ToxSci Advance Access originally published online on January 27, 2008
Toxicological Sciences 2008 103(1):169-180; doi:10.1093/toxsci/kfn016
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Respiratory Toxicity of Diacetyl in C57Bl/6 Mice
* Respiratory Toxicology, Laboratory of Molecular Toxicology, National Toxicology Program/National Institute of Environmental Health Sciences
Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
1 To whom correspondence should be addressed at Respiratory Toxicology, Laboratory of Molecular Toxicology, MD IF-00, NIEHS, Research Triangle Park, NC 27709. Fax: (919) 541-0356. E-mail: morgan3{at}niehs.nih.gov.
Received December 13, 2007; accepted January 17, 2008
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Abstract |
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Diacetyl, a component of artificial butter flavoring, is a potential etiological agent of obliterative bronchiolitis (OB); however, the toxic dose and mechanisms of toxicity remain controversial. We evaluated the respiratory toxicity of diacetyl in a murine model using several exposure profiles relevant to workplace conditions at microwave popcorn packaging plants. Male C57Bl/6 mice were exposed to inhaled diacetyl across several concentrations and duration profiles, or by direct oropharyngeal aspiration. Effects of diacetyl on the respiratory tract were evaluated by histopathology and BALF analyses. Subacute exposure to 200 or 400 ppm diacetyl for 5 days caused deaths, necrotizing rhinitis, necrotizing laryngitis and bronchitis. Reducing the exposure to 1 h/day (100, 200, 400 ppm) for 4 weeks resulted in less nasal and laryngeal toxicity, but led to peribronchial and peribronchiolar lymphocytic inflammation. A similar pattern was observed with intermittent high-dose exposures at 1200 ppm (15 min, twice a day, 4 weeks). Subchronic exposures to 100 ppm (6 h/day, 12 weeks) caused moderate nasal injury, and peribronchial lymphocytic inflammation accompanied by epithelial atrophy, denudation, and regeneration. Treatment with 400 mg/kg by oropharyngeal aspiration to bypass the nose caused foci of fibrohistiocytic proliferation with little or no inflammation at the junction of the terminal bronchiole and alveolar duct. Depending on the route and duration of exposure, diacetyl causes significant epithelial injury, peribronchial lymphocytic inflammation, or fibrohistiocytic lesions in the terminal bronchioles. Collectively these results indicate that clinically relevant diacetyl exposures result in a pattern of injury that replicates features of human OB.
Key Words: diacetyl, inhalation; mice; lymphocytic bronchitis; obliterative bronchiolitis; microwave popcorn; artificial butter flavoring.