Occupational Asthma

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Chapter 40 Occupational Asthma

The workplace environment can lead to the development of different types of work-related asthma (Figure 40-1), including occupational asthma (OA) (i.e., asthma caused by work) and work-exacerbated asthma (i.e., preexisting or coincident asthma exacerbated by nonspecific stimuli at work). OA is defined as a disease characterized by variable airflow limitation and/or bronchial hyperresponsiveness and/or airway inflammation secondary to factors and conditions attributable to a particular working environment and not to stimuli encountered outside the workplace. OA may result either from immunologically mediated sensitization to occupational agents (i.e., “allergic” OA, or “OA with a latency period”) or from exposure(s) to high concentrations of irritant compounds (i.e., irritant-induced asthma [IrIA], best typified by the reactive airways dysfunction syndrome [RADS]).

In recent years, a growing interest in occupational asthma (OA) has emerged, for several reasons:


Causal Agents

The workplace agents causing immunologically mediated OA usually are categorized as either high-molecular-weight (HMW) or low-molecular-weight (LMW) substances (i.e., with molecular weights above or below 5000, respectively). HMW agents are (glyco)proteins of vegetable and animal origin, whereas LMW agents include chemicals, metals, and wood dusts. The intrinsic characteristics of occupational agents that determine their sensitizing potential remain largely uncertain. Of note, however, LMW agents causing OA typically are highly reactive electrophilic compounds that are capable of combining with hydroxyl, amino, and thiol functionalities on airway proteins. Quantitative structure-activity relationship models have identified a number of reactive groups that are associated with a high risk of respiratory sensitization, such as isocyanate (NinlineCinlineO), carbonyl (CinlineO), and amine (NH2), particularly when two or more groups are present within the same molecule.

A very large number of substances (more than 400) used at work can cause the development of immunologically mediated OA. The most common causal agents and occupations are listed in Table 40-1. A few agents—specifically, flour, diisocyanates, latex, persulfate salts, aldehydes, animals, wood dusts, metals, and enzymes—account for 50% to 90% of OA cases. Nevertheless, the distribution of causal agents may vary widely across geographic areas, depending on the pattern of industrial activities. The highest rates of OA occur in bakers and pastry makers, other food processors, spray painters, hairdressers, wood workers, health care workers, cleaners, farmers, laboratory technicians, and welders.

Table 40-1 Principal Agents Causing Immunologic Occupational Asthma

  Agent Occupation/Industry
High-Molecular-Weight Agents
Cereals, flour Wheat, rye, barley, buckwheat Flour milling, bakers, pastry makers
Latex   Health care workers, laboratory technicians
Animals (food animals, other) Mice, rats, cows, seafood Laboratory workers, farmers, seafood processors
Enzymes α-Amylase, maxatase, alcalase, papain, bromelain, pancreatin Baking products manufacture, bakers, detergent production, pharmaceutical industry, food industry
Low-Molecular-Weight Agents
Diisocyanates Toluene diisocyanate (TDI), methylene diphenyl-diisocyanate (MDI), hexamethylene diisocyanate (HDI) Polyurethane production, plastic industry, molding, spray painters
Metals Chromium, nickel, cobalt, platinum Metal refinery, metal alloy production, electroplating, welding
Biocides Aldehydes, quaternary ammonium compounds Health care workers, cleaners
Persulfate salts   Hairdressers
Acid anhydrides Phthalic, trimellitic, maleic, tetrachlorophthalic acids Epoxy resin workers
Reactive dyes Reactive black 5, pyrazolone derivatives, vinyl sulfones, carmine Textile workers, printers, food industry workers
Woods Red cedar, iroko, obeche, oak, others Sawmill workers, carpenters, cabinet and furniture makers

All agents in exceedingly high concentrations can theoretically cause OA through nonimmunologic mechanisms, especially with agents occurring in vapor or gaseous form, by apposition to dry particles, such as chlorine and ammonia, but fire smoke and alkaline dusts, such as those released during the World Trade Center disaster, also have been incriminated in the development of persistent asthma.

Prevalence and Incidence

Cross-sectional surveys of workforces exposed to sensitizing agents found highly variable prevalence rates of OA. In general, the prevalence of OA caused by HMW agents is less than 5%, and that for LMW agents ranges from 5% to 10%. Cohort studies reported incidence rates of 2.7 to 3.5 cases of OA per 100 person-years among workers exposed to laboratory animals, 4.1 per 100 person-years among those exposed to wheat flour, and 1.8 per 100 person-years among dental health apprentices exposed to natural rubber latex. Estimates of the incidence of OA in the general population provided by voluntary notification schemes, medicolegal statistics, and population-based surveys are summarized in Table 40-2. Acute IrIA accounts for about 10% of all reported cases of OA.

Table 40-2 Estimates of Incidence of Occupational Asthma (OA)

Country Period Incidence of OA (Cases per 106 Workers)
Physician-Based Notification Schemes
United Kingdom (SWORD) 1989-1992 22
1992-1993 37
1992-1097 38 (34-41)*
1992-2001 87
West Midlands (SHIELD) 1991-2005 42 (37-45)*
United States (SENSOR)    
Michigan 1988-1994 29
1995 27 (58-204)
California 1993-1996 25 (23-27)*
British Columbia 1991 92
Quebec (PROPULSE) 1992-1993 42-79
France (ONAP) 1996-1999 24 (22-25)*
Italy (PRIOR) 1996-1997 24 (18-30)*
South Africa (SORDSA) 1997-1999 18
Australia (SABRE) 1997-2001 31 (27-36)*
Catalonia 2002 77 (66-90)*
Belgium (WAB) 2000-2002 24 (19-29)*
Medicolegal Statistics
Finland 1976 36
1989-1995 174
Quebec 1986-1988 25
1989-1999 13-24
Sweden 1990-1992 80 (70-90)*
Germany 1995 51
Belgium 1993-2002 29 (28-31)*
Population-Based Surveys
Finland 1986-1998 Men: 478
Women: 419
ECRHS 1990-1995

ECRHS, European Community Respiratory Health Survey; ONAP, Observatoire National des Asthmes Professionnels; PROPULSE, Projet Pulmonaire Sentinelle; SABRE, Surveillance of Australian Workplace-Based Respiratory Events; SENSOR, Sentinel Event Notification System for Occupational Risks; SHIELD, Midland Thoracic Society Rare Respiratory Disease Registry Surveillance Scheme of Occupational Asthma; SORDSA, Surveillance of Work-Related and Occupational Respiratory Diseases in South Africa; SWORD, Surveillance of Work-Related and Occupational Respiratory Diseases; WAB, Work-Related Asthma in Belgium.

* 95% confidence interval.

Estimated from the work-attributable fraction of asthma derived through linkage of two national registries—the Medication Reimbursement of the Social Insurance Institution for Asthma and the Finnish Register of Occupational Diseases for Occupational Asthma.

Risk Factors

OA results from complex interactions between environmental factors and individual susceptibility. The environmental and individual risk factors are summarized in Table 40-3, together with the level of evidence supporting their role. The intensity of exposure to sensitizing agents currently is the best-identified and the most important environmental risk factor for the development of OA. Characterization of the relationship between the level of exposure to occupational agents and the development of IgE sensitization and OA has been greatly enhanced by the use of personal sampling techniques, direct analytic methods for chemicals, and immunoassay techniques for the quantification of airborne protein allergens. Exposure-response relationships may be affected by the nature of the sensitizing agent, individual susceptibility, and timing of exposure. Some agents seem to be more potent than others in inducing sensitization; the dose-response relationship for IgE sensitization is steeper for the bakery enzyme alpha-amylase than for wheat allergens. Some evidence indicates that the exposure-response relationships are not linear for certain occupational agents (e.g., laboratory animals, wheat flour), thereby suggesting an unexplained protective effect of high-level exposures. The role of genetic susceptibility markers, such as certain human leukocyte antigen (HLA) class II alleles, may become more apparent at low levels of exposure to occupational agents. The timing of exposure also may play a role, because the frequency of onset of work-related asthma symptoms is consistently higher within the first 1 to 4 years of exposure to HMW agents, and exposure-response gradients are more clearly documented in this early period of exposure.

Table 40-3 Summary of Potential Risk Factors for Development of Occupational Asthma (OA)

Risk Factor Strength of Evidence Agents/Settings
Environmental Risk Factors    
High level of exposure +++ HMW agents: Wheat flour, α-amylase, laboratory animals, detergent enzymes, snow crab allergens
LMW agents: Platinum salts, acid anhydrides
++ Diisocyanates
Skin exposure + Diisocyanates
Cigarette smoking ++ IgE sensitization: Laboratory animals, snow crab, shrimp, salmon, psyllium, green coffee, enzymes, acid anhydrides, platinum, reactive dyes
+ Clinical OA: Laboratory animals, enzymes
Individual Risk Factors    
Atopy +++ HMW agents: Flour, laboratory animals, snow crab, psyllium, detergent enzymes, α-amylase
+ LMW agents: Platinum, acid anhydrides
Genetic Markers    
HLA class II alleles ++ LMW agents: Diisocyanates, red cedar, acid anhydrides, platinum salts
HMW agents: Laboratory animals, latex
Antioxidant enzyme* variants ++ Diisocyanates
TLR-4/8551 G variant + Laboratory animals
IL-4RA (I50V) II variant + Diisocyanates
Preexisting nonspecific bronchial hyperresponsiveness + Apprentices exposed to HMW agents (laboratory animals, flour, latex)
Preexisting rhinitis + IgE sensitization to HMW agents (laboratory animals, flour, latex)
Work-related rhinitis +++ Nonoccupational asthma in the general population and OA in cohorts of workers exposed to laboratory animals
Gender—female + Snow crab processors

HLA, human leukocyte antigen; HMW, high-molecular-weight; IgE, immunoglobulin E; IL-4RA, interleukin-4 receptor alpha chain; LMW, low-molecular-weight; TLR-4, Toll-like receptor-4.

* Glutathione S-transferase (GSTM) and N-acetyltransferase (NAT).

A number of studies indicate that exposure to cigarette smoke can increase the risk for IgE-mediated sensitization to some HMW and LMW agents, but the evidence supporting an association between smoking and the development of clinical OA is still very weak. The role of other environmental cofactors, such as non-respiratory routes of exposure and concomitant exposure to endotoxin and pollutants at work, remains largely uncertain.

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