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 μg/kg) and Han/Wistar (H/W; LD50 > 3000 μg/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 μg/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 μg/kg of TCDD; at 50 μg/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. 1990 Nordic Pharmacological Society