Implications of protein binding for predicting pesticide salivary transport using a combination experimental and computational approach

Details

• Personal Author:
  Carver ZA ; Smith J ; Timchalk C ; Weber TJ
• Description:
  Non-invasive biomonitoring with saliva has potential to significantly advance quantitative dosimetry as an integral component of epidemiology. However, quantitative predictions of chemical transport into saliva remain a challenge. In order to predict salivary clearance, a Transwell cellular transport system and accompanying computational model have been developed. By utilizing physiological protein levels representative of plasma and saliva, cellular systems are able to closely predict the in vivo saliva/blood concentration ratio (0.021 vs. 0.049) of 3,5,6-trichloro-2-pyridinol (TCPy), the major chemical-specific metabolite of chlorpyrifos. However, predicted cellular diffusion coefficients were slower than those observed in vivo. Here, we hypothesize that protein binding plays an important role in TCPy salivary transport. TCPy protein binding in cell culture medium and plasma were measured using ultracentrifugation and gas chromatography-mass spectrometry. Kinetic descriptions of protein binding were added to the cellular computational model and parameterized with data of TCPy protein binding in cell culture medium. Resulting model simulations predicted cellular transport data reasonable well. A physiologically based pharmacokinetic model (PBPK) for chlorpyrifos and TCPy was modified for congruent kinetic descriptions of protein binding and parameterized using TCPy plasma protein binding experimental data. Resulting PBPK model simulations accurately predicted in vivo concentrations of TCPy in rat saliva, suggesting that diffusion coefficients of unbound TCPy are consistent between cell culture systems and in vivo. Overall, these experiments demonstrate the importance of protein binding for salivary clearance of TCPy. This combination experimental and computational approach could serve as a platform to predict salivary transport of chemicals highly bound to proteins. [Description provided by NIOSH]
• Subjects:
  Blood Cells, Cultured Energy Metabolism Hematologic Tests Insecticides Laboratories Occupational Health Radiation Dosimeters Safety Toxicology
• Keywords:
  Analytical Models Biomonitoring Blood Analysis Blood Plasma Cell Cultures Cell Culture Techniques Cellular Effects Cellular Function Cellular Reactions Cellular Transport Mechanism Centrifugation Chemical Binding Chlorpyrifos Computerized Simulation Diffusion Analysis Dosimetry Gas Chromatography In Vivo Study Kinetics Laboratory Animals Mass Spectrometry Mathematical Models Metabolites Models Pesticides Pharmacology Physiological Factors Proteins Salivary Glands Simulation Methods

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• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Abstract or Summary
• Place as Subject:
  Maryland ; OSHA Region 10 ; OSHA Region 3 ; Washington
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  156
• Issue:
  1
• NIOSHTIC Number:
  nn:20049493
• Citation:
  Toxicologist 2017 Mar; 156(1):514
• CAS Registry Number:
  3,5,6-Trichloro-2-pyridinol (CAS RN 6515-38-4) ; Chlorpyrifos (CAS RN 2921-88-2)
• Federal Fiscal Year:
  2017
• 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 56th Annual Meeting and ToxExpo, March 12-16, 2017, Baltimore, Maryland
• End Date:
  20170831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:5bad6db01b557d6438595b2a328e70be1466bdf4bc49e1b41802465d7d727bbb57205cd5ce8b67d8f97eb1e66534cca18a48a47874cc53a87154bd4db265038f
• Download URL:
  https://stacks.cdc.gov/view/cdc/203934/cdc_203934_DS1.pdf
• File Type:
  [PDF - 945.82 KB ]