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Title: Evaluation of non-invasive biomonitoring of 2,4-Dichlorophenoxyacetic acid (2,4-D) in saliva

Abstract

The objective of this study was to evaluate the potential for noninvasive biomonitoring of 2,4-dichlorophenoxyacetic acid (2,4-D) in saliva. Using an in vitro rat salivary gland epithelial cell (SGEC) system, a collection of experiments investigating chemical protein binding, temporal and directional transport, as well as competitive transport with para-aminohippuric acid (PAH), a substrate for renal organic anion transporters, was conducted to identify cellular transport parameters required to computationally model salivary transport of 2,4-D. Additionally, a physiological protein gradient was implemented to mimic physiologically relevant concentrations of protein in rat plasma and saliva, and under these conditions the transfer of 2,4-D was markedly slower, driven by increased protein binding (i.e. reduced free 2,4-D species available to cross salivary barrier). The rate of transfer was directly proportional to the amount of unbound 2,4-D and demonstrated no indication of active transport. An in vivo assessment of 2,4-D exposure in rats revealed a non-linear protein binding response in plasma, indicating saturated protein binding and increased levels of free 2,4-D species at higher doses. A strong correlation between concentrations in saliva and free unbound species in plasma was observed (Pearson correlation coefficient = 0.95). Saliva:plasma 2,4-D ratios measured in vivo (0.0079) were comparable over dose,more » but significantly different than ratios measured in vitro (physiological conditions) (0.034), possibly due to 2,4-D concentrations in saliva not being at equilibrium with 2,4-D concentrations in blood, as well as physiological features absent in in vitro settings (e.g. blood flow). We demonstrated that 2,4-D is consistently transported into saliva using both in vitro and in vivo models, making 2,4-D a potential candidate for human non-invasive salivary biomonitoring. Further work is needed to understand whether current sensor limits of detection are sufficient to measure occupationally relevant exposures.« less

Authors:
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Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1503498
Report Number(s):
PNNL-SA-135310
Journal ID: ISSN 0300-483X
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Toxicology
Additional Journal Information:
Journal Volume: 410; Journal Issue: C; Journal ID: ISSN 0300-483X
Publisher:
Elsevier
Country of Publication:
United States
Language:
English

Citation Formats

Carver, Zana A., Han, Alice A., Timchalk, Charles, Weber, Thomas J., Tyrrell, Kimberly J., Sontag, Ryan L., Luders, Teresa, Chrisler, William B., Weitz, Karl K., and Smith, Jordan N. Evaluation of non-invasive biomonitoring of 2,4-Dichlorophenoxyacetic acid (2,4-D) in saliva. United States: N. p., 2018. Web. doi:10.1016/j.tox.2018.08.003.
Carver, Zana A., Han, Alice A., Timchalk, Charles, Weber, Thomas J., Tyrrell, Kimberly J., Sontag, Ryan L., Luders, Teresa, Chrisler, William B., Weitz, Karl K., & Smith, Jordan N. Evaluation of non-invasive biomonitoring of 2,4-Dichlorophenoxyacetic acid (2,4-D) in saliva. United States. doi:10.1016/j.tox.2018.08.003.
Carver, Zana A., Han, Alice A., Timchalk, Charles, Weber, Thomas J., Tyrrell, Kimberly J., Sontag, Ryan L., Luders, Teresa, Chrisler, William B., Weitz, Karl K., and Smith, Jordan N. Sat . "Evaluation of non-invasive biomonitoring of 2,4-Dichlorophenoxyacetic acid (2,4-D) in saliva". United States. doi:10.1016/j.tox.2018.08.003.
@article{osti_1503498,
title = {Evaluation of non-invasive biomonitoring of 2,4-Dichlorophenoxyacetic acid (2,4-D) in saliva},
author = {Carver, Zana A. and Han, Alice A. and Timchalk, Charles and Weber, Thomas J. and Tyrrell, Kimberly J. and Sontag, Ryan L. and Luders, Teresa and Chrisler, William B. and Weitz, Karl K. and Smith, Jordan N.},
abstractNote = {The objective of this study was to evaluate the potential for noninvasive biomonitoring of 2,4-dichlorophenoxyacetic acid (2,4-D) in saliva. Using an in vitro rat salivary gland epithelial cell (SGEC) system, a collection of experiments investigating chemical protein binding, temporal and directional transport, as well as competitive transport with para-aminohippuric acid (PAH), a substrate for renal organic anion transporters, was conducted to identify cellular transport parameters required to computationally model salivary transport of 2,4-D. Additionally, a physiological protein gradient was implemented to mimic physiologically relevant concentrations of protein in rat plasma and saliva, and under these conditions the transfer of 2,4-D was markedly slower, driven by increased protein binding (i.e. reduced free 2,4-D species available to cross salivary barrier). The rate of transfer was directly proportional to the amount of unbound 2,4-D and demonstrated no indication of active transport. An in vivo assessment of 2,4-D exposure in rats revealed a non-linear protein binding response in plasma, indicating saturated protein binding and increased levels of free 2,4-D species at higher doses. A strong correlation between concentrations in saliva and free unbound species in plasma was observed (Pearson correlation coefficient = 0.95). Saliva:plasma 2,4-D ratios measured in vivo (0.0079) were comparable over dose, but significantly different than ratios measured in vitro (physiological conditions) (0.034), possibly due to 2,4-D concentrations in saliva not being at equilibrium with 2,4-D concentrations in blood, as well as physiological features absent in in vitro settings (e.g. blood flow). We demonstrated that 2,4-D is consistently transported into saliva using both in vitro and in vivo models, making 2,4-D a potential candidate for human non-invasive salivary biomonitoring. Further work is needed to understand whether current sensor limits of detection are sufficient to measure occupationally relevant exposures.},
doi = {10.1016/j.tox.2018.08.003},
journal = {Toxicology},
issn = {0300-483X},
number = C,
volume = 410,
place = {United States},
year = {2018},
month = {12}
}