tion that A/D ratios are not necessarily consistent across species (Daston et al. 1991).
Which In Vivo Database? The database on humans is probably too heterogeneous to use for validation studies. For example, it is biased toward pharmaceuticals, and the exposure range is too small for most chemicals, so chemicals with reliable negative results are hard to identify. By default then, comparisons have been made with experimental mammal testing data. The information in this database is also heterogeneous in exposure times, routes, and doses; species; end points; and adverse outcomes. To avoid some of these problems but retain the use of existing data, perhaps the only option is to use data exclusively from orthodox segment II type tests in which animals are exposed during the period of major organogenesis. This approach eliminates many of the chemicals historically used in validation studies, because they have never been formally tested in vivo.
Chemicals for Validation. Much effort has been expended on the analysis of in vivo animal test data to produce a list of chemicals for use in validation studies. A prototype list produced by Smith et al. (1983) was subsequently found to be inadequate and an expert committee was set up to address that issue (Schwetz 1993). Because of the difficulty of the task, that committee was not able to complete its task. There has been considerable disagreement over what is and what is not developmentally toxic in vivo and over the severity of that action. There is currently no consensus on how to categorize, stratify, or quantify the developmental toxicity of chemicals. Most validation studies have used a binary classification: developmental toxicants or nontoxicants (Parsons et al. 1990; Uphill et al. 1990). This is a gross oversimplification of the richness of information available. More recently, chemicals have often been grouped informally into three or four categories: (1) toxic to development in all species, no maternal toxicity; (2) toxic to development in some species, no maternal toxicity; (3) toxic to development in some species, some maternal toxicity; (4) no evidence for developmental toxicity in any species tested. However, without formal definition of categories and consistent in vivo testing, there is disagreement in assigning chemicals to such groups (Wise et al. 1990; Daston et al. 1995; Newall and Beedles 1996; Spielmann et al. 1997). Many validation studies have been biased by the inherent toxicity inequality of chemicals selected (Brown 1987). It has been common to select chemicals of potent and general biological activity, such as antimetabolites, nucleotide or nucleoside analogs, and alkylating agents, as developmental toxicants. In contrast, the chosen nondevelopmental toxicants have frequently been endogenous intermediary biochemicals, such as acetate, glutamate, and lysine, or chemicals specifically designed to be nontoxic to mammalian cells, such as antibiotics, saccharin, and cyclamate. It comes as no surprise that developmental models respond differently to two such disparate groups. The proper strategy should be to select chemicals that are largely similar in their gen-