eral toxicity and potency, but different in specific developmental hazard (Schwetz and Harris 1993). This has never been achieved.

An additional problem in categorizing chemicals, even those tested according to standard protocols, is that toxicokinetics and metabolism are rarely investigated sufficiently to indicate whether a negative outcome in vivo is a reflection of a true lack of inherent developmental toxicity potential or a low embryonic exposure. This outcome can lead to a situation in which a chemical is correctly identified as a potential developmental toxicant from an in vitro test, but the effective exposure can never be achieved in vivo.

Existing and Extinct Alternative Tests for Primary Screening

Because there are no known common mechanisms of developmental toxicity on which to base a design for a primary screening test, three other approaches have been taken. These are the use of (1) mammalian embryos or parts of embryos in culture, (2) free-living nonmammalian embryos, and (3) cell cultures in which processes thought to be required for normal development are assayed (e.g., proliferation, adhesion, communication, and differentiation). More than 30 test systems have been devised and preliminarily assessed (see Table 3-1). All those test systems that use embryos monitor gross morphological end points. Few tests are actively used for screening purposes (Brown et al. 1995). Rodent embryo culture, micromass, and stem-cell assays are currently being validated in a European Union-sponsored trial (Spielmann et al. 1998). The validation of the frog embryo teratogenesis assay in Xenopus (FETAX) is being reviewed by the U.S. National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NIEHS 1997; Fort et al. 1998).

Rather than having been eliminated by objective criteria, most other systems were simply not adopted by scientists and were not pursued by their originators. For example, there have been no studies comparing several systems for relative performance or using more sophisticated molecular end points. A few systems have been eliminated by poor performance. The mouse ovarian tumor (MOT) cell-attachment method and the human embryonic palatal mesenchymal (HEPM) cell-proliferation method were simultaneously assessed by the U.S. National Toxicology Program (Steele at al. 1988) and shown to have a combined specificity of only 50%. The hydra assay is novel in having been designed specifically to estimate the A/D ratio. Although transiently popular, usage diminished with the demonstration that the A/D ratio is not consistent across species (Daston et al. 1991) and with other concerns about comparability with mammalian responses.

New Receptor-Based Tests

Endocrine disruptions by chemicals are beyond the scope of this report but are relevant in terms of the overlap in receptors involved and in the in vitro ap-



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