Metabolism and disposition of simultaneously inhaled m-xylene and ethylbenzene in the rat

Rats were exposed for 5 days (6 hr/day) to one of four concentrations of a mixture of m-xylene (XYL) and ethylbenzene (EB) in the air (0 + 0, 75, + 25, 300 + 100, or 600 + 200 ppm). XYL and EB were found in the fat after the 5th day of exposure in the same molar ratio (3:1) as in the inspired air. The urine of the rats in each group was collected in two daily portions. The excretion of urinary thioethers increased linearly up to 12-fold. The urinary excretion of the major metabolites of XYL (methylhippuric acid, dimethylphenols, and methylbenzyl alcohol) and EB (hippuric, mandelic, phenylglyoxylic, and phenaceturic acids, and 1-phenylethanol) were measured. XYL metabolites were excreted faster than EB metabolites in a manner pronounced with repetitive exposure and increasing dose. If the urinary elimination was expected to show the same molar ratio as in the inspired air (3:1), then total XYL metabolites were recovered in amounts lower than those of EB (about 2:1). The metabolite pattern of XYL showed no difference between mixed and pure equimolar exposures, whereas the pattern of EB metabolites was variable. The major problem met in quantitation of total output of EB was the estimation of metabolites (hippuric and phenaceturic acids) also formed endogenously. The apparent metabolic capacity for urinary solvent disposition vs the atmospheric concentration showed nonlinear correlation after a single mixed exposure. From the 2nd day onward, the metabolite excretion rates abruptly increased more than expected with the 600 + 200 ppm dose. This dose also increased microsomal drug-metabolizing activity in the liver. In conclusion, the mutual effects characteristic for mixed exposure to XYL + EB were, in a conspicuous manner, enhanced with the dose.