Capturing and Modeling Human Interindividual Differences for Health Risk Assessment: Hepatic Bioactivation of Chloroform

Details

• Personal Author:
  Du JT ; Kedderis GL ; Lipscomb JC ; Mahle DA ; Snawder, John E. ; Swartout JC
• Description:
  Chloroform (CF) is a volatile drinking water contaminant. Risks via the oral, but not inhalation route have been estimated. This study was conducted to adjust inhalation dosimetry between animals and humans and assess the impact of variability in some factors which may predispose humans to toxicity. CF partition coefficients were determined in tissues from young and mature rats, and in blood from adult and pediatric patients. CF metabolic rate constants and hepatic CYP2E1 protein concentrations were determined in liver tissue from adult rats and human adult and child organ donors. Vmax was extrapolated to intact tissue and scaled to body weight. The distribution of hepatic blood flow (HBF) as percent of cardiac output was determined from a total of 59 published individual values in human adults. These data were incorporated into physiologically based pharmacokinetic (PBPK) models constructed for mice; rats; and human adults, preadolescents and infants. Because of the relevance of the inhalation reference concentration to chronic, lifetime exposures, constant exposure to CF was simulated until steady state was reached rather than simulating intermittent exposure scenarios. Toxicity studies with mice demonstrate a duration-adjusted NOAEL (liver effects) of 0.9 ppm CF. Simulations indicated that the human equivalent exposure concentration, based on hepatic CF metabolism, was approximately 6 ppm. Among adults, increases in CYP2E1 content and activity, blood:air partitioning, and HBF produced approximately 1, 4 and 17% increases in CF metabolism, respectively. Children converted as much as 34% more CF to metabolites than equivalently exposed adults. These findings will be useful in determining the magnitude of PK variability in the risk relevant PK outcomes between species and among humans. [Description provided by NIOSH]
• Subjects:
  Animals Hazardous Substances Hematologic Tests Laboratories Occupational Health Risk Assessment Risk Factors Safety Water Purification
• Keywords:
  Animal-studies Bioactivation Blood-sampling Humans Laboratory-animals Models Risk-analysis Risk-factors Toxic-effects Toxins Water-analysis

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• ISSN:
  1096-6080
• Publisher:
  Society of Toxicology
• Document Type:
  Text
• Genre:
  Abstract or Summary
• Place as Subject:
  District of Columbia ; Maryland ; North Carolina ; Ohio ; OSHA Region 3 ; OSHA Region 4 ; OSHA Region 5
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  DART - Division of Applied Research and Technology
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  78
• NIOSHTIC Number:
  nn:20025178
• Citation:
  Toxicologist 2004 Mar; 78(S-1):362
• CAS Registry Number:
  Chloroform (CAS RN 67-66-3)
• Federal Fiscal Year:
  2004
• NORA Priority Area:
  Research Tools and Approaches: Exposure Assessment Methods
• Peer Reviewed:
  False
• Source Full Name:
  The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland
• Supplement:
  S-1
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:885480e742ce2af78d84bb7f7d3d7ce8eaef02d16d16530bc8bfa3e2e73a824e130809e2933d1ec92c9d06076011b2fb73a3b5dc65ceb18d3c774dd70f7d3cc4
• Download URL:
  https://stacks.cdc.gov/view/cdc/196661/cdc_196661_DS1.pdf
• File Type:
  [PDF - 56.93 KB ]