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

Annelies Noorlander*, Mengying Zhang, Bennard Van Ravenzwaay, Ivonne M.C.M. Rietjens

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)127-138
JournalToxicological sciences
Volume187
Issue number1
DOIs
Publication statusPublished - May 2022

Keywords

  • neurotoxicity
  • new approach methodology
  • physiologically based kinetic modeling
  • reverse dosimetry
  • tetrodotoxin (TTX)

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