Title
Prediction of in vivo embryotoxic effect levels with a combination of in vitro studies and PBPK modelling
Author
Verwei, M.
van Burgsteden, J.A.
Krul, C.A.M.
van de Sandt, J.J.M.
Freidig, A.P.
TNO Kwaliteit van Leven
Publication year
2006
Abstract
The new EU legislations for chemicals (Registration, Evaluation and Authorization of Chemicals, REACH) and cosmetics (Seventh Amendment) stimulate the acceptance of in vitro and in silico approaches to test chemicals for their potential to cause reproductive effects. In the current study seven compounds with known in vivo developmental effects were tested in the embryonic stem cell test (EST). The EST correctly classified 5-fluorouracil, methotrexate, retinoic acid, 2-ethoxyacetic acid and 2-methoxyacetic acid for their in vivo embryotoxic potential. The toxicity of 2-methoxyethanol and 2-ethoxyethanol was underestimated due to a lack of metabolic capacity in the EST. This study further investigated the possibility to use in silico techniques to extrapolate in vitro effect concentrations determined in the EST to in vivo exposure levels. This approach was evaluated by comparing in silico predicted in vivo effect levels with effect levels measured in rodents. The in vivo effect levels of 2-methoxyethanol, 2-ethoxyethanol, methotrexate and retinoic acid were correctly predicted with in silico modelling. Contrary, in vivo embryotoxicity of 5-fluorouracil was overestimated following this approach. It is concluded that a combination of in vitro and in silico techniques appears to be a promising alternative test method for risk assessment of embryotoxic compounds. © 2006 Elsevier Ireland Ltd. All rights reserved.
Subject
Biology
Biomedical Research
Alternative test method
Developmental toxicity
Embryonic stem cells
PBPK model
2 ethoxyethanol
2 methoxyethanol
acetic acid derivative
ethoxyacetic acid
fluorouracil
methotrexate
methoxyacetic acid
retinoic acid
unclassified drug
animal cell
article
computer model
controlled study
embryo
embryo development
embryonic stem cell
embryotoxicity
exposure
metabolism
mouse
nonhuman
prediction
priority journal
risk assessment
rodent
Animal Testing Alternatives
Animals
Cell Line
Cell Survival
Dose-Response Relationship, Drug
Embryo
Mice
Models, Biological
Predictive Value of Tests
Rats
Risk Assessment
Stem Cells
Teratogens
Toxicity Tests
Rodentia
To reference this document use:
http://resolver.tudelft.nl/uuid:d2d436ff-4805-486d-9180-6cbbac82249e
DOI
https://doi.org/10.1016/j.toxlet.2006.01.017
TNO identifier
239392
ISSN
0378-4274
Source
Toxicology Letters, 165 (1), 79-87
Document type
article