Modulation of benzene-induced lymphocytopenia in the rat by 2,4,5,2',4',5'-hexachlorobiphenyl and 3,4,3',4'-tetrachlorobiphenyl.

Repeated administration of benzene (440 mg/kg/day, s.c.) to 6-week-old male Fischer-344 rats resulted in a progressive decline in the number of circulating lymphocytes. Pretreatment of these animals with 2,4,5,2',4',5'-hexachlorobiphenyl (HCB) or 3,4,3',4'-tetrachlorobiphenyl (TCB) protected against benzene toxicity for as long as 7 days, but not after 10 days of repeated dosing. Representative phase I (mixed-function oxidase) and phase II (conjugating) enzyme activities were measured to determine whether the altered susceptibility to benzene toxicity in TCB- and HCB-pretreated rats could be correlated with changes in the profile of hepatic oxidative and detoxification pathways. Measurement of 7-ethoxycoumarin O-deethylase and benzphetamine N-demethylase activities indicated that the loss of protection by HCB or TCB against benzene toxicity after 7 days was not associated with changes in the activities of hepatic mixed-function oxidases inducible by 3-methylcholanthrene or phenobarbital. The time course for the stimulation by TCB and return to control values, of UDP-glucuronosyl transferase activity, a potential route for the elimination of benzene metabolites, mirrored the time course for the protection against toxicity. Epoxide hydratase activity was induced 2- to 3-fold by HCB. Although stimulation of this pathway could result in a decreased concentration of phenol, this activity did not decline with the loss of protection. Hepatic 10 000 X g supernatant fractions, prepared from livers of rats given TCB, were incubated with a non-saturating concentration of [14C] benzene (equivalent to 19 nmol/mg wet wt. tissue). Under these conditions the metabolism of benzene was depressed (40% of control) 2 days after pretreatment; after 14 days, the metabolism of benzene returned to control values. This pattern correlated temporarily with the protection against lymphocytopenia. The data indicate that the protection against benzene toxicity in rats pretreated with HCB or TCB is not necessarily related to the capacity of these compounds to induce phase I activities. In rats pretreated with TCB, the data suggest that decreasing the concentration of primary benzene metabolites, either by inhibiting the hepatic metabolism of benzene or increasing hepatic conjugation activity is an important factor modulating toxicity.