Application of an updated physiologically-based pharmacokinetic model for chloroform to evaluate CYP2E1-mediated renal toxicity in rats and mice

Details

• Personal Author:
  Genter MB ; Kedderis GL ; Li Z ; Lipscomb JC ; Rieth S ; Sasso AF ; Schlosser PM ; Snawder, John E.
• Description:
  Physiologically-based pharmacokinetic (PBPK) models are tools for interpreting toxicological data, and extrapolating observations across species and route of exposure. Chloroform (CHCl(3)) is a chemical for which there are PBPK models available in different species, and multiple sites of toxicity. Since chloroform induces toxic effects in the liver and kidneys via production of reactive metabolites, proper characterization of metabolism in these tissues is essential for risk assessment. While hepatic metabolism of chloroform is adequately described by these models, there is higher uncertainty for renal metabolism due to a lack of species-specific data and direct measurements of renal metabolism. Furthermore, models typically fail to account for regional differences in metabolic capacity within the kidney. Mischaracterization of renal metabolism may have a negligible effect on systemic chloroform levels, but it is anticipated to have a significant impact on the estimated site-specific production of reactive metabolites. In this paper, rate parameters for chloroform metabolism in the kidney are revised for rats, mice, and humans. New in vitro data were collected in mice and humans for this purpose and are presented here. The revised PBPK model is used to interpret data of chloroform-induced kidney toxicity in rats and mice exposed via inhalation and drinking water. Benchmark dose (BMD) modeling is used to characterize the dose-response relationship of kidney toxicity markers as a function of PBPK-derived internal kidney dose. Applying the PBPK model, it was also possible to characterize the dose-response for a recent dataset of rats exposed via multiple routes simultaneously. Consistent BMD modeling results were observed regardless of species or route of exposure. [Description provided by NIOSH]
• Subjects:
  Drinking Water Energy Metabolism Hazardous Substances Laboratories Methane Methyl Chloride Occupational Health Safety Toxicology
• Keywords:
  Analytical-models Analytical-processes Author Keywords: PBPK Chemical-kinetics Chloroform Chloromethanes Dose-response Drinking-water Humans In-vitro-study Kidney Kidneys Laboratory-animals Laboratory-testing Metabolic-rate Metabolism Metabolites Methanes Model Pharmacodynamics Physiological-chemistry Physiological-factors Physiological-testing Renal-toxicity Renal Toxicity Toxic-effects

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• ISSN:
  1096-6080
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  District of Columbia ; 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
• Pages in Document:
  360-374
• Volume:
  131
• Issue:
  2
• NIOSHTIC Number:
  nn:20041978
• Citation:
  Toxicol Sci 2013 Feb; 131(2):360-374
• Contact Point Address:
  A. F. Sasso, National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, 1200 Pennsylvania Avenue, NW, Washington, DC 20460, USA
• Email:
  sasso.alan@epa.gov
• CAS Registry Number:
  Chloroform (CAS RN 67-66-3)
• Federal Fiscal Year:
  2013
• NORA Priority Area:
  Construction ; Transportation, Warehousing and Utilities
• Peer Reviewed:
  True
• Source Full Name:
  Toxicological Sciences
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:16f06f8cd5df4db2bd0aa96a6ac9fc877372bd99af2809509865761e8119a893cae47dea14c63d62d776043e4338aa2c0afef18b145fe8476134f48d4ef257a9
• Download URL:
  https://stacks.cdc.gov/view/cdc/194364/cdc_194364_DS1.pdf
• File Type:
  [PDF - 3.63 MB ]