Joint Actions of Developmental Toxicants.

Abstract

Abstract : For the embryolethality tests, semicarbazide and isoniazid showed a slightly less-than-additive embryolethal response. Potentially different lethal modes of action may be observed for compounds that are thought to be teratogenic by the same mode of action. For the embryolethal binary mixture test of hydroxyurea and isoniazid the 3:1 mixture showed an antagonistic response, while the 1:1 and 1:3 mixtures were response additive, as expected. The antagonistic response may have been the result of poorer absorption of hydroxyurea by the severely malformed embryos, as isoniazid had a much greater concentration (in mg/L) than did hydroxyurea even though the effective (lethal) concentration for hydroxyurea was nearly three times that for isoniazid. Short-chain carboxylic acids showed concentration additive joint actions for induction of malformation. Combinations of DNA synthesis inhibitor showed response additive to antagonistic joint actions at malformation-inducing concentrations. Since each compound inhibits a different enzyme in the process of DNA synthesis inhibition, a response additive relationship was expected. The studies have shown that joint toxic action responses for the malformation endpoint are as seen in studies with other systems using other endpoints. The ten acid mixture study clearly showed that a series of chemicals, given at very low effect concentrations, can combine to produce a significant response.