FLAVORINGS-RELATED LUNG DISEASE
In general, flavoring chemicals are very volatile, so they evaporate into the air from their liquid or solid form and can be easily inhaled. They can also be inhaled in the form of a powder if airborne dust is created in the production process. Many of these chemicals are highly irritating to the eyes, respiratory tract, and skin. At flavoring and microwave popcorn production plants where workers developed severe lung disease, workers routinely handled or were exposed to open vessels containing flavorings or their chemical ingredients. In a sense, such plants are large kitchens where workers mix several chemical ingredients in large pots or other containers to produce various products. The application of heat in the production process can increase the amount of flavoring chemicals that get into the air. In addition to microwave popcorn and flavorings plants, other food industries with potential exposure to butter flavoring chemicals include snack foods (e.g. chips, pretzels), commercial and retail bakeries (e.g. cakes, cookies, bread), retail baking mix production, margarine and other vegetable oil-based cooking products, butter and other dairy products, and candy manufacturers. Use of butter-flavored cooking oil products to prepare meals in restaurants may also lead to worker exposures. While exposures in the flavoring industry and in microwave popcorn production have caused severe lung disease in some workers, the degree of risk to workers from exposures in other settings is currently unknown.
Flavorings are often complex mixtures of natural and manmade substances. The Food and Drug Administration evaluates flavoring ingredients to determine whether they are "generally recognized as safe" (GRAS) to be eaten. Even if they are safe to eat, these ingredients might still be harmful to breathe in the forms and amounts to which food and chemical industry workers may be exposed. Given the complexity of flavorings mixtures, and the lack of health data for many of the component materials, identifying the relative contributions of individual substances to causing flavoring-induced lung disease is a difficult challenge. As noted in the NIOSH Alert: Preventing Lung Disease in Workers Who Use or Make Flavorings, the flavorings industry has estimated that over a thousand flavoring ingredients have the potential to be respiratory hazards due to possible volatility and irritant properties (alpha, beta-unsaturated aldehydes and ketones, aliphatic aldehydes, aliphatic carboxylic acids, aliphatic amines, and aliphatic aromatic thiols and sulfides).
Diacetyl is a chemical that was found to be a prominent volatile constituent in butter flavoring and air at the microwave popcorn plant initially investigated by NIOSH. Diacetyl is also known as the alpha-diketone, 2,3-butanedione, or by its Chemical Abstracts Service (CAS) number, 431-03-08.
Workers in microwave popcorn manufacturing are exposed to many materials besides diacetyl. Thus, NIOSH's initial studies in a total of 6 microwave popcorn plants were not able to definitely determine if diacetyl exposure contributed to lung disease or was a marker for other hazardous substances that contributed to disease. Still, NIOSH studies in the initial plant documented a relationship between cumulative exposure to diacetyl vapor over time and having abnormal lung function as measured by a test of lung function called spirometry. Also, higher cumulative exposure to diacetyl in this plant was associated with having a lower level of forced expiratory volume in 1 second (FEV 1), an important measure of lung function. Across all six microwave popcorn plants studied by NIOSH, working as a mixer of butter flavorings and heated soybean oil was associated with higher exposure to diacetyl vapor than working in other areas of the plants. People who had ever worked as mixers had more chest symptoms and poorer lung function as measured by lower FEV 1 than people who had never worked as mixers. People who had worked as mixers for more than 12 months had more shortness of breath with exertion and lower FEV 1 than people who had worked as mixers for less than 12 months.
Subsequent studies have helped to clarify the role of diacetyl. Toxicology studies have shown that vapors from heated butter flavorings can cause damage to airways in animals (Hubbs et al, 2002). Studies in both rats and mice demonstrate that the cells lining airways can be damaged by inhaling diacetyl vapors as a single agent exposure in both acute and subchronic studies (Hubbs et al, 2008; Morgan et al, 2008). In mice, aspiration of diacetyl alone caused a pattern of injury that replicates some of the features of human obliterative bronchiolitis (Morgan et al, 2008). These findings support the hypothesis that diacetyl vapors are an inhalation hazard in the workplace. Also, a study from the Netherlands shows that chemical workers in a plant that manufactured diacetyl developed the same type of lung disease as microwave popcorn workers (van Rooy et al, 2007 and 2009). These chemical workers had less complicated exposures than microwave popcorn workers. Overall, current evidence points to diacetyl as one agent that can cause flavorings-related lung disease. Other flavoring ingredients may also play a role.
The alpha-diketone, 2,3-pentanedione, has received attention as a flavoring substitute for diacetyl. It is also known as acetyl propionyl or by CAS number 600-14-6. It is structurally very similar to diacetyl since 2,3-pentanedione is a 5-carbon alpha-diketone and diacetyl is a 4-carbon alpha-diketone. Published reports on the toxicity of 2,3-pentanedione were first published in abstract form in 2010 (Hubbset al. 2010b; Morgan et al. 2010). A recent NIOSH peer-reviewed publication documents that acute inhalation exposures to 2,3-pentanedione cause airway epithelial damage that is similar to diacetyl in laboratory studies (Hubbset al. 2012). In 2-week inhalation studies in rats, NIEHS researchers found that 2,3-pentanedione caused proliferation of fibrous connective tissue in the walls of airways and projections of fibrous connective tissue sometimes extended into the air passageways (Morganet al. 2012b). Preliminary data suggest that repeated exposures to either 2,3-pentanedione or diacetyl can cause airway fibrosis in rats (Morganet al. 2012a). In the acute inhalation study of 2,3-pentanedione, changes in gene expression were noted in the brain (Hubbset al. 2012). Preliminary data suggests that diacetyl can cause changes in the central nervous system that are similar to those caused by 2,3-pentanedione (Hubbset al. 2010a). As a group, these publications raise concerns that the toxicologic effects of diacetyl may be shared with alpha-diketones which are close structural analogs. Additional alpha-diketones of interest include, but are not limited to, those used in food manufacturing such as 2,3-hexanedione and 2,3-heptanedione (Dayet al. 2011).
Measurement of diacetyl exposures is likely to be helpful in preventing flavorings-induced lung disease, even though flavorings exposures are often more complex. Diacetyl may serve as a marker or surrogate for mixed exposures to some hazardous flavorings, as it has been an ingredient in flavorings mixtures where disease has been observed. In addition, as already noted, preliminary studies suggest that diacetyl has toxic properties as a single component that are similar to the effects of exposure to a butter flavoring mixture. Thus, measuring diacetyl exposures may help to identify hazards. Furthermore, these measurements can guide corrective actions, such as engineering controls, improved work practices, and respiratory protection, to reduce or eliminate exposures NIOSH researchers developed and published an analytical technique, Method 2557, to measure diacetyl in workplace air (Pendergrass 2004).. Subsequently, a laboratory study found that this method is adversely affected by absolute humidity, days to sample extraction, and diacetyl air concentration, resulting in underestimation of true concentrations. NIOSH developed a correction procedure to adjust diacetyl concentrations previously measured using the method [Cox-Ganser et al, 2011]. NIOSH Method 2557 should no longer be used to measure airborne diacetyl concentrations. The Occupational Safety and Health Administration (OSHA) has developed and validated methods that can be used for air sampling. OSHA Methods 1012 and 1013 can be used for diacetyl, and OSHA Method 1016 can be used for 2,3-pentanedione alone or simultaneously for diacetyl.
Cox-Ganser J, Ganser G, Saito R, Hobbs G, Boylstein R, Hendricks W, Simmons M, Eide M, Kullman G, Piacitelli C . Correcting diacetyl concentrations from air samples collected with NIOSH Method 2557. J Occup Environ Hyg 8(2):59-70.
Day, G., LeBouf, R., Grote, A., Pendergrass, S., Cummings, K. J., Kreiss, K., and Kullman, G. (2011). Identification and measurement of diacetyl substitutes in dry bakery mix production. J Occ Env 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 . Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol Appl Pharmacol 185:128–35.
Hubbs AF, Goldsmith WT, Kashon ML, Frazer D, Mercer RR, Battelli LA, Kullman GJ, Schwegler-Berry D, Friend S, Castranova V . Respiratory toxicologic pathology of inhaled diacetyl in Sprague-Dawley rats. Toxicol Pathol 36(2):330–344.
Hubbs, A. F., Moseley, A. E., Goldsmith, W. T., Jackson, M. C., Kashon, M. L., Battelli, L. A., Schwegler-Berry, D., Goravanahally, M. P., Frazer, D., Fedan, J. S., Kreiss, K., and Castranova, V. (2010b). Airway epithelial toxicity of the flavoring agent, 2,3-pentanedione. The Toxicologist CD — An official Journal of the Society of Toxicology 114, 319.
Hubbs, A. F., Cumpston, A., Goldsmith, W. T., Battelli, L. A., Kashon, M. L., Jackson, M. C., Frazer, D. G., Fedan, J. S., Goravanahally, M. P., and Sriram, K. (2010a). Acute central neurotoxicity of inhaled alpha-diketone butter flavoring compounds in the rat brain. Vet Path 47, 57S.
Hubbs, A. F., Cumpston, A. M., Goldsmith, W. T., Battelli, L. A., Kashon, M. L., Jackson, M. C., Frazer, D. G., Fedan, J. S., Goravanahally, M. P., Castranova, V., Kreiss, K., Willard, P. A., Friend, S., Schwegler-Berry, D., Fluharty, K. L., and Sriram, K. (2012). Respiratory and olfactory cytotoxicity of inhaled 2,3-pentanedione in Sprague-Dawley Rats. Am J Pathol 181, in press,.
Morgan, D. L., Jokinen, M. P., Johnson, C. L., Gwinn, W. M., Price, H. C., and Flake, G. P. (2012a). Bronchial fibrosis in rats exposed to 2, 3-butanedione and 2, 3-pentanedione vapors. Toxicol Sci (The Toxicologist) 126, 186.
Morgan, D. L., Jokinen, M. P., Price, H. C., Gwinn, W. M., Palmer, S. M., and Flake, G. P. (2012b). Bronchial and Bronchiolar Fibrosis in Rats Exposed to 2,3-Pentanedione Vapors: Implications for Bronchiolitis Obliterans in Humans. Toxicol Pathol 40, 448-465.
Morgan DL, Flake GP, Kirby PJ, Palmer SM . Respiratory toxicity of diacetyl in C57BL/6 mice. Toxicol Sci 103(1):169–180.
Morgan, D. L., Kirby, P. J., Price, H. C., Bosquet, R. W., Taylor, G. J., Gage, N., and Flake, G. P. (2010 ). Inhalation toxicity of acetyl proprionyl in rats and mice. The Toxicologist: Supplement to Toxicological Sciences 114, 316.
Pendergrass, SM . Method development for the determination of diacetyl and acetoin at a microwave popcorn plant. Environ. Sci. Technol. 38 (3): 858–861.
van Rooy FG, Rooyackers JM, Prokop M, Houba R, Smit LA, Heederik DJ . Bronchiolitis obliterans syndrome in chemical workers producing diacetyl for food flavorings. Am J Respir Crit Care Med 176(5):498–504.
van Rooy FG, Smit LA, Houba R, Zaat VAC, Rooyackers JM, Heederik DJ . A cross-sectional study of lung function and respiratory symptoms among chemical workers producing diacetyl for food flavorings. Occup Environ Med 66:105-110.
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