Toxicokinetic Interaction of 2,5-Hexanedione and Methyl Ethyl Ketone

Details

• Personal Author:
  Froines JR ; Hattis D ; Landaw EM ; Yu RC
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Animals Laboratories Nervous System Occupational Health Safety Toxicology
• Keywords:
  2,5-Hexanedione Animal Studies Author Keywords: Chemical Mixture Laboratory Techniques Metabolic Inhibition Methyl Ethyl Ketone Neurotoxic Effects Neurotoxicity Toxic Effects Toxicokinetic Interaction
• ISSN:
  0340-5761
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  California ; Massachusetts ; OSHA Region 1 ; OSHA Region 9
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  75
• Issue:
  11
• NIOSHTIC Number:
  nn:20057943
• Citation:
  Arch Toxicol 2002 Jan; 75(11-12):643-652
• Contact Point Address:
  John R. Froines, Center for Occupational and Environmental Health, UCLA School of Public Health, 650 Charles E. Young Drive South, Los Angeles, CA 90095, USA
• Email:
  jfroines@ucla.edu
• CAS Registry Number:
  2,5-Hexanediol (CAS RN 2935-44-6) ; Methyl ethyl ketone (CAS RN 78-93-3)
• Federal Fiscal Year:
  2002
• Performing Organization:
  University of California, Los Angeles, California
• Peer Reviewed:
  True
• Start Date:
  19950930
• Source Full Name:
  Archives of Toxicology
• End Date:
  19990929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:1957655d96e786f7820f02980e06a398ec1d9db9aadf6fc0170dbff33adb89d9eea6a7bfa9174015623a6192060807bcab4c12b7db0637241e7fe0559959ea4c
• Download URL:
  https://stacks.cdc.gov/view/cdc/215145/cdc_215145_DS1.pdf
• File Type:
  [PDF - 203.59 KB ]