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

Abstract

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.To be useful, in vitro assay systems for teratogenic agents should be able to provide aquarntitative estimate ofteratogenic potency *in laboratory animals or in humans. In vivo processes of absorption, placental transfer, and maternal and embryonic metabolism make it unlikely that any group ofin vitro systems will be able to predict in vivo potency precisely. However, as in vitro systems approach quantitative and qualitative correspondence with in vivo results, they will become increasingly useful in the assessment of the teratogenic risk associated with environmental agents.Our interest in the correspondence between in vitro and in vivo data stems from the need to evaluate the validity of a recently developed in vitro teratogen assay (1). Teratogens are identified in the assay by their ability to inhibit the attachment of tumor cells to plastic surfaces coated with concanavalin A. In general, nonteratogens do not inhibit attachment.The working hypothesis behind this assay system can be summarized as follows. Because morphogenic interactions play a central role in development (2), agents that interfere with these interactions can be expected to lead to aberrant development and congenital malformations. A substantial body of indirect evidence suggests that these interactions are mediated by cellto-cell or cell-to-extracellular matrix interactions involving carbohydrate to receptor binding (3-9). In vitro studies indicate that embryonic cell-to-cell interactions share several characteristics with cell attachment to lectin-coated surfaces. For example, both processes consist of two stages, the first being a passive ligand-receptor binding, and the second involving metabolic energy and cytoskeletal elements (6, 10, 11). In both cases, the involvement of cell surface carbohydrates in the interaction can be shown (12)(13)(14). These similarities suggest to us that the processes involved in both systems may be similar, although details such as specific ligands, receptors, and cell types differ. Thus, agents that interfere with the process oflectin-mediated attachment can be expected to interfere with the process involved in morphogenic interactions and, therefore, are potential ...

Chemical and toxicological characterization of residential oil burner emissions: II. Mutagenic, tumorigenic, and potential teratogenic activity.

“…Agents interfering with attachment may also interfere with these morphogenic interactions in the developing embryo and hence lead to congenital malfonnations. There is quantitative and qualitative correlation between inhibitory activity in vitro and teratogenic activity in vivo (12).…”

“…A large class of nonmutagenic teratogens inhibits attachment at concentrations related to those causing congenital defects in vivo (12). In addition, tumor promoters inhibit attachment (16).…”

“…In the current work we have used one of these new assay techniques to evaluate the teratogenic risk associated with oil burner effluents. The assay technique is based on the observation that most nonmutagenic teratogens (such as thalidomide metabolites) inhibit the attachment of cells to plastic surfaces coated with plant lectins (12). Attachment is thought to model morphogenic cell-cell or cell-extracellular matrix interactions.…”

“…Potential teratogenicity was measured using the attachment inhibition assay system of Braun et al (11)(12)(13) …”

Teratological Research Using In Vitro Systems. IV. Cells in Culture

“…Counts of adherent cells on the three disks are averaged and the number of counts adherent to bovine serum albumin-coated disks is subtracted as the control. Results are expressed as a percentage of attachment by untreated cells to concanavalin A-coated disks (1,3,4). Another measure used to assess an agent's effect is the concentration required in order to inhibit attachment by 50% (ID50).…”