Flavorings-Related Lung Disease

Diacetyl and 2,3-Pentandione

Diacetyl (also called 2,3-butanedione) is a chemical that has been used to give butter-like and other flavors to food products, including popcorn. This chemical has been used as a marker of exposure to flavoring vapors in investigations evaluating lung disease in microwave popcorn manufacturing facilities.1 Acetoin (also called acetyl methyl carbinol), 2,3-pentanedione, 2,3-hexanedione and 2,3-heptanedione are all structurally related to diacetyl and have been suggested as possible substitutes for diacetyl.

Effects of flavorings have been examined in animal studies. Severe respiratory tract injury was observed in rats after an acute inhalation exposure to butter flavorings.1, 2 Severe respiratory tract injury, similar to that observed with butter flavoring vapors exposure, was also observed following acute inhalation exposures of rats to diacetyl or 2,3-pentanedione and repeated inhalation exposures of mice to diacetyl and rats and mice to 2,3-pentanedione.3, 4, 5, 6, 7

NIOSH concluded:

Investigations of severe lung disease consistent with obliterative bronchiolitis among diacetyl-exposed employees . . . have provided substantial evidence of a causal relationship between diacetyl exposure and development of this disease. These findings in conjunction with laboratory experiments providing biological plausibility, meet the standard criteria used to determine causation: that an exposure is the likely cause of specific health effects [Gordis 1996; Hill 1965].7

NIOSH also expressed concern about 2,3-pentanedione based on its structural similarity to diacetyl and animal studies showing that it caused damage in the airways of animals, similar to that caused by diacetyl. Both diacetyl and 2,3 pentandione have the reactive α-dicarbonyl group that has been associated with the toxicity caused by those compounds. On the other hand, NIOSH concluded that acetoin, which lacks the α-dicarbonyl group, "is considerably less hazardous than dicacetyl." [Hubbs et al. 2016; National Toxicology Program 2015; Zaccone et al. 2013]7

1 Fixed Obstructive Lung Disease in Workers at a Microwave Popcorn Factory — Missouri, 2000–2002. Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report 51(16); 345-7 (April 26, 2002).

2 Hubbs A., et al. "Necrosis of Nasal and Airway Epithelium in Rats Inhaling Vapors of Artificial Butter Flavoring." Toxicology and Applied Pharmacology 185(2002): 128-135.

3 Hubbs AF, et al.. "Respiratory toxicologic pathology of inhaled diacetyl in Sprague-Dawley rats." Toxicologic Pathology. 36 (2002):330-44.

4 Hubbs AF, et. al.. "Respiratory and olfactory cytotoxicity of inhaled 2,3-pentanedione in Sprague-Dawley rats." American Journal of Pathology. 181 (2012):829-44.

5 Morgan DL, et. al. "Respiratory toxicity of diacetyl in C57BL/6 mice." Toxicological Sciences 103 (2008):169-80.

6 Morgan DL, et al.  "Bronchial and bronchiolar fibrosis in rats exposed to 2,3-pentanedione vapors: implications for bronchiolitis obliterans in humans." Toxicologic Pathology. 40(2012):448-65.

7 NIOSH, (2016). Criteria for a recommended standard: occupational exposure to diacetyl and 2,3-pentanedione. U.S. Department of Health and Human Services (DHHS), National Institute for Occupational Safety and Health (NIOSH) Publication No. 2016-111, (October 2016).