© 2007 American Thoracic Society doi: 10.1164/rccm.200706-837ED
Occupational Bronchiolitis Obliterans Masquerading as COPDNational Institute for Occupational Safety and Health, Morgantown, West Virginia Seven years ago, a cluster of severe bronchiolitis obliterans cases among former workers of a small rural microwave popcorn plant precipitated the detective work which identified the hazard of volatiles derived from butter flavoring. In the initial report (1), diacetyl, a diketone which imparts buttery aroma and flavor to foods, was described as a marker of flavoring exposure. Diacetyl exposure was associated with abnormal lung function, decreased forced expiratory volume in one second (FEV1), and the mixer job title that was subsequently shown to be highest risk in industry-wide investigation (2). The same severe fixed obstructive syndrome in many flavoring manufacturing workers (3, 4) substantiates the hazard of diacetyl, and biologic plausibility now exists in rodent toxicology studies (5–7). In the current issue of the Journal (pp. 498–504), van Rooy and coauthors (8) make several substantial contributions to the understanding of this newly recognized occupational hazard to flavoring-exposed workers. First, diacetyl manufacture produced at least four cases of severe bronchiolitis obliterans syndrome among 103 process operators in a historical cohort, including the post-study case found in one of the ten nonparticipants. Second, none of the four cases had been recognized as bronchiolitis obliterans or as occupationally related, which is typical of the cases being found throughout both microwave popcorn and flavoring manufacturing industries. To identify flavoring-related bronchiolitis obliterans, physicians need to consider the diagnosis. Third, the risk of flavoring-related pulmonary disease is not a new occurrence, but rather long-standing in industry, in that the first and most severe case occurred in 1970 after two years of employment. As in the microwave popcorn industry, two other cases in this diacetyl manufacturing plant had similar short latency between employment and symptom onset. Identifying excessive decline in pulmonary function before FEV1 becomes abnormal is particularly difficult over the short periods of time in which flavoring-related bronchiolitis obliterans can develop. Reference limits of longitudinal FEV1 decline depend on both precision (spirometry quality) and time interval (9, 10). With good quality spirometry, 8% or about 330 ml declines in FEV1 over 6 to 12 months can be used as a criterion for investigation and follow up (11). The excessive longitudinal FEV1 declines demonstrated in the two Dutch cases with spirometry data during employment would have been difficult to identify as abnormal early on, when prevention of an irreversible disease was most needed. Fourth, a cross-sectional approach to screening current workers at any point during the plant's existence would have missed the cluster and underestimated disease burden among those ever-employed at the plant. This observation should temper interpretation of low prevalences being found among current workers in flavoring-exposed workforces, since affected workers with severe airways obstruction commonly leave employment. In sum, the evidence marshaled by studying this historical worker cohort is daunting for physicians charged with early identification of this disease in workers with diacetyl and other flavoring component exposures. van Rooy and colleagues (8) appropriately emphasize the restricted set of exposures in diacetyl manufacture, in contrast to the complex mixture of chemicals in flavoring manufacture. The authors mention that the contribution of acetoin and acetaldehyde to bronchiolitis obliterans syndrome cannot be excluded, but historical acetaldehyde levels were far below the permissible exposure limit of 360 mg/m3. In the setting of calls for regulation, workers' compensation liability, and third-party litigation against suppliers of flavorings, any uncertainty regarding cause impedes preventive action. For the association between diacetyl and fixed obstructive lung disease, many criteria for causal inference have been fulfilled. (1) The strength of association between diacetyl exposure and severe fixed obstruction is about 10-fold in this plant, since FEV1s less than 40% predicted occur in 0.42% of never-smokers in the age range of these cases (50–72 yr) and in one of 1,000 never-smoking adults. Similar risk ratios have been found in production worker subsets of some flavoring and microwave popcorn facilities. (2) Consistency of the association exists in studies of workers in microwave popcorn, flavoring, and diacetyl manufacture. (3) The temporal requirement for the exposure to precede the health outcome was met for incident cases in the sentinel microwave popcorn plant, and control of exposure resulted in lowering of risk (4). (4) An exposure–response relation exists. (5) Biologic plausibility exists in experimental rodent toxicology studies. Thus, the collective evidence for diacetyl causing a respiratory hazard supports action to minimize exposure to diacetyl, even if contributions by other flavoring chemicals exist. The study by van Rooy and coworkers limits the candidates for new regulation to diacetyl and acetoin. Diacetyl is the more reactive, volatile, and concentrated of the two ketones, which often occur in the same work environments, and its control makes good sense as we await animal toxicology studies to evaluate the potential hazard of acetoin and several aldehydes. Although the hazard of diacetyl is not in question, uncertainties do remain. The spectrum of health effects related to flavorings may be broader than fixed obstruction. Asthma (12), bronchiolitis obliterans with organizing pneumonia (13), granulomatous pneumonitis (4, 14), tracheo- and bronchiomalacia (1, 8), fibrosis (4), and systemic symptoms (1) without obstruction have all been reported in flavoring-exposed workers. Safe levels of exposure are not yet clear, and little demonstration of the effectiveness of workplace intervention exists to date. Our understanding of toxicologic mechanism, genetic predisposition, and early markers of injury are all ripe for investigation. van Rooy and colleagues (8) observe that a diagnosis of chronic obstructive lung disease hinders investigation of occupational etiology. Perhaps bronchiolitis obliterans is a more common finding than we think in those with obstructive disease, including severe asthma with only partial reversibility. The occupational contribution to chronic obstructive lung disease is itself substantial, after taking cigarette smoking into account. The median population-attributable risk for the proportion of chronic bronchitis or chronic obstructive lung disease due to work-related factors is 15% among many recent studies (15). Among never-smokers, the attributable fraction may be as high as 31% (16). Never-smoking patients and young smokers with obstruction may be sentinels for new causes of airways disease that, like flavoring, have been present for decades but await recognition through clusters and epidemiologic study. FOOTNOTES The findings and conclusions in this editorial are those of the author and do not necessarily represent the views of the National Institute for Occupational Safety and Health. Conflict of Interest Statement: K.K. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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