Extrapolating salivary acinar cell in vitro pesticide transport to whole animals using computational modeling

Details

• Personal Author:
  Carver ZA ; Smith JN ; Timchalk C ; Weber TJ
• Description:
  Non-invasive biomonitoring with saliva has potential to significantly advance quantitative dosimetry as an integral component of epidemiology. However, predictions of which chemical and/or metabolites are excreted into saliva at detectable concentrations remain a challenge. In order to predict salivary clearance, a combination experimental and computational approach has been developed with 3,5,6-trichloro-2-pyridinol (TCPy) (the major chemical-specific metabolite of chlorpyrifos) to predict potential salivary levels. A Transwell in vitro rat salivary acinar cell system was utilized, where protein levels in the basolateral (27.2 mg/ mL) and apical (1.3 mg/mL) culture chambers, which represent blood and saliva compartments respectively, were altered using bovine serum albumin to more closely mimic physiological levels. TCPy was dosed to the basolateral chamber at two concentrations (250 and 2500 microM), and both chambers were sampled over time up to 24 hr. The rat salivary cell system maintained the protein gradient and tight junctions over the duration of the experiment as evidenced by consistent transepithelial electrical resistance levels. Levels of TCPy were quantified using gas chromatography-mass spectrometry, and at 24 hr, the predicted median saliva/blood concentration ratio was similar to published values measured in vivo (0.021 vs. 0.049). TCPy concentrations were modeled using a mechanistic computational cellular transport model. The resulting model simulations fit the data reasonably well, and fit parameters suggest that TCPy is transported across basolateral and apical cell membranes by passive diffusion. Model parameters were integrated into a physiologically based pharmacokinetic model, and reasonably predicted TCPy concentrations in rat saliva after intravenous administration of TCPy. This poster demonstrates the utility of this combination experimental and computational approach to predict chemical transport in saliva. [Description provided by NIOSH]
• Subjects:
  Animals Biological Assay Biomarkers Blood Cells, Cultured Cytology Energy Metabolism Environmental Exposure Epidemiology Insecticides Laboratories Occupational Health Radiation Dosimeters Safety Toxicology

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• Keywords:
  Acinar-glands Analytical-models Bioassays Biological-monitoring Blood Serum Cell-culture-techniques Cellular-reactions Cellular-transport-mechanism Cellular-uptake Chemical-kinetics Chemicals Cytopathology Diffusion Analysis Dosimetry Exposure Assessment Exposure Chambers Exposure Levels Gas Chromatography In-vitro-study Laboratory Animals Mass Spectrometry Metabolites Pesticides Pharmacodynamics Protein-chemistry Proteins Quantitative-analysis Salivary-glands

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• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Abstract or Summary
• Place as Subject:
  Louisiana ; OSHA Region 10 ; OSHA Region 6 ; Washington
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  30
• Volume:
  150
• Issue:
  1
• NIOSHTIC Number:
  nn:20047579
• Citation:
  Toxicologist 2016 Mar; 150(1):30
• CAS Registry Number:
  3,5,6-Trichloro-2-pyridinol (CAS RN 6515-38-4)
• Federal Fiscal Year:
  2016
• NORA Priority Area:
  Agriculture, Forestry and Fishing
• Performing Organization:
  Battelle Pacific Northwest Laboratories
• Peer Reviewed:
  False
• Start Date:
  20060901
• Source Full Name:
  The Toxicologist. Society of Toxicology 55th Annual Meeting and ToxExpo, March 13-17, 2016, New Orleans, Louisiana
• End Date:
  20170831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:1f9fd352ac46111a946bf0151de5aee3468597ec69b37e571302214d4e95c07877ff5139f091e642027acfe7fe302887e91f6ff37ea47cce61c0c6f1a446f3aa
• Download URL:
  https://stacks.cdc.gov/view/cdc/202596/cdc_202596_DS1.pdf
• File Type:
  [PDF - 2.16 MB ]