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., 1991). 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).

Metabolism of benzene to phenolic compounds and toluene to hippuric acid and ortho-cresol has been shown to be suppressed in workers exposed to a mixture of toluene and benzene (Inoue et al., 1988). In the case of benzene and toluene this is unlikely to be a problem if exposure is minimised, e.g., if concentrations remain below the threshold limit values (Sato and Nakajima, 1979).

Ethanol also affects toluene metabolism and the specific effect depends on whether ethanol ingestion is acute or chronic. Even a low blood ethanol concentration can decrease toluene metabolism (Baelum et al., 1993). Inhalation of toluene (80 ppm for 4 hours) and acute ingestion of ethanol (1.5 ml/kg of vodka after 3 hours of toluene exposure) resulted in a 42.5% increase in the blood toluene concentration. However, in this study workers who drank ethanol regularly had lower blood toluene concentrations than those who seldom drank, probably due to induction of liver enzymes by ethanol (Waldron et al., 1983). In another survey, workers with the highest exposure to toluene and ethanol had lower liver enzyme concentrations compared to controls with high ethanol but low toluene exposure (Boewer et al., 1988). The reason for this is unclear.

Experimental studies in volunteers have shown that ingestion of ethanol during inhalation exposure to toluene decreases the total uptake and the relative uptake (the fraction absorbed per breath). Ethanol also inhibits the distribution and/or elimination of toluene from the blood (Wallen 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 is 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).

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 concentration (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 that metabolic interaction of xylene and toluene is only likely to occur when the concentration of both solvents exceeds 50 ppm (Tardif et al., 1993).

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