Predicting Transport of 3,5, 6-Trichloro-2-Pyridinol into Saliva Using a Combination Experimental and Computational Approach

Details

• Personal Author:
  Carver ZA ; Smith JN ; Timchalk C ; Weber TJ
• Description:
  A combination experimental and computational approach was developed to predict chemical transport into saliva. A serous-acinar chemical transport assay was established to measure chemical transport with nonphysiological (standard cell culture medium) and physiological (using surrogate plasma and saliva medium) conditions using 3,5,6-trichloro-2-pyridinol (TCPy) a metabolite of the pesticide chlorpyrifos. High levels of TCPy protein binding were observed in cell culture medium and rat plasma resulting in different TCPy transport behaviors in the 2 experimental conditions. In the nonphysiological transport experiment, TCPy reached equilibrium at equivalent concentrations in apical and basolateral chambers. At higher TCPy doses, increased unbound TCPy was observed, and TCPy concentrations in apical and basolateral chambers reached equilibrium faster than lower doses, suggesting only unbound TCPy is able to cross the cellular monolayer. In the physiological experiment, TCPy transport was slower than nonphysiological conditions, and equilibrium was achieved at different concentrations in apical and basolateral chambers at a comparable ratio (0.034) to what was previously measured in rats dosed with TCPy (saliva:blood ratio: 0.049). A cellular transport computational model was developed based on TCPy protein binding kinetics and simulated all transport experiments reasonably well using different permeability coefficients for the 2 experimental conditions (1.14 vs 0.4 cm/h for nonphysiological and physiological experiments, respectively). The computational model was integrated into a physiologically based pharmacokinetic model and accurately predicted TCPy concentrations in saliva of rats dosed with TCPy. Overall, this study demonstrates an approach to predict chemical transport in saliva, potentially increasing the utility of salivary biomonitoring in the future. [Description provided by NIOSH]
• Subjects:
  Animals Behavior Blood Cells, Cultured Energy Metabolism Insecticides Laboratories Occupational Health Safety
• Keywords:
  Alternatives To Animal Testing Author Keywords: Biomonitoring Biological Modeling Biomonitoring Cell Cultures Chemicals Chlorpyrifos Exposure Assessment In Vitro And Alternatives In Vitro Study Kinetics Laboratory Animals Metabolites Models Pesticides Physiological Factors Proteins Risk Assessment Transport Mechanisms

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• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 10 ; Washington
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  438-450
• Volume:
  157
• Issue:
  2
• NIOSHTIC Number:
  nn:20051002
• Citation:
  Toxicol Sci 2017 Jun; 157(2):438-450
• Contact Point Address:
  Jordan Ned Smith, Health Impacts and Exposure Science, Pacific Northwest National Laboratory (PNNL), Richland, Washington 99352
• Email:
  jordan.smith@pnnl.gov
• CAS Registry Number:
  3,5,6-Trichloro-2-pyridinol (CAS RN 6515-38-4)
• Federal Fiscal Year:
  2017
• NORA Priority Area:
  Agriculture, Forestry and Fishing
• Performing Organization:
  Battelle Pacific Northwest Laboratories
• Peer Reviewed:
  True
• Start Date:
  20060901
• Source Full Name:
  Toxicological Sciences
• End Date:
  20170831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:c1666bba5f0aeac8e7b90c35ddec6af18ed670582240c09f34c3dd5f5066415966e3fe1ac40a148de7804a2bbf60a5693c3d9ac1df6fec6118e3b2afd1ff9080
• Download URL:
  https://stacks.cdc.gov/view/cdc/211147/cdc_211147_DS1.pdf
• File Type:
  [PDF - 689.14 KB ]