SUBCHRONIC TOXICITY OF BENZOTHIOPHENE ON RATS FOLLOWING DIETARY EXPOSURE

The systemic and neurobehavioral effects of benzo[b]thiophene (routine ly referred to as benzothiophene) were studied in rats following 13-wk oral exposure. Male (170 +/- 16 g) and female (146 +/- 12 g) Sprague- Dawley rats (10 animals per group) were fed diet containing 0.5 5, 50, or 500 ppm benzothiophene for 13 wk. Control animals were given rat f eed plus vehicle (corn oil) only. No clinical signs of toxicity and ne urobehavioral effects were observed using screening tests that include d cage-side observations, righting reflex, open field activities, and forelimb and hindlimb grip strength. Elevated serum aspartate aminotra nsferase activity and bilirubin level were observed in highest dose fe males. Except for a statistically significant decrease in hematocrit i n the highest dose males, benzothiophene exerted no marked effects on hematological parameters. Benzothiophene exposure did not result in al terations in hepatic alkaline phosphatase activity, or the typical hep atic phase I (aniline hydroxylase, ethoxyresorufin O-deethylase, pento xyresorufin O-dealkylase, aminopyrine N-demethylase) and phase II (UDP -glucuronosyltransferase, glutathione S-transferase) drug-metabolizing enzyme activities. No significant elevation in urinary ascorbic acid, protein, and N-acetylglucosaminidase activity was detected in the tre ated animals. Peribiliary fibrosis was the most significant histologic al change and occurred in the liver of females in the 50 and 500 ppm g roups. Mild epithelial hyperplasia in the renal pelvis was detected in the majority of 5 and 50 ppm females, with epithelial hyperplasia in the urinary bladder observed in the 50 ppm females. In males, increase d incidence and severity of mild binucleation of hepatocytes and mild thickening of the basement membrane in kidney cortex were observed at 500 ppm. Benzothiophene was not detected in the urine of high-dose ani mals at the termination of the experiment. Based on the kidney, hepati c, and hematocrit changes, the no-observed-adverse-effect level (NOAEL ) in the diet was determined to be 0.5 ppm (0.04 mg/kg/d) for females and 50 ppm (3.51 mg/kg/d) for males.