Sample Chapter

September 2007

Section 14

The lungs represent the major interface between humans and their environment. Consequently, the lungs are a common site of environmentally induced disease. Thousands of environmental toxins and commercial chemicals are now in use, the particles of which may become aerosolized or airborne in the form of fibers, fumes, mists, or dust. Inhabitants of major metropolitan areas may inhale more than 2 mg of dust each day, and workers in dusty occupations may inhale up to 100 times that amount.

Despite this exposure, pulmonary function in most persons is rarely affected because the lungs are equipped with a complex system to reduce the effect of potentially harmful inhaled toxins and to preserve the sensitive gas exchange mechanism of the alveolar surface. Nevertheless, the prevalence of lung disease has increased dramatically over the past several decades, in part because of exposure to respiratory toxins.

This chapter provides an organized approach to the identification of inhalation exposure as the cause of pulmonary disease and discusses the management of several specific forms of occupational pulmonary disease. The identification of inhalation exposure can be important, for a couple of reasons. First, it guides treatment of the patient; this is perhaps best illustrated by occupational asthma, in which diminishing the exposure to the inciting agent can result in improvement and even cure. In contrast, persistent exposure to the causative agent may lead to an increase in the need for medications and to accelerated progression of airway disease. Second, detection of occupational or environmental causes of lung disease provides the opportunity to identify and treat other persons suffering from exposure to the agent and to prevent disease in individuals who are at risk by instituting measures for reducing future exposures.

The development of environmentally induced lung disease in an individual is a function of the toxicity of the inhaled substance, the intensity and duration of exposure, and the physiologic and biologic susceptibility of the host. The physical state of the inhaled substance (e.g., solid, fume, or mixture) and its solubility and aerodynamic dimensions principally determine the initial site of disease activity. Smaller particles (0.1 to 1.0 µm) are more likely to reach the alveoli, but airborne toxins up to 5 µm in size may also do so. In general, larger particles (10 µm or greater) are trapped and removed by the mucus and cilia of the upper respiratory tract.

Although the respiratory tract is quite resilient in the face of the plethora of agents contacted in the environment, disruption of the alveolar clearance mechanism may occur if the individual is exposed to highly concentrated particles in certain working conditions or if exposure occurs during strenuous labor, when minute ventilation is increased and mouth breathing is more likely. Depending on the solubility and reactivity of the inhaled substance, acute or chronic reactions occur as particles are deposited on the alveolar surface. Acute reactions with associated edema or inflammation or more chronic reactions, characterized by fibrosis or granuloma formation, have been demonstrated after inhalation of many environmental agents.

Several factors may make certain individuals more susceptible to inhaled toxins in the workplace. These include genetic tendencies related to inflammation and fibrosis, ability to clear substances from the lower respiratory tract, the presence of coexisting pulmonary diseases, and the effects of concomitant exposures, such as to cigarette smoke.

Occupational and environmental lung disease can be challenging to diagnose and even more difficult to study epidemiologically because of the extended time from exposure to clinical expression of disease, which often ranges from years to decades. In addition, most individuals are exposed to a variety of substances at one time and may participate in a number of occupations in their lifetime. Thus, many factors may be involved in the development of lung disease.

The diagnosis of work-related or environment-related lung disease requires three distinct types of information: a relevant exposure history, definitive diagnosis of a specific type of lung disease, and reported evidence supporting an association between the exposure and the disease process.

Exposure Assessment

Occupational and environmental lung diseases do not have distinctive clinical presentations; consequently, the exposure history is an essential component of the evaluation and should be included in the initial workup of any patient with lung disease. Because the period between exposure and onset of lung disease is highly variable, a detailed history may be required to uncover distant exposure. Even in patients who present with acute toxicity from an inhaled agent, however, details of the exposure (e.g., the chemical agent, the extent of the exposure, and its inherent toxicity) contribute substantially to the clinical evaluation. The occupational history should include the following:

• Job process or any unusual exposure setting.

• Known toxic exposures.

• Degree of exposure.

• Temporal relationships between exposures and symptoms.

• Use of respiratory protective equipment.

Many patients have part-time or summer employment, have served in the military, or have hobbies that may account for additional exposure risks. Other nonoccupational risk factors, such as cigarette smoking, should also be considered. The goal of this exposure history is to establish a list of agents that could potentially cause or exacerbate the lung disease.

Identification of Specific Disease

With few exceptions, the diagnosis of occupational or environmental pulmonary disease involves standard diagnostic procedures used in pulmonary medicine. Lung function studies, although nonspecific in regard to etiologic diagnosis, are essential for characterizing the functional correlates of lung disease. However, care must be exercised in the use of standard nomograms to interpret the results of lung function studies in patients being evaluated for occupational lung disease. Physiologic factors that make workers suitable for specific jobs and that allow them to maintain those jobs despite physically stressful working conditions may contribute to higher baseline measures of lung function than would be seen in standard reference populations. Consequently, the most useful approach to assessment of lung function in such cases is to make repeated measurements over time, to see whether the rate of change is within the expected or acceptable range.

Although the chest radiograph is currently the cornerstone of diagnostic testing for the pneumoconioses, it is neither a sensitive nor a specific method for identifying the parenchymal or pleural manifestations of these diseases. For example, in 15% to 20% of patients with pathologic evidence of asbestosis, the parenchyma appear normal on the chest radiograph.¹ In addition, autopsy studies and studies using computed tomography scans indicate that the chest radiograph shows only 50% to 80% of the pleural plaques that are actually present. Moreover, the chest radiograph is not particularly effective in distinguishing asbestos-induced pleural fibrosis from subpleural fat (specificity of 71% in comparison with conventional CT scans).² Consequently, chest CT may provide substantially better noninvasive identification and quantification of parenchymal and pleural lesions caused by inhalation of fibrogenic agents. Although high-resolution CT (HRCT) scans can identify parenchymal abnormalities that are not evident on a plain chest x-ray, visual interpretation of the HRCT scan is prone to the same problems experienced with chest x-ray. A reliable and valid system has not been developed to evaluate the type and extent of interstitial or pleural lung disease identified on HRCT scans.³ Although attempts have been made to apply the International Labor Organization (ILO) criteria to the interpretation of CT scans, the ILO criteria have inherent problems with reliability and validity.

Supporting Literature

The medical literature establishing a clear relationship between occupational or environmental exposures and specific forms of lung disease is readily accessible through standard sources (e.g., medical texts and primary literature referenced on PubMed [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi]). Clinicians can obtain additional information from the relevant material safety data sheets (MSDS), which contain information on the potential health effects of toxic agents and are required by federal law to be available in the workplace. Occasionally, other less commonly used databases, such as Toxline or Chemline, are needed to access the relevant medical literature.

Clinicians should access the literature that links exposures with disease when considering the diagnosis of occupational or environmental lung disease. In cases where the temporal sequence of events or the histopathology strongly support an occupational or environmental etiology but convincing literature does not exist, the clinician should consider referral to an academic center for further evaluation and consideration.

Occupational and environmental lung diseases may arise from a vast array of exposures, representing every major category of toxins (natural) or toxicants (synthetic) [see Table 1]. These diseases fall along a continuum of several pathologic processes, with severity and onset of symptoms dependent on length and types of exposures and associated individual risk factors [see Pathophysiology, above]. Clinically, these diseases are classified into four categories: airways disease, parenchymal lung disease, mixed airway and parenchymal disease, and occupational neoplastic disease [see Table 2].

Occupational Asthma

Occupational or environmental asthma may be defined as reversible airflow obstruction associated with hyperreactivity of the airways that is either caused or exacerbated by exposure to excessive concentrations of irritants or contact with sensitizing agents in the workplace or environment.^4,5 Increased mucus production, cough, and bronchospasm are hallmarks of this disorder, with symptoms initially evident after exposure to inhaled dusts, gases, fumes, or vapors. Characteristically, patients with the most severe symptoms have the longest exposure histories and the most abnormal pulmonary function test results.

Epidemiology

Although the incidence of occupational asthma is not known, the prevalence has been estimated to be approximately 5% of all cases of asthma; however, one study suggests that occupational asthma may account for as much as 25% of the cases seen in the clinical setting.⁶ Importantly, some agents, such as isocyanates, organic dusts, and irritant gases in high concentrations, result in a much higher proportion of airway disease among exposed workers.

Pathogenesis

More than 200 chemicals or agents are reported to cause or precipitate occupational asthma. These compounds have been divided into three groups: (1) high-molecular-weight compounds, (2) low-molecular-weight compounds, and (3) highly concentrated gaseous or particulate toxic irritants.⁷

High-molecular-weight compounds, consisting mainly of biologic proteins, are often the inciting agents responsible for airway hyperreactivity associated with allergic mechanisms. Specific examples include animal dander, Bacillis subtilis enzymes, organic dusts, castor beans, and vegetable gums. Patients are usually atopic and test positive for dust extracts on skin-prick testing. Specific IgE antibodies to dust antigens may be identified using radioallergosorbent tests. However, nonallergic mechanisms may contribute to the development of airflow obstruction in individuals exposed to high-molecular-weight compounds.

Low-molecular-weight substances (i.e., compounds with a molecular weight of less than 2,000 daltons) are usually inorganic compounds. Examples include platinum compounds, concentrated fumes of epoxy resins, nickel sulfate, isocyanates, formaldehyde, and other chemicals. Although reactions to low-molecular-weight substances are not commonly mediated by acute inflammatory mechanisms, IgE or IgG antibodies have been identified in workers exposed to phthalic anhydrides; trimetallic anhydrides; and plicatic acid, the agent responsible for asthma in workers exposed to Western red cedar dust.

The pathogenesis of occupational asthma is multifactorial and may involve any of several mechanisms. Classic allergic mechanisms involving IgE, mast cells, eosinophils, and histamine are responsible for a small percentage of the cases of occupational asthma. In most cases, occupational asthma appears to be caused by inflammation and edema of the bronchial mucosa, with the stimulus for the inflammatory response originating from airway macrophages and airway epithelia. Neutrophils, eosinophils, and specific inflammatory cytokines appear to play an important role in the inflammatory lesion. Moreover, local production and release of inflammatory agents (i.e., cytokines, growth factors, arachidonic acid metabolites, and oxygen radicals) may contribute to the chronic airway remodeling observed in patients with persistent occupational asthma. Further understanding of the acute inflammatory response is likely to provide new directions for treatment and early diagnosis.

Diagnosis

The diagnosis of occupational or environmental asthma requires the demonstration of reversible airflow obstruction occurring in conjunction with inhalation of specific agents that have been reported to cause or exacerbate asthma. Therefore, the physician should initially focus on the diagnosis of asthma. Once this diagnosis is clearly established, further examination of occupational or environmental causes should be considered.

Pulmonary function testing is an essential component of the evaluation of patients suspected of having occupational asthma. Spirometric patterns of airflow obstruction and physiologic changes in patients with occupational or environmental asthma are identical to those in patients with other forms of asthma [see 14:I Pulmonary Function Testing and 14:XIX Asthma]. Unlike nonoccupational asthma, however, obstructive airways disease that is induced or exacerbated by workplace exposure is temporally related to the specific exposure. Physiologic testing—whether by spirometry, peak flow measurements, or periodic nonspecific bronchoprovocative challenges—should be used to evaluate the temporal relation between occupational exposures or environmental agents and the development of airflow obstruction. For instance, demonstration of consistent decreases in peak flows of at least 20% after exposure to a specific agent in the workplace not only helps establish the diagnosis of occupational asthma but also may assist in identifying the agent. Although specific airway challenges are the most definitive method of making the diagnosis, such testing is not entirely accurate, and very few centers are equipped to perform these potentially hazardous exposure-response studies.

Several laboratory tests have been proposed to evaluate patients with suspected or proven occupational or environmental asthma; however, their ultimate clinical usefulness is questionable. Serologic or immunologic testing can assist in determining atopic status with respect to environmental allergens. Testing of reactions to specific allergens is limited to the relatively few that have been completely purified (e.g., extracts of flour and grain dusts, animal products, and certain chemicals). Serum IgG or IgE antibodies may also be measured by radioimmunoassay or enzyme-linked immunosorbent assay (ELISA). Unfortunately, these tests lack the sensitivity and specificity required for making a definitive diagnosis; used in conjunction with other testing methods and a careful exposure history, however, these tests may help document a specific etiology.

Management

Once standard medical treatments have been initiated (e.g., with inhaled b-agonists, inhaled or oral corticosteroids, anticholinergics, cromolyn sodium, or leukotriene antagonists), emphasis should be placed on avoiding or minimizing further exposure. Isocyanates and other sensitizers must be completely eliminated from the environment of patients with occupational asthma caused by these agents.^7,8 In patients with irritant-induced asthma, however, continued exposure may be acceptable, as long as the exposure is reduced to tolerable levels. Even with complete avoidance of the offending agent, most patients have persistent symptoms. When complete avoidance of the offending agent is impractical or the exposure is occasional, the use of respirators or, preferably, improved local ventilation may alleviate symptoms. It is uncertain whether such measures halt airway injury, however, and these patients must be monitored very closely.

Industrial Bronchitis

Industrial bronchitis, a disorder characterized by dyspnea and cough productive of sputum for at least 3 months each year, is associated with occupational exposure to high concentrations of airborne dusts, mixed dusts, or to dusts and fumes.^9,10 Industries in which workers may incur significant mixed exposures include construction and demolition, mining and smelting, food processing, and animal confinement. Workers in industries that manufacture complex materials such as ceramics, furniture, or rubber are exposed to a variety of agents that may contribute to increased airway symptoms. Firefighters and emergency response workers are frequently exposed to complex mixtures of potentially harmful inhaled agents. Confounding the occupational exposures may be a history of cigarette smoking, which will further contribute to morbidity. Impaired pulmonary function may result in hypersecretion of mucus in the proximal airways. Treatment should be directed toward minimizing exposure to airway irritants, including smoking cessation, and using antibiotics with postural drainage to decrease any infected airway secretions.

Byssinosis

Workers in the textile industry who have long-term exposure to dust from cotton, flax, hemp, or jute may develop byssinosis, which is marked by chest discomfort, cough, or dyspnea. These organic dusts contain live microorganisms, endotoxin, mycotoxins, and tannins, all of which are capable of initiating an inflammatory response.^11,12 Direct epithelial cell injury may occur, and inflammatory cells such as macrophages may actively participate in the inflammatory response by releasing inflammatory cytokines.

Chronic byssinosis generally does not develop until after 10 or more years of inhaling the dust. Presenting symptoms may vary from mild cough and occasional chest discomfort to marked respiratory failure with dyspnea at rest. Characteristically, patients complain of so-called Monday morning fever; this term refers to the abrupt onset of symptoms with exposure after some time away from the work environment. A majority of patients with these symptoms experience a decrease in their forced expiratory volume in 1 second (FEV₁) over the course of a work shift and, at least initially, develop symptoms on exposure only after having been away from the inciting agent. As the disease progresses, the symptoms become persistent and are exacerbated throughout the workweek.

Byssinosis, like most inflammatory conditions caused by inhaled irritants, is managed by minimizing future exposures and treating the airway inflammation.

Persistent airway reactivity that follows acute exposure to respiratory irritants has been termed reactive airways dysfunction syndrome (RADS).^13,14 A variety of inhaled irritants have been associated with RADS, including sulfuric acid, chlorine, ammonia, household cleaners, and smoke. Most often, the initial inhalation injury results from a single, acute, high-intensity exposure. Symptoms of airflow obstruction, including cough, dyspnea, and wheezing, appear immediately or several hours after the end of the exposure and may persist for months to years. Previous exposure or sensitization to the toxic agent does not appear to be necessary. By definition, persons who develop RADS have no history of respiratory illness. Pulmonary function tests may be normal or may demonstrate airflow obstruction. Patients with RADS have persistent positive responses to methacholine challenge testing, even in the presence of normal pulmonary function tests. Nonspecific bronchial reactivity may persist for months to years after the initial inhalation injury.

Pathogenesis

Inhaled toxins exist in many forms and may be categorized in terms of their physical properties. General categories include gases, vapors, fumes, aerosols, and smoke [see Tables 3 and 4]. The initial pathologic responses to a harmful inhaled agent depend on a number of factors, including the concentration of the substance in the ambient air, the pH of the inhaled substance, the number and size of particles, the relative water solubility of the inhaled agent, the duration of exposure, and whether the exposure occurs in an enclosed space, as opposed to an area with adequate ventilation and free circulation of fresh air. In addition, a number of host factors, including age, smoking status, the presence of preexisting pulmonary or extrapulmonary disease, and the use of respirators or other protective breathing apparatus, affect an individual's response to the inhalation of a toxic substance.

Inhaled gases with potential irritant effects manifest their actions at different sites in the respiratory tract. In general, substances that are highly water soluble, such as ammonia, sulfur dioxide, and hydrogen chloride, can cause immediate irritant injury to the upper airway. The acute effects of highly water-soluble irritants on the upper airway, exposed skin, and other mucous membranes often produce such unpleasant symptoms that exposed persons quickly leave the area of exposure and avoid continued inhalation of the harmful toxins. In contrast, inhaled toxins that have low water solubility, such as phosgene, ozone, and oxides of nitrogen, often have little or no acute effect on the upper airway; instead, they produce irritant effects at the level of the terminal bronchiole and alveolus. Because agents of low water solubility do not produce immediately noticeable upper airway irritation (except in episodes of massive acute exposure), exposed persons may remain in the area of exposure and thus increase their duration of exposure to harmful inhalants. Agents that exhibit intermediate water solubility, such as chlorine, can have pathologic effects throughout the respiratory system. However, extreme exposure to any one of these irritants may result in upper and lower respiratory tract involvement. Furthermore, adsorption of any one of these irritants onto particulate matter may also alter the site of involvement.

Bronchial biopsies of patients with RADS demonstrate an inflammatory response characterized by epithelial desquamation and mucus cell hyperplasia. The exact mechanisms of the pathophysiology of RADS are unclear, but implicated mechanisms include altered neural tone and vagal reflexes, modified beta-adrenergic sympathetic tone, and the influences of a number of inflammatory mediators. The direct irritant injury may expose and damage subepithelial irritant receptors. Subsequently, repair mechanisms may result in alteration of the irritant receptor threshold and lead to airway hyperreactivity. Changes in epithelial permeability may also contribute to the resultant hyperreactivity. None of these proposed mechanisms is completely understood at this time.

Management

Treatment of RADS includes the use of corticosteroids to minimize inflammatory mechanisms and bronchodilators to reverse bronchospasm. There is limited, mostly anecdotal, evidence for the efficacy of corticosteroids. Bronchodilators may only partially reverse airflow obstruction, especially in later, chronic stages of the syndrome. Despite treatment with corticosteroids and bronchodilators, many patients may be left with persistent asthmalike symptoms, airflow obstruction, and nonspecific bronchial hyperreactivity.

Parenchymal lung disease may arise from a vast array of occupational exposures that represent every major industrial sector. The most important class of occupational lung diseases is made up of the pneumoconioses, which result from the inhalation of, and tissue reactions to, various naturally occurring or synthetic mineral dusts. Pneumoconioses are still relatively common in older men who have been employed in jobs with exposure to mineral dust. In fact, interstitial lung disease (ILD) is much more common than previously thought, and the pneumoconioses account for approximately 14% of the incident cases of ILD.^15,16 Before 1970, when the United States federal government began regulating the amount of concentrated particulate material to which workers could be legally exposed, workplace dust levels were often extremely high; those exposures that occurred 20 to 30 years ago are reflected in the manifestation of various pneumoconioses today.

Asbestosis and Asbestos-Induced Pleural Fibrosis

Exposure to asbestos (occupational and environmental) constitutes the most pervasive of the mineral dust exposures and has had the greatest impact on morbidity and mortality in these exposed workers. The National Institute for Occupational Safety and Health (NIOSH) estimated that in 1990, 568,000 workers in production and services industries and 114,000 workers in construction industries were potentially exposed to asbestos; as many as 25 million more persons in the United States had occupational exposure to asbestos between 1940 and 1980.¹⁷ Worldwide, about 125 million persons are exposed to asbestos at their workplace,¹⁸ and many of them remain at increased risk for asbestos-related diseases. Many millions more have environment exposures to asbestos from insulation, building products in homes and public buildings, brake and clutch facings, and demolition of asbestos-containing buildings in urban areas. Asbestos has been federally regulated by the Occupational Safety and Health Administration (OSHA) of the Department of Labor since OSHA's inception in 1972.

Asbestos refers to a group of six separate fibrous mineral silicates that can be woven and have the properties of being resistant to heat and acids.¹⁹ The vast majority of asbestos produced in North America consists of hydrated magnesium silicate and is called chrysotile or white asbestos. Other forms of asbestos include crocidolite (blue asbestos), amosite, anthophyllite, tremolite, and actinolite. Despite decreased demand for asbestos in Europe and North America, its production has remained stable as a result of its continued use in developing nations. Most exposures to asbestos occur during the milling and manufacture of asbestos, during installation and replacement of insulated packing around heating pipes and furnaces, or during the use of asbestos-containing cement. All of these applications cause the fibrous asbestos particles to become airborne.

Pathogenesis

Figure 1. Biologic Processes in Development of Fiber-Induced Pulmonary Fibrosis

The pathogenesis of asbestos-induced fibrosis of the lung parenchyma is unknown. Despite the absence of definitive knowledge regarding the biologic mechanisms that result in pulmonary fibrosis, it is very clear that the chronic inflammatory response is progressive, the inflammation and fibrosis is heterogeneously distributed throughout the lung, and the chronic inflammatory process is associated with extensive remodeling and fibrosis of the lower respiratory tract. Retention of fibers in the lung parenchyma appears to be associated with the severity of disease. Cigarette smoking, which may reduce the clearance of fibers, has been shown to enhance the risk of developing asbestosis. In the lung parenchyma, this chronic inflammatory process eventually leads to proliferation of mesenchymal cells, intra-alveolar fibrosis, and loss of alveolar capillary units. The mechanisms of asbestos-induced lung fibrosis are complex and likely to involve several types of cells, including neutrophils, macrophages, and lung epithelial cells, as well as cell mediators [see Figure 1].

Diagnosis

The diagnosis of asbestosis requires objective evidence of past exposure and current disease, in the absence of alternative explanations for the patient's clinical condition and test results.²⁰ In most cases, the diagnosis is made on the basis of a clear history of exposure that occurred at least 15 years before the onset of disease, along with typical radiographic features on a chest radiograph.

Clinical presentation Asbestosis and asbestos-induced pleural fibrosis, unlike silicosis or coal worker's pneumoconiosis, often present clinically as progressive dyspnea. The dyspnea in patients with asbestosis is often more prominent than tests of lung function would suggest. These patients have a dry cough and pleuritic chest pain. Physical findings include rales, which may be absent in early asbestosis and are best heard laterally over the lower thoracic wall. In advanced cases of asbestosis, clubbing and cyanosis may be observed.

Laboratory studies Evidence of asbestos-related lung disease includes the presence of asbestos fibers in bronchoalveolar lavage fluid or lung parenchyma, characteristic radiographic findings on chest radiography or high-resolution CT, and restrictive lung function or reduced diffusing capacity on pulmonary function tests. Pleural fibrosis with circumscribed pleural plaques and diffuse pleural thickening is the most common radiographic abnormality in patients who have been exposed to asbestos; these chest wall lesions have been found to be independently associated with progressive restrictive function.^21,22

Radiographically, asbestosis tends to progress slowly over several years, even in the absence of further exposure.⁸ The chest radiograph may reveal only pleural plaques and no clear evidence of the small linear opacities in the lower lung zones that are classically seen in asbestosis. Using HRCT, several groups of investigators have shown that clinically significant interstitial abnormalities are missed by standard chest radiography. With more advanced disease, diffuse linear opacities, often in association with pleural plaques, are observed in middle and lower lung zones. A pleural effusion may be caused by asbestos exposure and is believed to contribute to the formation of diffuse pleural thickening. In those patients who develop diffuse pleural thickening, the lower lung zones have a ground-glass appearance, making interpretation of small linear opacities difficult without the use of HRCT.

Because asbestosis initially affects the bronchioles, early stages of the disease may involve airflow obstruction. Alternatively, no detectable abnormalities may be demonstrated on routine pulmonary function testing. As the disease progresses, both asbestosis and asbestos-induced pleural fibrosis may result in a restriction of lung function. Asbestosis may also cause abnormalities in gas exchange (decreases in the diffusing capacity or increases in the alveolar-arterial oxygen difference).

Treatment and Prevention

Although there appears to be no effective treatment of asbestosis other than providing supportive therapy for patients who develop respiratory compromise, physicians should consider treating progressive asbestosis just as they treat other forms of interstitial lung disease. Because the risk of lung cancer is known to decrease with cessation of smoking, it is critical to provide strong incentives for asbestos-exposed workers to stop smoking.

Despite the fact that federal regulatory agencies have placed restrictions on the mining and use of asbestos, existing structures containing asbestos remain a potential source of exposure in the United States. In addition, asbestos continues to be used in developing countries because it remains a very inexpensive form of insulation.

Silicosis

The diagnosis of silicosis dates back to the time of Hippocrates and the ancient Egyptians. Despite being recognized for centuries as a preventable disease, both classic nodular silicosis and the rapidly fatal acute form, silicoproteinosis, continue to be diagnosed around the world.^23,24 In the United States, a diverse working population numbering more than 2 million is at risk for developing silicosis from exposure to so-called free or crystalline silica. Those at risk include persons working with silica abrasives, refractories, or ceramics and those involved in coal mining and milling, metal and nonmetal mining and milling, foundry work, filler manufacture and handling, quarrying, tunneling, and many other occupations.

Pathogenesis

It has been postulated that once silica is inhaled and penetrates into the alveoli, a series of inflammatory events leads to involvement of the alveolar macrophage. Macrophages ingest the foreign antigens and package the material into phagosomes that in turn release lytic enzymes, rupturing the phagosome and allowing the irritant to interact with the cytoplasm. The cell is then autolyzed when inflammatory mediators are released, and the silica is then reingested by additional macrophages, which perpetuates the inflammatory cycle. Tumor necrosis factor (TNF), released primarily by alveolar macrophages, may be an essential component of the inflammatory response to inhaled silica. In fact, one provocative animal study has shown that treatment with a TNF antagonist prevents the development of silica-induced pulmonary fibrosis.²⁵ Chronic inflammatory responses lead to fibrosis. Over time, collagenous fibers are deposited in concentric layers and undergo hyalinization, becoming a whorled nodule encapsulated by a mostly acellular, discrete layer of collagen. Silicotic particles may be seen pathologically as birefringent material under polarized light. Although the exact mechanisms of pathogenesis are unclear, the electrostatic charge on the surface of the silica particle appears to be an important component of the inflammatory response.

Diagnosis

Clinically, silicosis may appear in many different forms. These include chronic silicosis, progressive massive fibrosis, accelerated silicosis, and acute silicosis.

Chronic, or pure nodular, silicosis typically occurs after 20 to 40 years of low or moderate exposure to silica-containing dust with less than 35% quartz. Chronic silicosis is often first detected on a routine chest radiograph. In the early stages, patients may have no respiratory symptoms, except possibly a cough. With more advanced silicosis, patients are more often dyspneic and frequently complain of chronic cough and phlegm production. Lung sounds are usually normal or reflect concurrent airway disease. Radiographically, chronic silicosis is characterized by symmetrical, rounded opacities in the upper and middle lung zones. Hilar lymph nodes rimmed with calcium may also be seen on chest radiograph; these opacities are termed eggshell calcifications. It is well recognized, however, that a patient with dramatic radiographic evidence of silicosis may remain free of symptoms and functional impairment.

On lung function testing, patients with silicosis typically have a restrictive pulmonary impairment but may demonstrate a mixed obstructive-restrictive pattern or a purely obstructive pattern. Epidemiologic studies have shown that mild airflow obstruction may develop in workers exposed to silica, independent of the effect of cigarette smoking.

Silicosis typically progresses slowly over many years, even in the absence of further exposure. The long-term survival of patients without clinical or physiologic abnormalities and with lesions less than 5 mm in diameter is similar to that of the general population.

Progressive massive fibrosis (also known as complicated or conglomerate silicosis) may develop in a small percentage (< 5%) of patients with silicosis. These lesions result from coalescence of the initial fibrotic nodules, which engulf obliterated blood vessels and bronchi. The conglomerate masses typically appear symmetrically in the upper lung zones, may assume a butterfly distribution, and may correlate with cavitation; they are typically associated with scar emphysema. Patients with progressive massive fibrosis are severely impaired by end-stage dyspnea, which is the predominant symptom. The disease is usually progressive even if the patient has no further exposure to silica. Pulmonary function studies usually reveal both marked obstructive and restrictive pulmonary impairment. Patients with this disease are at increased risk for tuberculosis and other respiratory infections (e.g., influenza and pneumococcal pneumonia). It has been suggested that tuberculosis may contribute to the development of progressive massive fibrosis.^26,27

Accelerated silicosis is seen in workers such as sandblasters who receive more concentrated exposures of dust containing greater than 50% quartz. Lesions may develop after only 5 years of exposure. Radiographically, the nodules of accelerated silicosis appear somewhat smaller than those of classic silicosis and are concentrated in the middle zones of the lung.

Very high concentrations of silica may result in acute silicosis, also known as silicoproteinosis. This rapidly progressive and often fatal disease has been reported in the United States among workers using sand as an abrasive (a practice banned in many Western countries decades ago), among drillers of highly siliceous rock, among tombstone sandblasters, and among those workers milling silica to produce silica flour. These processes result in high concentrations of respirable particles with a high percentage of free silica—two important factors that magnify silica toxicity. Within months of exposure, patients may present with profound dyspnea, weight loss, and fatigue and may progress to death from respiratory failure. Lipids and proteinaceous material reactive to periodic Schiff reagent are found histologically in the alveoli. Lavage fluid that has a milky appearance and that contains high concentrations of surfactant is considered diagnostic of silica-induced pulmonary alveolar proteinosis. As in patients who have idiopathic alveolar proteinosis, whole-lung lavage has been successfully used in isolated cases to reverse the excess production of surfactant.

Treatment and Prevention

Avoidance of the exposure site and elimination of exacerbating factors such as cigarette smoking are the mainstays of therapy. In patients with progressive disease, tuberculosis should be considered and treated aggressively if present.^26,27

Coal Worker's Pneumoconiosis

For many years, the lung disease seen in coal miners was believed to be silicosis.²⁸ However, surveys of coal tipplers and graphite workers exposed to either coal dust or graphite, but not silica, revealed a form of pneumoconiosis that is radiographically indistinguishable from chronic silicosis but pathologically quite different. Although many miners are also exposed to silica and may therefore have both silicosis and coal worker's pneumoconiosis (CWP), the latter is recognized as a distinct form of pneumoconiosis that has its own natural history and pathology.

About 300,000 miners in the United States are exposed to coal dust each year. Increasingly, however, these workers are involved in strip mining, in which exposures are considerably lower than in underground mining. The exposure to coal dust for underground miners was greatly reduced as a result of the Federal Coal Mine Health and Safety Act of 1969, which provided benefits for miners with documented exposures and mandated that employers prevent workers from receiving exposures of coal dust greater than 2 mg/m³. The act was subsequently revised to include workers suffering disabilities not only from pneumoconiosis but also from chronic obstructive pulmonary disease arising from coal dust exposures. Today, more than 90% of mine sections are in compliance with federal standards. NIOSH provides an ongoing medical surveillance program for underground coal miners and reports that less than 5% of working miners have radiographic evidence of CWP. Those with advanced simple CWP or progressive massive fibrosis (PMF) typically have had mine exposures of 20 years or more.

Diagnosis

As with silicosis, the risk of CWP depends on the cumulative exposure burden (i.e., the dust concentration multiplied by the duration of exposure). Simple CWP, in the absence of other respiratory disease, usually is detected radiographically and most often is not accompanied by respiratory symptoms. Industrial bronchitis is common in coal miners, with a prevalence of 20% to 50%, and is clearly related to the cumulative dose of coal dust. Similarly, airflow obstruction and progressive loss of lung function have been observed to be dose related in cohorts of miners with high exposure to coal dust. Smoking does not appear to increase the incidence of simple CWP or PMF, but it does act in an additive fashion to increase the risk of airflow obstruction and bronchitis in coal miners. As in silicosis, CWP may present as a restrictive impairment, although obstructive and mixed patterns are more often observed. Simple CWP typically presents without dyspnea, but the patient often complains of chronic cough and phlegm production.

The chest examination is usually not helpful but may reveal breath sounds arising from airway obstruction. The earliest pathologic lesion of CWP, the classic coal macule, comprises a peribronchiolar accumulation of coal dust, macrophages, and fibrosis, together with adjacent focal emphysema. As particle deposits continue to accumulate, they typically form rounded micronodules (< 7 mm in diameter) and later macronodules (> 7 mm in diameter). Nodular pneumoconiosis arising from coal dust exposures typically occurs symmetrically and predominantly in the upper lobes of the lung. Rapidly developing nodules in the presence of CWP with rheumatoid arthritis is termed Caplan syndrome.

Unlike silicosis, simple CWP tends not to progress if dust exposure ceases. A small proportion (< 5%) of patients with simple CWP may progress to PMF. The risk of developing PMF depends on the extent of simple CWP and previous exposure to silica. Although patients with early PMF (defined as the presence of one or more large radiographic opacities greater than 1 cm in diameter) may not be impaired, patients with more advanced PMF typically have severe impairment, with progressive dyspnea and mixed obstructive-restrictive physiology. The lesions of PMF appear histologically as encapsulated dense fibrotic tissue surrounding coalesced coal macules, destroyed vascular tissue, collagen-containing scars, and proteinaceous acellular material saturated with coal dust. Investigators have suggested that alveolar macrophages contribute to pulmonary injury in CWP through generation of a superoxide anion, although the precise pathogenetic mechanisms remain unclear.

Treatment and Prevention

Therapy for symptomatic CWP is limited to treatment of complications; clinical intervention should focus on avoidance of the exposure site; elimination of additional exacerbating factors, such as smoking cigarettes; and treatment of the bronchitic phase of this disease. In addition, the presence of tuberculosis should be carefully considered in patients with progressive disease.

Silicate Pneumoconioses

In addition to asbestos, other silicates may cause pneumoconiosis, given sufficient dust concentration and duration of exposure. The occupational populations at risk for these exposures are diverse because of the wide distribution of these products in consumer goods. For most of these exposures, only limited environmental and epidemiologic data are available. The pneumoconioses arising from mining, milling, or subsequent processing of minerals are often more closely related to the more toxic components of the host rock, such as crystalline silica or fibrous amphibole asbestos. As a result, silicate pneumoconiosis may closely resemble silicosis or asbestosis. Of particular importance is talc, a widely used consumer product and industrial material. NIOSH estimated the population occupationally exposed to talc in 1980 to be 1.8 million. Cosmetic talcs, now regulated by the Food and Drug Administration to prevent fiber contamination, consist of platy talcs, which may produce a reticulonodular form of pneumoconiosis known as talcosis. Exposure to this type of talc has not been associated with lung cancer. Fibrous talcs, which have a range of industrial applications and are commonly contaminated with significant amounts of asbestiform fibers, produce lung lesions that are typical of the asbestos-related lung diseases and include interstitial fibrosis, pleural plaques, diffuse pleural thickening, lung cancer, and mesothelioma.

Other silicates are being more widely used as asbestos substitutes, despite the absence of adequate data on health effects. A fibrous calcium silicate, wollastonite, appears to be relatively nontoxic, causing at most mild pneumoconiosis in the small work forces that mine and mill it in the United States and Finland. Some vermiculite sources have been found to be contaminated with asbestiform fibers, exposure to which may result in lung fibrosis, lung cancer, and mesothelioma.

Miscellaneous Pneumoconiosis and Other Conditions

Occupational exposure to aluminum, barium, iron, and tin dusts may result in pneumoconiosis. These exposures result in nodular pneumoconiosis, often with striking chest radiographs caused by the deposition of metal in the lung. In most cases, in the absence of other respiratory risk factors, the radiographic findings are not associated with symptoms, physical findings, or impairment.

Exposure to cemented tungsten carbide (hard metal), commonly used as an abrasive or metal cutting tool, may result in hard metal lung disease. Patients with hard metal lung disease can present with either airflow obstruction or diffuse interstitial fibrosis. Clinically, patients have an asthmalike syndrome characterized by cough and chest tightness; these symptoms usually develop toward the end of the work shift or in the evening. This pneumoconiosis may develop within 1 year of employment, with the onset of cough, sputum, and dyspnea on exertion. Chest auscultation reveals basilar rales. The chest radiograph is characterized by irregular opacities with some hilar prominence.

Manufactured mineral fibers include slag wools, rock wools, glass wools and filaments, and ceramic fibers. These materials have numerous industrial applications and are frequently used as asbestos substitutes. Because the morphology of these fibers is similar to that of asbestos, there has been a good deal of concern about their potential for causing interstitial fibrosis, lung cancer, and mesothelioma. Epidemiologic studies reveal a disorder characterized by linear opacities on chest radiographs, similar to the radiographic appearance of mild asbestosis, occurring with a low prevalence among fiberglass manufacturing workers. However, exposure to manufactured mineral fibers does not appear to be associated with an excess risk of either lung cancer or mesothelioma.

Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis, also referred to as extrinsic allergic alveolitis, is a syndrome characterized by a granulomatous inflammatory reaction of the interstitium and terminal bronchioles.^29,30 The lung disease in hypersensitivity pneumonitis is often accompanied by systemic symptoms and is caused by exposure to airborne organic dusts and other agents. This disorder differs from allergic asthma in that the immunologically mediated inflammatory response occurs in the terminal bronchioles and interstitium rather than the more proximal airways; however, the two disorders can be caused by many of the same organic dusts. A wide variety of offending agents has been identified, but most of these agents are rare, and a few well-substantiated syndromes comprise the majority of reported cases.

Diagnosis

Diagnosis of hypersensitivity pneumonitis requires the recognition of a pattern of clinical, radiographic, and pathophysiologic criteria. Farmer's lung and pigeon breeder's disease are the prototypic syndromes in hypersensitivity pneumonitis.³¹

Hypersensitivity pneumonitis may be acute, subacute, or chronic, depending on the frequency and intensity of exposure to the causative agent. Acute disease is associated with symptoms such as cough, fever, chills, malaise, and dyspnea that may begin 6 to 8 hours after the initial exposure to the antigen and spontaneously resolve once further exposure has ceased. This latent period makes it difficult for the patient to directly relate the exposure to the symptoms. Pulmonary examination often reveals tachypnea and bibasilar crackles, but wheezes are usually absent. The subacute pattern is characterized by progressively worsening cough and dyspnea, which occur over weeks and may progress to severe dyspnea and cyanosis requiring hospitalization if the worker is repeatedly exposed to the antigen. Typically, these patients have fleeting infiltrates and a history of recurrent episodes of suspected pneumonia.

Fewer exposed persons develop chronic hypersensitivity pneumonitis, which involves progressive dyspnea with clinical features of interstitial fibrosis occurring after multiple symptomatic exposures. Fever is uncommon in chronic hypersensitivity pneumonitis. Evidence of cor pulmonale has been reported in advanced cases of pulmonary fibrosis associated with hypersensitivity pneumonitis.

On laboratory testing, a leukocytosis with neutrophil predominance is often seen in patients with acute hypersensitivity pneumonitis, with white blood cell counts approaching 30,000/ml. Most patients have acquired specific IgG antibodies to the antigen responsible for their symptoms, measurable as precipitins using radioimmunoassay or ELISA. Although establishing the quantity of a specific precipitin provides a valuable diagnostic clue, it does not by itself confirm the presence of the syndrome; it simply indicates that the patient has been exposed to a potentially hazardous organic dust. Pulmonary function testing often reveals a decrease in the forced vital capacity (FVC) and a corresponding elevation of the FEV₁/FVC ratio. Total lung capacity is usually decreased. Impairment of the carbon monoxide diffusing capacity may also be observed, with associated low arterial oxygen tension (P_aO₂) measured at rest. Importantly, in the acute phase of the disease, all of the physiologic changes are reversible. Radiographically, there are no findings specific for hypersensitivity pneumonitis, although many patients have bilateral alveolar infiltrates with involvement of both upper and lower lung fields. Occasionally these infiltrates present in different locations when imaged over time, but long-term exposure frequently results in interstitial infiltrates similar to those seen in other forms of interstitial lung disease.

Management

Although corticosteroids and supplemental oxygen may be administered for acute attacks, absolute avoidance of the inciting antigen is the mainstay of therapy. Respiratory protection is of little value because even small amounts of inhaled antigen may cause acute symptoms in a sensitized individual.

Bronchiolitis

Bronchiolitis represents an inflammatory injury to the bronchiolar epithelium that results in fibrosis and obliteration of the airway.^32,33 As the injury heals, granulation tissue proliferates excessively within the airway walls, on the lining, or both. The nomenclature for bronchiolitis is quite large; this condition is variously termed bronchiolitis obliterans, bronchiolitis fibrosa obliterans, bronchiolitis obliterans and organizing pneumonia (BOOP), cryptogenic organizing pneumonia, and follicular bronchiolitis. Bronchiolitis is associated with environmental exposure to toxic fumes.

Classification

Bronchiolitis can be classified clinically, on the basis of etiology (i.e., inhalation [see Table 4], infection, drug reaction, and idiopathic), or histopathologically (i.e., as proliferative or constrictive). Proliferative bronchiolitis is more common and is characterized by organizing intraluminal exudate with intraluminal fibrotic buds (Masson bodies) in respiratory bronchioles, alveolar ducts, and alveoli. This is primarily an inflammatory condition associated with collagen vascular diseases, acute infections, hypersensitivity pneumonitis, organ transplantation, or a reaction to drugs.

Constrictive bronchiolitis is characterized by damage to the membranous and respiratory bronchioles, with concentric narrowing or complete obliteration of the airway lumen; the alveolar ducts may be spared. Step sections through the specimen are often required to make the diagnosis. Constrictive bronchiolitis can be caused by the same conditions as proliferative bronchiolitis, but it may also result from inhalation of toxic fumes (e.g., nitrogen dioxide, sulfur dioxide, ammonia, chlorine, phosgene, ozone, chloropicrin, trichlorethylene, cadmium oxide, methyl sulfate, hydrogen sulfide, and hydrogen fluoride), mineral dust-induced airway disease (e.g., from asbestos, silica, iron oxide, aluminum oxide, talc, mica, and coal), or cigarette smoke [see Table 4].

Pathogenesis

Although the pathogenesis of bronchiolitis is unknown, it has been hypothesized that constrictive bronchiolitis is initiated by injury to the airway epithelia, and proliferative bronchiolitis primarily involves an alveolitis. It is thought that in constrictive bronchiolitis, the initial airway injury is followed by neutrophilic inflammation and that the repair process results in intramural and intraluminal fibrosis. In proliferative bronchiolitis, the primary alveolitis results in an inflammatory exudate in the distal airspace. Fibroblast proliferation causes the formation of Masson bodies and extracellular matrix that further occlude the lumen of the bronchioles and alveolar ducts.

Diagnosis

Although a lung biopsy is essential for the diagnosis of bronchiolitis (see above), several clinical features are suggestive of this disorder. The history is essential to establish the specific exposures or underlying inflammatory conditions. In constrictive bronchiolitis, the chest radiograph is often normal, but HRCT may show marked heterogeneity in lung density (e.g., ground glass infiltrates). In contrast, radiographs in patients with proliferative bronchiolitis demonstrate interstitial opacities that may be migratory. Whereas pulmonary function studies in patients with constrictive bronchiolitis show an obstructive pattern, patients with proliferative bronchiolitis typically show a restrictive or mixed pattern. However, there is no clear separation between the diagnostic categories of bronchiolitis; overlap clearly exists between constrictive and proliferative bronchiolitis.

Management

Corticosteroids are the mainstay of treatment of bronchiolitis. Proliferative bronchiolitis usually responds to steroids and can be cured with a prolonged course; many patients require 1 year of therapy. Prednisone is usually given at a dosage of 60 mg a day; the dosage is then tapered to 20 to 30 mg/day. Although corticosteroids should be used in constrictive bronchiolitis, this condition is relatively unresponsive and progressive, in spite of aggressive treatment.

Berylliosis

Metallic beryllium, simple salts of beryllium, and complex beryllium silicates, commonly referred to as beryllium compounds, cause both acute and chronic lung disease.^34,35 Beryllium is widely used in the production of copper and nickel alloys, dental alloys, computers, x-ray tubes, nuclear reactors, and foundry products; in tool and die manufacturing; and in the aerospace industry. NIOSH estimated in 1990 that as many as 1 million workers in the United States are potentially exposed to beryllium oxides.

Beryllium lung disease may be divided into acute and chronic forms. The acute disease comprises those beryllium-related conditions that last less than 1 year and that occur during beryllium exposure. Acute manifestations appear to be dose related and include dermatitis (which may ulcerate), conjunctivitis, nasopharyngitis, tracheobronchitis, and acute chemical pneumonia. Chemical pneumonitis is rare but can be fulminant and fatal. Patients present with dyspnea, cough, fatigue, blood-tinged sputum, and substernal pain. Rales, tachypnea, and cyanosis are seen in advanced cases. Radiographic findings include diffuse or patchy infiltrates. Lung volumes are reduced, and hypoxemia is common. Of the 892 cases of beryllium-induced lung disease in the Beryllium Case Registry, 212 were acute cases, and of these, only 17% progressed to chronic beryllium disease.³⁶

Chronic beryllium disease (berylliosis) is both a pulmonary and systemic granulomatous disease. Clinically, berylliosis is very similar to sarcoidosis. Berylliosis can be distinguished from sarcoidosis, however, by exposure history and the absence of either central nervous system disease or altered calcium metabolism. The duration of exposures may vary from months to years, with a latent period from initial exposure to disease manifestation of 10 to 15 years. As with uncomplicated pneumoconiosis, chronic beryllium disease may present as a radiographic finding without respiratory symptoms. Chronic berylliosis, however, may result in severe dyspnea and end-stage pulmonary fibrosis. Physical findings include bibasilar rales, peripheral lymphadenopathy, hepatosplenomegaly, clubbing, and skin lesions. Lung function abnormalities may include airflow obstruction, reduced lung volumes, and isolated diffusion defects. Bronchoalveolar lavage with measurement of the proliferative response of the lung lymphocytes to beryllium salts has been shown to be a sensitive marker for determination of chronic beryllium disease. The disease course is highly variable: with cessation of exposure, some cases progress, some remain stable, and some improve. Corticosteroid treatment is thought to promote resolution of chronic beryllium disease, but no controlled trial data are currently available.

Pathogenesis

Chronic beryllium disease is considered an immune-mediated systemic disorder, because of the variable susceptibility to the disease, the presence of noncaseating granulomas with mononuclear cell infiltrates on histologic examination of the lungs, an antigen-specific immune response, and the accumulation of major histocompatibility complex (MHC) class II-restricted beryllium-specific CD4⁺ T cells in the lungs of affected patients. Furthermore, in vitro experiments have shown that peripheral mononuclear cells and lung T cells proliferate and release lymphokines (TNF-a, interleukin-2 [IL-2], and IL-6) when exposed to beryllium salts. However, CD4⁺ T cells from the lungs exhibit greater beryllium-induced proliferation than do peripheral T cells, and the magnitude of the antigen-specific cellular response in the lung is strongly associated with the degree of the local inflammatory process. These findings suggest that the pulmonary immune response in chronic beryllium disease is compartmentalized, and that the inflammatory response is antigen specific and is mediated by activated CD4⁺ T cells.^35,37 However, the immunogenicity of this innocuous-appearing metal is not at all understood. It has been hypothesized that macrophages ingest aggregates of beryllium and then slowly release it, thereby promoting a chronic granulomatous response. Alternatively, beryllium has been hypothesized to combine with proteins and act as ahapten, although there are no data to support either of these hypotheses.

Nevertheless, awareness of beryllium-specific immunologic responses has provided a reliable method of distinguishing chronic beryllium disease from sarcoidosis. This ability is particularly important because the simple presence or absence of beryllium in lung tissue does not prove or exclude the diagnosis of berylliosis. The beryllium lymphocyte proliferation test (BeLPT) has been standardized, is an essential component of the diagnostic criteria for berylliosis, and gives negative results in patients with sarcoidosis.³⁸ The BeLPT quantifies the cellular proliferative immune response to beryllium and is positive in peripheral blood specimens in over 90% of patients with berylliosis. The remainder of patients with chronic beryllium disease will have abnormal BeLPT responses in lymphocytes obtained by bronchoalveolar lavage. The BeLPT also appears to be effective as a screening test, which is useful because exposed workers with a positive BeLPT may have subclinical granulomatous lung disease and are at excess risk of developing beryllium disease. In fact, a longitudinal study has shown that approximately 50% of workers with a positive BeLPT go on to develop chronic beryllium disease.³⁹

Allelic substitution of the HLA-DP gene may place individuals at higher risk of developing beryllium disease. Specifically, chronic beryllium disease has been found to be strongly associated with a base pair substitution that resulted in glutamic acid (rather than lysine) at position 69 of the HLA-DP gene.⁴⁰ Residue 69 of the HLA-DP gene, which is negatively charged when glutamic acid is present, may directly interact with beryllium and be involved in the immunopathogenesis of this disease. The finding that allelic alteration of the HLA-DP gene is associated with enhanced susceptibility to an immune-mediated lung disease is consistent with the finding that alterations in MHC class II genes (e.g., HLA-DR, HLA-DQ, and HLA-DP) are associated with susceptibility to autoimmune diseases. This finding may also be relevant to other forms of granulomatous lung disease. Moreover, these observations provide further evidence that host susceptibility may be an important determinant of occupational lung disease and indicate that minor genetic variations may result in substantially different biologic responses to environmental stimuli. Given the tools available in human molecular genetics, gene-environment interactions represent a feasible and very important area for further investigation in chronic beryllium disease, as well as other forms of occupational lung disease.

Occupational exposures can play an important role in the development of bronchogenic carcinoma. Mesothelioma, a malignancy originating from the cells that line the pulmonary surface (mesothelium), is exclusively associated with previous exposure to asbestos.

Bronchogenic Carcinoma

Epidemiology

Lung cancer is the leading cause of cancer deaths in both women and men in the United States and throughout the world. Preliminary data indicate that approximately 160,000 men and women in the United States died from lung cancer in 2004.⁴¹ This disease accounts for nearly one fourth of all cancer deaths. Occupational exposures may involve any one of the four major malignant cell types of bronchogenic carcinoma—large cell, small cell, squamous cell, or adenocarcinoma. Therapy for occupation-related lung tumors is dependent on the cell type and is no different from treatment of lung cancer resulting from other exposures.

Etiology

In the general population, cigarette smoking is the most important risk factor for developing pulmonary malignancies. Passive exposure to cigarette smoke also contributes to development of lung cancer. This trend is expected to gradually decline, however, as smoking decreases. Occupational exposures to cigarette smoke are important to consider because the carcinogenic potential of several substances encountered in the workplace can be greatly enhanced by concomitant exposure to cigarette smoke.

Asbestos inhalation is generally considered to have the highest carcinogenic risk in the workplace. Many studies have documented an increase in all forms of bronchogenic carcinoma in workers exposed to asbestos, and all fiber types have been implicated in carcinogenesis. Most asbestos-related pulmonary tumors have a long latency period (20 to 30 years), and a dose-response relation has been observed between the exposure and development of the tumor. Investigators estimate lung cancer risk is sixfold to eightfold higher in nonsmoking workers who are exposed to asbestos and 50- to 100-fold higher risk in asbestos workers who are heavy smokers.⁴² Lung cancer accounts for up to 25% of all deaths in asbestos-exposed workers.^43,44

Excess mortality from lung carcinoma has also been reported in workers exposed to other compounds and chemicals. Uranium miners were discovered to develop lung disease as a result of inhaling the breakdown products of uranium ore, one of which is radon, an inert gas found to increase the risk of lung cancer in a dose-dependent fashion.⁴⁵ Whether domestic radon exposure increases risk, however, remains controversial.

Chloromethyl ethers are one example of chemical carcinogens in the workplace.⁴⁶ These substances, which are used in the manufacture of a number of organic substances (e.g., water repellents, fireproofing agents, and pesticides), have been implicated in increasing small cell lung cancer rates. Chloromethyl ether causes small cell lung carcinoma even in persons who have never smoked. Workers exposed to chromium, beryllium, nickel, or cadmium also have higher lung cancer rates, and these metals are considered by the International Agency for Research on Cancer to be carcinogenic in humans.

Mesothelioma

Epidemiology

Mesothelioma was first reported in the 1940s. The annual incidence of this tumor of the cells lining the lung surface is very low but has increased continually, and is currently approximately 11 cases per million in the United States.⁴⁷ Asbestos exposure has been directly linked as a causative agent in almost all cases of this disease; isolated exposures to erionite (a mineral in the silicate zeolite family) and radiation may possibly contribute to the development of mesothelioma.⁴⁸ Unlike bronchogenic carcinoma, no specific association between mesothelioma development and cigarette smoking has been established. Latency periods for this disease are often longer than 30 years.

Pathogenesis

Although all fiber types have been found to cause mesothelioma, crocidolite has been noted to be the most carcinogenic.⁴⁹ Because chrysotile was the primary asbestos fiber to which workers in the United States were exposed, chrysotile asbestos accounts for a disproportionate number of the cases of mesothelioma in the United States. Development of mesothelioma appears to be dependent on the size of the fiber and its dimensions, but the exact mechanism of tumor development is not known.

Mesotheliomas often appear grossly as multiple gray or white nodules or granules on the visceral or parietal pleura. As the tumor load multiplies, the affected pleura becomes progressively thicker, and in its later stages, the tumor may eventually encase the entire hemithorax. The tumor may advance and spread to the diaphragm, liver, the parietal pleura of the opposite side, or even the pericardium. Hematologic spread has been identified in approximately half of affected patients.

Mesothelioma is classified into three discrete types: epithelial (50% of all cases), mesenchymal (16%), or mixed (34%). Epithelial tumors may appear in cordlike or sheetlike patterns, but they may also show papillary or tubular arrangements. Mesenchymal tumors have been described as having cells that are spindlelike and contain elongated nuclei. The mixed form has both spindle-shaped cells and features of the epithelial tumor.

Diagnosis

Malignant mesothelioma most commonly manifests in the sixth decade of life. Patients often present with nonpleuritic chest pain and dyspnea, although some have shoulder or upper abdominal pain referred from areas of diaphragmatic involvement. Pleural effusions are common at presentation; fever and weight loss may occur. Rarely, mesothelioma may metastasize to the skin, in which case biopsy of skin lesions can be used to establish a diagnosis.

Radiographs commonly show pleural effusions, along with pleural plaques in the opposite hemithorax. As the disease progresses, mediastinal widening, soft tissue masses, and enlargement of the cardiac silhouette are seen on chest radiograph. Chest CT scans are valuable in the evaluation of mesothelioma because large pleural effusions may make evaluation of pleural lesions quite difficult. Chest CT shows thickened pleura with a nodular margin. The major fissure may also be abnormal, as a result of fibrosis or tumor invasion.

Evaluation of pleural fluid reveals a cellular serosanguineous exudate that contains not only benign and malignant mesothelial cells but also varying numbers of lymphocytes and polymorphonuclear leukocytes. Pleural fluid pH and glucose levels may be significantly diminished in patients with mesothelioma.⁵⁰

Diagnostic tissue for malignant mesothelioma is obtained in nearly all patients by thoracoscopy or open thoracotomy. Because of the varying microscopic features in isolated lesions, multiple biopsies should be obtained. Histochemical staining using the periodic acid-Schiff method, immunohistochemical testing with monoclonal antibodies, and electron microscopy have all been used to differentiate malignant mesothelioma from metastatic adenocarcinoma. Definite pathologic diagnosis of a mesothelioma, however, relies on electron microscopic findings. Long microvilli, identified by electron microscopy, are characteristic of a mesothelioma and distinguish it from an adenocarcinoma, which characteristically has very short microvilli.

Management

Although chemotherapy, gene therapy, and surgical interventions have been attempted, there is currently no effective life-prolonging therapy for malignant mesothelioma. Mesotheliomas are not responsive to radiation. Median survival of patients with malignant mesothelioma has been reported at about 18 months.

Industrial hygiene involves recognizing and testing for hazards and modifying the work environment where occupational health hazards exist. Once a complete survey of the manufacturing or production process involved has been completed (including a thorough understanding of the workplace environment), specific exposures can be measured and compared with existing standards. Exposures may be measured by devices that monitor the air immediately surrounding an individual worker or that monitor an entire work area. If unacceptable levels of a substance are identified, all possible means of substituting that substance with a nontoxic product should be explored. Recommendations should be made for encouraging employers to minimize exposures among all employees through engineering controls and improved ventilation.

Personal respiratory protection may be required for workers exposed to substances that can cause pulmonary disease. However, personal protection is less desirable than other methods of preventing exposure (i.e., substitution and ventilation) because it is difficult to ensure that every worker uses the equipment properly. Respirators provide a method of temporary protection from airborne substances ranging from benign odoriferous fumes to toxic materials that are potentially life-threatening. Employers are responsible for instituting the use of respiratory protection, providing appropriate equipment, and ensuring that the equipment meets established standards. Programs for proper maintenance and inspection of the respirator must also be implemented.

Respirators fall into three general classifications: air-purifying respirators, atmosphere-supplying respirators, and a combination of the two. Air-purifying respirators contain a mechanical filter consisting of a fibrous padded mesh, which removes particulate matter from the air. Inhaled air is drawn in through filters before entering the face piece, and exhaled air is guided out through a different pathway, using a system of valves in the mask itself or through air-tight tubing. Cartridges and canisters are occasionally used for removal of specific gases or vapors. Atmosphere-supplying respirators provide a portable external source of oxygen and virtually eliminate exposure to worksite air.

In summary, a well-supervised control program emphasizes substitution of the inciting agent as a first line of prevention. If substitution is unrealistic or infeasible, then isolating the substance from the majority of workers through administrative controls, local exhaust ventilation, or personal protection may be required.

The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.

Figure 1 Seward Hung.