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10:00-11:00 am ET / 14:00-15:00 UTC

Featuring:

ASCCT 14th Annual Meeting Poster Award Recipient

ASCCT 14th Annual Meeting Travel Award Recipient

A brief Q&A session will follow each presentation.

ABSTRACTS

In 2023 the EPA issued a Test Order for hexafluoropropylene oxide (HFPO), under Section 4 of the Toxic Substances Control Act (TSCA).  Extant animal data linked inhalation of HFPO to adverse effects in the respiratory tract and the HFPO Test Order is the first to specifically require the use of in vitro respiratory models for the collection of data to evaluate human exposure effects.  We conducted single and 14-day repeated exposures to HFPO (100-2,500 ppm) on primary human cell-based air-liquid interface (ALI) co-culture models of the nasal, bronchial, and alveolar regions of the respiratory tract in multiple donors.  Acute exposures caused significant increases in cytotoxicity in the nasal (1,250 ppm) and bronchial (1,770 ppm) models.  Acute alveolar co-culture model exposures resulted in increased secretion of VEGFA, a key event in the adverse outcome pathway for pulmonary edema and a consistent finding animals exposed to higher HFPO concentrations from extant data.  The effects of 14-day exposures were evaluated in the nasal and bronchial models using two concentrations (880 and 1,770 ppm) determined based on the acute exposure outcomes. Repeated exposures increased epithelial barrier integrity and epithelial remodeling, but not cytotoxicity, in both models.  Collectively, the outcomes observed in the in vitro exposures reflect the outcomes of extant in vivo studies where applicable comparable data are available.  Observations from this study also demonstrate significant inter-individual variability across donors in some endpoints that supports the value of including more than a limited number of (e.g., 1-3) donors in future in vitro studies.

The oral epithelium, as the primary barrier to environmental exposures in the oral cavity, is increasingly threatened by ubiquitous substances, including flavoring additives, airborne particles, and e-cigarette liquids. These exposures have been linked to inflammation, tissue damage, and oral diseases, including cancer. However, little is known about how they affect oral basal progenitor cells (BPCs), which are responsible for renewing and maintaining the epithelial lining. In this study, we established a robust in vitro culture system for murine oral BPCs, enabling long-term propagation and organoid formation that recapitulates in vivo epithelial architecture. Using this model, we systematically assessed the toxicity of representative environmental agents. We found that the majority induced significant, dose-dependent BPC damage. Notably, flavoring agents and e-liquids caused pronounced cell loss at exposure levels relevant to consumer use. Mechanistic analyses revealed that reactive oxygen species and pro-inflammatory cytokines are central mediators of this toxicity. Importantly, we identified that a combination of generally safe antioxidant molecules effectively mitigated oxidative damage and restored BPC viability. Additionally, a widely used anti-inflammatory drug rescued BPCs from specific insults not addressed by antioxidants, suggesting distinct but complementary therapeutic pathways. Together, this work provides the first evidence that environmental exposures compromise oral epithelial homeostasis through BPC injury and identifies safe, small-molecule interventions with translational potential for oral mucosal protection and preventive healthcare.

ABOUT THE PRESENTERS

Dr. Shaun D. McCullough is a Senior Principal Respiratory Scientist at RTI International where he also leads the Predictive Toxicology and Exploratory Biology Group as well as the In Vitro Respiratory Modeling and Toxicity Testing Laboratory.  In his role at RTI, Dr. McCullough works closely with government, industry, non-profit, and community stakeholders on efforts to develop and deploy organotypic models of the respiratory tract in research and testing, build confidence in the use of in vitro systems and assays for inhaled chemical hazard identification, characterize inter-individual variability in primary cell based in vitro models, and establish cross sector harmonization of in vitro assays for inhalation toxicology to support regulatory acceptance.  In recent years, Dr. McCullough’s research has led to the development of two novel multicellular in vitro respiratory tract models, the demonstration of trans-epithelial effects of inhaled chemical exposures in vitro, and the most comprehensive characterization of inter-individual variability in in vitro models of the respiratory tract to date.  He has also served as a subject matter expert on in vitro models and assays for the review of guidance, policy, and scientific documents related to the use of in vitro models and data for a diverse range of organizations including the various federal agencies, academic and industry organizations, OECD, and the National Academy of Sciences.

Dr. Sezin Aday Aydin is a Research Associate at the University of Pennsylvania and a translational bioengineer focused on developing human-relevant microphysiological systems for mechanistic toxicology. Her current research focuses on organ-on-a-chip and vascularized tissue models that recapitulate human barrier function and tissue microenvironments to investigate injury mechanisms and identify predictive biomarkers. She has led interdisciplinary, government- and foundation-funded projects spanning inhalation toxicology, oral and mucosal exposure, and neurovascular biology, with the goal of advancing more predictive, human-relevant approaches while reducing reliance on animal models.

Please note that only Dr. McCullough's presentation will be recorded. The recording and select materials from this webinar will be posted on the ASCCT webinar archive: https://ASCCTox.org/Webinar-Archive