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

Journal Article · Sat Dec 01 00:00:00 EST 2018 · Toxicology

DOI:https://doi.org/10.1016/j.tox.2018.08.003· OSTI ID:1503498

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.

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.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 1503498
• Report Number(s): PNNL-SA-135310
• Journal Information: Toxicology, Vol. 410, Issue C; ISSN 0300-483X
• Publisher: Elsevier
• Country of Publication: United States
• Language: English