Toxicokinetics and structure‐activity relationships of nine para‐substituted phenols in rat embryos in vitro

Abstract

The purpose of this study was to examine the toxicokinetics of embryo uptake following exposure to a variety of chemically related phenols in rat embryo culture. The uptake of nine radiolabeled para‐substituted phenols by day 10(9–13 somite stage) rat embryos in vitro was determined from 1 to 42 hrs after being placed in culture media containing various phenols. Uptake was rapid, having a half‐life of 3 hr or less, with 7 of the nine compounds having uptake half‐times of less than one hour. The equilibrium concentration in the embryo ranged from 53 to 136% of the media concentration, indicating only a factor of 2 in maximum discrimination against the compound for any of the phenols studied. The fraction of radioactivity remaining unbound in the media decreased with increasing log P (octanol/water partition coefficient). The binding was calculated to be 50% for log P = 1.77 from the fitted regression equation and decreased by a factor of 5.9 for every decade increase in P. When hepatocytes were also present in the media the equilibrium concentration in the embryos was less than when hepatocytes were absent. With the limited data, four of the phenols appeared to have no (i.e., zero) equilibrium level when hepatocytes were present. Thus the metabolites produced by the hepatocytes appeared to have less affinity for the embryo than the parent phenol. Toxicodynamic information as given by the effective concentration of the phenol in the embryo to cause somite or tail teratological effects was best predicted by the measured unbound fraction. © 1993 Wiley‐Liss, Inc. Copyright © 1993 Wiley‐Liss, Inc., A Wiley Company