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Validation of Screening Assays for Developmental Toxicity: An Exposure-Based Approach
Citation:
DASTON, G. P., R. Chapin, A. Scialli, E. W. Carney, A. Piersma, J. M. ROGERS, J. M. Friedman, AND J. Kim. Validation of Screening Assays for Developmental Toxicity: An Exposure-Based Approach. Presented at Society of Toxicology (SOT) Annual Meeting, Washington, DC, March 06 - 10, 2011.
Impact/Purpose:
Present data on a method of validating in vitro screens for developmental toxicity
Description:
There continue to be widespread efforts to develop assay methods for developmental toxicity that are shorter than the traditional Segment 2 study and use fewer or no animals. As with any alternative test method, novel developmental toxicity assays must be validated by evaluating their performance in correctly classifying a list of test compounds into "positive" or "negative" categories. However, developmental toxicity is highly conditional on dose and timing of exposure, which makes it difficult to develop lists of compounds neatly assigned as developmental toxicants. We believe that a more reasoned approach to establishing a list of positive and negative standards is to base these classifications on exposure, as both dosage and intrinsic hazard potential are important in determining whether an adverse response will occur. Because most alternative assays are in vitro and model only the embryonic compartment, internal dose is far more relevant than administered dose; therefore, metrics such as maternal Cmax and AVC are the most appropriate for this classification system. We have identified exposure levels for a number of chemicals for which toxicokinetics data have been generated. As it is possible to identify levels that are associated with frank terata and levels that are clear NOAELs, it is possible to populate the positive and negative lists with different concentrations of the same compounds. We believe that this approach will lead to better interpretation of alternative assay results, and is also a more relevant starting point for chemical hazard and risk assessment. This abstract does not represent EPA pol