A comparative study on the reliablility of toxicokinetic parameters for predicting hepatotoxicity of DDT in rats receiving a single or repeated administration.
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 (R2) 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 R2 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 R2 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.
Tomiyama
Naruto
N
The Institute of Environmental Toxicology, 4321 Uchimoriya-machi, Mitsukaido-shi, Ibaraki 303-0043, Japan.
Watanabe
Momiko
M
Takeda
Makio
M
Harada
Takanori
T
Kobayashi
Hiroko
H
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D019540:Area Under Curve; D001219:Aspartate Aminotransferases / Q000097:blood; D001921:Brain / Q000378:metabolism; D003634:DDT / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D003633:Dichlorodiphenyl Dichloroethylene / Q000097:blood / Q000378:metabolism; D003632:Dichlorodiphenyldichloroethane / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D005723:gamma-Glutamyltransferase / Q000097:blood
D003633:Dichlorodiphenyl Dichloroethylene; D003634:DDT; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003632:Dichlorodiphenyldichloroethane