TOXICOKINETICS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 9 PARASUBSTITUTED PHENOLS IN RAT EMBRYOS IN-VITRO

The purpose of this study was to examine the toxicokinetics of embryo uptake following exposure to a variety of chemically related phenols i n rat embryo culture. The uptake of nine radiolabeled para-substituted phenols by day 10 (9-13 somite stage) rat embryos in vitro was determ ined from 1 to 42 hrs after being placed in culture media containing v arious 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 1 36% of the media concentration, indicating only a factor of 2 in maxim um discrimination against the compound for any of the phenols studied. The fraction of radioactivity remaining unbound in the media decrease d with increasing log P (octanol/water partition coefficient). The bin ding was calculated to be 50% for log P = 1.77 from the fitted regress ion equation and decreased by a factor of 5.9 for every decade increas e in P. When hepatocytes were also present in the media the equilibriu m concentration in the embryos was less than when hepatocytes were abs ent. With the limited data, four of the phenols appeared to have no (i .e., zero) equilibrium level when hepatocytes were present. Thus the m etabolites produced by the hepatocytes appeared to have less affinity for the embryo than the parent phenol. Toxicodynamic information as gi ven by the effective concentration of the phenol in the embryo to caus e somite or tail teratological effects was best predicted by the measu red unbound fraction. (C) 1993 Wiley-Liss, Inc.