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Development of a Generalized Inhalation Model for use with the High-Throughput Toxicokinetics (httk) Package in R
Citation:
Linakis, M., R. Sayre, R. Pearce, N. Sipes, H. Pangburn, J. Gearhart, AND J. Wambaugh. Development of a Generalized Inhalation Model for use with the High-Throughput Toxicokinetics (httk) Package in R. Presented at Society of Toxicology Annual Meeting, Baltimore, MD, March 10 - 14, 2019. https://doi.org/10.23645/epacomptox.9104819
Impact/Purpose:
This is a poster presented to the Society of Toxicology annual meeting in Baltimore, MD in March of 2019. This research addresses occupational exposure and is a collaboration with the US Air Force School of Aerospace Medicine.
Description:
Currently it is difficult to prospectively estimate human toxicokinetics (particularly for novel chemicals) in a high-throughput manner. The R software package httk has been developed, in part, to address this deficiency, however it is limited to oral and intravenous exposure routes. The aim of this investigation was to develop a generalized inhalation model for httk. The structure of the inhalation model was based on a published physiologically-based model. The model was evaluated with literature: A total of 46 volatile organic chemicals (VOCs) were identified with sufficient information available in literature (metabolism parameters and concentration vs. time data). Physicochemical data was obtained using the EPA’s CompTox Chemistry Dashboard, while fraction unbound in plasma was assumed to be 99%. In total, 116 dosing situations were tested (56 in humans, 60 in rats) in plasma or blood. Mean (range) molecular weight was 116.10 g/mol (32.04-252.32 g/mol) and mean log P was 2.2 (-0.6-6.1). The slope of the regression line of best fit between log-transformed predicted and measured plasma and blood concentrations for combined human and rat data was 0.45 with an R2 = 0.36 and an RMSE = 0.78. Individual species fits were similar. The RMSE of the same data against the identity line was 1.07. The VOCs examined in this investigation represent small, generally more lipophilic molecules. About 10% of the data points were censored due to concentrations that were below reasonably measurable levels. Goodness-of-fit values currently indicate relatively poor model fit to literature data, though this may improve with implementation of better fraction unbound in plasma estimations and saturable elimination. Future efforts will be focused on identifying trends in model fit relative to chemical properties and implementing determination of exhaled-breath concentrations. This abstract does not necessarily reflect U.S. EPA policy.
URLs/Downloads:
DOI: Development of a Generalized Inhalation Model for use with the High-Throughput Toxicokinetics (httk) Package in R
SOT_2019_POSTER_HTTKINHALATION_MLINAKIS_M.PDF (PDF, NA pp, 2068.096 KB, about PDF)