© 2006 American Thoracic Society doi: 10.1164/rccm.rccm2511002
Occupational and Environmental "Orphan" Respiratory DiseasesUniversity of California, San Francisco, San Francisco, California The report of Ghanei and coworkers in this issue of the Journal (pp. 304–309) adds yet another disease entity, tracheobronchomalacia, to the litany of adverse chronic respiratory tract outcomes linked to sulfur mustard war gas (1). It also lends further support to a body of evidence indicating that bronchiolitis obliterans (BO) can be a sequela of such exposure. Earlier reports had already shown convincing evidence of asthma, chronic bronchitis, and bronchiectasis among survivors of acute sulfur mustard lung injury. Much of this work has been performed at two research centers in Iran: Baqiyatallah Medical Sciences University in Teheran (1) and the Shiraz University of Medical Sciences in Shiraz (2, 3). Published data on the follow-up of Kurdish victims of sulfur mustard gas have been limited to case reports from centers remote to the region (4, 5). In the present study, lung function data among those with tracheobronchomalacia consistently showed increased residual volumes, but inconsistent impairment of flow measured in FEV1 (1). Information on flow at low lung volumes and descriptive summaries of flow-volume curves would have been particularly germane to the radiographic inferences made. The lack of direct visualization of collapse or of dynamic computed tomography data is also a limitation in this report. Nonetheless, there are important insights to be gained from the observation that a heterogeneous, albeit interrelated, group of respiratory conditions can all be the end result of a discrete toxic insult. Specific to this report, there are intriguing radiographic findings consistent with both tracheomalacia and bronchomalacia; yet the former, while not the latter, appeared to correlate with concomitant air trapping suggestive of BO (1). Thus, sulfur mustard toxicity appeared to manifest a skip pattern in the respiratory tract, preferentially attacking the trachea and the bronchioles, while relatively sparing the bronchi, at least insofar as bronchomalacia is concerned. This dose response may offer clues to mechanisms underlying cartilage destruction in the trachea as well as the development of constrictive (obliterative) pathology of the small airways. Unfortunately, the possibility of future sulfur mustard–exposed victims needing treatment and follow-up is not a purely theoretical proposition. But even if this were not the case, defining these toxic effects is relevant because both tracheobronchomalacia and BO have important idiopathic forms. Moreover, even though a major subset of BO cases is linked to a known trigger (transplantation), the underlying mechanisms remain to be clearly elucidated. There is ample precedent for environmental or occupational toxins to emerge as identifiable causes of what would otherwise be "orphan" idiopathic respiratory conditions. Other toxins have been found to exhibit a discrete cause-and-effect relationship, providing insights into basic mechanisms of more common diseases (emphysema and chronic bronchitis) typically linked to the mixed exposures in cigarette smoke that are difficult to tease out mechanistically. Although the capacity of environmental and occupational toxins to act in this manner has been long established, such observations remain underappreciated. Key follow-up studies of World War I gas survivors clearly identified asthma and chronic bronchitis as causally related sequelae (6). Indeed, it can be argued that this represents the first epidemiologic identification of irritant-induced asthma, an entity that would not be otherwise characterized as a discrete syndrome until the initial report of "reactive airways dysfunction syndrome," RADS (7). The model of irritant-induced asthma—that is, persistent airway hyperresponsiveness and symptomatic variable airflow following de novo from an irritant inhalation injury—is highly relevant to current issues in asthma, ranging from immunologic mechanisms of disease onset and the role of ongoing inflammation to the natural history of airway remodeling. Beyond the battlefield, occupational and environmental toxins have been linked to a variety of respiratory conditions, providing valuable critical clinical data and experimental models. Selected examples include the following: nitrogen dioxide (key to the initial pathologic understanding of BO) (8), metal exposures in emphysema or chronic bronchitis (9), and well-identified triggers of unusual occupational or environmental conditions that are otherwise largely idiopathic (e.g., pulmonary hemosiderosis and pulmonary alveolar proteinosis) (10). Moreover, outbreaks of novel toxin-related lung disease continue to emerge, such as Ardystil lung (an industrially caused BO organizing pneumonia, BOOP) (11), flock workers' lung (an interstitial lung disease due to small synthetic fibers) (12), and popcorn workers' lung (a disease with components of BO linked to diacetyl, an artificial butter flavoring compound) (13). An epidemiologist colleague of mine, making a presentation on occupational lung disease to an audience dominated by bench scientists somewhat disinclined to find this topic relevant, once argued the "modest proposal" that diseases endemic to working people must be acknowledged as important since at least their experience provides insights into what transpires in knock-out mice. With this admonition in mind, it is paramount to remember that as useful as the mechanistic and clinical insights alluded to above may be, the highest priority must always be to prevent these exposures in the first place. International elimination of all chemical weapons, once and for all, is one pivotal step. In the workplace and in the wider environment, we have also learned that legally mandated maximal permissible exposure levels are important. However, such defined exposure levels are no substitute for a targeted ban on the export, import, and use of the most egregious toxic hazards. We already have the precedent for such action, almost a century ago, in the successful international effort to eliminate yellow phosphorous in matches and thus prevent phosphorous necrosis of the jaw (14); the current call for an international ban on asbestos is based in part on this model (15). The new European Union program for the Registration, Evaluation, and Authorization of Chemicals (known as "REACH"), if fully implemented, holds out the hope that such controls may indeed come into effect (16). U.S. policy makers would do well to learn from this example. FOOTNOTES Conflict of Interest Statement: P.D.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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