Metabolic interactions

Some substances can potentiate the neurotoxicity of n-hexane. Consequently, chronic exposure to n-hexane, even at low concentrations, with concurrent exposure to another solvent may result in neuropathy. When evaluating n-hexane exposure using urinary 2,5-hexanedione as a bio-indicator it is important to consider co-exposure to other solvents such as MEK (Shibata et al., 1990). Also, because other compounds such as methyl n-butyl ketone cause similar toxic effects to n-hexane, exposure to solvent mixtures containing any neurotoxic hexacarbon should be minimised (Spencer et al., 1980).

The serum and nerve concentration of 2,5-hexanedione was significantly increased in rats treated with 2,5-hexanedione in combination with acetone, compared to 2,5-hexanedione alone. Methyl ethyl ketone and toluene were also tested with 2,5-hexanedione. The effect with acetone was weaker than that of methyl ethyl ketone but stronger than that of toluene (Zhao et al., 1998).

• Chloroform n-Hexane can potentiate the hepato- and nephrotoxicity of chloroform in animals (Hewitt et al., 1980).

Metabolism of both n-hexane and methyl n-butyl ketone results in production of the same neurotoxic metabolite, 2,5-hexanedione. The toxic effects are therefore additive and workers exposed to both solvents are likely to be at greater risk of neurotoxicity (Feldman, 1999).

• Methyl ethyl ketone (MEK, 2-butanone)

Methyl ethyl ketone potentiates the effects of n-hexane. MEK was first suspected of potentiating the neurotoxic effects of n-hexane after neuropathy was reported in 18 glue-sniffers following a formulation change. The glue had contained 31% n-hexane but neuropathy only developed after the concentration was reduced to 16% and MEK was added to the product. No further cases were reported after the MEK was removed (Altenkirch et al., 1978).

MEK potentiation of hexane neuropathy has been demonstrated in animals (Altenkirch et al., 1979). Studies have shown that co-exposure to 2,5-hexanedione and methyl ethyl ketone results in more rapid onset of neurotoxicity than administration of 2,5-hexanedione alone (Ralston et al., 1985). Methyl ethyl ketone is not itself neurotoxic. The mechanism of this phenomenon is unclear, it is not thought to be due to 2,5-hexanedione alone (Shibata et al., 1990). In animals exposed to the same concentration of n-hexane the level of urinary n-hexane metabolites depended on the concentrations of MEK involved in the co-exposure. The concentration of the main n-hexane metabolites, 2,5-hexanedione and 2-hexanol decreased as the MEK concentration increased (Shibata et al., 1990). However, a more recent study demonstrated that although urinary concentrations of 2,5-hexanedione decreased in the short-term with co-exposure to MEK, the concentration of 2,5-hexanedione actually increased with more prolonged exposure (Ichihara et al., 1998).

In a toxicokinetic study of human volunteers, co-exposure to methyl ethyl ketone had little effect on n-hexane toxicokinetics. However, there was a decrease in the rate of formation of 2,5-hexanedione suggesting inhibition of the metabolism of n-hexane (Van Engelen et al., 1997).

The serum and nerve concentration of 2,5-hexanedione was significantly increased in rats treated with 2,5-hexanedione in combination with methyl ethyl ketone, compared to 2,5-hexanedione alone. The effect was strongest with methyl ethyl ketone compared to co-exposure with acetone or toluene (Zhao et al., 1998).

The serum and nerve concentration of 2,5-hexanedione was significantly increased in rats treated with 2,5-hexanedione in combination with toluene compared to 2,5-hexanedione alone. The effect with toluene was weaker than that observed with acetone and methyl ethyl ketone (Zhao et al., 1998). Workers exposed simultaneous to methyl ethyl ketone and n-hexane had increased urinary excretion of 2,5-hexanedione, whereas simultaneous exposure to toluene and n-hexane reduced urinary excretion (Cardona et al., 1993).

• Solvent mixtures

Workers exposed to mixtures of n-hexane and one or more of toluene, ethyl acetate and acetone below the occupational exposure limits did not give rise to increased urinary concentrations of 2,5-hexanedione. It was concluded that in these low concentrations the solvents did not alter n-hexane metabolism (Kawai et al., 2000).

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