https://doi.org/10.1002/em.70000
Yuan Le1, Baiping Ren1, Levan Muskhelishvili2, Kelly Davis2, Yiying Wang1, William Gwinn3, Diego Rua4, Robert H. Heflich1, Xuefei Cao1
1Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas, USA
2Toxicologic Pathology Associates, Jefferson, Arkansas, USA
3Division of Translational Toxicology, National Institute of Environmental Health Sciences, Durham, North Carolina, USA
4Division of Biology, Chemistry, and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Heath, US Food and Drug Administration, Silver Spring, Maryland, USA
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.
