A further study on the reliability of toxicokinetic parameters for predicting hepatotoxicity in rats receiving a 28-day repeated administration of DDT.

We previously demonstrated a good correlation between the increased relative liver weight caused by DDT and the area under the concentration-time curve (AUC) of DDT or the total DDT (T-DDT) in plasma and liver of rats in a 7-day repeated dose study at 1000 ppm. To confirm the reliability of AUC for predicting toxic responses at different dose levels, we conducted a further 28-day repeated dose study of p,p'-DDT in male F344 rats at dietary levels of 50, 160, and 500 ppm. Concentrations of DDT and its metabolites in plasma, brain, liver, and fat for each dose group were measured at various time intervals during the study. The concentrations of DDT and T-DDT in plasma and liver were compared with their AUCs in relation to hepatotoxic responses including increased relative liver weight, microsomal enzyme induction (CYP2B1), and inhibition of gap junctional intercellular communication. The coefficient (R(2)) values of each toxic response in correlation with AUCs were generally much higher than those with concentrations at any dose levels, although the R(2) values vary considerably among toxic parameters. These results have confirmed that the AUC of DDT or T-DDT in plasma or liver is a reliable marker for predicting hepatotoxicity caused by DDT in repeated dose studies.