Hexachlorobenzene: Biochemical effects and synergistic toxic interactions with 2,3,7,8‐tetrachlorodibenzo‐<i>p</i>‐dioxin

Abstract

Abstract Hexachlorobenzene (400 μimol/kg) induced rat hepatic microsomal aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O‐deethylase (EROD), however at dose levels up to 3000 μmol/kg, the induced enzyme levels were less than 50% of the maximum induced activities caused by either 3‐methylcholanthrene (MC) or 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD). HCB did not significantly induce these monooxygenases in the thymus or lung but some time‐dependent induction of AHH and EROD was observed in the rat kidney. In contrast, MC induced microsomal AHH and EROD in the rat liver, lung and kidney but not the thymus. Cotreatment of HCB (400 μmol/kg) plus 2,3,7,8‐TCDD (10 or 30 μg/kg) resulted in some small but significant dose‐ and organ‐dependent modulation of the activity of 2,3,7,8‐TCDD as an inducer of AHH and EROD. The 30 μg/kg dose of 2,3,7,8‐TCDD was toxic and this may account for the lower induced enzyme levels observed in the kidney and thymus of animals cotreated with HCB plus 2,3,7,8‐TCDD compared to rats given 2,3,7,8‐TCDD alone. Animals cotreated with 2,3,7,8‐TCDD (10 μg/kg) plus HCB exhibited decreased AHH and EROD activities in the liver and thymus but increased enzyme levels in the kidney. In a separate study, it was shown that over a 14‐day period, HCB caused significant decreases in both the lung and kidney aryl hydrocarbon (Ah) receptor binding levels but no significant long‐term changes in hepatic or thymic receptor levels. The role of the HCB‐mediated changes in receptor binding levels and its relationship to the induction of AHH and EROD by 2,3,7,8‐TCDD is unclear. The most dramatic interactive effects of HCB (400 μmol/kg) and 2,3,7,8‐TCDD (10 or 30 μg/kg) were observed with two Ah receptor‐mediated toxic effects, namely body weight loss and thymic atrophy. HCB synergistically exacerbated both body weight loss and thymic atrophy caused by 2,3,7,8‐TCDD whereas HCB administered at doses as high as 3000 μmol/kg did not cause any significant body weight loss or thymic atrophy in the rats. The mechanism of these toxic interactions are unknown.