This Alert describes health effects that may occur because of workplace exposure to some flavorings or their ingredients, gives examples of workplace settings in which illness has occurred, and recommends steps that companies and workers should take to prevent hazardous exposures.

BACKGROUND

NIOSH has investigated the occurrence of severe lung disease in workers at a microwave popcorn packaging plant. Eight former workers at this plant developed illness characterized by fixed airways obstruction on lung function tests [Akpinar-Elci et al. 2002]. An evaluation of the current workforce at this plant showed an association between exposure to vapors from flavorings used in the production process and decreased lung function [Kreiss et al. 2002a]. Similar fixed obstructive lung disease has also occurred in workers at other plants that use or manufacture flavorings [NIOSH 1986; Lockey et al. 2002]. In animal tests, inhaling vapors from a heated butter flavoring used in microwave popcorn production caused severe injury to airways [Hubbs et al. 2002a].

Medical test results in affected workers (including some lung biopsy results) are consistent with bronchiolitis obliterans, an uncommon lung disease characterized by fixed airways obstruction [Akpinar-Elci et al. 2002]. In bronchiolitis obliterans, inflammation and scarring occur in the smallest airways of the lung and can lead to severe and disabling shortness of breath. The disease has many known causes such as inhalation of certain chemicals, certain bacterial and viral infections, organ transplantation, and reactions to certain medications [King 2000]. Known causes of bronchiolitis obliterans due to occupational or other environmental exposures include gases such as nitrogen oxides (e.g., silo gas), sulfur dioxide, chlorine, ammonia, phosgene, and other irritant gases [King 1998]. Recent NIOSH investigations strongly suggest that some flavoring chemicals can also cause bronchiolitis obliterans in the workplace. (Some workers exposed to flavorings in one of these plants were also found to have occupational asthma.)

HEALTH EFFECTS

The main respiratory symptoms experienced by workers affected by fixed airways obstruction include cough (usually without phlegm) and shortness of breath on exertion. These symptoms typically do not improve when the worker goes home at the end of the workday or on weekends or vacations. The severity of the lung symptoms can range from only a mild cough to severe cough and shortness of breath on exertion. Usually these symptoms are gradual in onset and progressive, but severe symptoms can occur suddenly. Some workers may experience fever, night sweats, and weight loss. Before arriving at a final diagnosis, doctors of affected workers initially thought that the symptoms might be due to asthma, chronic bronchitis, emphysema, pneumonia, or smoking. Severe cases may not respond to medical treatment. Affected workers generally notice a gradual reduction or cessation of cough years after they are no longer exposed to flavoring vapors, but shortness of breath on exertion persists. Several with very severe disease were placed on lung transplant waiting lists. Workers exposed to flavorings may also experience eye, nose, throat, and skin irritation. In some cases, chemical eye burns have required medical treatment.

Medical Evaluation

Medical testing may reveal several of the following findings:

CURRENT EXPOSURE LIMITS

Flavorings are composed of various natural and manmade substances. They may consist of a single substance, but more often they are complex mixtures of several substances. The Flavor and Extract Manufacturers Association evaluates flavoring ingredients to determine whether they are “generally recognized as safe” (GRAS) under the conditions of intended use through food consumption. Though considered safe to eat, ingredients may be harmful to breathe in the forms and concentrations to which food and chemical industry workers may be exposed.

Occupational exposure guidelines have been developed for only a small number of the thousands of ingredients used in flavorings. For example, Occupational Safety and Health Administration (OSHA) permissible exposure limits (PELs) and/or NIOSH recommended exposure limits (RELs) have been established for only 46 (<5%) of the 1,037 flavoring ingredients considered by the flavorings industry to represent potential 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) [Hallagan 2002] (see Appendix). Material safety data sheets (MSDSs) contain information about known occupational hazards of specific chemicals, but they may not be based on the most up-to-date information in the case of newly recognized occupational health risks.

CASE CLUSTER REPORTS

Case Cluster 1

Four men and four women, aged 29 to 53, who had worked at a single microwave popcorn packaging plant (popcorn plant A) developed fixed obstructive airways disease. One of these former workers and another worker later identified at the same plant had lung biopsy findings consistent with bronchiolitis obliterans [Akpinar-Elci et al. 2002]. The cases occurred sporadically over several years. Four had worked as mixers of a heated soybean oil, salt, and butter flavoring mixture; the butter flavoring was poured by hand from open buckets into open mixing tanks (see Figure 1). The other four had packaged microwave popcorn near the room where the oil and flavorings were mixed. Five had never smoked or smoked very little. Initial symptoms included cough, shortness of breath on exertion, and wheeze. Most had gradual onset of symptoms between 5 months and 5 years after starting work at the plant. Spirometry testing revealed severe airways obstruction in six workers. All eight had normal chest X-rays; four of six tested had normal DLCOs. Medical treatment with corticosteroid medication was not effective. Most had severe disease by the time they were referred to lung specialists and four were placed on lung transplant lists. Their coughs diminished months to years after leaving employment, but their shortness of breath on exertion did not.

Spirometry tests of 117 of 135 current workers employed at this plant revealed that the number of workers with airways obstruction was 3 times higher than expected [Kreiss et al. 2002a]. Almost all chest X-rays and DLCOs in these workers were normal. Workers with greater past exposure to flavoring vapors were significantly more likely to have abnormal spirometry test results than those with less exposure. Quality control workers, each of whom popped about 100 bags of microwave popcorn each shift in a small room with little ventilation, also had higher rates of abnormal lung function. Many workers also reported developing skin problems after starting work at the plant.

Case Cluster 2

Five workers at a flavorings manufacturing company developed fixed airways obstruction [Lockey et al. 2002]. All five affected workers were relatively young and none smoked. One was a 38-year-old worker who became short of breath and started coughing within seconds after adding 30 gallons of acetaldehyde to a flavoring mixture. Her shortness of breath resolved after a few minutes, but her cough persisted. Two months later, she noted shortness of breath on exertion. Spirometry tests done after the onset of symptoms showed fixed airways obstruction; spirometry test results before starting work at the plant had been normal. She did not respond to treatment with medications. Similar symptoms were experienced by the other four workers who developed fixed airways obstruction while working at the plant. No further lung function loss was noted over several years after removal from exposure.

Case Cluster 3

Two young, nonsmoking, previously healthy workers at a plant producing flavorings for the baking industry developed severe fixed airways obstruction within several months of starting to work at the plant [NIOSH 1986]. Both worked in a room where liquid and powdered flavorings were combined with starch and flour in large mixers. Both developed shortness of breath on exertion and persistent cough. Spirometry tests revealed severe fixed airways obstruction. DLCOs and chest X-rays were normal. Neither worker had a significant clinical improvement in response to bronchodilator and corticosteroid medications. After being away from the workplace for several months, both affected workers had persistent severe shortness of breath on exertion. Two former mixing room workers who were tested were also found to have mild to moderate airways obstruction.

Case Cluster 4

A 54-year-old mixer of oil and butter flavorings at a microwave popcorn plant (popcorn plant B) was referred for evaluation of a chronic cough [Parmet and Von Essen 2002]. Spirometry tests indicated fixed airways obstruction. This worker reported having a chronic cough since beginning work at the plant 3 years earlier. His cough became noticeably worse when he used a new butter flavoring mixture. He experienced some improvement in respiratory symptoms and lung function with cessation of exposure and treatment with corticosteroid medication. Five of the six workers exposed to flavoring vapors in the plant developed chemical eye burns after using the new flavoring mixture. Their eye problems resolved over several weeks with medical treatment and cessation of exposure [Kanwal 2002a].

Case Cluster 5

A NIOSH investigation at a microwave popcorn plant (popcorn plant C) found an obstructive pattern on lung function testing in 11 of 41 production workers—between 2 and 3 times the number expected. The obstruction was fixed (i.e., did not respond to bronchodilator medication), and DLCO was normal in most of the affected workers who underwent diffusing capacity testing. In this plant, the mixing and holding tanks for heated oil and butter flavoring were located in a room where the packaging lines and all production workers were also located [Sahakian 2003].

Case Cluster 6

A 37 year-old mixer of heated soybean oil and flavorings at a microwave popcorn plant (popcorn plant D) was found to have severe fixed airways obstruction. He had worked as mixer for 7 years. Spirometry testing done during his first 3 years as a mixer revealed that his lung function was declining at a greater than expected rate. He developed progressive shortness of breath on exertion starting in his fourth year as a mixer. In this plant, the mixing and holding tanks for heated soybean oil and flavorings have local exhaust ventilation and are located in a room that has separate ventilation from the rest of the plant. A NIOSH investigation found an excess of abnormal spirometry tests among current workers who had worked as mixers (6 of 13; half with fixed obstruction). No significant excess of spirometry abnormalities was found among packaging line workers. Respirators (protective breathing masks) were provided but not always used by mixers when exposed to flavorings [Kanwal 2002b].

CONCLUSIONS

Case clusters of fixed obstructive lung disease, one with biopsy evidence of bronchiolitis obliterans, have been documented among workers at several different plants where flavorings are used or where chemicals are handled in the production of flavorings. Recent attention has been largely focused on workers exposed to volatile chemicals in butter flavorings at microwave popcorn plants, but other reports indicate that other flavoring and food manufacturing workers exposed to various flavorings may also be at risk.

Little is currently known about which chemicals used in flavorings have the potential to cause lung disease and other health effects, and what workplace exposure concentrations are safe. As part of ongoing investigations into airways disease in microwave popcorn workers, NIOSH has recently undertaken animal experiments to evaluate individual butter flavoring chemicals. Results of an animal study indicate that exposure to vapors from diacetyl, a chemical used to impart butter-like flavor, causes airway injury, though perhaps to a smaller extent than that caused by exposure to vapors from the intact butter flavoring mixture itself [Kreiss et al. 2002b; Hubbs et al. 2002b].

Most chemicals used in flavorings have not been tested for respiratory toxicity via the inhalation route, and occupational exposure limits have been established for only a relatively small number of these chemicals. Although much remains unknown regarding the toxicity of flavoring-related chemicals, employers and workers can take steps to address working conditions and work practices that place workers at risk.

RECOMMENDATIONS

The following recommendations are provided to reduce hazardous exposures associated with the use or manufacture of flavorings. In general, NIOSH recommends that employers and workers implement controls to limit worker exposure. In order of preference, the major types of controls include the following:

Substitution

Substituting a less hazardous material can effectively reduce an existing hazard. However, substitution does not always represent a feasible or definitive approach. An adequate substitute may not exist; or, as with flavoring mixtures, the exposures may be complex and toxicities may be inadequately understood. Therefore, do the following when considering substitution:

Engineering Controls

Engineering controls are the primary methods for minimizing exposure associated with the use or manufacture of potentially hazardous flavorings. Examples include closed production systems (e.g., to eliminate handling open containers of flavorings or their chemical ingredients for placement into mixing tanks), adequate ventilation, and isolation.

Administrative Controls

Employer and Worker Education

Employer awareness of hazardous exposures in the production process and communication of this information to workers are vital elements in an optimal occupational safety and health program.

Personal Protective Equipment

Whenever the substances and amounts present in a plant or work area pose a potential hazard, provide personal protective equipment to protect workers from skin, eye, and respiratory tract irritation and other adverse health effects.

Skin and eye protection

Respiratory protection

The use of respirators is the least preferred method of controlling worker exposures to respiratory hazards.

^*Code of Federal Regulations. See CFR in references.

Exposure Monitoring

Worker Health Monitoring

Surveillance and Disease Reporting

Physicians, workers, and employers should report to the NIOSH Division of Respiratory Disease Studies (800–232–2114) and their State health department any cases of lung disease with fixed airways obstruction or any other significant work-related lung disease in workers exposed to flavorings or flavoring ingredients. The information from such reports can help identify high-risk work settings and guide efforts to prevent additional cases.

ACKNOWLEDGMENTS

The principle contributors to this Alert were Richard Kanwal, Greg Kullman, Kathleen Kreiss, Robert Castellan, Joe Burkhart, Kenneth Hilsbos, Muge Akpinar-Elci, Chris Piacitelli, and Randy Boylstein. The Flavor and Extract Manufacturers Association of the United States reviewed a draft of this document and provided helpful comments and suggestions. Please direct comments, questions, or requests for additional information to the following:

Director
Division of Respiratory Disease Studies
National Institute for Occupational Safety
and Health
1095 Willowdale Road, Suite 2900
Morgantown, WV 26505

Telephone: (304) 285–5705; or call 1–800–35–NIOSH.

We greatly appreciate your assistance in protecting the health of U.S. workers.

REFERENCES

ACGIH [2001]. Industrial ventilation: a manual of recommended practice. 24th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists.

Akpinar-Elci M, Kanwal R, Kreiss K [2002]. Bronchiolitis obliterans syndrome in popcorn plant workers. Am J Respir Crit Care Med 165:A526.

ATS [1995]. Standardization of spirometry. Am Rev Respir Crit Care Med 152:1107–1136.

CFR. Code of Federal regulations. Washington, DC: U.S. Government Printing Office, Office of the Federal Register.

Conning DM [2000]. Toxicology of food and food additives. In: Ballantyne B, Marrs TC, Syversen T, eds. General and applied toxicology. 2nd ed. London: Macmillan Reference Ltd., pp. 1977–1992.

Hallagan JB [2002]. Letter of November 26, 2002, from J.B. Hallagan, Flavor and Extract Manufacturers Association of the United States, to R. Kanwal, Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Department of Health and Human Services.

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 [2002a]. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol Appl Pharmacol 185:128–135.

Hubbs A, Castranova V, Jones W, Porter D, Goldsmith W, Kullman G, Battelli L, Friend S, Mercer RR, Schwegler-Berry D, Kreiss K [2002b]. Workplace safety and food ingredients: the example of butter flavoring. In: Abstracts of papers, 224th ACS National Meeting, Boston, MA, August 18–22, 2002. Washington, DC: American Chemical Society, AGFD–148.

Kanwal R [2002a]. Letter of April 19, 2002, from R. Kanwal and S. Martin, Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Department of Health and Human Services, to Keith Heuermann, B. K. Heuermann Popcorn, Inc., Phillips, Nebraska.

Kanwal R [2002b]. Letter of November 18, 2002, from R. Kanwal, Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Department of Health and Human Services, to Greg Hoffman, American Pop Corn Company, Sioux City, Iowa.

King TE [1998]. Bronchiolitis. In: Fishman AE, ed. Pulmonary diseases and disorders. New York: McGraw-Hill, pp. 825–847.

King TE [2000]. Bronchiolitis. Eur Respir Mon 14:244–266.

Kreiss K, Gomaa A, Kullman G, Fedan K, Simoes EJ, Enright PL [2002a]. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N Engl J Med 347:330–338.

Kreiss K, Hubbs A, Kullman G [2002b]. Correspondence: bronchiolitis in popcorn-factory workers. N Engl J Med 347:1981–1982.

Lockey J, McKay R, Barth E, Dahlsten J, Baughman R [2002]. Bronchiolitis obliterans in the food flavoring manufacturing industry. Am J Respir Crit Care Med 165:A461.

NIOSH [1986]. Hazard evaluation and technical assistance report: International Bakers Services, Inc., South Bend, IN. Cincinnati, OH: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health, NIOSH Report No. HETA 85–171–1710.

Parmet AJ, Von Essen S [2002]. Rapidly progressive, fixed airway obstructive disease in popcorn workers: a new occupational pulmonary illness? J Occup Environ Med 44:216–218.

Pollitt FD [2000]. Regulation of food additives and food contact materials. In: Ballantyne B, Marrs TC, Syversen T, eds. General and applied toxicology. 2nd ed. London: Macmillan Reference Ltd., pp. 1653–1660.

Sahakian N [2003]. Letter of January 13, 2003, from N. Sahakian, Division of Respiratory Disease Studies, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Department of Health and Human Services, to Gary Sanders, Agrilink Foods, Ridgeway, Illinois.

APPENDIX