THE THEORETICAL AND EMPIRICAL CASE FOR IN-VITRO DEVELOPMENT TOXICITY SCREENS, AND POTENTIAL APPLICATIONS

In vitro assays for the screening of developmental toxicity potential have been under development for approximately 15 years. During that pe riod, we have learned that assays consisting of primary cultures of em bryonic tissues or cells, intact embryos in culture, or free-living em bryos are capable of distinguishing between mammalian developmental to xicants and nondevelopmental toxicants with an accuracy of greater tha n or equal to 80%. Despite this level of performance, there is still c onsiderable reluctance among the scientific community to employ these assays for preliminary screening. In this paper, I review the theoreti cal basis for the predictiveness of these assays, outline the empirica l data indicating their utility in screening toxicants, discuss the ma jor limitations of in vitro assays and how they can be managed, and su ggest applications for in vitro pre-screens. The embryo-derived assays should work because they continue to develop in vitro, and the underl ying cellular and molecular processes driving this development are the same as those in the mammalian embryo in situ, and therefore, suscept ible to the same insults. The assays do work, as specific mechanisms o f developmental toxicity have been demonstrated in vitro, and because extensive validation studies have shown them to be highly concordant w ith traditional in vivo screens. The assays are inherently limited by the fact that they do not include all the levels of complexity of the maternal-embryonic unit; however, these limitations can be minimized b y thoughtful assay selection, study design, and interpretation. Potent ial applications are suggested that complement but do not replace in v ivo testing. Pre-screens will make product development more efficient and add to our knowledge about the developmental toxicity of previousl y untested compounds. In vivo screening would still be conducted on al l classes of substances that are currently tested for developmental to xicity; however, fewer chemicals with high likelihood of being develop mentally toxic, and therefore not appropriate for further commercial c onsideration, would be evaluated in these costly screens. (C) 1996 Wil ey-Liss, Inc.