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Toluene, a potentially neurotoxic substance, is found in trace amounts in groundwater. Adult male CD-1 mice were continuously fed drinking water ad libitum containing 0, 17, 80, and 405 mg/liter toluene. After a 28-day treatment, animals were tested for endogenous levels of the biogenic monoamines norepinephrine (NE), dopamine (DA), and serotonin (5-HT) and their respective metabolites. 3-methoxy-4-hydroxymandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), in six discrete brain regions. The maximum toluene-induced increases of biogenic amines and their metabolites generally occurred at a toluene concentration of 80 mg/liter. In the hypothalamus, a major NE-containing compartment, the concentrations of NE significantly increased by 51, 63, and 34% in groups dosed with 17, 80, and 405 mg/liter, respectively. Significant increases of NE were also observed in the medulla oblongata and midbrain. Concomitantly, concentrations of VMA increased in various brain regions. Concentrations of DA were significantly higher in the corpus striatum and hypothalamus. Alterations in levels of DA metabolites, DOPAC and HVA, were marginal. Toluene significantly increased concentrations of 5-HT in all dissected brain regions, except cerebellum, and increased the 5-HIAA levels in the hypothalamus, corpus striatum, and cerebral cortex.

Benzene and toluene are known neurotoxicants that may interact in vivo. The effect of combined treatment with benzene and toluene on the endogenous concentrations of the catecholamines norepinephrine (NE) and dopamine (DA), the catecholamine metabolites vanillylmandelic acid (VMA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the indoleamine serotonin (5-HT) and its metabolite 5-hydroxy-indoleacetic acid (5-HIAA), were investigated in six discrete brain regions of CD-1 mice. Groups of male, adult mice were continuously exposed to benzene (166 mg/l), toluene (80 and 325 mg/l), and combinations of benzene + toluene (80 or 325 mg/l) in drinking water for 4 weeks. Benzene produced increases of NE in the hypothalamus, cortex, midbrain and medulla oblongata, DA in the hypothalamus and corpus striatum, and 5-HT in all dissected brain regions except cerebellum. Elevated levels of various monoamine metabolites were also observed in these brain areas. Toluene ingestion alone also significantly increased the concentrations of NE, DA, 5-HT, and their metabolites in several brain regions. Mice given the combined treatments exhibited raised regional neurochemical levels when compared to the untreated controls. Increased concentrations of biogenic amine metabolites in several brain regions were greater in the combined exposures of benzene and toluene than when either chemical was used alone. The findings were different from those observed on immune parameters using similar treatment protocols, where simultaneous exposure to toluene prevented the immunotoxic effects of benzene.

Toxicity of environmental pollutants may be expressed as combined effects of a chemicals. Benzene, a proven hematotoxic agent, frequently occurs with toluene in cocontaminated groundwater. Groups of CD-1 male mice were exposed continuously for 4 weeks to benzene (166 mg/l), toluene (80 and 325 mg/l), and combinations of benzene (166 mg/l) + toluene (80 mg/l or 325 mg/l) in drinking water. Benzene-induced anemia was alleviated by simultaneous toluene treatment. Leukopenia and lymphopenia were observed in the case of benzene only and benzene + toluene (80 mg/l)-treated mice. The cytopenia, however, was less severe in the benzene + toluene (325 mg/l)-treated group. Immunotoxicity induced by benzene treatment alone was characterized by involution of thymic mass and suppressions of both B- and T-cell mitogeneses, mixed lymphocyte culture response to alloantigens, the tumor lytic ability of cytotoxic T-lymphocytes as determined by 51Cr-release assay, and antibody production response to T-dependent antigen (sheep red blood cells). IL-2 secretion by Con A-stimulated mouse T-cells was decreased in the benzene-treated group. Toluene (325 mg/l) completely inhibited these adverse effects when it was coadministered with benzene, while the low dose of toluene (80 mg/l) did not protect against benzene-induced depressions of immune functions. Toluene administered alone at levels up to 325 mg/l showed no obvious immunotoxic effects. Results of this study demonstrated that toluene, in sufficient amounts, has an antagonistic effect on benzene immunotoxicity.