Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict in Vivo Acute Toxicity of Tetrodotoxin in Rodents

In this study, the ability of a new in vitro/in silico quantitative in vitro-in vivo extrapolation (QIVIVE) methodology was assessed to predict the in vivo neurotoxicity of tetrodotoxin (TTX) in rodents. In vitro concentration-response data of TTX obtained in a multielectrode array assay with primary rat neonatal cortical cells and in an effect study with mouse neuro-2a cells were quantitatively extrapolated into in vivo dose-response data, using newly developed physiologically based kinetic (PBK) models for TTX in rats and mice. Incorporating a kidney compartment accounting for active renal excretion in the PBK models proved to be essential for its performance. To evaluate the predictions, QIVIVE-derived dose-response data were compared with in vivo data on neurotoxicity in rats and mice upon oral and parenteral dosing. The results revealed that for both rats and mice the predicted dose-response data matched the data from available in vivo studies well. It is concluded that PBK modeling-based reserve dosimetry of in vitro TTX effect data can adequately predict the in vivo neurotoxicity of TTX in rodents, providing a novel proof-of-principle for this methodology.

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Main Authors: Noorlander, Annelies, Zhang, Mengying, Van Ravenzwaay, Bennard, Rietjens, Ivonne M.C.M.
Format: Article/Letter to editor biblioteca
Language:English
Subjects:neurotoxicity, new approach methodology, physiologically based kinetic modeling, reverse dosimetry, tetrodotoxin (TTX),
Online Access:https://research.wur.nl/en/publications/use-of-physiologically-based-kinetic-modeling-facilitated-reverse-2
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spelling dig-wur-nl-wurpubs-5979352025-01-14 Noorlander, Annelies Zhang, Mengying Van Ravenzwaay, Bennard Rietjens, Ivonne M.C.M. Article/Letter to editor Toxicological sciences 187 (2022) 1 ISSN: 1096-6080 Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict in Vivo Acute Toxicity of Tetrodotoxin in Rodents 2022 In this study, the ability of a new in vitro/in silico quantitative in vitro-in vivo extrapolation (QIVIVE) methodology was assessed to predict the in vivo neurotoxicity of tetrodotoxin (TTX) in rodents. In vitro concentration-response data of TTX obtained in a multielectrode array assay with primary rat neonatal cortical cells and in an effect study with mouse neuro-2a cells were quantitatively extrapolated into in vivo dose-response data, using newly developed physiologically based kinetic (PBK) models for TTX in rats and mice. Incorporating a kidney compartment accounting for active renal excretion in the PBK models proved to be essential for its performance. To evaluate the predictions, QIVIVE-derived dose-response data were compared with in vivo data on neurotoxicity in rats and mice upon oral and parenteral dosing. The results revealed that for both rats and mice the predicted dose-response data matched the data from available in vivo studies well. It is concluded that PBK modeling-based reserve dosimetry of in vitro TTX effect data can adequately predict the in vivo neurotoxicity of TTX in rodents, providing a novel proof-of-principle for this methodology. en application/pdf https://research.wur.nl/en/publications/use-of-physiologically-based-kinetic-modeling-facilitated-reverse-2 10.1093/toxsci/kfac022 https://edepot.wur.nl/570931 neurotoxicity new approach methodology physiologically based kinetic modeling reverse dosimetry tetrodotoxin (TTX) https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/ Wageningen University & Research
institution WUR NL
collection DSpace
country Países bajos
countrycode NL
component Bibliográfico
access En linea
databasecode dig-wur-nl
tag biblioteca
region Europa del Oeste
libraryname WUR Library Netherlands
language English
topic neurotoxicity
new approach methodology
physiologically based kinetic modeling
reverse dosimetry
tetrodotoxin (TTX)
neurotoxicity
new approach methodology
physiologically based kinetic modeling
reverse dosimetry
tetrodotoxin (TTX)
spellingShingle neurotoxicity
new approach methodology
physiologically based kinetic modeling
reverse dosimetry
tetrodotoxin (TTX)
neurotoxicity
new approach methodology
physiologically based kinetic modeling
reverse dosimetry
tetrodotoxin (TTX)
Noorlander, Annelies
Zhang, Mengying
Van Ravenzwaay, Bennard
Rietjens, Ivonne M.C.M.
Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict in Vivo Acute Toxicity of Tetrodotoxin in Rodents
description In this study, the ability of a new in vitro/in silico quantitative in vitro-in vivo extrapolation (QIVIVE) methodology was assessed to predict the in vivo neurotoxicity of tetrodotoxin (TTX) in rodents. In vitro concentration-response data of TTX obtained in a multielectrode array assay with primary rat neonatal cortical cells and in an effect study with mouse neuro-2a cells were quantitatively extrapolated into in vivo dose-response data, using newly developed physiologically based kinetic (PBK) models for TTX in rats and mice. Incorporating a kidney compartment accounting for active renal excretion in the PBK models proved to be essential for its performance. To evaluate the predictions, QIVIVE-derived dose-response data were compared with in vivo data on neurotoxicity in rats and mice upon oral and parenteral dosing. The results revealed that for both rats and mice the predicted dose-response data matched the data from available in vivo studies well. It is concluded that PBK modeling-based reserve dosimetry of in vitro TTX effect data can adequately predict the in vivo neurotoxicity of TTX in rodents, providing a novel proof-of-principle for this methodology.
format Article/Letter to editor
topic_facet neurotoxicity
new approach methodology
physiologically based kinetic modeling
reverse dosimetry
tetrodotoxin (TTX)
author Noorlander, Annelies
Zhang, Mengying
Van Ravenzwaay, Bennard
Rietjens, Ivonne M.C.M.
author_facet Noorlander, Annelies
Zhang, Mengying
Van Ravenzwaay, Bennard
Rietjens, Ivonne M.C.M.
author_sort Noorlander, Annelies
title Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict in Vivo Acute Toxicity of Tetrodotoxin in Rodents
title_short Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict in Vivo Acute Toxicity of Tetrodotoxin in Rodents
title_full Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict in Vivo Acute Toxicity of Tetrodotoxin in Rodents
title_fullStr Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict in Vivo Acute Toxicity of Tetrodotoxin in Rodents
title_full_unstemmed Use of Physiologically Based Kinetic Modeling-Facilitated Reverse Dosimetry to Predict in Vivo Acute Toxicity of Tetrodotoxin in Rodents
title_sort use of physiologically based kinetic modeling-facilitated reverse dosimetry to predict in vivo acute toxicity of tetrodotoxin in rodents
url https://research.wur.nl/en/publications/use-of-physiologically-based-kinetic-modeling-facilitated-reverse-2
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