A Further Study on the Reliability of Toxicokinetic Parameters for Predicting Hepatotoxicity in Rats Receiving a 28-Day Repeated Administration of DDT

Abstract

-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.

Low dose effects of dichlorodiphenyltrichloroethane (DDT) on gene transcription and DNA methylation in the hypothalamus of young male rats: implication of hormesis-like effects

“…Twenty-four hours after the last injection of paraoxon, no abnormalities were observed in the animals pretreated with DDT. galanin involved in inhibition of acetylcholine release (Fisone et al that the CpG island on the transcription start site was sigPreviously, we reported that DDT and its metabolites in the brain were excreted gradually over a few weeks and were then deposited in the adipose tissue (Tomiyama et al, 2003(Tomiyama et al, , 2004. Taken together, we speculate that the effect of hypomethylation induced by a low dose of DDT in the young period may appear after direct transcriptional down-regulation by DDT has disappeared.…”

“…This report indicates that effect of low dose of DDT in the infant period persisted for a long time. Previously, we reported that DDT and its metabolites in the brain were excreted gradually over a few weeks and were then deposited in the adipose tissue (Tomiyama et al, 2003(Tomiyama et al, , 2004. Thus, we speculate that low dose of DDT may have epigenetic effects including DNA methylation in the young brain.…”

Two‐generation reproduction toxicity study in rats with 1,1,1‐trichloro‐2,2‐bis(4‐chlorophenyl)ethane (p,p′‐DDT)

“…obs.). As DDT and its metabolites are highly lipophilic and blood concentrations can be reduced by being stored in the adipose tissues (Tomiyama et al 2003(Tomiyama et al , 2004, the present observations might be related in part to the sex differences in body fat percentage (Dale et al 1962). In addition, disappearance of maternal toxic symptoms during the lactation period and slightly lowered pup viability in the highest dose group might be due in part to excretion of DDT and/or its metabolites into maternal milk since DDT is widely detected in breast milk (Snedeker 2001) and the concentration of DDT in the whole suckling rat is reported to increase rapidly as that in the maternal tissues decrease (Ando 1978).…”

“…obs.). As DDT and its metabolites are highly lipophilic and blood concentrations can be reduced by being stored in the adipose tissues (Tomiyama et al . 2003, 2004), the present observations might be related in part to the sex differences in body fat percentage (Dale et al .…”

Human Blood Concentrations of Dichlorodiphenyltrichloroethane (DDT) Extrapolated from Metabolism in Rats and Humans and Physiologically Based Pharmacokinetic Modeling

“…for 3 days, based on a NOAEL dose. [20][21][22][23] This study was approved by the experimental animal committee of Showa Pharmaceutical University. Liver microsomes from male rats (7 weeks old) treated with DDT (10 mg/kg) and from untreated controls were prepared as described previously.…”