Further studies on ketone neurotoxicity and interactions

Area of Science:

• Toxicology
• Neuroscience
• Occupational Health

Background:

• Ethyl n-butyl ketone (EBK) has not been previously associated with neurotoxicity via oral or inhalation routes.
• Understanding the neurotoxic potential of industrial chemicals like EBK is crucial for occupational safety.
• The role of co-exposure to other solvents, such as methyl ethyl ketone (MEK), in modifying EBK toxicity is not well-defined.

Purpose of the Study:

• To investigate the neurotoxic effects of ethyl n-butyl ketone (EBK) in rats.
• To determine if methyl ethyl ketone (MEK) potentiates EBK-induced neurotoxicity.
• To explore the metabolic pathways involved in EBK neurotoxicity, specifically the role of gamma-diketones.

Main Methods:

• Rats were administered EBK via gavage at high doses (2 g/kg/day) for 14 weeks.
• Co-administration of EBK with MEK or 5-methyl-2-octanone was performed via gavage and inhalation.
• Urinary and serum levels of neurotoxic gamma-diketones (2,5-heptanedione and 2,5-hexanedione) were analyzed.

Main Results:

• High-dose EBK induced central-peripheral distal axonopathy with axonal swelling and neurofilamentous hyperplasia.
• MEK co-exposure potentiated EBK neurotoxicity and increased urinary excretion of 2,5-heptanedione and 2,5-hexanedione.
• Inhalation co-exposure to EBK and MEK significantly increased serum 2,5-heptanedione levels, suggesting enhanced metabolism.

Conclusions:

• EBK neurotoxicity appears to result from its metabolism into neurotoxic gamma-diketones.
• MEK potentiates EBK neurotoxicity, likely by stimulating the metabolic conversion of EBK to these toxic metabolites.
• The high doses required to induce toxicity and previous negative findings suggest a low neurotoxic hazard for EBK under typical exposure conditions.