Building a predictive model for polycyclic aromatic hydrocarbon dosimetry in organotypically cultured human bronchial epithelial cells using benzo[a]pyrene

Colvin, Victoria C.; Bastin, Kelley M.; Siddens, Lisbeth K.; Vermillion Maier, Monica L.; Williams, David E.; Smith, Jordan N.; Tilton, Susan C.

doi:10.1016/j.toxrep.2025.102133

Building a predictive model for polycyclic aromatic hydrocarbon dosimetry in organotypically cultured human bronchial epithelial cells using benzo[a]pyrene

Journal Article · Sun Sep 28 00:00:00 EDT 2025 · Toxicology Reports

DOI:https://doi.org/10.1016/j.toxrep.2025.102133· OSTI ID:3000221

Colvin, Victoria C. ^[1]; Bastin, Kelley M. ^[1]; Siddens, Lisbeth K. ^[1]; Vermillion Maier, Monica L. ^[1]; Williams, David E. ^[1]; Smith, Jordan N. ^[2]; ^[1]

Oregon State Univ., Corvallis, OR (United States)
Oregon State Univ., Corvallis, OR (United States); Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

The airway epithelium is a primary route of exposure for inhaled toxicants, and organotypic culture models represent an important advancement for toxicity testing compared to simple in vitro models that may lack metabolic capability and multicellular structure/communication associated with the bronchial epithelium in vivo. A quantitative understanding of chemical dosimetry is key for interpreting and extrapolating study results; however, dosimetry is understudied in organotypic models limiting ability to predict toxicity. We developed a dosimetry model for primary human bronchial epithelial cells (HBECs) cultured at the air-liquid interface (ALI) using benzo[a]pyrene (BAP), a representative polycyclic aromatic hydrocarbon. Dose and time course evaluation of metabolite formation and enzyme activity and expression were utilized to parameterize a cellular dosimetry model to improve the utility of ALI-HBECs for assessing chemical risk. Dosimetry analysis demonstrated absorption of BAP into cells and an increase in Phase 1 and 2 metabolites over time that correlated with regulation of metabolizing enzymes. BAP was cleared from cells by 48 h after exposure, and the primary metabolites generated in ALI-HBECs were BAP-3-phenol, BAP-4,5-dihydrodiol, BAP-7,8-dihydrodiol, BAP-9,10-dihydrodiol, BAP-7,8,9,10-tetrol, BAP-3-phenol-glucuronide, BAP-4,5-dihydrodiol-glucuronide, and BAP-9,10-dihydrodiol-glucuronide. The resulting dosimetry model described BAP and 7,8-dihydrodiol toxicokinetics in ALI-HBECs and suggested active excretion of 7,8-dihydrodiol. Overall, this study demonstrates metabolic competency of ALI-HBECs for BAP metabolism, demonstrates the usefulness of complex in vitro systems for human-relevant toxicity data, and exhibits how in silico models can be utilized for understanding the dosimetry of test compounds to aid in in vitro to human extrapolation of toxicity data for risk assessments.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE; USDA; National Institute of Environmental Health Sciences

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 3000221

Report Number(s):: PNNL-SA--215565

Journal Information:: Toxicology Reports, Journal Name: Toxicology Reports Vol. 15; ISSN 2214-7500

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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Unraveling the Health Effects of Environmental Mixtures: An NIEHS Priority Carlin, Danielle J.; Rider, Cynthia V.; Woychik, Rick Environmental Health Perspectives, Vol. 121, Issue 1 https://doi.org/10.1289/ehp.1206182	journal	January 2013
Effects of Fatty Acids on Benzo[a]pyrene Uptake and Metabolism in Human Lung Adenocarcinoma A549 Cells Barhoumi, Rola; Mouneimne, Youssef; Chapkin, Robert S. PLoS ONE, Vol. 9, Issue 3 https://doi.org/10.1371/journal.pone.0090908	journal	March 2014
The US Federal Tox21 Program: A strategic and operational plan for continued leadership Thomas, Russell ALTEX https://doi.org/10.14573/altex.1803011	journal	January 2018
Xenobiotic-Metabolizing Enzymes Involved in Activation and Detoxification of Carcinogenic Polycyclic Aromatic Hydrocarbons Shimada, Tsutomu Drug Metabolism and Pharmacokinetics, Vol. 21, Issue 4 https://doi.org/10.2133/dmpk.21.257	journal	January 2006
A critical review of in vitro dosimetry for engineered nanomaterials Cohen, Joel M.; DeLoid, Glen M.; Demokritou, Philip Nanomedicine, Vol. 10, Issue 19 https://doi.org/10.2217/nnm.15.129	journal	October 2015
Phase 0 and phase III transport in various organs: Combined concept of phases in xenobiotic transport and metabolism Döring, Barbara; Petzinger, Ernst Drug Metabolism Reviews, Vol. 46, Issue 3 https://doi.org/10.3109/03602532.2014.882353	journal	January 2014
Oxidative Metabolism of Polycyclic Aromatic Hydrocarbons to Ultimate Carcinogens Levin, Wayne; Wood, Alexander; Chang, Richard Drug Metabolism Reviews, Vol. 13, Issue 4 https://doi.org/10.3109/03602538209011087	journal	January 1982
Differential Gene Expression Patterns Between Apical and Basal Inner Hair Cells Revealed by RNA-Seq Tang, Feng; Chen, Xiaoling; Jia, Lifeng Frontiers in Molecular Neuroscience, Vol. 12 https://doi.org/10.3389/fnmol.2019.00332	journal	January 2020
New Approach Methods to Evaluate Health Risks of Air Pollutants: Critical Design Considerations for In Vitro Exposure Testing Zavala, Jose; Freedman, Anastasia N.; Szilagyi, John T. International Journal of Environmental Research and Public Health, Vol. 17, Issue 6 https://doi.org/10.3390/ijerph17062124	journal	March 2020
Competitive Metabolism of Polycyclic Aromatic Hydrocarbons (PAHs): An Assessment Using In Vitro Metabolism and Physiologically Based Pharmacokinetic (PBPK) Modeling Smith, Jordan N.; Gaither, Kari A.; Pande, Paritosh International Journal of Environmental Research and Public Health, Vol. 19, Issue 14 https://doi.org/10.3390/ijerph19148266	journal	July 2022
Benzo[a]pyrene—Environmental Occurrence, Human Exposure, and Mechanisms of Toxicity Bukowska, Bożena; Mokra, Katarzyna; Michałowicz, Jaromir International Journal of Molecular Sciences, Vol. 23, Issue 11 https://doi.org/10.3390/ijms23116348	journal	June 2022
Leveraging Multiple Data Streams for Prioritization of Mixtures for Hazard Characterization Rivera, Brianna N.; Ghetu, Christine C.; Chang, Yvonne Toxics, Vol. 10, Issue 11 https://doi.org/10.3390/toxics10110651	journal	October 2022

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