Extending the high-throughput toxicokinetics R package to include brain and adipose compartments
7 affiliations
- 1Applied Research Associates, Inc.
- 2Inotiv
- 3Biocomplexity Institute, Intelligent Systems Engineering, Indiana University
- 4School of Public Health, University of Nevada Reno
- 5Ramboll Americas Engineering Solutions, Inc.
- 6Chemical Insights Research Institute, UL Research Institutes
- 7National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, Division of Translational Toxicology, National Institute of Environmental Health Sciences
Abstract
Chemical risk assessment has traditionally been performed based on in vivo studies. These studies have limited throughput, consequently leading to limited toxicity information for the majority of chemicals in industrial and commercial use. In addition, the translation from animal to human effects can be challenging. To increase human-relevant toxicity knowledge, high-throughput in vitro approaches have been developed. However, one challenge in employing these assays for hazard and risk assessment is the translation of in vitro bioactive concentrations to in vivo doses and internal tissue concentrations. To improve decision-making in chemical risk assessment, as well as drug discovery for humans, the U.S. Environmental Protection Agency has developed a simple physiologically based toxicokinetic (PBTK) model as part of the High-throughput Toxicokinetics open-source R package (httk ). In this study, the PBTK model was extended to include compartments for the brain and adipose tissues. The model incorporates a blood–brain barrier to control chemical penetration and disposition, which is essential for predicting neurotoxicity. The integration of an adipose tissue compartment further enables the prediction of bioaccumulation, particularly for lipophilic chemicals. The model’s performance was evaluated by comparing predicted chemical concentrations against experimental data from both oral and intravenous routes. This PBTK model extends the applicability of httk to allow for assessing potential neurotoxicity and chronic exposure to lipophilic chemicals and better evaluate chemical pharmacokinetics. Moreover, this PBTK model can act as a tool for optimizing dosages and other study parameters to reduce and refine the design of in vivo studies.
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BibTeX
@article{unnikrishnan2026extending,
title = {{Extending the high-throughput toxicokinetics R package to include brain and adipose compartments}},
author = {Aswani Unnikrishnan and Anna Kreutz and Xiaoqing Chang and James P. Sluka and Dingsheng Li and Matthew W. Linakis and John F. Wambaugh and Nicole Kleinstreuer and Helena T. Hogberg},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1895108},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1895108/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Extending the high-throughput toxicokinetics R package to include brain and adipose compartments
AU - Aswani Unnikrishnan
AU - Anna Kreutz
AU - Xiaoqing Chang
AU - James P. Sluka
AU - Dingsheng Li
AU - Matthew W. Linakis
AU - John F. Wambaugh
AU - Nicole Kleinstreuer
AU - Helena T. Hogberg
PY - 2026
DA - 2026/10/28
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1895108
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1895108/full
AB - Chemical risk assessment has traditionally been performed based on in vivo studies. These studies have limited throughput, consequently leading to limited toxicity information for the majority of chemicals in industrial and commercial use. In addition, the translation from animal to human effects can be challenging. To increase human-relevant toxicity knowledge, high-throughput in vitro approaches have been developed. However, one challenge in employing these assays for hazard and risk assessment is the translation of in vitro bioactive concentrations to in vivo doses and internal tissue concentrations. To improve decision-making in chemical risk assessment, as well as drug discovery for humans, the U.S. Environmental Protection Agency has developed a simple physiologically based toxicokinetic (PBTK) model as part of the High-throughput Toxicokinetics open-source R package (httk ). In this study, the PBTK model was extended to include compartments for the brain and adipose tissues. The model incorporates a blood–brain barrier to control chemical penetration and disposition, which is essential for predicting neurotoxicity. The integration of an adipose tissue compartment further enables the prediction of bioaccumulation, particularly for lipophilic chemicals. The model’s performance was evaluated by comparing predicted chemical concentrations against experimental data from both oral and intravenous routes. This PBTK model extends the applicability of httk to allow for assessing potential neurotoxicity and chronic exposure to lipophilic chemicals and better evaluate chemical pharmacokinetics. Moreover, this PBTK model can act as a tool for optimizing dosages and other study parameters to reduce and refine the design of in vivo studies.
SN - 1663-9812
ER -