README.md

Supplemental Material

Impact of Gut Permeability on Estimation of Oral Bioavailability for Chemicals in Commerce and the Environment

Abstract

Administered equivalent dose (AED) estimation using in vitro hazard and high throughput toxicokinetics (HTTK) can be improved by refining assumptions regarding fraction absorbed ($F_{abs}$) through the intestine, a component of oral bioavailability ($F_{bio}$). Although in vivo data to inform $F_{abs}$ are often unavailable for non-pharmaceuticals, in vitro measures of apparent permeability ($P_{app}$) using the Caco-2 cell line have been highly correlated with $F_{abs}$ when used in in vitro-in vivo extrapolation (IVIVE) modeling. To address data gaps for non-drug chemicals, bidirectional $P_{app}$ was evaluated using the Caco-2 assay for over 400 chemicals. A random forest quantitative structure-property relationship (QSPR) model was developed using these and peer-reviewed pharmaceutical data. Both Caco-2 data ($R^2$=0.37) and the QSPR model ($R^2$=0.3) were better at predicting human bioavailability compared to in vivo rat data ($R^2$=0.2). The httk-predicted plasma steady state concentrations ($C_{ss}$) for IVIVE were updated, leading to modest changes for poorly absorbed chemicals. Experimental data were evaluated for sources of measurement uncertainty, which was then accounted for using the Monte Carlo method. Revised AEDs were subsequently compared with exposure estimates to evaluate influence on bioactivity:exposure ratios as a surrogate for risk. Ultimately, $P_{app}$ incorporation to adjust for $F_{bio}$ in httk modeling improves AED estimations used in HT risk prioritization.

Data Analysis Vignettes

The following R vignettes were written in R Markdown using RStudio:

1. Caco-2 Data Organization and Analysis.
2. Machine Learning QSPR for Caco-2 Permeability.
3. Using QSPR for New Chemicals.
4. Comparison of Oral Absorption Predictions to In Vivo Data.
5. Impact of Bioavailability on Risk Prioritization.

Authors

Principal Investigators

John Wambaugh [[email protected]]

Elaina Kenyon [[email protected]]

Barbara Wetmore [[email protected]]

Full Author List

Gregory Honda¹

Elaina M. Kenyon¹

Sarah Davidson-Fritz¹

Roger Dinallo²

Hisham El-Masri¹

Evgenia Korel-Bexell¹

Li Li²

Robert Pearce¹

Risa Sayre¹

Christopher Strock²

Russell Thomas¹

John F. Wambaugh¹

Barbara A. Wetmore¹

1. U.S. Environmental Protection Agency, Office of Research and Development, Center for Computational Toxicology and Exposure, Research Triangle Park, NC 27711, USA
2. Cyprotex, Framingham, MA, USA

License

License: GPL-3 https://www.gnu.org/licenses/gpl-3.0.en.html