  
pp. 470-484 ◽  
Author(s):  
Jochem Louisse ◽  
Esther de Jong ◽  
Johannes J. M. van de Sandt ◽  
Bas J. Blaauboer ◽  
Ruud A. Woutersen ◽  
...  
Keyword(s):  
Kinetic Modeling ◽  
Dose Response ◽  
Developmental Toxicity ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Glycol Ethers ◽  
Response Curves ◽  
Physiologically Based

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

2017 ◽  
Vol 266 ◽  
pp. 85-93 ◽  
Author(s):  
Hequn Li ◽  
Mengying Zhang ◽  
Jacques Vervoort ◽  
Ivonne M.C.M. Rietjens ◽  
Bennard van Ravenzwaay ◽  
...  
Keyword(s):  
Kinetic Modeling ◽  
Developmental Toxicity ◽  
In Vitro Toxicity ◽  
Toxicity Data ◽  
Reverse Dosimetry ◽  
Physiologically Based

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

2019 ◽  
Author(s):  
Mengying Zhang ◽  
Bennard van Ravenzwaay ◽  
Ivonne M C M Rietjens
Keyword(s):  
Dose Response ◽  
In Vitro Toxicity ◽  
Proliferation Assay ◽  
Screening Assay ◽  
Response Data ◽  
Physiologically Based ◽  
Estrogenic Chemicals ◽  
Mcf 7

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.

scholarly journals Integrating in vitro data and physiologically based kinetic modeling-facilitated reverse dosimetry to predict human cardiotoxicity of methadone

2020 ◽  
Vol 94 (8) ◽  
pp. 2809-2827
Author(s):  
Miaoying Shi ◽  
Hans Bouwmeester ◽  
Ivonne M. C. M. Rietjens ◽  
Marije Strikwold
Keyword(s):  
In Vitro Toxicity ◽  
Response Curves ◽  
Chemical Safety ◽  
Safety Testing ◽  
Reverse Dosimetry ◽  
Physiologically Based ◽  
Vitro Data ◽  
In Vitro Data

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.

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

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.

scholarly journals Physiologically based kinetic modelling based prediction of in vivo rat and human acetylcholinesterase (AChE) inhibition upon exposure to diazinon

2021 ◽  
Author(s):  
Shensheng Zhao ◽  
Sebastiaan Wesseling ◽  
Bert Spenkelink ◽  
Ivonne M. C. M. Rietjens
Keyword(s):  
Dose Response ◽  
Kinetic Modelling ◽  
Ache Inhibition ◽  
Response Curves ◽  
Alternative Testing ◽  
Dose Response Curves ◽  
Physiologically Based Kinetic Modelling ◽  
Point Of Departure

AbstractThe present study predicts in vivo human and rat red blood cell (RBC) acetylcholinesterase (AChE) inhibition upon diazinon (DZN) exposure using physiological based kinetic (PBK) modelling-facilitated reverse dosimetry. Due to the fact that both DZN and its oxon metabolite diazoxon (DZO) can inhibit AChE, a toxic equivalency factor (TEF) was included in the PBK model to combine the effect of DZN and DZO when predicting in vivo AChE inhibition. The PBK models were defined based on kinetic constants derived from in vitro incubations with liver fractions or plasma of rat and human, and were used to translate in vitro concentration–response curves for AChE inhibition obtained in the current study to predicted in vivo dose–response curves. The predicted dose–response curves for rat matched available in vivo data on AChE inhibition, and the benchmark dose lower confidence limits for 10% inhibition (BMDL10 values) were in line with the reported BMDL10 values. Humans were predicted to be 6-fold more sensitive than rats in terms of AChE inhibition, mainly because of inter-species differences in toxicokinetics. It is concluded that the TEF-coded DZN PBK model combined with quantitative in vitro to in vivo extrapolation (QIVIVE) provides an adequate approach to predict RBC AChE inhibition upon acute oral DZN exposure, and can provide an alternative testing strategy for derivation of a point of departure (POD) in risk assessment.

Histamine tachyphylaxis in canine airways despite prostaglandin synthesis inhibition

1988 ◽  
Vol 65 (5) ◽  
pp. 1944-1949 ◽  
Author(s):  
P. J. Antol ◽  
S. J. Gunst ◽  
R. E. Hyatt
Keyword(s):  
Smooth Muscle ◽  
Dose Response ◽  
Prostaglandin Synthesis ◽  
Response Curves ◽  
Synthesis Inhibition ◽  
High Concentrations ◽  
Alpha Chloralose ◽  
Prostaglandin Synthesis Inhibitors

Tachyphylaxis to aerosolized histamine was studied in dogs anesthetized with thiamylal after pretreatment with prostaglandin synthesis inhibitors. Three consecutive histamine dose-response curves were obtained in nine dogs pretreated with 5 mg/kg indomethacin; two of these nine were also pretreated with 10 mg/kg indomethacin. Seven of the nine dogs were pretreated with 4 mg/kg sodium meclofenamate; four of these seven were also pretreated with 12 mg/kg. All dogs had tachyphylaxis at high concentrations of histamine regardless of inhibitor used. Pretreatment with indomethacin while the dogs were under alpha-chloralose-urethan anesthesia gave similar results. Histamine tachyphylaxis was also studied both in the presence and in the absence of indomethacin in tracheal smooth muscle strips obtained from seven additional dogs. A decrease in the median effective dose to histamine was observed in the indomethacin-treated strips, but tachyphylaxis to histamine remained. We conclude that prostaglandin synthesis inhibition does not reverse histamine tachyphylaxis either in vivo or in vitro. Thus the mechanism of histamine tachyphylaxis remains unexplained.

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