© 2003 American Thoracic Society
Proceedings of the First Jack Pepys Occupational Asthma SymposiumTHIS STATEMENT OF THE AMERICAN THORACIC SOCIETY (ATS) WAS APPROVED BY THE ATS BOARD OF DIRECTORS, MARCH 2002I. Introduction Moira Chan-Yeung, Jean-Luc Malo, Susan M. Tarlo II. A Historical Perspective of Occupational Asthma with a Special Account on the Contribution by Professor Jack Pepys Leonard Bernstein III. How Often Does It Occur? Jean-Luc Malo and Denyse Gautrin IV. Occupational Asthma With Latency (Sensitizer-Induced Occupational Asthma): Factors Predisposing To Sensitization, Development and Persistence Of Symptoms Christina Mapp and A. Newman-Taylor V. Immunochemical Measurement Of Occupational Aeroallergenic Bioaerosols: Determination of Permisable Exposure Limits? Mark C. Swanson VI. Exposure To Chemical Agents Guy Perrault and Jaques Lesage VII. RADS – A Special Entity? The Role Of Irritant Exposures In Asthma Paul D. Blanc VIII. Diagnosis And Management Of Occupational Asthma Susan M. Tarlo and Olivier Vandenplas* IX. Why And How To Compensate Workers Who Develop Occupational Asthma? Andre Cartier X. Prevention Of Occupational Asthma Jean-Luc Malo XI. Recommendations Of Working Groups XII. Addendum: Lung Health and the Canadian Environment: a review of results of this study to date which are relevant to this workshop Margaret R. Becklake and Moira Chan-Yeung
Because Canada has played a leading role in the field, we thought this country would be an appropriate venue for the workshop. We took advantage of the ATS meeting held in Toronto to schedule the event. Together we chose to name the workshop after Jack Pepys as a tribute to the memory of this outstanding clinician and researcher, a man justifiably known as the "father of occupational asthma." There were two purposes for this meeting. First, for the specialists in the field, and there were about 50 of us here, it presented an opportunity to discuss the major issues and gave us the contact we needed to prepare recommendations for international studies. Second, for the general audience interested in occupational asthma (OA), it provided a state-of-the-art into the state of scientific knowledge about the condition as well as its controversies and challenges. We were honored to have the support of several prestigious organizations for this meeting: the American Thoracic Society, the workers' compensation agencies in Québec, the Commission de la santé et sécurité du travail, and in Ontario, the Workplace Safety and Insurance Board, as well as the Research Institute of the WCB in Quebec, the Institut de recherche en santé en sécurité du travail. We are indebted to the other international members of the scientific committee, Tony Newman Taylor, David Bernstein, and Cristina Mapp for their insightful criticism and input into the scientific program. The working definition that was used during the symposium is the one achieved by consensus in the most recent edition of Asthma in the Workplace; that is: "Occupational asthma is a disease characterized by variable airflow limitation and/or airway hyperresponsiveness due to causes and conditions attributable to a particular occupational environment and not to stimuli encountered outside the workplace. Two types of occupational asthma are distinguished by whether they appear after a latency period: 1) Immunological, characterized by a latency period, encompassing a) that caused by high and low-molecular-weight agents for which an immunologic (IgE) mechanism has been proven, and b) that caused by agents (e.g., western red cedar) for which a specific immune mechanism has not been identified. 2) Nonimmunological i.e., irritant induced asthma or reactive airways dysfunction syndrome (RADS) which may occur after single or multiple exposures to non-specific irritants at high concentrations" (1).
The evolution of OA as a specific clinical entity was only possible after a unique convergence of advances in immunology and pulmonary pathophysiology at the mid-20th century mark. Therefore, this appears to be the most appropriate vantage point for comparing the earliest stepping stones with contemporary progress that now facilitate the diagnosis and prevention of OA.
HISTORICAL PERSPECTIVE OF OCCUPATIONAL ASTHMA It was not until the Italian renaissance that a direct connection between the occupational environment and pulmonary diseases was first observed by physicians in the famous Italian medical schools of that era (2). Magnus described respiratory symptoms among threshers of grain in 1555. Both Paracelsus and Agricola recognized the harmful effects of metallic dusts in the sixteenth century. But it remained for Bernardino Ramazzini to clearly describe occupational diseases for the first time in bakers, handlers of old clothes, and workers with flax, hemp, and silk (2). The illnesses that he recognized in sifters and measurers of grain probably included asthma, mill fever, and hypersensitivity pneumonitis. Moreover, he noted that working in ghettos where underventilated, crowded conditions prevailed was a special risk factor in workers repairing old mattresses and/or carding used wool. The next step arose with the Industrial Revolution in the UK. Charles Thackrah published in 1832 a fine book on the effects of arts, trades, and professional and civic status and habits of living on health and longevity in which he mentioned the occurrence of probable asthma and/or respiratory symptoms in coffee roasters, malters, hairdressers, and pharmacists (2). The classic complex of Monday morning symptoms that occurs in flax and textile workers was reported by Mareska and Heyman in 1845, and Proust introduced the term "byssinosis" in 1877. In the same years, Dr. Charles Blackley inhaled a grass pollen extract and, in this, paved the way to the use of inhalation challenges in humans, a topic which will represent a major contribution of professor Jack Pepys in the field of OA one century later. The confluence of accelerated progress in immunology and pulmonary pathophysiology in the 20th Century played a key role in the evolution of OA as a clinical entity. On the one hand, namely in the field of allergy, landmark contributions about the role of allergy were made by Freeman (3) and Cooke (4). Squire modified Blackley's scratch test into a prick/puncture test (2). In addition, without Karl Landsteiner's basic research on the specificity of hapten-protein conjugates, none of the recent investigations about the role of chemical hypersensitivity in the workplace would have been possible (5). The histopathologic nature of asthma was first described by Huber/Koessler in the early 1930s. Ishizaka and coworkers discovered IgE, and Wide and colleagues adapted it as a pragmatic serologic test for specific hypersensitivity (5, 6, 7). These diagnostic techniques ultimately proved to be essential for evaluating many types of OA induced by proteins. On the other hand, namely in the field of lung physiology, John Hutchinson's invention of the spirometer in 1841 as a means of measuring vital capacity paved the way for a series of elegant experiments by Baldwin/Cournand and Richards dealing with normal and abnormal pulmonary physiology, which later won two of them the Nobel Prize. These investigators were succeeded by a brilliant young generation of pulmonary physiologists (Riley, Forster, Tiffeneau, and Dubois), who discovered clinically practical ways of measuring gas transfer, airway resistance, and elastic recoil of the lungs. These findings made possible the assessment of airway caliber and responsiveness through the use of bronchial challenges from the 1840s onwards, when almost simultaneously and in rapid succession a spate of bronchoprovocation studies by American and European investigators were reported. The concept of nonspecific bronchial hyperresponsiveness was also elucidated by several of these early pioneers. The post-World War II technological era created several key, iatrogenic problems vis-a-vis bronchial asthma in the workplace. Polyurethanes and resins, the basic commodities of the plastic industry, required highly reactive chemicals such as polyisocyanates and the acid anhydrides (2). The advent of enzymes in the detergent industry resulted in a significant incidence of OA among heavily exposed workers (2). This experience served as a prototype for recognizing the potential hazards of protein sensitizers and how to prevent their ill effects by controlling exposure in the workplace. Many workers developed asthma after exposure to wood dust in Canada and the United States (2). Finally, a new phenomenon of nonimmunologic asthma or the reactive airways dysfunction syndrome was recognized as occurring after the first exposure to a variety of fumes, gases, and many irritant chemicals (8). What will the current century bring? As with naturally occurring asthma, there will be more emphasis on mechanisms (2). Applications of animal models—wild type, knockout, and transgenic—will be pursued more vigorously. The roles of cytokines, chemokines, and the Th1/Th2 paradigm will be explored. Genetic susceptibility will most certainly be in the forefront. Finally, research about the why and hows of RADS will be expanded.
CONTRIBUTION OF PROFESSOR JACK PEPYS His first major work was a combined immunologic clinical investigation about the role of Aspergillus species in a spectrum of pulmonary diseases ranging from asthma to hypersensitivity pneumonitis (9). In particular, his findings contributed greatly to establishing diagnostic criteria for allergic bronchopulmonary aspergillosis, a condition first identified in 1952 by Hinson, Moon, and Plummer. His laboratory was the first to emphasize the importance of precipitins to various peptide and polysaccharide antigens of Aspergillus fumigatus. He also extended these studies to Candida albicans (9). His next project, which was almost contemporary to the pioneer work of Barbee and coworkers in establishing the cause of farmer's lung, was a comprehensive series of investigations of extrinsic allergic alveolitis caused by a variety of thermoactinomycetes, vegetable dusts, and protein antigens. By a combination of inhalation and serologic tests, it was established that Micromonospora faeni was the agent in moldy hay causing farmer's lung (9). The principles elaborated in this study provided a sound basis for investigation of other organic dusts and proteins subsequently assessed in his and other laboratories. Jack was an avid teacher. Teaching has its own rewards, but Jack received one that was totally unexpected. An occupational physician by the name of Dr. Michael Flindt had attended one of Jack's lectures in 1966. Two years later, when Flindt first suspected that detergent enzymes were human sensitizers, he consulted Jack for assistance and collaboration. Jack prepared the first enzyme skin prick test reagents that elicited positive results in symptomatic enzyme workers(10). One month later, Fred Hargreave and Jack demonstrated positive inhalation tests in three of these workers. These findings were soon confirmed in other clinics in the UK and the United States (11). There followed a rapid succession of clinical studies dealing with OA induced by a variety of chemicals including isocyanates, drugs, colophony, and acid anhydrides (2). As the modern father of OA, Jack Pepys was highly respected by students and peers alike. A significant proportion of future progress in OA during the next millennium will be based on Jack's unique contributions to OA. A researcher/teacher can experience no greater fulfillment of a life's work than to be honored in this way, by a named symposium dedicated to Jack Pepys as the modern father of OA. As Jack Pepys' collegial peer who respected his work and advice, I want to thank him on behalf of all of us, especially as we anticipate that much future progress of OA in the next millennium will be based on Jack's unique contributions to OA.
In recent years, an important development in the field of OA is related to a broader and more satisfactory estimate of the frequency of this condition. The role of epidemiology and methodologic issues of this discipline, with detailed discussion of study designs as well as of outcome measurements (questionnaires, immunologic assessment, functional evaluation) and assessment of risk factors (exposure and host markers), in the specific field of OA have been thoroughly reviewed in a recent contribution (12). Two points are worth being outlined: (1) looser definitions and means are used to ascertain OA for epidemiologic studies than for medical or medicolegal purposes; and (2) selection bias due to the "healthy" worker effect is a more important concern in OA than in other occupational lung diseases. The features considered essential to establishing a clinical diagnosis of OA may differ among clinicians and jurisdictions. In epidemiologic studies the definition of OA usually varies according to the circumstances and purposes of the study (12).
EPIDEMIOLOGICAL CONSIDERATIONS
How Often Does OA Occur? Estimates of incidence vary considerably between countries, ranging from 3–18 per million per year in the United States (16) to 187 per million per year in Finland (18), with 20–40 per million in the UK (6) and about 50 per million in Canadian sentinel projects as reported by Meredith and Nordman (19). In Quebec, medicolegal statistics indicate an annual incidence of 25 per million (19). These differences are likely due in part to the varying purposes for which the information was collected and the different methods used; they may also be a reflection of the differences in local industrial activities. However, within-country differences are an important source of information for time trends (12). Several studies suggested an increase in the incidence over the 1980s (18, 20). Cases of work-related asthma may include new-onset asthma caused by workplace exposure to sensitizers or irritants and work-aggravated asthma; in the United States, the incidence of OA was estimated at 80.9% among cases of work-related asthma (16). Few valid prospective studies in workers at risk of developing OA have been performed, partly because of the difficulty of maintaining a high participation rate. In a three-and-a-half-years prospective study, Cullinan and coworkers looked at the incidence of work-related symptoms in a cohort of 342 laboratory-animal workers in the UK (21). They found that 37 subjects (11%) seen every 6 months for 3.5 years developed skin reactivity to rat urine and symptoms (eye/nose, chest, or skin), an incidence of 4.1/100 person-years, whereas 36 employees developed work-related chest symptoms, an incidence of 3.5/100 person-years (21). In Canada, in a prospective study investigating the incidence of OA among 769 apprentices in animal health technology, pastry-making, and dental hygiene, a questionnaire and skin-prick tests with work-related allergens were administered on entry and at follow-up visits at the end of each year of the three- to four-year programs; responsiveness to inhaled methacholine was also assessed at baseline and at follow-up in apprentices who developed a new skin sensitization to laboratory animal–derived allergens. The incidence of specific skin sensitization to animal-derived antigens in the animal health program was 8.9/100 person-year (22). The incidence of skin sensitization to latex was 2.5/100 person-year in the dental hygiene program (23).Twenty-eight apprentices (7.5%) in the animal health technology program satisfied the study definition for incident OA, the incidence of OA being 2.7/100 person-year (24).
Prevalence. Recently, a number of community-based studies performed in several countries have shown a consistent relationship between occupational exposure and wheezing. Despite some limitations of this type of study, significant relationships were found between wheezing complaints and occupational exposure to dust alone or dust with fumes and/or gases in most of these studies, as summarized in the article by Becklake and coworkers (12). Among studies performed following the protocol for the European Community Health Survey, there were large differences in the frequency of wheezing attributable to occupational exposures (from 3 to 20%) despite the fact that the same methodology was used. A recent study performed in six Canadian cities proposes a figure of work-attributable risk as high as 36% for what is referred to as possible or probable OA (25). Recently, Blanc and Toren reviewed and assessed citations from 1966 to 1999 to extract or derive risk estimates of asthma attributable to workplace factors; they came to the conclusion that "occupational factors are associated with about 1 in 10 cases of adult asthma, including new onset disease and reactivation of preexisting asthma" (15). The frequency of adult-onset asthma with an occupational component can be estimated from data in medical records by determining the proportion of subjects with asthma seen in a general or specialized practice for whom OA can be suspected. This approach has recently been favored by Tarlo and coworkers (26). These authors found that out of 731 adult subjects with asthma seen in a secondary and tertiary asthma clinic, 435 had adult-onset asthma; of these, 310 were employed at the time of the visit. Fifty-one of the 310 subjects (16%) reported that their asthma was worse at work. The particular interest of this study lies in the fact that the authors tried to estimate the likelihood of OA in these 51 subjects by reviewing their charts for objective evidence to support a work relationship, though the investigational tools were clearly incomplete for many subjects. Sixteen subjects—5% of the 310 adult-onset subjects with asthma who were employed at the time of the visit—had probable OA.
Frequency of Irritant-induced Asthma The number of cases of OA accepted by the WCB in Québec has remained relatively stable in recent years, accounting for approximately 50 to 70 new cases each year. In Finland, the number of accepted cases doubled from 1981 to 1991, at which time there were almost 400 accepted claims (28). It would also be relevant to document the frequency of OA in developing countries where no surveys have been performed. The impact of prevention programs and screening measures on incidence figures needs to be assessed.
Important Causes of Occupational Asthma Although textbooks, review articles, and web sites (see www.cssst.qc.ca) do present extensive tables of all documented causes of OA, the information should also be made available in a form that is classified by occupation at risk. Such combined information has been prepared by Henriette Dhivert-Donnadieu and coworkers in Montpellier on the asthmanet.com web site.
Conclusions In field studies, questionnaires should be combined with skin testing and/or assessment of bronchial responsiveness. The information on frequency, causal agents, and jobs at risk should be provided on web sites, some currently existing. Finally, irritant-induced asthma is a significant problem but not yet to the extent of OA due to "sensitization."
INTRODUCTION In common with asthma developing in childhood, OA is probably the outcome of an interaction between multiple genetic, environmental, and behavioral influences. Investigation of the determinants of OA has several advantages over similar investigations of asthma in childhood. Cases of asthma can be accurately identified, as can their denominator population, together with the relevant (often measured) exposures experienced; the second and third of these can prove particularly difficult in studies of non-OA. Several studies of OA have investigated exposure–response relationships in relation to a specific cause of asthma, the effect of behavioral influences (particularly cigarette smoking), potential genetic susceptibility, and, in a few cases, genetic–environmental interactions. Environmental factors can be either high-molecular-weight agents, usually allergens such as proteins from laboratory animals, flour, or plants, or low-molecular-weight-agents, usually chemicals, such as diisocyanates, biocides, or drugs. The mechanism for sensitization to high- and some low-molecular-weight agents is IgE-mediated. Although some studies suggest that environmental factors could be a direct cause of asthma, more likely they are an indirect cause, leading to asthma in a two-phase process. The first step involving a phase of induction (immunologic memory development favoring allergic sensitization) is regulated by interactions between Th1 and Th2 cytokines. The second effector phase involves the expression of Th2 inflammation in target tissues of sensitized individuals (29). Although considerable insight has been gained into the immune mechanisms involved in the pathogenesis of OA, much remains to be learned. This section will discuss first what is known about the mechanisms that lead to the development of sensitization to allergens and/or chemicals, and then the mechanisms that lead to the expression and persistence of OA. We then briefly discuss animal models for studying OA and end by suggesting directions for future studies. This section considers only OA that develops after a latency period, not the uncommon type of OA that develops without a latency period, for example following spills, or high concentrations of irritants or chemicals.
CAUSES OF SENSITIZATION Adult asthma includes persistent childhood asthma, early-onset asthma that is reactivated in adulthood, and new-onset disease. Occupational factors are associated with about 1 in 10 cases of adult asthma (15), including both reactivation and new-onset disease (22, 33–37). Occupational studies have provided some evidence for a direct causal role of allergen and/or chemical exposure in the development of asthma. However, as in the case in the general population, specific allergen exposure may determine the specificity of sensitization in susceptible individuals (30). It is well established that genetic determinants play a role in the susceptibility to the development of asthma (33). It is likely that asthma is a polygenic disease in which many genetic variants may determine the genetic–environmental interactions that determine susceptibility to asthma. The search for the genes involved in OA is just beginning. To date, no genes that cause OA have been definitely identified. Evidence for human leukocyte antigen (HLA) associations is available only for a few sensitizing agents (34–37), and has not been confirmed for any of them (38, 39). Evidence for a significant association can imply a causal relationship, but can occur by chance (because of multiple comparisons, often made without prior hypothesis) by confounding from population admixture, or from linkage disequilibrium. Confidence in a significant association between a particular HLA polymorphism and sensitization or asthma comes from its strength and repeatability in two or more study populations. However, two pools of genes that might be involved in causing OA have been suggested. First, it has been shown that HLA class II molecules encoded by the major histocompatibility (MHC) complex genes on chromosome 6p are required for the presentation of an antigen to a T cell receptor to initiate the chain of events that leads to an antibody response. Preliminary data obtained in occupational studies suggest that MHC class II proteins may be important factors for the specificity of the response to occupational sensitizers such as acid anhydrides, diisocyanates, and platinum salts. Several studies have now reported significant associations between HLA haplotype and sensitization or asthma. Young and colleagues reported an association between HLADR3 and specific IgE to TMA, with an odds ratio of 16 in comparison to factory referents with a similar duration and intensity of exposure (35). Interestingly, this relationship was not observed in cases with specific IgE to phthalic anhydride (PA). In a study of South African platinum refinery workers, Newman Taylor and colleagues found in cases with a skin test response to ammonium hexachloroplatinate (ACP) an excess of ‘HLA DR3 and deficit of HLA DR6, as compared with referents matched on ethnic origin, intensity, and duration of exposure (40). The odds of a case being HLA DR3–positive or HLA DR6–negative were greater in the "low" than in the "high" exposure groups. A second pool of candidate genes that could be involved in causing OA is that containing the members of the glutathione-S-transferase (GST) superfamily. This superfamily of genes is critical for protecting cells from the formation of reactive oxygen species (ROS). ROS, which can be generated by several types of airway cell, including macrophages, eosinophils, and neutrophils, form in response to oxidative stress (41). Oxidative stress, a key component of airway inflammation, is a main feature of asthma. Evidence supporting the possibility that GST superfamily genes lead to asthma is that individuals differ in their ability to deal with an oxidative burden, and such differences are in part genetically determined. We recently found that, in OA induced by diisocyanates, the frequency of GSTP1 Val/Val genotype was significantly lower in individuals with asthma. Similarly, the frequency of this genotype was significantly lower in subjects with moderate/severe airway hyperresponsiveness to methacholine suggesting that homozygosity for the GSTP1*Val allele confers protection against the development of toluene diisocyanate asthma and nonspecific airway hyperresponsiveness. The protective effect increases in proportion to the duration of exposure to the sensitizing agent (42). GSTP1 may play a role in modulating and maintaining airway inflammation and airway hyperresponsiveness in both allergen- and chemical-induced asthma. The relative role of genetic factors and environmental factors (i.e., exposure to a sensitizing agent) at the onset of sensitization has been examined in IgE-mediated sensitization (43, 44). Atopy, much more than the degree of exposure, was the principal determinant in the development of symptoms. Atopy is an important risk factor for sensitization to high-molecular-weight agents. Studies that assessed the natural history of OA from the time of exposure to high-molecular-weight allergens in the workplace began have demonstrated that in this type I immune response, the risk of specific sensitization to these allergens is related to atopy and nonspecific airway responsiveness, that immunologic sensitization may occur after a short latency period, that the concentration level of aeroallergens is not the only determinant for the development of sensitization, and that some allergens are more potent than others (e.g., laboratory animals more than flour or latex) (22). Low-molecular-weight agents are also well-recognized causes of OA. In the case of immunologic asthma, some agents (e.g., anhydrides) induce asthma via a type I IgE-mediated mechanism, whereas for others (e.g., diisocyanates, plicatic acid) the mechanism is less defined. Atopy is not a risk factor for asthma induced by either red cedar (45) or diisocyanates (46), but a link to the HLA system has been demonstrated for these agents, suggesting the role of genetic factors for the expression of the disease (36, 37). Tobacco smoking increases the risk of sensitization and asthma, particularly to its low-molecular-weight chemical causes, such as complex platinum salts (47) and the acid anhydride (48) tetrachlorophthalic anhydride (TCPA), chemicals which cause asthma that is associated with specific IgE production. In contrast, smoking does not increase the risk of asthma caused by agents such as isocyanates and colophony, where specific IgE does not unusually accompany the development of asthma. In one study of platinum refinery workers, smoking was shown to interact with exposure, increasing the risk of sensitization in those in both high- (> 2 µg/m3) and low (< 2 µg/m3)-exposure categories (49). Exposure has not been reported in other studies in a manner which would allow analysis of a possible interaction. It is likely that low-molecular-weight agents act as haptens, combining with human proteins in the respiratory tract to become complete immunogens. Evidence for a structural basis for human respiratory sensitization due to chemicals, usually of low-molecular weight, is that certain structural fragments are related to respiratory sensitizing chemicals, and that certain physical properties of chemicals, such as molecular weight and water solubility, are associated with chemicals that cause respiratory sensitization (50). The isocyanate fragment, anhydrides, and some substituted aromatic fragments are electrophilic functionalities which can react with nucleophilic moieties, such as amino groups of proteins. Sensitizers had greater hydrophilicity and lower log P (octanol/water partition coefficient) than did nonsensitizers. Because airways contain hydrophilic secretions, molecules with hydrophobic regions may less readily reach reactive sites on respiratory cells. The findings that structural fragments are associated with activity are based on only forty active chemicals that met the criteria for inclusion in the structure-activity model of chemicals. However, the model yielded a sensitivity of 0.95, and a specificity of 0.95 (51). Sensitization to low-molecular-weight agents requires a shorter interval than sensitization to high-molecular-weight agents (52). Among those with OA, approximately 40% of subjects exposed to western red cedar and diisocyanates developed symptoms within the first year after exposure started, whereas only 18% of subjects exposed to high-molecular-weight agents developed asthma during this period.
IMMUNOLOGIC ASTHMA
The inflammatory process is modulated or prolonged by mediators released in the IgE response. In the IgE response, antigen binds to surface-bound IgE and stimulates mast cell release of histamine, leukotrienes, prostaglandin D2, thromboxane B2, platelet-activating factor (PAF), and several cytokines, including tumor necrosis factor- Although OA studies generally treated sensitization and asthma as equivalent outcomes, the progression from a normal state to the development of OA after exposure to allergens or chemicals may not be concurrent with the development of sensitization (54). Although in most cases, OA induced by high-molecular-weight agents is accompanied by the production of allergen-specific IgE antibodies, for OA induced by low-molecular-weight agents, only in some cases are specific antibodies detectable (55–57). The absence of antibodies in some patients with OA has led some investigators to suggest nonimmunologic mechanisms for the development of asthma. However, the evidence for an immunologic basis of asthma induced by two low-molecular-weight agents, such as diisocyanates and western red cedar, is quite strong. One line of evidence is that the pathology of low-molecular-weight asthma, based on BAL, bronchial biopsy, and induced sputum is similar to that of atopic asthma: subepithelial fibrosis and increased numbers of T-lymphocytes and eosinophils that exhibit signs of activation (58–60). A second line of evidence is provided from inhalation challenge and genetic studies. Evidence for T cell-mediated immunity has also been provided for asthma induced by cobalt and nickel (61, 62), and for OA induced by high-molecular-weight agents (63). This asthma may be driven and maintained by the persistence of a specialized subset of chronically activated T-memory cells sensitized against an array of allergenic, viral, or occupational agents (64). T cells lead the inflammatory process, and key effector cells, such as eosinophils, mast cells, epithelial cells, and neutrophils, through the release of several inflammatory mediators, cause the characteristic pathologic phenotype of asthma, i.e., smooth muscle contraction, mucus hypersecretion, plasma exudation, edema, and epithelial damage. In long-term follow-up studies, OA has been shown to be permanent, both in individuals removed and not removed from exposure (65). When an individual is no longer exposed to the sensitizing agent, asthma improves but is generally not cured. When patients who are no longer exposed to occupational agents are treated with glucocorticoids, the asthma is further improved, though again not cured (66). These findings suggest that structural changes ("remodeling") in the airways are important for the persistence of OA (67). However, the factors that initiate remodeling and contribute to its progression and how these changes alter airway function are poorly understood. Thus, the association between asthma severity and airway remodeling remains controversial (68). Recent findings are beginning to shed some light on this association. One recent study showed that ongoing inflammation and subepithelial fibrosis are linked to the persistence of exacerbations and nonspecific airway hyperresponsiveness (69). Chronic airway inflammation may contribute to remodeling by promoting turnover of extracellular matrix, producing profibrogenic factors, and damaging the epithelium (70). In support of these possibilities, in chronic asthma, epithelium manifests increased fragility and a phenotype characterized by a continuous source of proinflammatory products as well as growth factors that drive airway wall remodeling (71). The effector cells that secrete these products and thus maintain airway inflammation and contribute to airway remodeling may be airway smooth muscle cells, which can secrete several cytokines, chemoattractants (72), growth factors, and matrix metalloproteinases (73). In addition, bronchial vessels may play a role in airway remodeling by increasing the airway wall thickness through the processes of angiogenesis, dilatation, or permeability (74). Further, sensory neuropeptides may play a role in inflammation as well as in repair (75). Finally, key cells such as eosinophils and macrophages are important factors in the development of fibrosis (76, 77). Eosinophils produce ECP, MBP, metalloproteinases (MMP-3, -9), and reactive oxygen species (ROS), and macrophages secrete growth-promoting factors for fibroblasts, cytokines, and growth factors, such as fibroblast growth factor (b-FGF), transforming growth factor-ß (TGFß), and insulin growth factor (IGF), which can be important in fibrosis. Thus, epithelial cells, smooth muscle cells, bronchial vessels, neuropeptides, eosinophils, and macrophages may all contribute to airway remodeling and thus maintain airway inflammation in workers with asthma who are no longer exposed to allergens or chemicals in the occupational environment.
ANIMAL MODELS
SUMMARY
Determination of Permissable Exposure Limits? Site air sampling and immunochemical analysis are a prerequisite to understanding the magnitude and extent of airborne dispersion of workplace aeroallergens and planning abatement measures. Measurements are also a valuable and underused approach for inclusion in clinical documentation of OA. Once a problem is recognized, occupational aeroallergen monitoring can improve the effectiveness of preventive health measures, thereby reducing health care costs while maintaining or increasing the quality of life in the work environment.
REVIEW AND COMMENTS ON QUANTITATION OF AIRBORNE PROTEINACEOUS OCCUPATIONAL AGENTS
Air Sampling and Equipment Proper filter selection is essential, including low airflow resistance and efficient retention of respirable particles. The filter should permit high yields of allergen recovery and allow extraction in small volumes (1 ml or less) so that concentration of the extract is not needed. Special bilaminate polytetrafluoroethylene (PTFE or Teflon) filters offer these features. Area sampling is the most appropriate means to indicate the presence or absence of offending allergens and to confirm the identity of the allergen. Automated samplers with programmable filter-changing devices simplify collection of sequential samples, and are well suited for unattended long-term collections to monitor the success of control measures. Personal breathing zone sampling is used to define particular job tasks that are associated with heavy and likely dangerous exposure. Such equipment also allows evaluation of remedial measures that have been taken.
Immunoassay Reference Standards It is also useful to visualize the relevant allergens extracted from complex source material by immunoblotting.
Antibodies For some applications, it is best to employ human IgE antibody. It may be the only antiserum available, and has the advantage of assuring that the substance causing the disease is being measured when the identity of the allergenic molecules is uncertain or the dust contains a complex mixture of allergens. If a human IgE system is adopted for the study, it is desirable to obtain a large pool, at least 250 ml from each of five to ten donors, to assure sufficient antibody to complete the entire project. The antibody remains stable for several years stored at –70°C.
Assay Design In addition, it is possible to use an animal polyclonal antiserum for capture and a human IgE antibody containing serum for detection. The amount of IgE antibody bound to the plate in this sandwich assay is measured with anti-IgE. Inhibition assays are used when there is only a single antibody available.
TOWARD THE DEVELOPMENT OF "PERMISSIBLE EXPOSURE LIMITS" Certainly, in situations where a purified allergen is aerosolized, such as enzymes, these concentration ranges will no doubt be too liberal by as much as an order of magnitude. There is general agreement that the TLV for subtilisins (60 ng/m3) was set because of analytical limitation and not clinical observation. These analytical limits no longer apply, and considerable thought and study should be given to the exposure–response relationships involved with OA associated with these bioaerosols. In the same way as stringent standards have been proposed and applied for exposure to inorganic dusts such as silica and asbestos, it is of outmost importance to evolve toward a situation in which international standards will be adhered to. Although it remains to be determined whether peak exposures or mean exposures are more relevant in inducing sensitization and development of OA, studies in bakers have shown that sensitization is unlikely to occur below concentrations of 0.5 mg/m3 of dust during a workshift (85). Similar standards have to be established for other high-molecular-weight agents as presented and discussed (86). In conclusion, in recent years, assessment of the working environment has improved due to improvement in methodology and the use of personal sampling. The use of immunologic techniques has enabled the measurement of high-molecular-weight allergens in the workplace. These technical achievements should pave the way to the establishment of PEL at which sensitization is unlikely to occur.
INTRODUCTION This section is an overview on assessment of exposure to low-molecular-weight asthma agents by chemical assays, which is proposed in greater details in a recent chapter (87). Herein, we plan to outline and propose discussion of some key features.
EVALUATION STRATEGY AS RELATED TO OA
MONITORING METHODS
Sampling Techniques and Analytical Methods Various analytical methods are used to quantify the sample. This includes gas chromatography, HPLC, atomic absorption spectrophotometry in the case of metallic atoms, spectrometry, infrared spectrophotometry, ion chromatography, mass-spectometry, etc. It is beyond the scope of this presentation to discuss the indications, limitations, and advantages of each of this processes.
Evaluation of Exposure to Specific Sensitizing Agents
Acid anhydrides.
Formaldehyde and other aldehydes.
Amines.
Colophony and fluxes.
Metals.
Other substances.
CONCLUSIONS
The Role of Irritant Exposures in Asthma The issue of irritant-induced asthma has engendered a fair amount of controversy since the specific syndrome descriptor, Reactive Airways Dysfunction Syndrome (RADS), was first introduced by Brooks and coworkers in 1985 (8). The purpose of this review is to place irritant-induced asthma in its epidemiologic context. By doing so, the goal is to better understand the determinants of irritant-induced asthma, thus gaining insights into its mechanisms, natural history, and potential public health importance. The initial debate over irritant-induced asthma was focused on its acceptance or rejection as a discrete syndrome which occurs sporadically if not predictably. The subsequent case report literature has more than put that matter to rest. These reports have been well summarized by the excellent review of Alberts and DoPico (92), which included 28 published reports through 1994 involving 113 individuals with irritant-induced asthma consistent with the original syndrome criteria of RADS. Those RADS-defining criteria were a brief, high-intensity irritant inhalation exposure followed by acute-onset, persistent respiratory symptoms and ongoing airway hyperresponsiveness. Moreover, there has been a wider recognition that irritant-induced respiratory illness has ample historical precedent, dating back to bronchitis among 19th-century bleaching workers and asthma and bronchitis among survivors of WWI irritant gas attacks (93). Subsequent to the case experience summarized by Alberts and DoPico (92), a number of additional case reports have appeared as reviewed (94). Taken as a group, the RADS case experience is dominated by several large outbreak series that have contributed more than one-third of the reported cases (metam sodium, zinc chloride, and 2-diethylaminoethanol). Of the remaining cases, the most common single agents have included chlorine gas or hypochlorite bleach misadventures releasing chlorine, acids, other discrete irritants (for example, bromine or ammonia), and isocyanates (the latter chemical group being both an irritant and a sensitizer). Unfortunately, these case reports have added little to our understanding of the role of irritants in potentially causing asthma, beyond establishing the accuracy of the original observation of RADS. The obvious limitations of this literature include the referral biases inherent in specialty-based or medical-legal referral cases (a common feature of many but not all of these reports), a potential "publication bias" tending to favor novel exposures or unusual exposure scenarios, and, most importantly, the absence in most of the reports (with a few exceptions) of any estimate of the exposed population from which the cases emerge. Without knowing this "denominator" value, the incidence of the syndrome cannot be estimated, nor can predictors of adverse outcome be quantified. One attempt at incidence estimation was based on poison control center cases after chemical inhalation exposure. In a 6-month prospective series of 323 interviewed subjects, 6% had symptoms lasting 14 days or longer (95). Although half the group reported exposure to chemicals independently classified as moderate to severe irritants, the irritant potential of the chemicals was not a predictor of persistent symptoms. In a second study also based on poison control cases, a subgroup of symptomatic subjects were recruited for methacholine challenge (96). Of these, 8 of 10 had airway hyperresponsiveness at 2 weeks; 7 of these 8 were still hyperresponsive at 3 months, even though 4 of the 8 had ceased to be symptomatic. Taken together, these two studies suggest that persistent irritant-induced respiratory symptoms are uncommon after inhalations over a wide spectrum of irritant intensity and severity, but when such symptoms are present they correlate with airway hyperresponsiveness. Three separate cohort investigations (acetic acid, n = 33 subjects; metam sodium, n = 197; and nitrogen tetroxide, n = 234) have estimated new-onset asthma incidence after acute irritant inhalation to range from 3 to 20% (97–99). Another incidence estimate, based on surveillance data in the UK, found that of 589 irritant exposure cases, 26% were symptomatic at 1 month, whereas only 8% were still symptomatic at 3 months (17). Combining all of the cases together (n = 1387) yields a follow-up incidence of 7.2% (95% confidence interval [CI], 6.8–7.6%). Another indirect measure of the incidence of irritant-induced asthma is its frequency relative to "classic" OA in referral-clinic based series and in surveillance data. Classic OA refers to new-onset OA associated with exposure followed by an immunologic response to a high- or low-molecular-weight sensitizer. Although one important investigation of an occupational lung clinic found that cases meeting criteria for RADS had a 1:5 ratio to classic asthma (27), two more recent clinical series (100, 101) have observed ratios closer to 1:1. In contrast, limited data published from the US "SENSOR" surveillance program of work-related asthma still suggests that irritant-induced asthma is less common than classic OA, but these data may reflect the biases inherent in workers' compensation insurance data (16). Comparisons between irritant-induced asthma and classic sensitizer-induced OA may also be useful for the mechanistic insights their differences and similarities may provide. The primary differences between sensitizer- and irritant-induced OA are threefold. Sensitizer-induced asthma requires a latency period, is immunologic, manifesting an anamnestic response by definition, and is marked by specific airway responsiveness upon appropriate challenge with the causative agent. Irritant-induced asthma as defined by RADS criteria is of immediate onset, does not involve specific sensitization, and is characterized by nonspecific airway hyperresponsiveness. Although these differences may be straightforward, the similarities between irritant- and sensitizer-induced asthma are also worth noting: in both, inflammatory cellular responses are a component of their pathophysiology, and antiinflammatory treatment, therefore, is commonly employed in their treatment regimens. As importantly, both can be disabling, even without further exposure (94). Although it is now generally accepted that the phenomenon of irritant-induced asthma does occur, there is no steadfast delineation of its terminology or diagnostic criteria. RADS, in its originally proposed clinical criteria, intentionally excluded exacerbations of preexisting lung disease. It also focused attention on high-intensity, single exposures rather than repeated, intermediate, or lower lever inhalations (8). The broader concept of "irritant-induced asthma" includes scenarios of repeated exposure, although this less narrow definition in and of itself does not advance our understanding of the syndrome or syndromes involved. Overlap in causal agents, particularly asthma after high-level exposure to isocyanates, adds to the nosologic confusion (92, 102). In addition, the range of possible chronic sequelae after irritant respiratory tract exposures, including bronchiolitis obliterans, bronchiectasis, vocal cord dysfunction, cough without airway hyperreactivity, and isolated nasal deficits, including the entity of Reactive Upper Airway Disorder (RUDS) (103, 104), only further serves to complicate the picture. Nonetheless, there are several potential models of human irritant-induced asthma that could provide important information. Smoke inhalation is one of the most overlooked of these. Studies of wildland and urban firefighters, of smoke inhalation victims, and controlled human smoke exposure studies have all demonstrated exposure-related changes in airway responsiveness relevant to mechanisms of irritant-induced asthma (94). Chlorine exposure has also provided a rich vein for research, in part because periodic high-intensity exposures, or "gassings," are endemic to industries where compressed chlorine gas is used (93) and because chlorine, too, can be studied in controlled human exposures. Potroom asthma in the primary aluminum smelting industry may prove to be one of the most important models for irritant-induced asthma (105), although this, like the isocyanate model, may be complicated by overlapping sensitization cases. Candidate industries for the study of lower level, chronic irritant effects include ammonia use in fertilizer, vanadium in metal refining, and oxides of nitrogen from explosives used in mining, one of the earliest irritants systematically studied in terms of airflow obstruction. Future research in the study of irritant-induced asthma must address a critical need for prospective studies with adequate baseline data. Both intermittent, high-level exposures and lower-intensity, chronic exposures are of interest. The potential roles of atopy and cigarette smoking status should also be studied prospectively. Without such studies, we cannot hope to delineate risk factors for the irritant-induced asthma and thus adequately plan prevention strategies. Linking epidemiologic methods with detailed biologic studies in systematically selected subsets of patients should also be a research priority, if we are to better understand the mechanisms of this disease. This has already begun to happen in innovative and important studies of bronchoalveolar lavage after exposure to chlorine (99, 106), sulfur mustard (107), and methyl isocyanate (108). Finally, more attention should be paid in our research agenda to the aggravation of preexisting lung disease if we are to fully meet the challenges of irritant-induced asthma (109).
DIAGNOSIS OF OCCUPATIONAL ASTHMA There is some suggestion that OA remains largely unsuspected by health care providers. A recent survey of asthmatic members of a health maintenance organization in the United States found that only 15% of medical records documented asking about work-related symptoms by general practitioners (109). Furthermore, allergists and chest physicians addressed work-related asthma symptoms in only 50% of the referred patients (109). Improved detection implies that the possibility of OA should be considered by all physicians (general practitioners, chest physicians, allergists, and occupational health physicians) in all working-age individuals with asthma. An occupational history should be part of the initial evaluation of all adults with asthma. However, exposure to potential asthma inducers may remain unrecognized when exposure is indirect or intermittent. The absence of a known sensitizer does not exclude OA, because new causes of OA are reported each year due to rapidly evolving manufacturing processes. Physicians should systematically question patients with asthma about the temporal relationship between symptoms and work exposure by asking whether symptoms improve after several days away from work. Health surveillance programs should periodically assess whether respiratory symptoms develop in workers and whether such symptoms are temporally associated with exposure at work (110). Epidemiologic surveys suggest that questionnaires are sensitive but not specific for identifying OA (12). Physicians should, however, be mindful that questionnaires can be falsely negative, because workers may remain unaware of the association between work and asthma when the onset of OA symptoms is progressive, when there is poor perception of airway obstruction, or when exposure to the offending agent is indirect or intermittent. In addition, fear of job loss may lead workers to deny symptoms on a surveillance questionnaire. The diagnosis of OA should be investigated before advising workers to leave their workplace, because prolonged avoidance of exposure may influence the reliability of diagnostic procedures (111). It may be easier to perform investigations for OA, such as serial peak expiratory flow monitoring or inhalation challenges, at work when the subject has not resigned his or her job. The diagnosis should be investigated as soon as possible to prevent deterioration of asthma. Appropriate medical management and compensation decisions require an objective assessment of suspected OA as advised by recent guidelines (112) and consensus statements (113). The differential diagnosis of asthma in the workplace besides OA includes coincidental non-OA which is common and frequently has its initial onset in adult life (or recurrence after childhood asthma), which can complicate diagnosis of OA. Another possible diagnosis is the work-related aggravation of asthma in a nonspecific manner by exposure to dust, smoke, fumes, and low-level irritant chemicals, or by cold, dry air or exercise at work. In addition, symptoms that mimic asthma may be due to other conditions such as chronic bronchitis, hyperventilation, vocal cord dysfunction, or rhinitis. Therefore, although a history of asthma symptoms starting during a working period, especially with improvement on weekends or holidays off work, is suggestive of OA, evidence is needed (1) to verify that symptoms truly are on the basis of asthma, and (2) to document the relationship of asthma to the workplace exposure. The diagnosis of asthma is objectively reached by spirometry pre- and postbronchodilator, and/or a histamine or methacholine challenge test, preferably performed toward the end of a typical work week and within 24 hours of the occurrence of symptoms. Results at this time which do not show evidence of asthma virtually exclude a diagnosis of OA. Assessment of the work exposure from the patient's history can be supplemented by means of material safety data sheets (MSDS) from the workplace, and occupational hygienist worksite visit reports when available. However, agents present as less than 1% of the content of a material, and previously unrecognized respiratory sensitizers may not be identified by these means. Lists of reported sensitizers have been published (114) and are available on the internet (see www.cssst.qc.ca or www.asmanet.com), but additional agents are described each year and may not be listed in the MSDS. The diagnosis of irritant-induced asthma or RADS currently remains circumstantial, based on the history, objective evidence of asthma, no previous known lung disease to explain the findings, and where possible, some supportive information to document a high-level exposure to a respiratory irritant within 24 hours before symptom-onset. Objective investigations can, however, be used to assess other workplace relationships of asthma. A methacholine or histamine challenge that improves significantly while off work supports a diagnosis of OA unless explained by confounding factors. A provocation concentration causing a 20% fall in FEV1 (PC20) that increases more than threefold after a period of a few weeks off work, when measured within 8 weeks of the test at work, is significant (115), whereas a twofold increase is of possible significance. However, some sensitized individuals with asthma (perhaps those with longer duration of OA) can require more than a few weeks away from exposure before significant improvement occurs. Symptom and medication diary recordings, including monitoring of serial peak expiratory flow rates (PEF), or spirometry (using inexpensive PEF meters or more expensive hand-held electronic devices which store serial peak flow and/or spirometry results), can add to other OA investigations (116), despite the frequent lack of good compliance with such studies. Comparison of PEF readings with serial FEV1 recordings using a portable ventilometer showed better sensitivity (at 73%) and specificity (at 100%) for peak flow recordings, |
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Introduction
A Historical Perspective of...
(TNF-