Objectives

1. To understand the clinician’s role in recognizing new occupational lung diseases.
2. To identify resources for workplace follow-up of suspected causes of new occupational diseases.
3. To explore public health implications of occupational lung disease.
4. To consider implications of occupational etiologies for patient management.
5. To describe recent examples of newly recognized occupational lung disorders and their etiologies.

Abbreviations

AMT = 3-amino-5-mercapto-1,2,4-triazole; NIOSH = National Institute for Occupational Safety and Health; OSHA = Occupational Safety and Health Administration

As the work environment changes, new occupational lung disorders emerge. Their recognition is critical to both patient management and prevention of disease in coworkers as well as in wider industries. Often the recognition of an occupational etiology is delayed for years or even decades despite severe clinical cases. This lesson explores recently emerging novel occupational lung diseases and newly recognized occupational causes of established pulmonary diseases, in order to elucidate the conditions in which astute physicians can contribute to new medical understanding.

New infectious diseases in the workplace, such as the severe acute respiratory syndrome (SARS) caused by coronavirus, are easily recognized. The striking risk of health-care workers caring for hospitalized patients illustrates the importance of epidemiology in recognition of occupational risk. Even when the nature of the SARS infectious agent was uncertain in early 2003, control measures were taken by public health authorities and the health-care industry to prevent further cases through quarantine and isolation, use of personal protective equipment, and increased attention to appropriate ventilation of patient rooms. In contrast, new diseases caused by noninfectious agents in the workplace pose greater difficulty in recognition, although public health responses can similarly ameliorate the hazards involved. New industries, processes, or chemicals are all common settings for the emergence of unexpected occupational lung diseases. Ill workers seeking clinical care are the “sentinels” for risk requiring public health action to identify the responsible conditions in the workplace and to help employers decrease exposures in order to prevent others from becoming ill as well.

This lesson describes the recognition of (1) a novel interstitial lung disease in nylon flock workers; (2) asthma in pesticide workers resulting from a new chemical cause; and (3) bronchiolitis obliterans among microwave popcorn workers. Other examples of emerging occupational lung conditions exist, such as asthma in office workers in buildings that have sustained water damage and hypersensitivity pneumonitis in metal workers (Table 1). In each of these examples of emerging occupational lung disorder, the clinicians involved eventually precipitated a public health response that utilized multidisciplinary resources to clarify the occupational etiology and implications for management and prevention.

Table 1. Newly Recognized or Emerging Occupational Lung Disorders or Etiologies by Industry and Agent

Flock Worker’s Lung

The flock industry produces velvet-like upholstery fabric and other flock-coated objects by embedding very short fibers at right angles to adhesive-coated surfaces. The industry has existed since the 19th century (for example, in making fuzzy ribbons and patterned wall-papers), but it expanded greatly with the use of synthetic fibers. Bundled continuous nylon (or other synthetic) filaments are cut in millimeter lengths to make synthetic flock. The flock is coated with proprietary ingredients. The chemical producers of nylon and the flock industry had no reason to suspect a respiratory hazard a priori, because the filament and flock dimensions were too large to be respirable and nylon was considered quite inert.

Dr. David Kern, an internist formerly at Memorial Hospital of Rhode Island, deserves much credit for recognizing a potential occupational hazard in the flock industry. In 1995, he had evaluated a young man who worked in the flock industry and had interstitial lung disease of unknown etiology. A second patient with interstitial lung disease was referred to his occupational medicine clinic 1 year later with similar employment. Both workers were initially diagnosed with hypersensitivity pneumonitis. Dr. Kern’s suspicion of an occupational etiology in their lung disease was triggered by the rarity of interstitial lung disease, the youth of the two patients, and their common employment in a dusty factory.

These two were not the first two cases of what became described as flock worker’s lung.¹ A pathologically confirmed case had occurred in 1985 in an employee at the same plant, but its attribution to the flocking process was delayed until the later systematic investigation and description of the many cases at the plant. Moreover, a cluster of similar cases had occurred in Canada in the early 1990s among employees at a plant owned by the same company.² However, the investigators of the Canadian outbreak had prematurely attributed the disease to fungal contamination of the adhesive used in the plant. Replacement of the adhesive with fresh, uncontaminated adhesive did not stem the occurrence of new cases, but this was realized only after the fact.¹

Dr. Kern persuaded the company to request a Health Hazard Evaluation, a free consultation from the National Institute for Occupational Safety and Health (NIOSH). NIOSH can investigate nongovernmental workplaces with multidisciplinary teams at the request of an employer, a labor union, or three current workers whose identity can be kept confidential. This “right of entry” allows access that is frequently not available to academic investigators or even public health authorities in many jurisdictions.

NIOSH investigators from the Division of Respiratory Disease Studies surveyed the workforce with questionnaires, pulmonary function tests, and chest radiographs. They documented that the workplace air around the flocking operations had high concentrations of respirable dust.³ The epidemiologic investigation identified high-risk processes linked to symptom-based indices of interstitial disease, such as cough and shortness of breath on exertion. Overtime work (greater duration of exposure) and using compressed air to clean flock out of machines (thus generating dust) were salient risk factors for disease. A series of cases independently reported by Dr. Kern became an important systematic documentation of flock worker’s lung.⁴ Removal from further occupational dust exposure at the plant allowed slow clinical improvement over months to years, consistent with a potentially reversible (at least in part) interstitial disease.

Confirmation of the role of nylon flock dust in this disease process included documentation of microscopic “tails” of nylon at the cut ends of the nylon flock that mechanically separated during subsequent milling⁵; finding that samples of size-fractionated respirable dust collected at the facilities had the physical properties of nylon; and demonstrating that this respirable dust caused intense acute pulmonary inflammation when instilled intratracheally in animals.⁶ NIOSH convened chest pathologists to review biopsy material from case-patients in the Canadian and Rhode Island outbreaks, as well as from two additional flock plants in Massachusetts. The workshop documented a unique new pathology of lymphocytic bronchiolitis and peribronchiolitis.^1,7

Since the Rhode Island plant evaluation, NIOSH has conducted Health Hazard Evaluations at two additional plants, each having a case of flock worker’s lung. Although dust concentrations were much lower than those found at the Rhode Island plant, considerable “subclinical” disease appeared to exist.^8,9 The industry trade association has organized assistance for its members in establishing respirator programs to protect workers using high-hazard processes while engineering controls and other strategies are implemented to minimize the respirable-dust hazard associated with flock operations.

Dr. Kern’s suspicion of a new occupational lung disease proved to be correct. Establishing causality for a previously unsuspected etiology, however, required demonstrating that multiple cases existed and were not uniformly distributed at the plant. Few clinicians have the time or tools to conduct cross-sectional screening at a given workplace, even with a cooperative employer.

The solution of this new occupational disease puzzle required industrial hygienists, microscopists, animal toxicologists, and epidemiologists in addition to clinicians. With the delineation of the unsuspected hazard of inhaling respirable nylon particles, prevention of further cases could begin by informing companies of the hazard and control measures. Guidance for clinicians managing patients includes removal from further exposure, which may result in eventual dissolution of the synthetic nylon particulate deposited in the lungs.

Asthma in Manufacture of a New Pesticide

In 1998 to 1999, a company consulting physician referred eight workers to pulmonary physicians at one medical center in Massachusetts. Each worker had new-onset asthma with a work-related pattern of symptoms. Some of the patients were given peak flow meters, which provided an objective measure of work-related airflow limitation. The cases were reported in compliance with a Massachusetts regulation requiring physicians to report work-related asthma to the state health department. The clustering of the cases by time and employment allowed recognition of an occupational lung disease outbreak by both the physicians and the health department, but no known cause of asthma was immediately evident in the workplace. The state health department requested assistance from NIOSH in exploring whether a new cause of asthma existed in this company, which manufactured several pesticides.

NIOSH conducted screening of the current workforce for asthma, identifying several additional workers with new onset of work-related respiratory symptoms and airways hyperresponsiveness.¹⁰ The onset of symptoms correlated with production using 3-amino-5-mercapto-1,2,4-triazole (AMT), a feedstock in the manufacture of a proprietary herbicide named DE-498 (flumetsulam). No toxicologic information was available about AMT, although structurally related triazoles were noted to have some respiratory health effects. NIOSH explored biologic plausibility with an animal model involving skin exposure, demonstrating that AMT, but not DE-498, acted as a sensitizer.

The recognition of a new cause of occupational asthma in this instance was dependent upon several cases occurring in the same workforce in a relatively short period of time. Had the cases seen physicians who were not conferring with each other, the likelihood of recognition and reporting to public health authorities would have been low. The exploration of potential causes was facilitated by mobilizing public health resources to explore the epidemiology and toxicology of candidate exposures found in the workplace. Even so, the pesticide manufacturer, bound by contractual arrangements with the chemical supplier, claimed proprietary trade secret status; this temporarily delayed dissemination of the NIOSH results.

Recognition of occupational etiology is critical in affecting prognosis in occupational asthma cases. Workers with occupational asthma can be cured of asthma if they are removed from the implicated exposure by work restriction, reassignment, or substitution of a safer agent soon after symptoms arise (for example, long before they become steroid-dependent). Delay in recognition often results in continuation of asthma as a chronic disease even after affected workers leave the exposure or workplace in which asthma developed. Although clinicians can manage individual case-patients without knowing the specific etiologic agent by restricting them from further exposure, many workers are unable to receive workers’ compensation benefits for a transition to new employment in the absence of information about a specific occupational cause. The prevention of occupational asthma in coworkers and across many work sites requires systematic public health follow-up and documentation that a chemical can cause asthma and that exposures need to be controlled to health-protective levels.

Bronchiolitis and Airways Obstruction in Microwave Popcorn Workers

Between 1993 and 1998, two pulmonary physicians in southwestern Missouri conferred with each other about several case-patients with severe fixed airways obstruction, all of whom had worked in a microwave popcorn plant that employed about 130 people in a tiny town nearby. Several patients had smoked minimally or not at all. None responded to asthma medications. After referring these cases to each other, they referred several of them, one by one, to national referral centers, including National Jewish Medical and Research Center and the Mayo Clinic. One referral letter mentioned the treating pulmonologist’s suspicion of bronchiolitis obliterans and concern about similar cases from the same manufacturing facility. Four patients were eventually referred for transplant evaluation. One of the pulmonologists called the Occupational Safety and Health Administration (OSHA) in 2000 to report concern over so many severe cases of lung disease in a single manufacturing facility. OSHA inspectors visited the plant but concluded that no lung hazards existed.

In the meantime, the wife of a worker with severe work-related contact dermatitis and breathing difficulties made a list of four additional coworkers her husband had indicated were also chronically ill with respiratory symptoms. She shared her concerns about possible occupational disease with her lawyer son, who passed the worker contact information to an attorney handling workers’ compensation cases. These workers identified other coworkers with similar difficulties, for a total of nine suspect cases. When medical records were compiled, the lawyer requested their review by Alan Parmet, MD, an occupational medicine physician in Kansas City. Recognizing the improbability of four lung transplant–listed workers from a small plant in rural Missouri, Dr. Parmet contacted the Missouri Department of Health. The environmental staff person receiving the call was experienced in sanitation, but had little preparation for understanding the significance of severe lung disease in a workplace. He called the Centers for Disease Control and Prevention in Atlanta, GA, who referred the call to NIOSH. A NIOSH physician suggested that medical records be obtained and diagnoses confirmed. When this did not happen over a period of several months, NIOSH contacted the Missouri state epidemiologist. Within days, the Missouri Department of Health requested assistance from NIOSH for a joint investigation of the plant.

The sentinel patients did not at first suspect an occupational cause of their disease. Once they had begun coughing, often insidiously, they never improved on weekends or away from the microwave popcorn plant. Most had worked at the plant only a few years, and none reported an accidental overexposure that might explain subsequent respiratory illness. When respiratory impairment prevented continued employment, none substantially improved. Often the cases had not overlapped each other very long at the plant, even though some had trained their successors in the mixing of chemical flavorings, and the successors subsequently became ill as well.

The NIOSH epidemiologic investigation showed a threefold excess of airflow obstruction in the current workforce above referent rates, nearly all unresponsive to bronchodilator.¹¹ The excess in never-smokers was nearly 11-fold, in comparison with age-standardized national data. Those in microwave popcorn production, particularly in the flavoring mixing and quality control processes, bore the brunt of the disease excess. Animal studies confirmed that the complex butter flavoring, at diacetyl (major flavoring component) concentrations within the range of peak exposures experienced by the flavoring mixers, caused intense respiratory epithelial sloughing.¹² Diacetyl alone caused similar but less intense injury. NIOSH recommended increasing controls over flavoring exposures, as follow-up surveys of health and environmental concentrations documented continuing risk to new mixers at the plant.

The report of this outbreak led to recognition that these were not the first or only cases of bronchiolitis obliterans among workers exposed to flavorings. Cases in the flavoring industry were reported by an occupational lung disease physician providing confidential services to a flavoring manufacturer in the mid-1990s. Biopsy-documented bronchiolitis obliterans cases at two other flavoring plants have also been reported to NIOSH. In the microwave popcorn industry, NIOSH has found cases of fixed airways obstruction in four of five other manufacturing plants. The industry-wide picture has helped the formulation of prevention recommendations, with a focus on respiratory protection and medical surveillance for mixers and those who pop many bags of popcorn per shift in quality control, isolation of heated tanks containing flavorings, and institution of closed transfers of flavorings. Trade associations have played an important role in disseminating information about flavoring hazards and their prevention to their members.

The two pulmonary physicians were correct in their suspicions that the cluster of severe cases might have an occupational etiology, yet an initial call for public health assistance from one of the two physicians was ineffectual in addressing the problem. Of note, a legal suit was initiated against one of the pulmonologists for public health–related inaction. Unfortunately, seeking appropriate assistance from public health officials is far from straightforward. Despite its regulatory role, OSHA has limited disease-related expertise and concentrates on known occupational hazards.

Public health agencies may be better choices for calls about suspected occupational disease problems than labor agencies, but local and even state health departments often have limited resources and expertise. Some states, such as California, Wisconsin, and Texas, have dedicated broad-based programs in occupational/environmental epidemiology at the state level. Some states conduct focused surveillance of specified occupational conditions (eg, New Jersey, Michigan, California, and Massachusetts, among others, have programs targeting work-related asthma). In the absence of sufficient resources, as in Missouri, local and state public health units can seek assistance from NIOSH. Even an individual physician who encounters suspected occupational lung disease cases can contact NIOSH directly at (800) 232-2114 (see Table 2 for other resources). NIOSH can assist in obtaining a Health Hazard Evaluation request to ensure “right of entry” when needed or can work with local public health authorities to investigate a workplace when the state has appropriate authority.

Table 2. Resources for Physicians Who Suspect an Occupational Etiology for a Patient's Lung Disorder

The following salient features led to the delineation of an occupational lung hazard in microwave popcorn production: the cases occurred in a small plant population in a rural area; the severity of disease in such a sparsely populated area with few pulmonary physicians facilitated recognition of the cluster of cases; the youth of some patients made tobacco-related airways obstruction implausible, despite high smoking prevalence among workers; and finally, a family member’s advocacy brought “detective” attention from a young lawyer who compiled a case series for review by a consultant physician who, in turn, brought the case cluster to public health attention.

Many questions about the popcorn-flavoring disease outbreak remain. The extent of flavoring hazards in food production is unexplored. Reactive volatile organic compounds, similar to flavoring ketones and aldehydes, are used in many industries. Scientists have not explored whether these other chemical exposures are also inhalation hazards in occupational settings. The slow evolution of obstructive disease (subacute to chronic) without a work-related pattern of symptom exacerbation may not prompt consideration of occupational etiology, particularly in cigarette smokers. Inhalation toxicologic screening for chemicals prior to their introduction into the workplace is virtually nonexistent. Even the demonstration that the butter flavoring mixture is hazardous has not resulted in inhalation toxicology testing of component chemicals other than diacetyl. Pathologic tissue diagnosis is rare in cases of obstructive disease and, in the microwave popcorn cases, has not been definitive in every case in which a biopsy was performed. It appears that the fixed airways obstruction seen in these case-patients may represent a new entity, even though it is physiologically similar to bronchiolitis obliterans in its pulmonary function manifestations.

Common Elements

The three examples presented in this lesson—flock worker’s lung, AMT-induced asthma in pesticide manufacture, and bronchiolitis in microwave popcorn workers—demonstrate that previously unrecognized occupational lung diseases still occur in the workplace. Although it might be facile to label the workers exposed to novel agents as “guinea pigs,” unlike laboratory animals, they are not observed carefully for ill effects related to workplace dusts and chemicals, whether newly introduced, such as in the AMT-exposed workers, or in long-standing exposures, such as encountered in the flock and flavoring industries. Fewer and fewer companies have in-house occupational medicine expertise, and corporate physicians often devote the bulk of their effort to administrative and personnel health-policy matters. Surveillance of occupational disease in the United States is rudimentary where present at all, either at the industry or the public health level.

In the absence of premarketing inhalation toxicity testing, clinicians’ alertness to the possibility of occupational lung disease is critical to the identification and treatment of disease. Such astuteness can both advance medical knowledge pertinent to preventing disease and help individual patients navigate the complexities of the workers’ compensation insurance system. Unfortunately, training in occupational lung disease is meager for most physicians, including academically based subspecialists. Even finding out whether an industry or chemical has been associated with lung disease can be a challenge. Resources for pulmonary physicians faced with questions about occupational lung hazards are listed in Table 2.

Factors that may alert clinicians to new causes of lung disease include unusual diseases, such as fixed airways obstruction or unique interstitial pathology; occurrence of severe obstruction in young people in whom smoking-related obstruction would occur only in midlife or later; and clusters of disease. For the last, cluster recognition may be easier when collegial relationships allow sharing of puzzling cases, when a few physicians serve a single catchment area, or when patterns of referral to a health maintenance organization or designated provider allow real-time statistical analyses. These circumstances are unusual, and sporadic cases are unlikely to be pursued.

In each example in this lesson, alert clinicians laid the groundwork for evaluation of a suspected emerging occupational lung disease. In these examples, their efforts to involve public health authorities resulted in multidisciplinary resources critical to establishing a link between an industrial exposure and adverse health outcomes. In each example, additional workers suffered from the same diseases but had not yet come to medical attention. The cases suspected by physicians were sentinel events, no less than a single case of food poisoning might be from a source with ongoing contamination. Finally, primary prevention of additional cases requires clinicians’ initiation of public health action to change the conditions of work.

Although these three examples may be the clearest recent examples of newly recognized occupational lung disease for didactic purposes, they are not unique. An example of an emerging occupational lung disease is asthma in nonindustrial workers whose buildings have been water-damaged.^13,14 In these instances, which occur in every community in the country, office workers or school staff report onset of asthma and its exacerbation in relation to building occupancy. Flat roofs and cutting of building maintenance budgets have resulted in water incursion that has presumably allowed the amplification of microorganisms. Requests for NIOSH Health Hazard Evaluations concerning indoor air quality mention asthma more and more frequently. NIOSH has a research initiative to elucidate the bioaerosol correlates of such cases and effective environmental remediation methods.

Another emerging occupational lung hazard is hypersensitivity pneumonitis in metal workers exposed to aerosols of water-based metalworking fluids. These fluids are sometimes contaminated with biocide-resistant mycobacteria, which are plausible agents for inducing a cell-mediated lung response. Similar disease has occurred in users of hot tubs and therapy pools contaminated with mycobacteria. As in building-related asthma, the frequency of clusters of occupational lung disease in the automotive industry has contributed to recognition of new settings of risk.¹⁵

A further example of emerging occupational asthma is that caused by cleaning agents. In this instance, the many physician reports of case-patients to state health departments conducting surveillance of occupational asthma allowed aggregation and analysis of cases at a multistate level.¹⁶

Summary

Astute clinicians are critical to detection of new occupational lung diseases and new causes of asthma and hypersensitivity pneumonitis. Alertness to the opportunity to discover a new agent or disease is increased by understanding that inhalation toxicity testing is not required for chemicals and dusts; that absence of surveillance systems in industry and in public health agencies results in missing occupational lung disease outbreaks, even when illness is serious and long-standing; and that workers commonly have few resources with which to protect themselves. When occupational lung disease is a possibility, physician activation of public health response can lead to a multidisciplinary approach to assess whether a hazard exists, to identify similar cases, to develop guidance for patient management, and to recommend preventive interventions.

References

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2. Lougheed MD, Roos JO, Waddell WR, et al. Desquamative interstitital pneumonitis and diffuse alveolar damage in textile workers. Chest 1995; 108:1196–1200
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8. Hazard evaluation and technical assistance report: Claremont Flock Corporation, Claremont, New Hampshire. Morgantown, WV: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health (NIOSH) Publication No. HETA 98-0212-2788, 2003
9. Hazard evaluation and technical assistance report: Spectro Coating Corporation, Leominster, Massachusetts. Morgantown, WV: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health (NIOSH) Publication No. HETA 98-0238-2789, 2003
10. Hazard evaluation and technical assistance report: ChemDesign Corporation, Fitchburg, Massachusetts. Morgantown, WV: US Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health (NIOSH) Publication No. HETA 2000-0096-2976, 2003
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15. Kreiss K, Cox-Ganser J. Metalworking fluid-associated hypersensitivity pneumonitis: a workshop summary. Am J Ind Med 1997; 32:423–432
16. Rosenman KD, Reilly MJ, Schill DP, et al. Cleaning products and work-related asthma. J Occup Environ Med 2003; 45:556–563