期刊
BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY
卷 83, 期 2, 页码 104-111出版社
WILEY-LISS
DOI: 10.1002/bdrb.20148
关键词
Embryonic Stem Cell Test; EST; pharmaceutical compounds; embryotoxic; developmentally toxic
BACKGROUND: The European Centre for the Validation of Alternative Methods (ECVAM) designed the Embryonic Stem Cell Test (EST) as a tool for classifying developmentally toxic compounds. An in vitro tool to assess developmental toxicity would be of great value to the pharmaceutical industry to help with toxicity-associated attrition. METHODS: ECVAM's EST protocol was used, but employing a different mouse embryonic stem cell (ESC) line and an alternative differentiation medium. A subset of the compounds used to validate the EST assay along with a number of in-house pharmaceutical compounds plus marketed pharmaceutical compounds were used to assess the EST performance with receptor-mediated compounds. RESULTS: Our results with ECVAM compounds mirrored ECVAM's. Compounds that were developmentally toxic in vivo were classified by the EST as moderate risk. Overall, the accuracy was 75% with the current set of data and the predictivity of low-, moderate-, and high-risk compounds was 90, 71, and 60% while the precision was 59, 86, and 100%, respectively. Interestingly, a number of the non-developmentally toxic compounds had values for the 3T3 IC50 values, which were lower than the ESC IC50 and ID50, a situation not taken into account by ECVAM when designing the EST algorithm. CONCLUSIONS: The assay as currently constructed has a significant false-positive rate (similar to 40%), but a very low false-negative rate (similar to 7%). Additional moderate- and high-risk compounds need to be assessed to increase confidence, accuracy, and understanding in the EST's predictivity.
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