Structure-activity relationships in the developmental toxicity of substituted phenols: in vivo effects

Hansch analysis, a quantitative approach relating the physical-chemical properties of molecules to biological effects, was applied to a series of substituted phenols tested for developmental toxicity. The physical-chemical properties included a hydrophobic parameter (log P), an electronic parameter (Hammett sigma), and a bulk parameter (molar refractivity (MR]. Biological activities (potencies) were obtained for 27 congeners in a Chernoff/Kavlock Assay performed in Sprague-Dawley rats exposed on day 11 of gestation. The potencies discussed in this report are the following: the dose to decrease maternal weight gain by 10 g at 24 and 72 hours after treatment (MTOX1 and MTOX2); the dose to increase postimplantation loss by 1 over the concurrent control value (PLOSS); and the dose required to decrease total litter weight by 10% on postnatal day 6 (BIO6). A quantitative structure-activity relationship QSAR was developed for the maternal data (1/MTOX1 = (0.0344*log P) + (-0.1503*sigma) + 0.1195; n = 22, r = 0.81, P less than .0001), which related increasing lipophilicity and decreasing electron-withdrawing ability of the substituent on 22 para-phenols to increasing toxicity. Another QSAR was developed from eight para-phenols that had the greatest postimplantation loss potencies (i.e., less than 100 mmol/kg). The model (1/PLOSS = (-0.2676*log P) + (-0.1827*sigma) + (0.0265*MR) + 0.4420; n = 8, r = 0.93, P less than .0298) related decreasing lipophilicity and electron-withdrawing ability and increasing bulk properties to the decreased viability of implantation sites. However, no descriptor was identified that distinguished the more potent from the less potent congeners for postimplantation loss, and no QSAR was found for litter weight on postnatal day 6 (even when limiting the analysis to the more potent congeners). Congeners were also grouped on a qualitative level according to whether they induced a biological effect below a dose of 6 mmol/kg (termed active), between 6 and 11 mmol/kg (moderately active), or greater than 11 mmol/kg (inactive). Overall, 14 of 27 congeners were classified as active in terms of maternal effects, but only 50% of these were active for developmental effects. Seven of the nine overall active developmental toxicants were active maternal toxicants. Four of the developmental toxicants produced a syndrome of effects that may be related to a similar mechanism of action or common metabolic pathway. Thus, from both quantitative and qualitative viewpoints, the properties of these phenolic congeners that promote maternal toxicity are different from those that contribute to developmental toxicity. It is therefore likely that the mechanisms of toxicity behind these effects are also different.