Characterizing the Pulmonary Toxicity and Potential Mutagenicity of Formaldehyde Fumes in a Human Bronchial Epithelial Tissue Model

ABSTRACT Formaldehyde (FA) is a highly reactive aldehyde that is regarded as an inhalation hazard and human carcinogen. Herein, we report a follow‐up study evaluating the effects of exposure duration on the toxicity and mutagenicity of FA using a human in vitro air‐liquid‐interface (ALI) airway tissue model. Previously we exposed ALI cultures to 7.5, 15 and 30‐ppm FA fumes 4 h/day for 5 days; currently, we have increased the exposure duration of cultures exposed to 7.5 and 15 ppm FA to 5 days/week for 4 weeks, followed by a 28‐day recovery. Due to its toxicity, cultures exposed to 30 ppm FA were treated for 5 days, followed by the recovery. Tissue responses were evaluated following the treatment and recovery. DNA damage was measured using the Comet‐Chip assay after 3 days of exposure, and mutagenesis was evaluated by duplex sequencing following the recovery. The toxicity detected following the 4‐week exposure was similar to that seen previously with the 5‐day exposures: both 7.5 and 15 ppm FA induced moderate decreases in tissue integrity, FANCD2 DNA‐repair enzyme expression and IL‐6 release, and moderate increases in IL‐1RA release. Effects on cell proliferation, ciliary function and tissue structure were minimal. Additionally, neither the 4‐week exposure to 7.5 and 15 ppm FA nor the 5‐day exposure to 30 ppm FA induced DNA damage or mutations. Using this experimental design, exposure of human ALI airway cultures to FA fumes does not produce genotoxicity or mutagenicity, even when exposures are conducted over a 28‐day period.