Physiologically based pharmacokinetic modeling of salivary concentrations for noninvasive biomonitoring of 2,4-dichlorophenoxyacetic acid (2,4-D)

Han, Alice; Timchalk, Charles; Carver, Zana A.; Weber, Thomas J.; Tyrrell, Kimberly J.; Sontag, Ryan L.; Gibbins, Teresa M.; Chrisler, William B.; Weitz, Karl K.; Du, Dan; Lin, Yuehe; Smith, Jordan N.

doi:10.1093/toxsci/kfz206

Title: Physiologically based pharmacokinetic modeling of salivary concentrations for noninvasive biomonitoring of 2,4-dichlorophenoxyacetic acid (2,4-D)

Journal Article · Mon Dec 02 00:00:00 EST 2019 · Toxicological Sciences

DOI:https://doi.org/10.1093/toxsci/kfz206· OSTI ID:1577982

Han, Alice ^[1]; Timchalk, Charles ^[1]; Carver, Zana A. ^[1];

^[1]; Tyrrell, Kimberly J. ^[1]; Sontag, Ryan L. ^[1]; Gibbins, Teresa M. ^[1]; Chrisler, William B. ^[1]; Weitz, Karl K. ^[1]; Du, Dan ^[2];

^[2]; Smith, Jordan N. ^[1]

BATTELLE (PACIFIC NW LAB)
WASHINGTON STATE UNIV

Saliva has become a favorable sample matrix for biomonitoring due to its non-invasive attributes and overall flexibility in collection. To ensure measured salivary concentrations reflect the exposure, a firm understanding of the salivary transport mechanism and relationships between salivary concentrations and other monitored matrices (i.e. blood, urine) is needed. Salivary transport of a commonly applied herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), was observed in vitro and in vivo and a physiologically based pharmacokinetic (PBPK) model was developed to translate observations from the cell culture model to those in animal models and further evaluate 2,4-D kinetics in humans. While apparent differences in experimental in vitro and in vivo saliva/plasma ratios (0.034 and 0.0079) were observed, simulations with the PBPK model demonstrated dynamic time and dose-dependent saliva/plasma ratios, elucidating key mechanisms affecting salivary transport. The model suggested that 2,4-D exhibited diffusion limited transport to saliva and was additionally impacted by protein binding saturation and permeability across the salivary gland. Consideration of sampling times post-exposure and potential saturation of transport mechanisms are then critical aspects for interpreting salivary 2,4-D biomonitoring observations. This work utilized PBPK modeling in in vitro to in vivo translation to explore benefits and limitations of salivary analysis for occupational biomonitoring.

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Research Organization:: Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE

DOE Contract Number:: AC05-76RL01830

OSTI ID:: 1577982

Report Number(s):: PNNL-SA-143610

Journal Information:: Toxicological Sciences, Vol. 171, Issue 2

Country of Publication:: United States

Language:: English

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