Quantitative correspondence between the in vivo and in vitro activity of teratogenic agents.

We have tested 74 teratogenic and 28 nonteratogenic agents in a recently developed in vitro teratogen assay system. The assay identifies teratogens by their ability to inhibit attachment of ascites tumor cells to plastic surfaces coated with concanavalin A. There is a qualitative agreement between in vivo animal data and in vitro activity for 81 of the 102 agents (79%). Quantitative analysis shows a highly significant correlation coefficient of 0.69 between the inhibitory in vitro dose and the lowest reported teratogenic dose for 54 of the 60 inhibitory teratogens. The doses analyzed ranged over 5 orders of magnitude. We interpret these results to mean that attachment inhibition in concert with other, complementary, in vitro assay systems can become a useful method for the assessment of the teratogenic potential of environmental agents.

Inhibition of tumor cell attachment to concanavalin A-coated surfaces as an assay for teratogenic agents: approaches to validation.

Four environmental agents have been tested for activity in a recently developed in vitro teratogen assay system. All four agents inhibited attachment. The agents were 40-fold concentrated drinking water (ID50 = 0.45 ml/ml), whole cigarette smoke condensate (ID50 = 85 micrograms/ml), kerosene soot (ID50 = 90 micrograms/ml), and commercial formulations of the pesticide carbaryl (ID50 approximately 150 micrograms/ml). On the basis of these examples appropriate criteria for the validation of in vitro teratogen assay systems are discussed. It is concluded that criteria are critically dependent on the specific applications of the assay system. For example, the false-positive rate must be minimized to make a wide-ranging screen of water samples useful. On the other hand, an investigation of impurities in commercial compounds requires low false-negative rates. In every case a quantitative measure of the potential teratogenic potency, in vivo, is desirable.

Teratogenic drugs inhibit tumour cell attachment to lectin-coated surfaces.

Interactions between embryonic cells are generally thought to have a central role in the control of development. When these morphogenic interactions are interrupted by either physical intervention or genetic defects, normal development is impaired. In accord with these experiments, specific interactions between embryonic cells have been demonstrated in several in vitro systems. Many investigators have described homotypic aggregation of chick embryo cells, and heterotypic specificity has been described. Because of the importance of morphogenic cell-cell interactions in development it follows that agents that interfere with these interactions, regardless of the interference mechanism, are potential teratogens. Here we have used a simple in vitro cell to surface recognition system in an attempt to screen for potential teratogens. We have found a very high correlation between inhibitory activity in the in vitro assay and reported teratogenic activity in human or animal studies. This suggests that many teratogenic agents may act by interfering, in an as yet unknown way, in normal cell to cell interactions.