A different approach to validating screening assays for developmental toxicity.

BACKGROUND There continue to be many efforts around the world to develop assays that are shorter than the traditional embryofetal developmental toxicity assay, or use fewer or no mammals, or use less compound, or have all three attributes. Each assay developer needs to test the putative assay against a set of performance standards, which traditionally has involved testing the assays against a list of compounds that are generally recognized as "positive" or "negative" in vivo. However, developmental toxicity is highly conditional, being particularly dependent on magnitude (i.e. dose) and timing of exposure, which makes it difficult to develop lists of compounds neatly assigned as developmental toxicants or not. APPROACH Here we offer an alternative approach for the evaluation of developmental toxicity assays based on exposures. Exposures are classified as "positive" or "negative" in a system, depending on the compound and the internal concentration. Although this linkage to "internal dose" departs from the recent approaches to validation, it fits well with widely accepted principles of developmental toxicology. CONCLUSIONS This paper introduces this concept, discusses some of the benefits and drawbacks of such an approach, and lays out the steps we propose to implement it for the evaluation of developmental toxicity assays.