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

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Abstract

Toxicological hazard and risk assessment largely rely on animal testing. For economic and ethical reasons, the development and validation of reliable alternative methods for these animal studies, such as in vitro assays, are urgently needed. In vitro concentration-response curves, however, need to be translated into in vivo dose-response curves for risk assessment purposes. In the present study, we translated in vitro concentration–response data of the antifungal compound tebuconazole, obtained in the ES-D3 cell differentiation assay, into predicted in vivo dose–response data for developmental toxicity using physiologically based kinetic (PBK) modeling-facilitated reverse dosimetry. Using the predicted in vivo dose–response data BMD(L)10 values for developmental toxicity in rat were calculated and compared with NOAEL values for developmental toxicity data in rats as reported in the literature. The results show that the BMDL10 value from predicted dose–response data are a reasonable approximation of the NOAEL values (ca. 3-fold difference). It is concluded that PBK modeling-facilitated reverse dosimetry of in vitro toxicity data is a promising tool to predict in vivo dose-response curves and may have the potential to define a point of departure for deriving safe exposure limits in risk assessment.
Original languageEnglish
Pages (from-to)85-93
JournalToxicology Letters
Volume266
DOIs
Publication statusPublished - 2017

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Dosimetry
Toxicity
Rats
Risk assessment
No-Observed-Adverse-Effect Level
Kinetics
Assays
Animals
Toxicology
Cell Differentiation
Hazards
Economics
tebuconazole
In Vitro Techniques
Testing

Keywords

  • Developmental toxicity
  • Embryonic stem cell test
  • In vitro–in vivo extrapolation
  • Physiologically based kinetic modeling
  • Reverse dosimetry
  • Tebuconazole

Cite this

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title = "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 = "Toxicological hazard and risk assessment largely rely on animal testing. For economic and ethical reasons, the development and validation of reliable alternative methods for these animal studies, such as in vitro assays, are urgently needed. In vitro concentration-response curves, however, need to be translated into in vivo dose-response curves for risk assessment purposes. In the present study, we translated in vitro concentration–response data of the antifungal compound tebuconazole, obtained in the ES-D3 cell differentiation assay, into predicted in vivo dose–response data for developmental toxicity using physiologically based kinetic (PBK) modeling-facilitated reverse dosimetry. Using the predicted in vivo dose–response data BMD(L)10 values for developmental toxicity in rat were calculated and compared with NOAEL values for developmental toxicity data in rats as reported in the literature. The results show that the BMDL10 value from predicted dose–response data are a reasonable approximation of the NOAEL values (ca. 3-fold difference). It is concluded that PBK modeling-facilitated reverse dosimetry of in vitro toxicity data is a promising tool to predict in vivo dose-response curves and may have the potential to define a point of departure for deriving safe exposure limits in risk assessment.",
keywords = "Developmental toxicity, Embryonic stem cell test, In vitro–in vivo extrapolation, Physiologically based kinetic modeling, Reverse dosimetry, Tebuconazole",
author = "Hequn Li and Mengying Zhang and Jacques Vervoort and Rietjens, {Ivonne M.C.M.} and {van Ravenzwaay}, Bennard and Jochem Louisse",
year = "2017",
doi = "10.1016/j.toxlet.2016.11.017",
language = "English",
volume = "266",
pages = "85--93",
journal = "Toxicology Letters",
issn = "0378-4274",
publisher = "Elsevier",

}

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T1 - 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

AU - Li, Hequn

AU - Zhang, Mengying

AU - Vervoort, Jacques

AU - Rietjens, Ivonne M.C.M.

AU - van Ravenzwaay, Bennard

AU - Louisse, Jochem

PY - 2017

Y1 - 2017

N2 - Toxicological hazard and risk assessment largely rely on animal testing. For economic and ethical reasons, the development and validation of reliable alternative methods for these animal studies, such as in vitro assays, are urgently needed. In vitro concentration-response curves, however, need to be translated into in vivo dose-response curves for risk assessment purposes. In the present study, we translated in vitro concentration–response data of the antifungal compound tebuconazole, obtained in the ES-D3 cell differentiation assay, into predicted in vivo dose–response data for developmental toxicity using physiologically based kinetic (PBK) modeling-facilitated reverse dosimetry. Using the predicted in vivo dose–response data BMD(L)10 values for developmental toxicity in rat were calculated and compared with NOAEL values for developmental toxicity data in rats as reported in the literature. The results show that the BMDL10 value from predicted dose–response data are a reasonable approximation of the NOAEL values (ca. 3-fold difference). It is concluded that PBK modeling-facilitated reverse dosimetry of in vitro toxicity data is a promising tool to predict in vivo dose-response curves and may have the potential to define a point of departure for deriving safe exposure limits in risk assessment.

AB - Toxicological hazard and risk assessment largely rely on animal testing. For economic and ethical reasons, the development and validation of reliable alternative methods for these animal studies, such as in vitro assays, are urgently needed. In vitro concentration-response curves, however, need to be translated into in vivo dose-response curves for risk assessment purposes. In the present study, we translated in vitro concentration–response data of the antifungal compound tebuconazole, obtained in the ES-D3 cell differentiation assay, into predicted in vivo dose–response data for developmental toxicity using physiologically based kinetic (PBK) modeling-facilitated reverse dosimetry. Using the predicted in vivo dose–response data BMD(L)10 values for developmental toxicity in rat were calculated and compared with NOAEL values for developmental toxicity data in rats as reported in the literature. The results show that the BMDL10 value from predicted dose–response data are a reasonable approximation of the NOAEL values (ca. 3-fold difference). It is concluded that PBK modeling-facilitated reverse dosimetry of in vitro toxicity data is a promising tool to predict in vivo dose-response curves and may have the potential to define a point of departure for deriving safe exposure limits in risk assessment.

KW - Developmental toxicity

KW - Embryonic stem cell test

KW - In vitro–in vivo extrapolation

KW - Physiologically based kinetic modeling

KW - Reverse dosimetry

KW - Tebuconazole

U2 - 10.1016/j.toxlet.2016.11.017

DO - 10.1016/j.toxlet.2016.11.017

M3 - Article

VL - 266

SP - 85

EP - 93

JO - Toxicology Letters

JF - Toxicology Letters

SN - 0378-4274

ER -