Effects of methyl ethyl ketone, acetone, or toluene coadministration on 2,5-hexanedione concentration in the sciatic nerve, serum, and urine of rats

Zhao, Wenyuan; Misumi, Jyuji; Yasui, Takato; Aoki, Katsumi; Kimura, Takashi

doi:10.1007/s004200050275

Cited by 6 publications

(1 citation statement)

References 26 publications

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“…Yasui et al (1995) showed that MEK is capable of prolonging the 2,5-HD T 1/2 in the blood, which was thought to relate to the potentiation of 2,5-HD neurotoxicity by MEK. Zhao et al (1998) showed that MEK (as well as acetone and toluene) decreased the elimination rate constants of 2,5-HD in co-administration groups. These empirical observations consistently suggest a qualitative relationship between 2,5-HD T 1/2 and 2,5-HD and MEK concentrations.…”

Section: Parametermentioning

confidence: 97%

Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone

Yu¹,

Hattis²,

Landaw³

et al. 2001

Arch Toxicol

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Co-exposure to methyl ethyl ketone (MEK) potentiates the neurotoxicity of n-hexane in humans as well as in animals. This effect is associated with increased persistence of 2,5-hexanedione (2,5-HD) in blood, probably due to inhibition of 2,5-HD phase II biotransformation by MEK. There is no previous quantitative toxicokinetic model to describe this interaction. In this study we constructed a toxicokinetic model to depict the inhibition of 2,5-HD metabolism and elimination by MEK. Experimental data on 2,5-HD blood concentrations in rats from a published study were used to estimate model parameters. Three different inhibition mechanisms were evaluated: competitive, uncompetitive, and noncompetitive inhibition. Extrapolation from high to low doses was made to assess the interactive effects of MEK on 2,5-HD beyond experimental conditions. The models developed successfully described the toxicokinetic behavior of 2,5-HD when inhibited by MEK. The competitive inhibition model yielded a much lower estimate for the constant (65.5 mg/l) of 2,5-HD inhibition by MEK than did the uncompetitive and noncompetitive models (403 and 440 mg/l, respectively). The apparent half-life of 2,5-HD appeared to be a linear function of the Michaelis-Menten constant, and 2,5-HD and MEK concentrations in rats. The area under the curve of 2,5-HD in blood of rats was a nonlinear function of 2,5-HD and MEK concentrations in the blood. This study highlights the importance of the interactive effect of MEK on deactivation and elimination of 2,5-HD, and further illustrates the advantage of toxicokinetic modeling to investigate chemical interactions associated with exposure to multiple chemical agents.

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Section: Parametermentioning

confidence: 97%

Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone

Yu¹,

Hattis²,

Landaw³

et al. 2001

Arch Toxicol

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Ketones of Four or Five Carbons

O’Donoghue

2023

Patty's Toxicology

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Several billion pounds of ketones are produced annually for industrial use in the United States and worldwide. Those with the highest production volumes include acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, 4‐hydroxy‐4‐methyl‐2‐pentanone, isophorone, mesityl oxide, and acetophenone. Common methods used to manufacture ketones include aliphatic hydrocarbon oxidation, alcohol dehydration with subsequent oxidation, dehydrogenation of phenol, alkyl aromatic hydrocarbon oxidation, and condensation reactions. Ketones are commonly used in industry as solvents, extractants, chemical intermediates, and, to a lesser extent, flavor and fragrance ingredients. Although a common effect of excessive ketone exposure is CNS depression some ketones have pulmonary effects that are well below levels that cause acute CNS effects. For example, ketones such as diacetyl and chemically similar chemicals used for flavoring foods, coffee, and e‐cigarettes provide opportunities for widespread exposure and very debilitating pulmonary disease including bronchiolitis obliterans.

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Acetone

Morgott¹

2001

Patty's Toxicology

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Acetone is a clear, colorless liquid that is highly flammable and infinitely soluble in water. Years of clinical study, laboratory testing, and practical experience have shown that acetone can be used safely and without harm in many industrial and commercial applications. The long‐standing interest in the biochemical, pharmacological, and toxicological properties of acetone can be traced to three important characteristics of the chemical: Acetone is a normal by‐product of mammalian metabolism; levels within the body can, however, be altered by changes in nutrition or energy balance. Acetone is a highly volatile organic solvent that is miscible with water; thus large amounts of the vapor can be absorbed through the lungs and quickly distributed throughout the body. Acetone is manufactured and used in large amounts in a variety of commercial and industrial applications; thus the potential for exogenous human exposure is widespread.

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Effects of methyl ethyl ketone, acetone, or toluene coadministration on 2,5-hexanedione concentration in the sciatic nerve, serum, and urine of rats

Abstract: Coadministration of 2,5-HD with MEK, AC, or TO can increase the concentration and AUC of 2,5-HD in serum and the sciatic nerve, and these increases can be further enhanced by an increase in the concomitant doses of MEK and AC.

Cited by 6 publications

References 26 publications

Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone

Toxicokinetic interaction of 2,5-hexanedione and methyl ethyl ketone

Ketones of Four or Five Carbons

Acetone

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