Title
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
Author
de Jong, E.
Louisse, J.
Verwei, M.
Blaauboer, B.J.
van de Sandt, J.J.M.
Woutersen, R.A.
Rietjens, I.M.C.M.
Piersma, A.H.
TNO Kwaliteit van Leven
Publication year
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. © The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
Subject
Chemistry
Toxicology and Applied Pharmacology
Alternatives to animal testing
Developmental toxicology
Embryonic stem cells
Glycol ethers
butoxyacetic acid
ethoxyacetic acid
glycol ether alkoxy acid metabolite
methoxyacetic acid
phenoxyacetic acid
toxin
unclassified drug
animal cell
article
cell differentiation
chemical analysis
chemical structure
concentration response
controlled study
cytotoxicity test
developmental disorder
developmental toxicity
embryonic stem cell
embryonic stem cell test
embryotoxicity
heart muscle cell
in vivo study
mouse
nonhuman
sensitivity analysis
toxicokinetics
Animal Testing Alternatives
Animals
Biotransformation
Cell Differentiation
Cell Survival
Dose-Response Relationship, Drug
Embryonic Development
Embryonic Stem Cells
Glycols
Kinetics
Mice
Models, Statistical
Myocytes, Cardiac
Predictive Value of Tests
Reference Standards
Structure-Activity Relationship
Teratogens
Animalia
To reference this document use:
http://resolver.tudelft.nl/uuid:12305f7e-d8b0-425c-8146-39f77bdf1b82
DOI
https://doi.org/10.1093/toxsci/kfp083
TNO identifier
241606
ISSN
1096-6080
Source
Toxicological Sciences, 110 (1), 117-124
Document type
article