A Comparative Study on the Reliability of Toxicokinetic Parameters for Predicting Hepatotoxicity of DDT in Rats Receiving a Single or Repeated Administration.

Abstract

-A comparative study on the reliability of toxicokinetic parameters for predicting hepatotoxicity was conducted in male F344 rats receiving a single (106 mg/kg by gavage) or 7-day repeated (1000 ppm in feed, 97 mg/kg/day) administration of p,p'-DDT. DDT was selected as the test substance because it is known as a hepatotoxic agent and its metabolic pathway is well documented. Concentrations of DDT and its metabolites (DDE and DDD) in the plasma, brain, and liver were measured at various time intervals during the study and the results were compared with the area under the concentration-time curve (AUC) in relation to hepatotoxic response. Increases in the absolute and relative (ratio to body weight) liver weights were observed as a typical toxic response after a single or repeated exposure to DDT. The coefficient (R 2 ) of correlation between the increases in the relative liver weight and the concentrations or AUC of DDT and its metabolites in the plasma and liver was estimated. The values of R 2 between the relative liver weight and AUC of DDT or the total DDT (T-DDT) in the plasma and liver were found to be more consistent and higher than those with their concentrations in the repeated dose study. In addition, the R 2 values in correlation with their AUCs after a single exposure were lower than those in the repeated dose study. These results indicate that the AUC of DDT or T-DDT in the plasma and liver would be more reliable than their concentrations for predicting hepatotoxicity caused by DDT, especially in the repeated dose study.

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.…”

“…This reducalthough the detailed mechanism underlying this response is obscure. Kinoshita et al (2003) reported that low-dose treatment with phenobarbital, which is a nongenotoxic carcinogen like DDT (Harada et al, 2003), induced a and enzyme induction.…”

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

“…However, information on the relationship between TK parameters of DDT and its toxic effects is still limited, especially in long-term repeated dose studies, because toxicokinetic data on pesticides have not been required for registration by regulatory agencies. In our previous study (Tomiyama et al, 2003), we compared the reliability of toxicokinetic parameters for predicting hepatotoxicity in rats receiving a single or 7-day repeated administration of p,p'-DDT. The results indicated that the area under the concentration-time curve (AUC) of DDT or the total DDT (T-DDT) including metabolites in plasma and liver would be more reliable than their concentrations for predicting hepatotoxicity caused by DDT, especially in the repeated dose study.…”

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.…”