Nearly everyone knows how it feels to swallow a bite of food or sip of beverage that “goes down the wrong pipe”, what physicians call “pulmonary aspiration”. We cough, sputter, and turn red from the physical blockage and irritation. Food and food ingredients on a bulk scale (as food on the plate) are more healthful when eaten than when breathed. Similarly, but on a less than bulk scale, airborne particles or molecules of a food ingredient that is Generally Recognized as Safe (GRAS) for consumption aren’t necessarily safe when breathed in. This is true for many food ingredient substances that are naturally volatile (such as fragrances and flavorings) or are handled in ways that promote volatility, such as spraying, harsh mixing (especially of dry powders), or heating to high temperatures.
How serious the differentiation between ingestion toxicity and inhalation toxicity can be started becoming apparent in May 2000 when a physician specializing in occupational medicine reported a cluster of eight cases of fixed obstructive airways disease to the Missouri Department of Health and Senior Services (MDHSS).1 All eight individuals had previously worked in the same microwave popcorn facility for periods ranging from 8 months to 9 years between 1992 and 2000. All presented with respiratory illness consistent with bronchiolitis obliterans (BO), a fixed obstructive airways disease that initially manifests as shortness of breath, coughing, and fatigue, but can produce fibrosis and obstruction of the small airways such that a lung transplant may be required. Four of the eight subjects in the physician’s report were on a waiting list for lung transplant; in response to the report, the MDHSS contacted the Center for Disease Control (CDC).
The initial findings of the CDC investigation indicated that exposure to flavorings had placed the microwave popcorn workers at risk of developing BO. Further investigation narrowed the potential causes down to the butter-flavoring volatiles. Although more than 100 volatile organic compounds were identified in air samples collected from the mixing room, one butter-flavoring volatile, a substance called diacetyl, was consistently predominant.2
Diaceytl (also known as, 2,3-butanedione and butane-2,3-dione) is a small diketone flavoring molecule (Fig. 1) that is a by-product of yeast fermentation and a natural component of butter and wine. Synthetically produced diacetyl is a yellow to green liquid used to impart a buttery flavor to foods including butter-flavored popcorn, cooking sprays and unsalted butter. Diacetyl, when used as a flavoring agent with use not exceeding current Good Manufacturing Practice [21 CFR §184.1278], has been GRAS since the early 1980s. When consumed, diacetyl has low toxicity; the no-observed-adverse-effect level (NOAEL) based on a 90-day study in rats is 90 mg/kg bw day. 
Figure 1. Molecular structure of diacetyl
In the U.S., daily intake of diacetyl from food sources is estimated to be <0.3 mg/ day.3 In 2005, >228,000 pounds of diacetyl were used by the food industry.3 By weight, paste and liquid butter flavors contain 6-10.6% diacetyl with powdered butter flavors containing up to 6%.4 Buttermilk flavorings used in the production of dry bakery mixes have contained as much as 15-20% diacetyl in a liquid flavoring.5 In comparison, naturally occurring concentrations of diacetyl in butter are only about 0.0014%.4
Although suspected of being the causative agent, proof that inhalation exposure to diacetyl caused BO was needed. A number of research studies clarified the relationship. In 2002, Hubbs et al. demonstrated that the vapors of an artificial butter flavoring damaged the epithelium of upper and lower airways in a rat inhalation model.6 In 2006, the epithelial barrier function of isolated guinea pig trachea preparations were shown to become compromised after exposure to diacetyl, the main volatile flavor component in most artificial butter flavorings.7 In 2007, diacetyl was recognized as the cause of BO in workers in chemical production and flavor manufacturing plants in addition to food processing plants that made or used diacetyl.8 Depending on the unprotected exposure level and duration, a worker could develop severe fixed airway obstruction within seven months9; the workers that carried the greatest exposure risk were the mixers in flavor manufacture and microwave popcorn production plants.
When heated (but not actively stirred/handled), finished microwave popcorn flavoring mixtures released up to 11.4 ppm diacetyl in the air; dry powders emitted up to 1.62 ppm diacetyl, with liquid butters releasing up to 17.2 ppm diacetyl and wetted powders up to 54.7 ppm.4 At 16 small- to medium-sized flavoring facilities, the routine handling and processing of liquid butter flavorings generated mean levels of 2.02 ppm diacetyl in the air; mean levels of diacetyl from handling and processing powder flavorings were 4.24 ppm, but could reach up to 525 ppm for certain processing activities.3 These measured levels were generally within the same ranges as those found at the microwave popcorn facilities, although duration and frequency of worker exposure in flavor processing were less.3
In 2007, Rep. Lynn Woolsey, D-CA, introduced a bill compelling OSHA to issue an interim standard that would minimize worker exposure to diacetyl in manufacturing and microwave popcorn facilities. OSHA had earlier initiated a National Emphasis Program to address the diacetyl concern by assigning inspection resources to the workplaces with high exposures. California, which operates an OSHA State Plan program, began developing its own standard for diacetyl and other food-flavoring chemicals. By 2009, a number of lawsuits worth several hundred million dollars – and charging diacetyl as a cause of lung disease in factory workers – had been brought against chemical companies that synthesized diacetyl and food flavoring manufacturers that used diacetyl.10
Within the past few years, it was realized that on rare occasions consumers could also be exposed to levels of diacetyl that were comparable to those associated with lung disease in industry workers. In 2012, three biopsy-confirmed cases of BO in consumers were identified.11 Most famously, a Colorado man and self-admitted “popcorn fanatic” who consumed two bags of microwave popcorn a day for ten years and enjoyed intentionally inhaling the vapors of the freshly popped corn, was diagnosed with BO; the manufacturer and retailer in this case were made to pay millions to this consumer who developed “popcorn lung”.12
Diacetyl is a small molecule that has caused some big problems. Unfortunately, this is not anticipated to be an isolated occurrence. The flavorings industry estimates that ~1040 flavor ingredients could become respiratory hazards if inhaled rather than consumed.13 Ingredients viewed to be potential inhalation risks are generally irritants and naturally volatile or have a high likelihood of being handled or processed in a manner that promotes volatility. Because in our less than ideal world, all possible conditions cannot be predicted for all substances and all substances cannot undergo all testing, it behooves us to remember that GRAS refers only to “intended use” and that intended use is “consumption”.
 Four had worked in the room where the flavoring agents were mixed and four had worked in the popcorn packaging area (Kreiss et al., 2002).
 Prior to being linked with diacetyl, bronchiolitis obliterans syndrome was viewed as a primary graft dysfunction; it most commonly occurred in lung transplant recipients where its onset was recognized as the main cause of late mortality after transplant (Todd and Palmer, 2011; Verleden et al., 2005).
 Report No. 94. “Diacetyl”; GRAS Substances (SCOGS) Database, last updated October 2006. <http://www.accessdata.fda.gov/scripts/fcn/fcnDetailNavigation.cfm?rpt=scogsListing&id=103>; site accessed November 26, 2012.
 <http://www.osha.gov/SLTC/flavoringlung/index.html>; site accessed March 1, 2013.
 Preventative measures for microwaved popcorn consumers include allowing the popcorn bag to cool before opening it and not directly inhaling fragrant vapors from the bag (Egilman and Schilling, 2012)
- MMWR (2002) Fixed obstructive lung disease in workers at a microwave popcorn factory–Missouri, 2000-2002. Morbidity and Mortality Weekly Report, 51:345-347.
- Kreiss, K, Gomaa, A, Kullman, G, Fedan, K, Simoes, EJ, Enright, PL. (2002) Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant, New England Journal of Medicine (NEJM), 347:330-338.
- Martyny, JW, Van Dyke, MV, Arbuckle, S, Towle, M, and Rose, CS (2008) Diacetyl exposures in the flavor manufacturing industry. Journal of Occupational and Environmental Hygiene, 5: 679-688.
- Rigler, MW and Longo, WE (2010) Emission of diacetyl (2,3 butanedione) from natural butter, microwave popcorn butter flavor powder, paste, and liquid products. International Journal of Occupational and Environmental Health, 16:291-302.
- Day G, LeBouf R, Grote A, Pendergrass S, Cummings K, Kreiss K, Kullman G. (2011) Identification and measurement of diacetyl substitutes in dry bakery mix production. Journal of occupational and environmental hygiene, 8:93-103.
- Hubbs, AF, Battelli, LA, Goldsmith, WT, Porter, DW, Frazer, D, Friend, S, Schwegler-Berry, D, Mercer, RR, Reynolds, JS, Grote, A, Castranova, V, Kullman, G, Fedan, JS, Dowdy, J, Jones, WG. (2002) Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicology and Applied Pharmacology. 185:128-135.
- Fedan, JS, Dowdy, JA, Fedan, KB, Hubbs, AF. (2006) Popcorn worker’s lung: In vitro exposure to diacetyl, an ingredient in microwave popcorn butter flavoring, increases reactivity to methacholine. Toxicology and Applied Pharmacology, 215:17-22.
- Van Rooy, FGBGJ., Rooyackers, JM, Prokop, M, Houba, R, Smit, LAM, Heederik, DJJ. (2007) Bronchiolitis obliterans syndrome in chemical workers producing diacetyl for food flavorings. American Journal of Respiratory and Critical Care Medicine, 176:498-504.
- Kanwal, R. (2008) Bronchiolitis obliterans in workers exposed to flavoring chemicals. Current Opinion in Pulmonary Medicine, 14:141-146.
- Reisch, MS. (2009) The problem with butter flavor. Chemical and Engineering News, 87:24-26.
- Egilman, DS, Schilling, JH. (2012) Bronchiolitis obliterans and consumer exposure to butter-flavored microwave popcorn: A case series. International Journal of Occupational and Environmental Health, 18:29-42.
- FCN (2012) Manufacturer and retailer made to pay millions to consumer with “popcorn lung”. Food Chemical News, 54, Sept 28, 2012.
- CDC (December 2003) NIOSH Alert: Preventing Lung Disease in Workers Who Use or Make Flavorings. DHHS (NIOSH) Publication Number 2004–110.
- Todd, JL and Palmer, SM (2011) Bronchiolitis obliterans syndrome: The final frontier for lung transplantation. Chest, 140:502-508.
- Verleden, GM, Dupont LJ, Van Raemdonck DE (2005) Is it bronchiolitis obliterans syndrome or is it chronic rejection: a reappraisal? European Respiratory Journal (ERJ), 25:221-224.