The study further implicates diacetyl, a key component of butter flavouring, in the spate of BOS cases at popcorn manufacturing plants and could add fuel to calls for manufacturers to take preventative action in their plants or ban its use.
The new research examined a population of workers at an unnamed chemical plant that produced diacetyl and found a cluster of previously undiagnosed BOS cases said Frits van Rooy, lead author of the study.
"This supports the conclusion that an agent in the diacetyl production process has caused BOS," said Rooy, a scientist at the Universiteit Utrecht's department of environmental epidemiology.
Diacetyl is an artificial butter flavoring used in microwavable popcorn, pastries, frozen foods and candies, and has previously been linked to lung disease in employees of popcorn plants.
Research suggests that during processing the flavouring could be hazardous when heated and inhaled over a long period.
By investigating the BOS status of former workers of the diacetyl plant, researchers hoped to determine whether there was a link between diacetyl exposure and the development of BOS.
Diacetyl was identified early on as a marker for exposure among popcorn workers.
Its specific role, if any, however, in the development of BOS was not known.
No cases of BOS had previously been identified outside of North America or in chemical production plants related to flavouring.
Van Rooy and colleagues traced 196 former workers who were still living and who had been employed at the diacetyl production plant between 1960 and 2003, when the plant closed.
They identified 175 who consented to complete exposure and respiratory health questionnaires and undergo lung function tests and clinical assessments.
Of the 102 process workers considered to be at the highest risk for exposure, researchers positively identified three cases of BOS, and later, a fourth, in a worker who had initially declined to participate in the research.
"This is the first study where cases of BOS were found in a chemical plant producing diacetyl," wrote van Rooy.
While the researchers said they were unable to rule out contributions of other chemicals to the development of BOS, the study significantly narrows the field of suspects to diacetyl and the components and byproducts of its manufacturing process.
"The spectrum of exposures is much smaller in this production plant compared with the popcorn processing plants where a wide range of chemicals was identified," the researchers wrote.
"This population-based survey establishes the presence of BOS, or popcorn worker's lung, in chemical workers manufacturing a flavoring ingredient with exposures to diacetyl, acetoin and acetyldehyde.
Any or all of these exposures may contribute to the risk of this emerging occupational disease."
The novel finding of four cases of BOS in workers at the diacetyl plant has important implications for practicing physicians and public health officials.
"None of the four cases had been recognized as bronchiolitis obliterans or as occupationally related," wrote Kathleen Kreiss, a medical doctor who wrote an accompanying editorial to the research paper.
"To identify flavoring-related bronchiolitis obliterans, physicians need to consider the diagnosis."
She also believes that "the collective evidence for diacetyl causing a respiratory hazard supports action to minimise exposure to diacetyl, even if contributions by other flavoring chemicals exist."
In the US there are currently no enforceable Occupational Safety and Health Act (OSHA) standards requiring exposures to be controlled.
And while unions push for the regulatory loophole to be addressed, employees in popcorn plants continue to be diagnosed with BOS, while flavour manufacturers continue to fork out settlement charges in cases brought against them.
The research was reported in the first issue for September of the American Journal of Respiratory and Critical Care Medicine, which is published by the American Thoracic Society.
BOS leads to inflammation and obstruction of the lungs through rapid thickening or scarring of the small airways.
The disease is irreversible, progressive and can cause death.
There is no cure for BOS.
The only treatment is a lung transplant.
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.
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 safety of chemicals is usually established for humans consuming small amounts in food, not for food industry workers inhaling them.
Production workers employed by flavoring manufacturers, or those who use flavorings in the production process, often handle a large number of chemicals, many of which can be highly irritating to breathe in high concentrations.
About 150 former popcorn plant workers have filed suits against companies supplying or making the butter flavorings involved.
The industry has paid out about $100 million in jury awards and settlements.
About 30 suits are still pending according to an Associated Press report.
Butter flavoring oils in the US market - tipped to hit $4.4 billion (€3.4bn) by 2007 - are used in biscuit and confectionery manufacturing as well as margarines and soft spreads.
Last year the International Brotherhood of Teamsters and the United Food and Commercial Workers petitioned the US Occupational Safety and Health Administration to promulgate an emergency temporary standard to protect workers from the deleterious health effects of inhaling diacetyl vapours.
In 2007, California legislator Sally Lieber introduced a bill to ban diacetyl in the workplace by 2010.
In the EU mono- and diacetyl tartaric acid esters of mono- and diglycerides are generally permitted for use in foodstuffs.
Mono- and diacetyl tartaric acid esters of mono- and diglycerides are used as dough conditioners for all baked products, particularly yeast-leavened products, white bread and rusks, and in ready-mixed flours.