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]).

Figure 40-1 Various types of work-related asthma. RADS, reactive airways dysfunction syndrome.

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

• The frequency of asthma has increased progressively during the past 2 decades, with a recent plateau, and occupational exposure may be a contributing factor.

• Epidemiologic data indicate that approximately 18% of cases of asthma in adults are attributable to workplace exposures.

• The number of agents that can cause OA is steadily increasing (www.asthme.csst.qc.ca).

• OA, together with diseases related to exposure to asbestos dust, has become the most prevalent occupational lung disease in many developed countries, resulting in an increased burden to society.

• OA is an excellent model to study the epidemiology, pathophysiology, genetics, and other aspects of asthma in humans.

Epidemiology

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 (N inline C inline O), carbonyl (C inline O), 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
Michigan	1995	27 (58-204)
California	1993-1996	25 (23-27)*
Canada
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)*
Spain
Catalonia	2002	77 (66-90)*
Belgium (WAB)	2000-2002	24 (19-29)*
*Medicolegal Statistics*
Finland	1976	36
Finland	1989-1995	174
Canada
Quebec	1986-1988	25
Quebec	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 1998-2003	250-300

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
High level of exposure	++	Diisocyanates
Skin exposure	+	Diisocyanates
Cigarette smoking	++	IgE sensitization: Laboratory animals, snow crab, shrimp, salmon, psyllium, green coffee, enzymes, acid anhydrides, platinum, reactive dyes
Cigarette smoking	+	Clinical OA: Laboratory animals, enzymes
*Individual Risk Factors*
Atopy	+++	HMW agents: Flour, laboratory animals, snow crab, psyllium, detergent enzymes, α-amylase
Atopy	+	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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