Temporal and dose-response features of monochlorobenzene hepatotoxicity in rats

Abstract

Time- and dose-dependent correlations of monochlorobenzene (CB) hepatotoxic effects were studied in view of (1) assumed mechanistic similarities to bromobenzene (BB), (2) the paucity of these data for CB, and (3) the relatively greater environmental importance of CB compared with BB. An ip dosage of 9.8 mmol/kg CB (⋍LD10) produced evidence of liver toxicity over a 72-hr time course. Sulfobromophthalein (BSP) retention was maximized 3–16 hr post-treatment and normalized after 72 hr, whereas plasma alanine aminotransferase activity (ALT) and morphological evidence of damage were maximized about 48 hr after dosing. Maximal covalent binding to liver protein (3.07 nmol/mg) had occurred by 24 hr and approximately 36% of the administered dose had appeared in the urine by 48 hr. Liver and plasma CB concentrations were proportionally increased over the dosage range 2.0–14.7 mmol/kg but marked centrolobular necrosis and ALT elevations were seen only at the two highest dosages (9.8 and 14.7 mmol/kg). On the other hand, all doses depressed hepatic glutathione (GSH) to between 30 and 40% of control by 4 hr. Evidence of rapid recovery was evident at 2.0 and 4.9 mmol/kg but GSH levels remained low through 8 hr after 9.8 or 14.7 mmol/kg. Liver/body weight ratios were increased to a similar extent at all dosages when measured 24 hr post-treatment. Urinary excretion ranged from 59% at the low dosage to only 19% at the highest dosage by 24 hr. Dose-related covalent binding to liver protein at 24 hr occurred up to 9.8 mmol/kg but the binding associated with 14.7 mmol/kg was equivalent to that seen with the 4.9 mmol/kg dosage (1.6 nmol/mg protein). Cytochrome P-450 levels were depressed to between 50 and 80% of control 24 hr post-treatment with no clear dose relationship. While the hepatotoxic effects of CB and BB appear similar, these data suggest that some mechanistic differences are involved.