Application of a human bronchoepithelial-air-liquid interface model to assess respiratory hazard of VOCs using a benchmark concentration modeling approach.

OBJECTIVE: Volatile organic compounds (VOCs) are prevalent in both indoor and outdoor environments and have been linked to health effects. This study aimed to assess VOC-induced effects on the respiratory epithelium using an in vitro human bronchial epithelial air-liquid interface (ALI) model. METHODS: A human bronchial epithelial cell line, 16HBE, was cultured at ALI and exposed to relevant concentrations of two representative VOCs, acrolein or formic acid, and matched filtered air (control) in a CelTox exposure system for two hours to replicate an acute inhalation exposure. Cells were allowed to recover for 24 h before cell lysate and culture media were collected for analysis. RESULTS: Cytotoxicity, based on LDH activity, significantly increased at the highest doses tested for both VOCs. A dose-dependent increase in barrier permeability was observed for confluent cells exposed to acrolein and formic acid. Acrolein and formic acid exposure induced IL-8, TNFα, and HMOX-1 expression, genes indicative of proinflammatory signaling and oxidative stress, respectively. Formic acid, but not acrolein, exposure also increased expression of PINK1, a gene indicative of mitophagy. Benchmark concentration (BMC) modeling of in vitro acrolein data yielded a BMCL (benchmark concentration lower confidence limit) that substantiates the stringency of OSHA's 8-hour permissible exposure limit (PEL). In contrast, BMC modeling of in vitro formic acid data produced BMCLs below existing regulatory exposure thresholds. CONCLUSION: Collectively, these findings demonstrate that this model is a plausible in vitro tool to investigate VOC-induced effects on the airway and supports its utility in VOC safety evaluation.