Metabolic interactions

Benzene, styrene, xylene and toluene are metabolised by the same enzyme systems and may competitively inhibit the metabolism of each other (Cohr and Stokholm, 1979; Tardif et al., 1992). Consequently, there may be an increased concentration of unchanged solvent in the blood and decreased or delayed urinary excretion of metabolites (Tardif et al., 1991; Tardif et al., 1992). This may result in overestimation of the toxic risk where blood concentrations are used for monitoring, or underestimation where the urinary metabolites are used (Tardif et al., 1992).

Xylene exposure can result in enzyme induction. This causes enhanced microsomal drug metabolising enzyme activities and increased cytochrome P450 concentrations in the liver and kidneys of rats. It has been shown to resemble the type of induction caused by the drug phenobarbital (Toftgärd and Nilsen, 1982; Toftgärd et al., 1983). This may result in synergistic toxic effects following simultaneous exposure to xylene and other chemicals metabolised by cytochrome P450. For example, rats pretreated with xylene and then exposed to n-hexane had higher serum concentrations of 2,4-hexanedione, the neurotoxic metabolite of n-hexane (Toftgärd et al., 1983). Induction is thought to be an adaptive process for increasing the metabolism of xylene (Riihimäki and Hänninen, 1987).

Exposure to m-xylene and administration of acetylsalicylic acid (aspirin) in volunteers caused a significant reduction in the urinary concentration of the metabolites (m-methylhippuric acid and salicyluric acid) of both substances. Both these metabolites are glycine conjugates and it is likely that there is mutual inhibition of conjugate formation. Any worker exposed to xylene who has taken aspirin may have an artificially low urinary methylhippuric acid concentration (Campbell et al., 1988).

The metabolism of both ethanol and xylene involves the enzymes alcohol dehydrogenase and aldehyde dehydrogenase. In an experimental study of the metabolic interaction of ethanol and m-xylene, ingestion of a moderate dose of ethanol (0.8 g/kg) before exposure to xylene (6 or 11.5 mmol/m3 (145 or 280 ppm) for four hours) raised the blood xylene concentration by 1.5-2 fold. The urinary concentration of methylhippuric acid decreased by about 50%, whereas the excretion of the minor metabolite 2,4-xylenol was unchanged or increased. Some individuals had a transiently raised acetaldehyde concentration and this may have been the cause of their dizziness and nausea (Riihimaki et al., 1982). Another volunteer study found that ethanol is only likely to affect m-xylene kinetics at high concentrations, i.e., above the occupational exposure limit. Ingestion of ethanol (the night before) and then inhalation of m-xylene at 400 ppm for two hours, resulted in lower m-xylene concentrations in blood and alveolar air compared to exposure at 100 ppm. Urinary excretion of m-methylhippuric acid was increased at 400 ppm. This study showed that ingestion of ethanol for two days prior to xylene exposure was enough to alter the kinetics of xylene, but only at a high xylene concentration (Tardif et al., 1994). Ethanol exposure has also been shown to modify xylene kinetics in animal studies (Savolainen et al., 1978).

• Ethylbenzene

In a volunteer study, concomitant exposure to ethylbenzene and m-xylene (both at 150 ppm for four hours) resulted in a significant decrease in urinary metabolites of both solvents (Engstrom et al., 1984).

• Methylene chloride

Studies in rats have shown that a single oral administration of an aromatic hydrocarbon (benzene, toluene or m-xylene) 16-24 hours before the administration of methylene chloride increases the peak concentration of carboxyhaemoglobin (carbon monoxide is a metabolite of methylene chloride). The half-life of methylene chloride in blood was shorter, indicating that the metabolic degradation of methylene chloride is enhanced by the aromatic hydrocarbons. This effect on the peak carboxyhaemoglobin concentration was dependent on the time interval between aromatic hydrocarbon and methylene chloride treatment, since earlier administration of toluene or m-xylene decreased the carboxyhaemoglobin elevation. Disulfiram treatment blocked the carboxyhaemoglobin elevation completely and corresponding increases in the concentration and half-life of methylene chloride were observed (Kim and Kim, 1996).

MEK appears to inhibit the metabolism of xylene, possibly by interaction with the initial monooxygenase catalysed step of biotransformation. In volunteers exposed to m-xylene and MEK the blood xylene concentration increased almost 2-fold compared to the concentration following exposure to xylene alone. Although the clearance of m-xylene and excretion of its metabolite, methylhippuric acid, were reduced, there appeared to be no effect on the biotransformation of MEK. Exposure to MEK 20 hours before exposure to m-xylene did not affect xylene metabolism (Liira et al., 1988).

• Smoking and drinking

Male workers who both smoked and drank ethanol were found to have decreased metabolism of xylene isomers and therefore lower urinary concentrations of methylhippuric acids (Inoue et al., 1993).

In a volunteer study, co-exposure to xylene (40 ppm) and toluene (50 ppm) did not affect the concentration of solvent in blood or inhaled air; the urinary excretion of metabolites was unchanged. However, exposure to higher concentrations (80 ppm and 95 ppm respectively) resulted in an increase in the blood and end-exhaled air concentration of these solvents. Excretion of the toluene metabolite (hippuric acid) was affected, but excretion of methylhippuric acid was unchanged (Tardif et al., 1991). Animal studies suggest metabolic interaction of xylene and toluene is only likely to occur when the concentration of both solvents exceeds 50 ppm (Tardif et al., 1993).

• 1,1,1-Trichloroethane

The time to peak m-xylene concentration was not affected by co-exposure to 1,1,1-trichloroethane (Savolainen et al., 1982).

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