Daston George P, Chapin Robert E, Scialli Anthony R, Piersma Aldert H, Carney Edward W, Rogers John M, Friedman Jan M
Procter & Gamble, Cincinnati, Ohio, USA.
Birth Defects Res B Dev Reprod Toxicol. 2010 Dec;89(6):526-30. doi: 10.1002/bdrb.20276.
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.
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.
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.
世界各地仍在进行许多努力，以开发比传统胚胎-胎儿发育毒性试验更短的试验，或使用更少或不使用哺乳动物，或使用更少的化合物，或具备所有这三个特性。每个试验开发者都需要根据一套性能标准来测试假定的试验，传统上这涉及针对一系列在体内通常被认为是“阳性”或“阴性”的化合物来测试试验。然而，发育毒性具有高度的条件性，尤其取决于暴露的程度（即剂量）和时间，这使得难以编制出被明确归类为发育毒物或非发育毒物的化合物清单。
在此，我们提供一种基于暴露评估发育毒性试验的替代方法。在一个系统中，根据化合物和内部浓度，将暴露分类为“阳性”或“阴性”。尽管这种与“内部剂量”的联系不同于最近的验证方法，但它与广泛接受的发育毒理学原理非常契合。
本文介绍了这一概念，讨论了这种方法的一些优缺点，并列出了我们提议为评估发育毒性试验而实施该方法的步骤。
