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ToxSci Advance Access originally published online on April 28, 2009
Toxicological Sciences 2009 110(1):117-124; doi:10.1093/toxsci/kfp083
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Relative Developmental Toxicity of Glycol Ether Alkoxy Acid Metabolites in the Embryonic Stem Cell Test as compared with the In Vivo Potency of their Parent Compounds

Esther de Jong*,{dagger},1, Jochem Louisse{ddagger},§,¶, Miriam Verwei{ddagger}, Bas J. Blaauboer{dagger}, Johannes J. M. van de Sandt{ddagger}, Ruud A. Woutersen{ddagger},§,¶, Ivonne M. C. M. Rietjens§,¶ and Aldert H. Piersma*,{dagger}

* National Institute of Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands {dagger} Institute for Risk Assessment Sciences, Utrecht University, The Netherlands {ddagger} TNO Quality of Life, 3700 AJ Zeist, The Netherlands § Division of Toxicology, Wageningen University, 6703 HE Wageningen, The Netherlands TNO/WUR Centre for Innovative Toxicology, 6700 EA Wageningen, The Netherlands

1 To whom correspondence should be addressed at National Institute of Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands. Fax: +31-30-274-4446. E-mail: Esther.de.Jong{at}rivm.nl.

Received March 13, 2009; accepted April 17, 2009


  Abstract

The embryonic stem cell test (EST) has been proposed as an in vitro assay that might reduce animal experimentation in regulatory developmental toxicology. So far, evaluation of the EST was not performed using compounds within distinct chemical classes. Evaluation within a distinct class of chemically related compounds can define the usefulness of the assay for the chemical class tested. The aim of the present study was to evaluate the relative sensitivity of the EST for a selected series of homologous compounds and to compare the data to the relative developmental toxicity of the compounds in vivo. To this end a series of proximate developmentally toxic glycol ether alkoxy acid metabolites was tested in the EST. All glycol ether alkoxy acid metabolites tested showed a concentration-dependent inhibition of cardiomyocyte differentiation at noncytotoxic concentrations, with methoxyacetic acid as the most potent compound followed by ethoxyacetic acid, butoxyacetic acid, and phenoxyacetic acid, respectively. The potency ranking of the compounds in the EST corresponds with the available in vivo data. The relative differences between the potencies of the compounds appeared more pronounced in the in vivo studies than in the EST. A possible explanation for this discrepancy could be the difference in the kinetics of the compounds in vivo as compared with their in vitro kinetics. This study illustrates that the EST can be used to set priorities for developmental toxicity testing within classes of related compounds.

Key Words: embryonic stem cells; glycol ethers; alternatives to animal testing; developmental toxicology.


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