Physiologically based pharmacokinetic modeling of salivary concentrations for noninvasive biomonitoring of 2,4-dichlorophenoxyacetic acid (2,4-D)
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.
Revised: February 25, 2020 |
Published: December 2, 2019
Han A., C. Timchalk, Z.A. Carver, T.J. Weber, K.J. Tyrrell, R.L. Sontag, and T.M. Gibbins, et al. 2019.Physiologically based pharmacokinetic modeling of salivary concentrations for noninvasive biomonitoring of 2,4-dichlorophenoxyacetic acid (2,4-D).Toxicological Sciences 171, no. 2:330–343.PNNL-SA-143610.doi:10.1093/toxsci/kfz206