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Diacetyl and Bronchiolitis Obliterans

Drs. Galbraith and Weill question whether the subjects described in our article (1) have bronchiolitis obliterans syndrome (BOS) and whether their small numbers are worthy of concern. In response, we make the following points.

To find 4 out of 103 operators with severe impairment from airway obstruction is an excessively high number, arguing for an occupational cause. The BOS diagnosis is best made by high-resolution computed tomography showing air trapping on expiratory films. Lung biopsy has not proved to be sensitive in cases of flavoring-related BOS (2, 3), and absence of a confirmatory biopsy is no reason to dispute or diminish the findings of this study.

Operators were exposed during several tasks in the process. The production process was open from 1960 until 2001. In 2001, the control measures introduced were to enclose the batch process, which lowered exposures. We have no information on use of respiratory protection measures employed by operators. All cases became symptomatic before control measures were taken in 2001. As our 2005 study participants no longer worked at the diacetyl plant, which closed in 2003, we did not collect information on recalled irritative symptoms that might have been expected with high historical exposures.

Our previously published abstract and current article are consistent with respect to exposure–response analyses. Historic exposure data are limited, subject to misclassification, and likely insufficient to support quantitative exposure–response relations for cumulative exposure, if they existed. Findings suggestive of an exposure–response relationship include the clustering of cases among operators, who also had significantly lower FEV₁ values than other workers in the group.

Hubbs and colleagues (4–6) confirm airway injury in animals following exposure to butter flavoring or diacetyl vapor. Akpinar-Elci and colleagues (3) demonstrated upper airway and bronchiolar injury in humans. Morgan and coworkers (7) demonstrated fibrosis at the bronchoalveolar junction in mice exposed to diacetyl. Thus, both animal and human studies demonstrate upper airway and bronchiolar injury following exposure to butter flavoring and/or diacetyl under some exposure conditions.

Despite the limitations of a small cohort and scant exposure data, our study contributes to narrowing the potential causative agents of occupational BOS seen in microwave popcorn workers and flavoring manufacturing workers to the chemicals found in diacetyl production. Our study is consistent with the likely role of diacetyl in causing this lung disease. The precautionary principle dictates action to protect workers from these potentially very hazardous exposures.

Frits G. B. G. J. van Rooy

Utrecht University
and
Netherlands Expertise Centre for Occupational Respiratory Disorders
Utrecht, The Netherlands

Jos M. Rooyackers

Netherlands Expertise Centre for Occupational Respiratory Disorders
and
University Medical Centre Utrecht
Utrecht, The Netherlands

Mathias Prokop

University Medical Centre Utrecht
Utrecht, The Netherlands

Remko Houba

Netherlands Expertise Centre for Occupational Respiratory Disorders
Utrecht, The Netherlands

Lidwien A. M. Smit and Dick J. J. Heederik

Utrecht University
Utrecht, The Netherlands

FOOTNOTES

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

1. van Rooy FGBGJ, Rooyackers JM, Prokop M, Houba R, Smit LAM, Heederik DJJ. Bronchiolitis obliterans syndrome in chemical workers producing diacetyl for food flavorings. Am J Respir Crit Care Med 2007;176:498–504.[Abstract/Free Full Text]
2. Kreiss K, Gomaa A, Kullman G, Fedan K, Simoes EJ, Enright PL. Clinical bronchiolitis obliterans in workers at a microwave-popcorn plant. N Engl J Med 2002;347:330–338.[Abstract/Free Full Text]
3. Akpinar-Elci M, Travis WD, Lynch DA, Kreiss K. Bronchiolitis obliterans syndrome in popcorn production plant workers. Eur Respir J 2004;24:298–302.[Abstract/Free Full Text]
4. Hubbs AF, Battelli LA, Goldsmith WT, Porter DW, Frazer D, Friend S, Swegler-Berry D, Mercer RR, Reynolds JS, Grote A, et al. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol Appl Pharmacol 2002;185:128–135.[CrossRef][Medline]
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6. Hubbs AF, Kreiss K, Kanwal R, Kullman G, Frazer D, Goldsmith WT, Kashon ML, Mercer RR, Schwegler-Berry D, Battelli LA,et al. Pulsed and continuous patterns of diacetyl (2,3-butanedione) inhalation cause rhinitis, laryngitis, tracheitis, and bronchitis in rats [abstract]. Vet Pathol 2007;44:5.
7. Morgan DL, Flake G, Kirby PJ, Burka LT, Kleeberger SR, Garantziotis S, Germolec DR, Palmer SM. Respiratory tract toxicity of diacetyl in c57bl/6 mice [abstract]. Vet Pathol 2007;44:732–785.[Free Full Text]

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