Citation:

Linakis, M., R. Sayre, R. Pearce, Mark A. Sfeir, N. Sipes, H. Pangburn, J. Gearhart, AND J. Wambaugh. Development and Evaluation of a High Throughput Inhalation Model for Organic Chemicals. Journal of Exposure Science and Environmental Epidemiology . Nature Publishing Group, London, Uk, 30(5):866-877, (2020). https://doi.org/10.1038/s41370-020-0238-y

Impact/Purpose:

EPA has worked to develop curated PBTK tools and an extensive library of HTTK chemical data that may now be used to simulate gas exposures. Inhalation is an important route of exposure for many chemicals and scenarios, particularly occupational scenarios. This research expands EPA’s high throughput toxicokinetic (HTTK) tool to include a generic physiologically-based toxicokinetic (PBTK) model that includes a gas inhalation route of exposure. The model was evaluated using data of chemical concentration in plasma obtained from published literature for 42 volatile organic chemicals across 143 exposure scenarios in human and rat. The model performed well overall, and was shown to predict plasma concentration, peak plasma concentration, and time-integrated plasma concentration (area under the curve or AUC).

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, and the aim of this investigation was to develop a generalized inhalation model for httk. The structure of the inhalation model was developed from two previously published physiologically-based models from Jongeneelen et al. (2011) and Clewell et al. (2001) while calculated physicochemical data was obtained from EPA’s CompTox Chemicals Dashboard. In total, 143 exposure scenarios across 42 volatile organic chemicals were modeled and compared to published data. The slope of the regression line of best fit between log-transformed simulated and observed combined measured plasma and blood concentrations was 0.59 with an r2= 0.54 and a Root Mean Square Error (RMSE) of direct comparison between the log-transformed simulated and observed values of 0.87. Approximately 3.6% (n = 73) of the data points analyzed were > 2 orders of magnitude different than expected. Additionally, log-transformed maximum concentration (Cmax) and area under the curve (AUC) values were compared, resulting in direct comparison RMSEs of 0.50 and 0.55 respectively. The volatile organic chemicals examined in this investigation represent small, generally lipophilic molecules. Ultimately this paper details a generalized inhalation component that integrates with the httk physiologically-based pharmacokinetic model to provide high-throughput estimates of inhalation chemical exposures.

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