Studies on the role of lipid peroxidation in the acute toxicity of TCDD in rats.

Lipid peroxidation has been shown to be enhanced following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), but its role in TCDD toxicity is unclear. The present study was undertaken to further elucidate the relations between lipid peroxidation and TCDD lethality. A time course and dose-response experiment in Long-Evans (L-E; LD50 ca. 10 micrograms/kg) and Han/Wistar (H/W; LD50 greater than 3000 micrograms/kg) rats showed that hepatic lipid peroxidation, measured as the amount of thiobarbituric acid-reactive substances (TBA-RS), was induced by TCDD dose-dependently in L-E, but not in H/W rats. Hepatic glutathione peroxidase activity was suppressed in much the same manner in both strains. Lipid peroxidation correlated with body weight loss in L-E rats alone. When 500 micrograms/kg of TCDD was given to L-E rats, lipid peroxidation increased about 3-fold on Day 11 in the liver, while no change was seen in cardiac or renal TBA-RS. The pair-fed controls did not survive the 11-day test period and exhibited gastrointestinal hemorrhages. At 6 days, liver atrophy and elevated (over 2-fold) TBA-RS values were recorded in pair-fed controls but not in their TCDD-treated counterparts. TCDD decreased hepatic glutathione peroxidase activity by almost 50% at 6 days, while pair-feeding was without effect. Liver morphology was different between TCDD-treated and pair-fed rats. Moreover, the livers of TCDD-treated L-E rats contained much higher concentrations of probably peripheral fat-derived fatty acids than did the livers of pair-fed or ad libitum control rats. Restricted feeding over 6 days induced hepatic lipid peroxidation more in H/W than in L-E rats. Endotoxin increased liver TBA levels similarly in both strains having an additive effect with high doses of TCDD in H/W rats. Added as a 0.5% concentration in chow, butylated hydroxyanisole (BHA), but not ethoxyquin, tended to increase survival rate and time in L-E rats exposed to 20 micrograms/kg of TCDD; at 50 micrograms/kg the only survivor was again in the BHA group. However, neither antioxidant had any effect on initial body weight loss. It is concluded that lipid peroxidation mainly arises as a secondary phenomenon in TCDD toxicity, is not the cause of the typical histopathological liver lesion, but may contribute to lethality.