Strategies to Address Occupational Asthma Caused by Respirable Allergens
Respiratory Sensitizers
Editor’s note: This article is a sequel to “Dermal Sensitizers,” which was published in the November 2019 issue of The Synergist. The digital version of this article contains additional information on respiratory sensitizers that could not be included in print due to space limitations. Click or tap on red-underlined text to open pop-up boxes with information special to the digital edition. Other information not included in the print version is marked “digital extra.”
A respirable allergen or respiratory sensitizer is a compound that will cause respiratory sensitization following its inhalation. Respiratory sensitization leading to occupational asthma (OA) is an unwanted immunological reaction that represents a worrisome workplace hazard that is growing in prevalence worldwide. An article published in European Respiratory Review in 2017 describes an incidence of approximately two to five cases of OA per 100,000 population each year, or roughly 15 to 20 percent of the overall adult-asthma burden. Approximately 90 percent of OA cases are caused by inhalation exposure to respiratory sensitizers and 10 percent by inhalation exposure to a very high concentration of irritants, according to a study published in 2017 in Clinical & Experimental Allergy.

OA caused by sensitizers can be life-threatening. Symptoms manifest very quickly, and limited toxicological and clinical data as well as insufficient clinical experience can hamper the diagnosis of cases and the identification of potential respiratory sensitizers. Due to enormous individual differences in susceptibility, rigorous health surveillance is necessary. As sensitization does not follow a clear dose-response relationship, it is also difficult to calculate reliable, protective occupational exposure limits, which makes it challenging in practice to adequately judge and prevent critical exposures. Despite all the complexities associated with prediction, diagnostics, and assessment of exposures, it is feasible and important to implement a strategy to control the risk of these life-threatening reactions in specific individuals.  SYMPTOMS OF EXPOSURE The symptoms caused by respiratory sensitizers and respiratory irritants differ, so they require different strategies to deal with OA in the workplace. OA caused by a sensitizer might require complete avoidance of the sensitizer because exposure to even extremely low quantities can exacerbate the asthma. Symptoms caused by exposure to a respiratory irritant, however, will generally not worsen with repeated exposures. The authors of a 2008 U.K. Health and Safety Laboratory study intended to document key clinical differences between irritation and sensitization in the workplace. They observed that workers reporting respiratory symptoms attributable to allergen exposure and sensitization were more likely to report cough and chest tightness (both hallmarks of asthma), as well as eye irritation, than those exposed to an irritant. In addition, they were more likely to have abnormal lung function tests. Those exposed to an irritant instead typically reported wheeze and nasal irritation.    Respiratory sensitizer-induced OA should be suspected if a worker’s symptoms begin during work, are worse at work or in the evenings after work, and diminish during weekends or holidays. According to a 2003 paper published in the Annals of Allergy, Asthma & Immunology, irritant-induced OA should be suspected if the symptoms first begin within 24 hours after accidental inhalation of a high concentration of an irritant. In some cases, sensitization can occur prior to the first exposure to a sensitizer due to cross-reactive epitopes. This can happen when part of a sensitizer is recognized by the immune system as another similar sensitizer that previously induced a sensitization response. For example, an individual is exposed to Product A, which caused a sensitization response. The person hasn’t yet been exposed to Product B, but the immune system mistakes Product B for Product A, leading to asthma symptoms after the first exposure to Product B. The diagnosis of OA caused by a sensitizer must be confirmed by a doctor.
Table 1. Examples of High Molecular Weight and Low Molecular Weight Respiratory Sensitizers Found in the Workplace

Sources: Oasys and Occupational Asthma, a website that hosts a free computer program used to help diagnose OA from serial peak flow records; CNESST, Québec’s commission on occupational health and safety standards; and the Association of Occupational and Environmental Clinics (links to these resources can be found at the end of this article). These sources also contain information regarding the professions in which these sensitizers are present.
Respiratory sensitizers are widespread. An article published in 2012 in Clinics in Chest Medicine states that over 400 agents are known or suspected to cause respiratory sensitization and possibly OA. Table 1 provides an overview of these substances from several resources, which are listed below the table.

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There are two main classes of respiratory sensitizing agents that can cause sensitizer-induced asthma: high molecular weight (HMW)—usually proteinaceous—and low molecular weight (LMW). Some of these products have been clearly labeled as respiratory sensitizers with the GHS hazard statement H334, “May cause allergy or asthma symptoms or breathing difficulties if inhaled.” This information can be found on products’ safety data sheets or from other sources such as the PubChem database and the European Chemicals Agency’s Classification and Labelling (C&L) Inventory. Unfortunately, some products that could lead to respiratory sensitization are not yet formally classified as sensitizers. TOXICOLOGY  There are two phases of respiratory sensitization: induction and elicitation. Induction is defined as the tolerance of the exposure by the immune system, whereas elicitation is the reaction from a sensitized person. As with other types of hypersensitivity, both an induction and elicitation phase are needed to invoke a response. The initiation of sensitization occurs as soon as specific antibodies are present in the blood following exposure to a foreign protein. The presence of antibodies does not necessarily mean that a noticeably ill effect such as asthma will occur directly. An individual becomes sensitized following the first or repeated contact with the respiratory antigen; however, the stronger, immediate reaction will only take place once a subsequent exposure occurs. This is the elicitation phase, which can happen at a much lower concentration. Clinical symptoms of respiratory sensitization occur during the elicitation phase. Figure 1 illustrates the main mechanism of immune- mediated respiratory sensitization, which involves two important elements: T helper 2 (Th2) lymphocytes and a specific type of antibody, Immunoglobulin E, or IgE (meaning a type I hypersensitivity reaction).  
It is not well understood why only certain people develop this immunological reaction (as described in Figure 1) and not all sensitizers will induce it, but there is some evidence of a genetic component influencing the mechanism and severity. The third edition of Immunotoxicology and Immunopharmacology explains that other individual risk factors such as smoking, obesity, and barrier abnormalities from the lungs likely play a role.
Figure 1. Schematic representation of how immune-mediated respiratory sensitization takes place.
During induction, dendritic cells are primed in the epithelia of the lungs with an antigen and will present it to T lymphocytes. They will further differentiate to Th2 lymphocytes, which will help the maturation of the B lymphocytes. B cells are then activated to memory and plasma B cells that will produce and release the antibodies (IgEs), which can activate strong immune effector cells in case of a second exposure to the antigen during the elicitation phase. IgE and the antigen can bind to immune cells as mast cells that secrete immune mediators such as histamines and leukotrienes. Histamines contained in the granules of mast cells will lead to acute symptoms such as sneezing and spasming of the airways, and leukotrienes from mast cell membranes will lead to prolonged symptoms of the airways such as breathlessness and wheeze. Symptoms such as inflamed and constricted airways can be treated using antihistaminic agents.
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CHALLENGES OF CALCULATING OELS There are currently no universally accepted models applicable to humans that permit the determination of the dose-response relationship or relative potency of HMW or LMW chemicals that can cause production of allergen-specific antibodies or symptoms of allergy via the inhalation route. In fact, predictive toxicological assays (in silico, in vitro, and in vivo) are not fully validated for the detection of respiratory sensitization. Moreover, the intraspecies differences and the complexity of their associated immune response led to difficulty in identifying animal models for these type I (IgE-mediated) allergens, as noted in a 2010 Toxicology article on defining OELs for enzyme protein respiratory allergens and in the fifth revised edition of the GHS. Specifically, in vitro (such as GARDair, a new method using genomics and machine learning) and in silico assays have limited applicability, while in vivo assays (for example, guinea pig intratracheal instillation test, mouse intranasal test, mouse IgE tests, and cytokine profiling) have limited predictivity for human asthmatic response potency.   Relationships between dermal sensitization in vivo tests and respiratory sensitization can be used to inform risk assessments. To date, with very few outliers, most LMW respiratory sensitizers seem to also be dermal sensitizers, while only a small minority of LMW dermal sensitizers (less than 1 percent) are also respiratory sensitizers. This is shown in papers published over the last several years, including studies on phthalic anhydride in the Journal of Immunotoxicology, interrelationships between different classes of chemical allergens in the Journal of Applied Toxicology, and chemical-induced asthma in Regulatory Toxicology and Pharmacology. HMW substances—for example, pollen or enzymes such as trypsin or α-amylase—are generally not considered effective dermal sensitizers due to impossibility of skin penetration. Some products might be falsely identified as positive sensitizers due to their corrosive or irritative properties, which can cause a local immune response. Similarly, some very fine irritating powders can cause sensitization to develop over time. Exposure to such products should be limited in any case due to their strong irritative and corrosive effects.  Taking all of this into account, the primary focus in assessing potential respiratory sensitization leading to OA is the weight of evidence based on the understanding of IgE involvement and epidemiology. Consequently, dose- response assessment is very difficult and cannot provide a precise determination of potency, making it difficult to provide a reliable OEL.  CALCULATING AND INTERPRETING OELS Controlling occupational exposures to respiratory sensitizers is critical to prevent OA and can be done with the assistance of OELs, but practitioners must understand the associated limitations. Although OEL derivation approaches are well established for non-immunological endpoints based primarily on dose-response relationships, they are often less suitable for allergic reactions, particularly respiratory IgE-mediated ones. While the risk of becoming sensitized is concentration-dependent, it is challenging to determine an exposure limit that is safe for everyone. In general, OELs for type I allergens are derived primarily by human data, according to a 2012 paper in The Annals of Occupational Hygiene. Both the 2012 paper and another published in 2015 in the Journal of Occupational and Environmental Hygiene explain that OELs should be selected to avoid the induction and not the elicitation phase of sensitization. In any case, a sensitized worker must not be exposed to a sensitizer at any level of concentration in air. Considerations for acceptable daily exposure (ADE) derivations described by Gould et al. in the August 2016 issue of Regulatory Toxicology and Pharmacology also apply for OELs. Table 2 summarizes methods for the determination of OELs based on respiratory sensitization effects. The assumed IgE mechanism of action is an important aspect to consider for the predictive methods, while the medical surveillance and monitoring data are key points for the retrospective methods. This information is based on what we have experienced in industry.  A good example of Method A in application in detergent manufacturing is the use of an existing OEL of 60 ng/m³ for subtilisins (serine protease enzymes), which can also be applied to other bacterial and fungal enzymes. However, literature data could support the use of less stringent limits. If there is concomitant exposure to detergents/surfactants, the general use of exposure limits could be reduced by three to 10 times, according to guidelines for the safe handling of enzymes published by AISE, the International Association for Soaps, Detergents and Maintenance Products. Methods B through F are based on the identification of a human IgE type of mechanism (see Table 1 and its sources for more information). They are reliable, as they are based on data supporting an IgE type of mechanism; however, the studies, literature information, or updated regulatory values must exist and be accessible. Methods G and H are considered retrospective as they are based on exposure monitoring and  medical surveillance data (from internal data or literature). They could be needed to adapt OELs that were preventatively set due to the absence of human exposure data—to make them more reliable. 
Table 2. Methods for Determining OELs for Respiratory Sensitizers with Relative Pros and Cons
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REDUCING THE POTENTIAL FOR SENSITIZATION Regardless of whether an OEL is available, it is important to take the proper precautions and minimize exposure to sensitizers as much as possible. The following suggestions are usually identified in a risk assessment and implemented to reduce the risk and control exposures for the general population.  Substitution. Substitute a sensitizer for a non-sensitizer, if possible. Other examples include replacing fine powders or granules with flakes or pellets, encapsulating the product (typically used for enzymes), and replacing powders with liquids. Technical controls. High-containment solutions help to prevent exposures. Dedicated equipment or segregation of the operations helps ensure that sensitizers do not contaminate other areas. In the pharmaceutical industry, for example, this solution is applied for beta lactams and antibiotics.  Consider non-routine operations. Workers may not be exposed during “normal” operations, but sensitization (induction) may occur during tasks that could potentially be overlooked during the risk assessment (for example, a filter change or when a worker opens a centrifuge to manually remove the product). They may experience symptoms when exposed to a minimal amount of product later on.  Training. It is critical to perform work practices in a certain manner, especially those that might provoke a peak exposure (docking or undocking packaging and then disposing of it, for example). Limiting the number of workers who perform these tasks helps prevent differing work practices. Informing employees that a history of asthma and smoking habits lead to a higher risk of OA increases awareness.  Personal protective equipment. If PPE is the control method of choice, practitioners should thoroughly review proper donning and doffing of PPE and decontamination of the work zone. Limiting the work zone will help reduce contaminated areas. Respiratory protection may be considered as a safety net, even when technical controls are in place.   Medical surveillance. Medical surveillance programs for sensitizers can include lung function testing, in vitro testing for specific IgE (if available), and blood tests. In some cases, medical surveillance may include specific allergy testing, a respiratory questionnaire, or spirometry. Prick testing is rarely conducted. Challenges remain for individuals who present increased sensitivity due to pre-existing asthma or genetic predisposition. Exposure and medical surveillance are two key elements in ensuring early identification of potential new OA cases. Exposure monitoring helps to validate the controls in place and indicates whether improvements should be made. Medical surveillance allows for the identification of the predisposed working population and any new cases. Both approaches aid in the confirmation of suspected cases.    SAMANTHA CONNELL, MSPH, CIH, is an industrial hygienist at Lonza in Visp, Switzerland. SELENE ARAYA, PhD, is a toxicologist at Lonza in Basel, Switzerland. Acknowledgement: The authors would like to thank Thomas Pfister, F. Hoffmann-La Roche, for reviewing this article. Send feedback to The Synergist.

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AISE: “Enzyme Safety Management: A Series of Web-Based Training and Information Sessions Developed and Presented by the AISE Enzyme Safety Task Force” (PDF, November 2015). AISE: Guidelines for the Safe Handling of Enzymes in Detergent Manufacturing (PDF, 2018). Annals of Allergy, Asthma & Immunology: “Workplace Irritant Exposures: Do They Produce True Occupational Asthma?” (May 2003). Applied Occupational and Environmental Hygiene: “Safe Use of Detergent Enzymes in the Workplace” (2001). Association of Occupational and Environmental Clinics: “Exposure Code Lookup.” Clinical & Experimental Allergy: “Diagnosing Occupational Asthma” (January 2017). Clinics in Chest Medicine: “Occupational Asthma: New Deleterious Agents at the Workplace” (2012). CNESST: “Occupational Asthma.”  CRC Press: Immunotoxicology and Immunopharmacology, 3rd Edition, Chapter 33, “Respiratory Allergy and Occupational Asthma” (2006). European Respiratory Review: “Current and New Challenges in Occupational Lung Diseases” (December 2017). EXCLI Journal: “Toluene Diisocyanate (TDI) Airway Effects and Dose-Responses in Different Animal Models” (2012). Health and Safety Laboratory for the Health and Safety Executive: “Irritancy and Sensitization” (PDF, 2008). Journal of Applied Toxicology: “Inter-Relationships Between Different Classes of Chemical Allergens” (July 2013). Journal of Immunotoxicology: “Phthalic Anhydride: Illustrating a Conundrum in Chemical Allergy” (2016). Journal of Occupational and Environmental Hygiene: “Setting Occupational Exposure Limits for Chemical Allergens—Understanding the Challenges” (2015). Oasys and Occupational Asthma. Regulatory Toxicology and Pharmacology: “Chemical-Induced Asthma and the Role of Clinical, Toxicological, Exposure and Epidemiological Research in Regulatory and Hazard Characterization Approaches” (November 2017). Regulatory Toxicology and Pharmacology: “Special Endpoint and Product Specific Considerations in Pharmaceutical Acceptable Daily Exposure Derivation” (August 2016). The Annals of Occupational Hygiene: “Experiences from Occupational Exposure Limits Set on Aerosols Containing Allergenic Proteins” (October 2012). Toxicology: “Defining Occupational and Consumer Exposure Limits for Enzyme Protein Respiratory Allergens Under REACH(February 2010). United Nations: “Globally Harmonized System of Classification and Labelling of Chemicals (GHS),” 5th Revised Edition (2013).

Digital Extra: Learn more about the diagnosis of OA.
A study focused on the safe use of detergent enzymes in the workplace that appeared in Applied Occupational and Environmental Hygiene in 2001 found that well controlled facilities in the detergent industry would not exceed an incidence of three percent per year for new sensitizations. This could be used as a reference point in other industries, suggesting that the OEL be revised and lowered when an exceedance of cases occurs.

When working with sensitizers, the typical notion of the time-weighted average (TWA) no longer applies. If an OEL exists, it has to be applied as a ceiling exposure that must not be exceeded at any time. The goal is to prevent the opportunity for peak exposures and therefore avoid the different thresholds for the induction of antibodies and the elicitation of symptoms. As observed by AISE in the pharmaceutical industry, low doses with peak exposures are enough to invoke sensitization when working with respiratory OA sensitizers such as enzymes. With respect to toluene diisocyanate, one prospective epidemiology study published in EXCLI Journal found that exposure to high concentrations resulted in IgE antibody formation, but exposures of low concentrations (less than 0.02 ppm or 0.14 mg/m3) for up to three years did not result in hypersensitivity or the production of specific antibodies. A short-term exposure limit would be useful in this case, but according to the European Commission’s Scientific Committee on Occupational Exposure Limits, a scientifically based value is impossible for many chemicals.

Digital Extra: Conflicting Exposure Limits
Flour dust, a high molecular weight respiratory sensitizer, and phthalic anhydride, a low molecular weight respiratory sensitizer, are two examples that illustrate how countries’ exposure limits can drastically differ—even when the products and mode of action should be the same. The values given in these examples are time-weighted averages. Figure 2 further illustrates the range of occupational exposure limits for these two substances.

The GESTIS International Limit Values database, which contains occupational limit values for hazardous substances from more than 30 countries, reports OELs for flour dust that range from 0.5 mg/m3 to 10 mg/m3 (these limits are in line with the ACGIH Threshold Limit Value and the U.K. Health and Safety Executive Workplace Exposure Limit, respectively). OSHA has no proposed exposure limit for flour dust, while the EU’s Scientific Committee on Occupational Exposure Limits recommends a limit of 1 mg/m3.

According to GESTIS, phthalic anhydride has OELs ranging from 0.2 mg/m3 to 12 mg/m3. The most commonly reported OEL is 6 mg/m3. However, a document that recommends changing the Workplace Exposure Standard in New Zealand proposes a limit of 0.01 mg/m3 as a limit of 6 mg/m³ is higher than the limit reported to induce respiratory sensitization, or OA). ACGIH recently reviewed this limit, and the 2020 TLV for phthalic anhydride is 0.002 mg/m3.

Figure 2. Range of Occupational Exposure Limits for Flour Dust and Phthalic Anhydride
Columns with standard deviation show the high variability of these OELs. For flour dust, the sensitization occurred at dust levels as low as 0.5 mg/m³, with a significant risk at ≥1 mg/m³ (dotted line), according to Nielsen et al. (2012). For phthalic anhydride, the sensitization in workers rarely resulted following an average exposure below 0.01 mg/m³ (dotted line), according to Safe Work Australia.

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Disadvantages of being unacclimatized:
  • Readily show signs of heat stress when exposed to hot environments.
  • Difficulty replacing all of the water lost in sweat.
  • Failure to replace the water lost will slow or prevent acclimatization.
Benefits of acclimatization:
  • Increased sweating efficiency (earlier onset of sweating, greater sweat production, and reduced electrolyte loss in sweat).
  • Stabilization of the circulation.
  • Work is performed with lower core temperature and heart rate.
  • Increased skin blood flow at a given core temperature.
Acclimatization plan:
  • Gradually increase exposure time in hot environmental conditions over a period of 7 to 14 days.
  • For new workers, the schedule should be no more than 20% of the usual duration of work in the hot environment on day 1 and a no more than 20% increase on each additional day.
  • For workers who have had previous experience with the job, the acclimatization regimen should be no more than 50% of the usual duration of work in the hot environment on day 1, 60% on day 2, 80% on day 3, and 100% on day 4.
  • The time required for non–physically fit individuals to develop acclimatization is about 50% greater than for the physically fit.
Level of acclimatization:
  • Relative to the initial level of physical fitness and the total heat stress experienced by the individual.
Maintaining acclimatization:
  • Can be maintained for a few days of non-heat exposure.
  • Absence from work in the heat for a week or more results in a significant loss in the beneficial adaptations leading to an increase likelihood of acute dehydration, illness, or fatigue.
  • Can be regained in 2 to 3 days upon return to a hot job.
  • Appears to be better maintained by those who are physically fit.
  • Seasonal shifts in temperatures may result in difficulties.
  • Working in hot, humid environments provides adaptive benefits that also apply in hot, desert environments, and vice versa.
  • Air conditioning will not affect acclimatization.
Acclimatization in Workers

PPE is always the last line of defense, but this is especially true when working with respiratory sensitizers. If PPE is the choice of protection, it is also likely that there is not a proper way to decontaminate it before an employee leaves the working zone. This increases the potential to contaminate other areas where the product is not expected to be present, or for the product to be present in the air again while the employee is removing PPE and is no longer protected.

Why Is the Prevalence of Asthma Increasing?
It is not clear why the prevalence of asthma has increased, but a 2019 journal article focused on the epidemiology of asthma in children and adults describes several hypotheses that have been considered over the years:
  1. increased exposure to indoor allergens due to tighter insulation in modern housing as well as the increased use of plush furniture and carpets has contributed to an increase in asthma and other allergies
  2. reduced exposure to “unhygienic environments” early in life may lead to the increased prevalence of asthma and similar conditions
  3. the “microbial diversity” hypothesis, which suggests that “microbial diversity in the gut mucosa and respiratory tract are the key factors in priming and regulating the immune system” (therefore a lack of exposure to nonpathogenic microbes might explain the increased prevalence of asthma and other allergic diseases)