DOSE-DEPENDENT, ROUTE-DEPENDENT, AND SEX-DEPENDENT URINARY-EXCRETION OF PHENOL METABOLITES IN B6C3F(1) MICE

Phenol is the major oxidized metabolite of benzene, a known human leuk emogen and ubiquitous environmental pollutant. Unlike benzene, phenol does not induce tumors in mice following oral exposure; benzene also e xhibits sex-related differences in genotoxicity to bone marrow cells t hat are not observed following phenol administration. We studied the u rinary excretion or phenol metabolites in mice as a means to further i nvestigate the metabolic basis for differences in benzene- and phenol- induced toxicity. Male and female B6C3F, mice (n = 3/group) were expos ed to 15, 40, 100, or 225 mu mol [C-14]phenol/kg by iv tail vein injec tion (6 mu Ci/mouse). First-pass intestinal metabolism of phenol was e valuated by comparison of urinary excretion oi phenol metabolites foll owing iv administration with additional groups of male mice that recei ved the same dose levels by oral gavage. Mice were placed in glass met abolism cages, and urine was collected over dry ice for 48 h. Urinary metabolites were separated by high-pressure liquid chromatography (HPL C) and quantified by liquid scintillation spectrometry. Urinary excret ion of conjugated metabolites oi phenol was dose-dependent in both mal e and female mice administered phenol by iv injection or gavage. The m ajor urinary metabolites of phenol were phenol sulfate (PS), phenol gl ucuronide (PG), and hydroquinone glucuronide (HQC). Sulfation was the dominant pathway at all dose levels, but decreased as a percent of the excreted dose with a concomitant increase in glucuronidation as the d ose level increased. Male mice consistently excreted a higher proporti on of phenol as the oxidized conjugated metabolite, HQC, compared to f emale mice, suggesting that male mice oxidize phenol to hydroquinone m ore rapidly than female mice. Increased oxidation of phenol to hydroqu inone by male mice compared to female mice is consistent with both the greater sensitivity of male mice to the genotoxic effects of benzene and the greater potency oi hydroquinone compared to phenol as a genoto xicant. Intestinal conjugation of phenol prior to absorption was signi ficant only at low doses and thus alone does not provide an explanatio n for the lack of carcinogenicity of phenol in bioassays conducted at much higher dose levels.