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Incorporating a dermal absorption route into high throughput toxicokinetic modeling

Journal of Exposure Science & Environmental Epidemiology (2026) Cite this article

Abstract

Background

Dermal absorption of chemicals represents an important route of exposure in pharmaceutical, occupational, and environmental settings. Thousands of chemicals with little toxicity or toxicokinetic (TK) data are in use. However, in many cases, in vitro bioactivity data are available. While it is not feasible to collect in vivo TK data, TK may be estimated using high-throughput methods.

Objective

This study developed a generalized physiologically-based TK (PBTK) dermal exposure model for in vitro-in vivo extrapolation (IVIVE). This model estimates dermal exposures that result in systemic concentrations comparable to those associated with in vitro bioactivity.

Methods

The PBTK model simulated dermal exposures for 22 unique exposure scenarios across 12 chemicals with published in vivo concentration time course TK data. Two different methods for estimating chemical- and vehicle-specific skin permeability were evaluated: Potts-Guy [1] and Surrey [2]. Root mean squared log10 errors (RMSLE) were calculated on a per-chemical and method basis.

Results

Given only 12 chemicals with in vivo TK data to permit evaluation, a single, optimal method for predicting dermal permeability could not be identified. IVIVE was performed separately using both permeability methods to calculate administered equivalent doses (AEDs) relevant to potential occupational exposure for 561 chemicals with in vitro bioactivity data. AEDs were defined here as parts per million (ppm) solution concentrations that would result in bioactive plasma concentrations after eight hours of submerged hands. The Potts-Guy method indicated that AED concentrations were not achievable for many chemicals.

Significance

The new dermal PBTK model works with a pre-existing database of more than one thousand compounds including industrial chemicals and pesticides. Regardless of method, IVIVE indicated that dermal exposures can lead to bioactive plasma concentrations for only a small fraction of the chemicals with in vitro bioactivity data examined. Gloves might be recommended for handling those chemicals.

Impact statement

Rapid estimation of risk posed by chemicals through dermal contact is an important need for occupational settings. A generic PBTK model was developed to characterize dermal absorption using chemical-specific in vitro data for metabolism and protein binding and physico-chemical properties. The model was evaluated using in vivo toxicokinetic data for multiple chemicals. The data were equivocal with respect to different dermal absorption assumptions. The new model allows for conversion of in vitro chemical bioactivity data from high-throughput toxicity screening to solution concentrations that would result in bioactive plasma concentrations in occupationally relevant conditions.

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Fig. 1: Dermal In vitro-In vivo Extrapolation (IVIVE) measurement/modeling diagram.
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Fig. 2: Concentration vs time (CvT) observed data and corresponding simulation predictions.
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Fig. 3: A heatmap of Root Mean Squared Log Error (RMSLE) between simulations and observations.
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Fig. 4: Change in RMSLE vs. the boiling point (BP).
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Fig. 5
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Data availability

R package “httk”, including R scripts, data files, and C code, is freely distributed via the Comprehensive R Archive Network (CRAN – https://cran.r-project.org/). The “httk” codebase is provided in a public GitHub repository (https://github.com/USEPA/CompTox-ExpoCast-httk). A change log describing revisions is available at: https://cran.r-project.org/web/packages/httk/news/news.html.

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Acknowledgements

This document has been reviewed in accordance with U.S. Environmental Protection Agency policy and approved for publication. We thank EPA internal reviewers Dr. Peter Egeghy, Dr. Michael Devito, and Dr. Alison Harrill for their helpful comments.

Funding

The United States Environmental Protection Agency (U.S. EPA) through its Office of Research and Development (ORD) funded the research described here. ORD scientists contributed to the research described here. This project was supported by appointments to the Internship/Research Participation Program at ORD and administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the United States Department of Energy and U.S. EPA.

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Authors and Affiliations

  1. Center for Computational Toxicology and Exposure, United States Environmental Protection Agency, Research Triangle Park, NC, USA

    Annabel Meade, Marina V. Evans, Alex George, Rachael Cogbill, Risa R. Sayre & John F. Wambaugh

  2. Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA

    Annabel Meade

  3. Center for Public Health and Environmental Assessment, United States Environmental Protection Agency, Research Triangle Park, NC, USA

    Celia M. Schacht

  4. Oak Ridge Associated Universities, Oak Ridge, TN, USA

    Rachael Cogbill

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  1. Annabel Meade
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  2. Celia M. Schacht
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  4. Alex George
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  5. Rachael Cogbill
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  6. Risa R. Sayre
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  7. John F. Wambaugh
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Contributions

Annabel Meade: led development of model and initial data analysis, Celia Schacht: led writing and revision of manuscript and revised analysis, Marina V Evans: contributed to development of analysis writing initial draft, model development, Alex George: contributed to model development and data analysis, Rachael Cogbill: contributed to model development, Risa Sayre: contributed to data extraction, John Wambaugh: provided project management and funding and contributed to development of analysis and writing and revision of manuscript.

Corresponding author

Correspondence to Celia M. Schacht.

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The authors declare no competing interests.

Ethical approval

The chemical-specific in vitro measurements are based on previously published experiments using human primary cells. In the previously published studies, the vendors providing the cells had obtained relevant consent. ThermoFisher states that “Yes, we comply with country-specific legal and ethical standards for procurement of human liver tissue, including the global ICH Guidelines, and the US’s HIPAA, Uniform Anatomical Gift Act, National Organ Transplant Act, and Hospital Internal Review Board (IRB) approval processes.” The chemical-specific in vivo data measurements are from experiments that have been curated from the literature [28]. The names of the IRB’s used by the vendors in the literature studies are not available.

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Meade, A., Schacht, C.M., Evans, M.V. et al. Incorporating a dermal absorption route into high throughput toxicokinetic modeling. J Expo Sci Environ Epidemiol (2026). https://doi.org/10.1038/s41370-026-00881-8

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  • DOI: https://doi.org/10.1038/s41370-026-00881-8

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