In vivo and in vitro structure-dosimetry-activity relationships of substituted phenols in developmental toxicity assays☆☆☆

Abstract Structure-dosimetry-activity relationships (SDARs) of a series of substituted phenols were evaluated following exposure of gestation day 11 rats in vivo and in comparable stage embryos in vitro. In the in vivo study, 27 congeners were assayed and log P (a term used synomously with lipophilicity in this paper) and Hammett sigma values (a measure of the electronic withdrawing ability of the substituent) were shown to correlate with maternal toxicity; however, no relationships between these parameters and developmental effects were observed. In the in vitro system, 13 congeners were evaluated and molar refractivity and/or lipophilicity were shown to correlate with the ability of the phenols to induce embryonic growth retardation and structural defects in the absence of the hepatocytes. In contrast, when a metabolic activating system (primary hepatocytes) was present in the in vitro system, the potential to induce growth retardation was inversely related to lipophilicity, although the relationships were weaker than the positive relationship seen without the hepatocytes. The binding of the phenols to macromolecules in the culture medium was highly correlated with log P. Correcting the in vitro potency data for the variable amount of binding improved the predictiveness of the quantitative structure-activity relationships (QSARs). The potential to induce embryotoxicity in vitro was not well correlated with the potential to induce developmental toxicity in vivo: whereas the in vitro data demonstrates that the phenols are intrinsically embryotoxic, few of them actually produced significant developmental toxicity in the in vivo system, and there were few positive correlations between effects observed in the two systems. Embryonic dosimetry obtained for the in vitro assay system indicated that the principal determining factor in producing embryotoxicity of a phenol in vitro is the ability to gain access into the embryo, but that once in the embryo, the lipophilic phenols are more toxic on a per molecule basis. Furthermore, embryonic dosimetry data for two phenols indicated that for a given exposure, in vitro embryos will accumulate more of a phenol than will the in vivo embryos. In summary, we have undertaken a systematic study of the response of in vivo and in vitro embryos to a series of structural analogues, and attempted to relate the potency of the congeners to specific physicochemical properties. While different conclusions were reached about the potency of the phenols in the two systems, the assessment of pharmacokinetic parameters provided insight into the deposition and activity of these congeners in the embryo and have pointed us in the direction of determining the reason(s) for the differences that we observed.