Experimental studies on hydrocarbon neuropathies induced by methyl-ethyl-ketone (MEK)

Abstract

An outbreak of neuropathies among Berlin solvent sniffers was closely related to the denaturation by methyl-ethyl-ketone (MEK) of the mixture used. The solvent was composed of n-hexane, toluene and ethyl-acetate. Nervous system responses to chronic repeated exposure to 10,000 ppm pure n-hexane, 10,000 ppm MEK/n-hexane (ratio 1:9) and 6000 ppm pure MEK were investigated in rats. Motor neuropathy of the dying back type with giant swelling of axons in the peripheral and central nervous system developed in animals exposed to MEK/n-hexane and n-hexane. Severe potentiation of n-hexane neurotoxicity and shortened onset of morphological and clinical signs were demonstrated in animals exposed to MEK/n-hexane. MEK alone did not produce neuropathy under these conditions. The findings suggest that commercial solvent mixtures containing MEK/n-hexane should be avoided.

Characterization of the toxicological hazards of hydrocarbon solvents

“…As one example, the effects of n-hexane can be enhanced by co-exposure to substances that inhibit the breakdown and elimination of the toxic 2,5-hexanedione intermediate by competing for metabolizing enzymes. Crit Rev Toxicol, 2015; 45(4): 273-365 288 R. H. Mckee et al There is evidence for an interaction between n-hexane and methyl ethyl ketone (Altenkirch et al 1977(Altenkirch et al , 1978 in which the effects of n-hexane are exacerbated. There are also studies in which the effects of benzene have been modified by coexposure to other aromatics to either enhance or inhibit the formation of reactive metabolites (Bird et al 2010, Medinsky et al 1994, Tardif et al 1992, Travis et al 1992.…”

“…The study by Krasavage and colleagues (1980) showed that the production of the g-diketone metabolite is a requirement for the histopathological changes in proximal and distal nerves that are the hallmark of n-hexane-mediated neuropathy. This is also bolstered by evidence showing that stimulation of liver CYP2E1 (the liver enzyme responsible for n-hexane metabolism) by methyl ethyl ketone (which by itself does not produce neurological effects) potentiates the neuropathic response with n-hexane exposure (Altenkirch et al 1978). In addition, n-heptane, which is also metabolized to a g-diketone (2,5-heptanedione) but much less efficiently than n-hexane, does not cause peripheral neuropathy (Bahima et al 1984, Takeuchi et al 1980.…”

Acetone-induced changes in the toxicokinetics of 2,5-hexanedione in rabbits.

“…For some years it has been known that the ketone methyl ethyl ketone potentiates the neurotoxicity of n-hexane (2). The mechanism is not fully understood (9,II), but experimental data support the idea that the potentiation is partly due to the persistence of the neurotoxic metabolites in the blood or due to the formation of more of the metabolites of n-hexane, changes in the protein binding of 2,5-HD, or changes in the distribution of the metabolites (9,II) .…”

Ultrastructural Alteration of Intrapulmonary Nerves after Exposure to Organic Solvents

“…Systematic studies of the lung tissue, particularly that in the region of the plexus peribronchialis have shown that, as had been expected, the autonomic nervous sys tem exhibited alterations comparable to those described for the peripheral nerves. Observations by several authors [2,3,5,II,16] describing axonal swellings in peri pheral nerves due to neurofilament accu mulation could also be clearly confirmed for the lung tissue. They were, however, considerably less frequent than in the pre ceding findings.…”