In Vitro to In Vivo Translation of Salivary Concentrations for Non-Invasive Biomonitoring of 2,4-Dichlorophenoxyacetic Acid (2,4-D)

Details

• Personal Author:
  Carver ZA ; Han AA ; Smith JN ; Timchalk C ; Weber TJ
• Description:
  Biomonitoring practices generally examine blood and urine to acquire insight regarding chemical exposures. Saliva has become a favorable sample matrix due to its non-invasive attributes and overall flexibility in collection. Relating concentrations measured in saliva to concentrations in blood or urine can be challenging due to gaps in knowledge of mechanisms driving salivary transport. We employed a Transwell in vitro system under physiological conditions to monitor and measure salivary chemical transport of a commonly applied herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D). High levels of protein binding (> 92%) were observed, resulting in transport (primarily via passive diffusion) to the salivary compartment limited by formation of free unbound species, predicting a saliva/plasma ratio of 0.034. Comparatively, a saliva/plasma ratio of 0.0079 was produced from an in vivo study, orally dosing male Sprague-Dawley rats with 30-150 mg/kg 2,4-D and collecting plasma and saliva 1 hour post-exposure. A physiologically based pharmacokinetic (PBPK) model was developed to translate observations from the cell culture model to those in animal models. The PBPK model notably incorporated descriptions of protein binding, salivary/plasma partitioning, and permeation. While apparent differences in in vitro and in vivo saliva/plasma ratios (0.034 and 0.0079, respectively) were observed, simulations with the PBPK model demonstrated dynamic saliva/plasma ratios over time and concordance between the two experimental systems. This indicated that 2,4-D exhibits diffusion limited transport to saliva in vivo, with saliva/plasma ratios requiring longer time after exposure to reach equilibrium, compared to other small organic chemicals like trichloropyridinol. Sampling time after exposures is then a critical component for interpreting salivary 2,4-D biomonitoring data. This work demonstrates the role of PBPK modeling in linking observations made with in vitro and in vivo approaches and additionally allows for further extrapolation of salivary concentrations for human biomonitoring. [Description provided by NIOSH]
• Subjects:
  Cells, Cultured Environmental Exposure Herbicides Laboratories Occupational Health Safety Toxicology
• Keywords:
  2,4-D 2,4-Dichlorophenoxyacetic Acid Analytical Models Biochemical Indicators Biological Materials Biological Monitoring Biological Transport Cell Cultures Cell Culture Techniques Chemical Indicators Chemical Kinetics Diffusion Analysis Exposure Assessment Exposure Levels In Vitro Study In Vivo Study Kinetics Laboratory Animals Laboratory Testing Pharmacodynamics Physiological Factors Physiological Measurements Physiological Response Proteins Salivary Glands Sampling

  More +
• 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:
  168
• Issue:
  1
• NIOSHTIC Number:
  nn:20054955
• Citation:
  Toxicologist 2019 Mar; 168(1):210
• CAS Registry Number:
  (2,4-Dichlorophenoxy)acetic acid (CAS RN 94-75-7)
• Federal Fiscal Year:
  2019
• NORA Priority Area:
  Agriculture, Forestry and Fishing
• Performing Organization:
  Battelle Pacific Northwest Laboratories, Richland, Washington
• Peer Reviewed:
  False
• Start Date:
  20160901
• Source Full Name:
  The Toxicologist. Society of Toxicology 58th Annual Meeting and ToxExpo, March 10-14, 2019, Baltimore, Maryland
• End Date:
  20200831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:edb2a466880b5e3c1023cbc7c5eda654ad7494c341dd982fa01ef387a1ef5d34f094728d4f6ad7ca02e9c202e402acdce172bc86b3ee4b81dfa5f80fd5a7151c
• Download URL:
  https://stacks.cdc.gov/view/cdc/217361/cdc_217361_DS1.pdf
• File Type:
  [PDF - 865.08 KB ]