Metabolism of a dithiocarbamate fungicide thiram to carbon disulfide in the rat and its hepatotoxic implications.

Thiram, tetramethylthiuram disulfide, is used extensively as an agricultural fungicide whose toxicity is largely dependent on its metabolism. The following experiments were carried out to investigate whether carbon disulfide (CS2) is a metabolic product of microsomal monooxygenase catalyzed metabolism of thiram in rats. Adult male Sprague-Dawley rats (160-200 g) were given thiram (60 mg/kg, b.wt.) in corn oil by intraperitoneal injection and placed individually in a metabolic apparatus. Concentration of CS2 in the breath was determined by drawing the expired air through a series of traps containing a CS2 complexing agent. Expiration of CS2 was almost complete within 5 hrs following thiram administration. The formation of CS2 from thiram was increased by pretreatment of rats with phenobarbital and decreased by SKF 525-A. Furthermore, measurement of the activities of hepatic microsomal and serum enzymes at 5 hrs and 24 hrs following thiram treatment indicated that thiram caused significant loss of cytochrome P-450 and benzphetamine N-demethylase activity only at 24 hrs interval whereas there was significant elevation of sorbitol dehydrogenase (SDH) and serum glutamic oxalacetic transaminase (SGOT) activity at 5 and 24 hrs after treatment. The data confirm that CS2 is an in vivo metabolite of thiram and may be, in part, responsible for the observed hepatotoxicity.