Poster: AIT – Association of Inhalation Toxicologists Conference, June 3-5 2025, Milton Keynes, United Kingdom
WM Gwinn1, GK Roberts1, P-L Yao1, MD Stout1, K Ryan1, A Gupta2, S Pearson2, J Richey2, B Moyer2, J Shaw2, S Mukherjee2, M Snyder2, and D Fallacara2
1Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC;
2Battelle, Columbus, OH
Introduction
Occupational exposure to volatile components of artificial butter flavoring (ABF) via inhalation has been reported to be associated with airway fibrosis in the form of bronchiolitis obliterans (BO), mostly in workers in the microwave popcorn packaging and flavoring industry exposed to 2,3-butanedione (BD, also commonly called diacetyl). BO is a potentially fatal lung disease that is frequently found in lung transplant patients and is characterized by bronchiolar wall inflammation and fibrosis resulting in constrictive bronchiolitis with restricted airflow. 2,3-pentanedione (PD) is also a highly volatile component of ABF. PD has been used as a major substitute for BD in some ABF due to concerns about the respiratory toxicity of BD. However, PD is structurally similar to BD (both are alphadiketones) (Fig. 1) and has been shown to exhibit toxicological potency similar to BD in the induction of airway epithelial injury with BO-like fibrotic lesions in rats, following acute (2-week) inhalation exposure, that are similar to the BO lesions observed in occupational exposures (Morgan et al. 2012 and 2016). In addition, organotypic in vitro human air-liquid interface (ALI) airway epithelial culture models have been previously used, mostly with BD, to help elucidate the mechanisms of airway injury and fibrosis induced by these chemicals. In a proof-ofconcept study, PD was selected as a test article for the characterization and optimization of a VITROCELL 48 2.0 plus exposure system (Fig. 2) together with human and rat ALI airway tissues to evaluate PD vapor-induced airway toxicity in vitro (and between species). The toxicity endpoints selected for Analysis are relevant to previously reported in vivo rat (BD and PD) and in vitro human ALI (BD) airway findings as well as key events in an Adverse Outcome Pathway (AOP 280: “α-diketone-induced bronchiolitis obliterans”) [Fig. 3].
