Toxicity stem cell applications

Therefore, a validation exercise with a variety of compounds with unknown mechanisms of developmental toxicity has only limited value if only used to derive an overall predictability rate of a single assay. It is more useful to elucidate the applicability domain of the assay in terms of the mechanisms of development covered, and to validate that aspect by testing compounds that do or do not affect the applicability domain. For single end point assays such as specific receptor activation assays, this exercise is relatively straightforward. For more complex assays such as those involving embryonic cell differentiation, the understanding of the applicability domain is more complex, as extensive research with the embryonic stem cell test has learned (27, 47). Whole embryo cultures are probably more straightforward in terms of applicability domain as they involve the entire embryo in a limited window of development, but such assays are complex and not animal free. 

Due to the limited applicability of in silico SAR approaches for developmental toxicity, there is more reliance on in vitro screening. From what has been publicly disclosed, it is evident that the four in vitro tests used for industrial screening are chick embryonic neural retina (CENR) micromass culture, whole embryo culture (WEC, rodent or rabbit), and mouse embryonic stem cells (EST). Recently, there has been significant interest within the pharmaceutical industry in the use of zebrafish for developmental toxicity testing,30 but because this aspect is in its infancy, there is little that has been publicly disclosed except limited abstracts and slide decks at several workshops.31 Although reviewed in considerable detail elsewhere,30-32 36 each test will be briefly compared and contrasted here. 

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