An IgE-mediated allergic reaction is mediated by IgE antibody and mast cells and is sometimes called immediate-type hypersensitivity (Type I). It involves the initiation of T helper 2 cytokines, such as interleukin (IL)-4 and IL-13, leading to IgE production by B cells. Once IgE is produced and secreted, it binds to mast cells and basophils. Upon activation, these cells degranulate and release soluble allergic mediators, such as histamine and leukotrienes, which act on smooth muscles, sensory nerves, mucous glands, arteries, and eosinophils.²⁴ Common clinical outcomes of an IgE-mediated reaction are increased vascular permeability, smooth muscle cell contraction, and vasodilation. IgE-mediated reactions manifest within minutes to hours of exposure. Depending on the site(s) and frequency of allergen exposure, these reactions may occur in one or more organs resulting in diseases such asthma, allergic rhinitis, urticaria, and anaphylaxis.

A non-IgE-mediated or delayed type hypersensitivity response (Type IV) is T cell-mediated and characterised by excessive inflammation. The most distinctive feature of a non-IgE-mediated hypersensitivity response is the delay observed between allergen exposure and immune response. Following sensitisation, subsequent exposures result in elicitation of the non-IgE-mediated response, characterised by the secretion of proinflammatory cytokines (granulocyte-macrophage colony-stimulating factor, interferon-γ IL-3, IL-12, and tumour necrosis factor-β) that activate and recruit macrophages and other immune cells. Due to the time it takes for these cytokines to attract and activate macrophages at sites of exposure, the effector phase typically occurs 24 hours following exposure and it generally peaks at 48–72 hours after exposure.²⁴ ACD is an example of a non-IgE-mediated hypersensitivity reaction.

LMW chemical allergens are diverse in structure, reactivity, and application; however, there are several common attributes that are associated with immunogenicity including: haptenation potential (protein reactivity), ability to access the epithelium, and irritancy potential.^27,28 Thousands of chemicals have been identified as causative agents of skin sensitisation resulting in ACD, while substantially fewer chemical allergens (<100) have been identified as causative agents of asthma.²⁹ For the majority of LMW sensitisers, the immunologic response has no proven mechanisms and often can result in non-IgE and IgE-mediated responses.²⁷

One of the most common occupationally-relevant chemical allergens, toluene diisocyanate (TDI), is a highly reactive chemical utilised in the automobile industry and in the manufacture of polyurethane foams, paints, elastomers, and coatings. TDI is a potent allergen and exposure can lead to a variety of diseases, including asthma, rhinitis, and ACD.^20,30 The incidence of asthma related to occupational TDI exposure has been estimated at ≤5.5% for the total workforce.¹³ Based on the majority of the available epidemiological data, persulphate salts are reported as another common occupational allergen and may cause ACD, urticaria, rhinitis, and asthma.^10,11 Persulphate salts (ammonium, potassium, and sodium) are inorganic salts used as oxidising agents in hair bleaches and hair-colouring preparations at concentrations of ≤60%.³¹ TDI and persulphate salts are generally classified as IgE-mediated sensitisers but may also induce a non-IgE-mediated response.^32,33 However, while animal studies support an IgE-mediated mechanism, TDI asthmatics often have no measurable TDI-specific IgE. Similar findings have been reported for persulphate.^34,35 The complete immunological mechanisms of sensitisation for these chemicals and other LMW sensitisers are not fully understood.

Numerous LMW chemical allergens are used in the healthcare profession. These include biocides (formaldehyde, glutaraldehyde, and orthophthaldehyde) commonly used to sterilise medical devices that are sensitive to normal heat or steam sterilisation processes and as disinfectants for surfaces (quaternary ammonia compounds).³⁶ Aldehydes and quaternary ammonia compounds have been identified as some of the most common non-IgE-mediated allergens.²⁵ In addition, medical gloves containing certain rubber accelerators (thiuram mix and carba mix), and antibacterial hand sanitisers and soaps (chloroxylenol and cocamide diethanolamine), have also been identified as common sources of allergens.³⁶ The above examples represent some of the most common occupational LMW allergens; however, many other occupationally relevant LMW allergens exist.

Since the majority of allergies induced by HMW allergens are IgE-mediated, detection and quantification of specific IgE that recognises the responsible protein is used for confirmation of allergy. This can be evidenced through positive skin prick tests or immunoassays.³⁷ Several challenges exist in the diagnosis and identification of HMW allergy. The HMW allergens in some compounds, such as wheat and latex, have been better characterised than others. Additionally, while most recombinant proteins are available for testing, multiple proteins may be responsible and individuals may have different sensitivities to different proteins which may present a challenge for the identification of the suspect agent.³⁷ In addition, LMW chemicals may be a component of the crude allergen (introduced via processing or manufacturing) and may also result in non-IgE-mediated responses.

It is estimated that 6–17% of healthcare workers suffer from latex allergy, with rubber gloves being the most common cause.³⁸ Latex allergy can manifest as urticaria, rhinitis, conjunctivitis, asthma, anaphylaxis, and ACD. Latex is extracted from the Hevea brasiliensis tree (rubber tree) and contains an array of cellular proteins, lipids, and amino acids. The responsible allergens in latex have not been fully characterised but a list of 15 allergens (Hev b 1–Hev b 15) has been established with Hev b 5, Hev b 6.01, and Hev b 6.02 identified as the most common occupational latex allergens.³⁹ Chemicals such as thiurams, stabilisers, and antioxidants (thiocarbamates, diphenylamine, dihydroquinoline, and phenylenediamine), which may be added to the latex during the manufacturing of rubber, have been recognised to induce ACD.⁴⁰

Flour is another very common HMW occupational allergen and epidemiological reports have revealed that asthma, rhinitis, and ACD are the major health effects due to exposure.⁴¹ Flour is a complex organic dust containing cereals which have been processed by milling. Flour dust usually contains various components which play an important role in dough improvement, such as a variety of enzymes (α-amylase, cellulose, hemicellulose, malt enzymes), additives (baker’s yeast, egg powder, milk powder, sugar), flavourings, spices, and chemical ingredients (preservatives, antioxidants, bleaching agents). Wheat is the main flour used in the baking industry and has been found to contain at least 40 allergens which represent about 10–15% of the dry weight of the grain.⁴² Baker’s asthma is one of the most frequently occurring forms of occupational asthma and most studies indicate that wheat and rye flour proteins are allergens for 60–70% of bakers with workplace-related respiratory problems.⁴³ The enzyme α-amylase (added to improve baking characteristics), thioredoxin, plain lipid transfer proteins, and serine proteinase inhibitors are among the main factors associated with baker’s asthma and studies have found that the highest frequency of specific IgE measurements were identified for α-amylase inhibitors Tri a 28 and Tri a 29.01.⁴¹ Chemical components in flour such as preservative and bleaching agents have also been shown to cause ACD in bakers.⁴⁴

Exposure to laboratory animals has been shown to result in occupational allergy and is commonly observed among technicians, animal caretakers, physicians, and scientists who work in pharmaceutical industries, university laboratories, and animal breeding facilities.⁴⁵ Rodents such as mice and rats, that are frequently used in animal research, are the most common causes of occupational allergy to laboratory animals. Mouse sensitisation is increasing in laboratory animal technicians and researchers due to the dramatic increase in the use of mice in experimental models. It is estimated that between 5% and 8% of this population is affected with some estimates suggesting an increase of ≤23% over a 2-year period in the USA. Urine is the main source of the allergenic protein in both mice and rats but allergens can also be found in dander, hair, saliva, and serum.⁴⁶ As with most mammals, the major inhaled allergens in mice and rats are lipocalins (Mus m 1 and Rat n 1, respectively). These allergens share 64% homology between their amino acid structures. Mouse urinary protein has shown IgE cross-reactivity with rat urinary protein and Equ c 1 (a major horse allergen).⁴⁷

Metals are considered to be one of the most common occupational allergens and it is estimated that 10–15% of the population have allergies to at least one species of metal.⁴⁸ Occupational exposure to metals can result in varying levels of morbidity and mortality due to the induction of a wide range of allergic diseases including ACD, occupational asthma, and anaphylaxis. Surprisingly, little is known about the immunologic mechanisms driving the reaction behind metal allergy.^26,48 Metals are thought to interact directly with the surface of human lymphocytes to stimulate the adaptive immune response, however the exact mechanism is not fully understood.⁴⁹ Recent research also supports a role for the involvement of the innate immune system (specifically toll-like receptors) in the allergic responses to metals.⁵⁰ Numerous metals including gold, chromium, cobalt, platinum, nickel, palladium, and mercury are known to induce allergic responses resulting in ACD and asthma.¹⁹ Following patch testing of 4,454 patients (not all due to occupational exposure), nickel sulphate (19.0%), cobalt chloride (8.4%), and potassium dichromate (4.8%) were among the most common allergens, with nickel being identified as the most frequent positive allergen.¹⁹ Sources of occupational allergen exposure include releases from dental tools and alloys,⁵¹ scissor and nail instruments used by cosmetologists and nail technicians,⁵² coin handling operations,⁵³ and metal processing.⁵⁴

Occupational allergy has significant social and economic implications for workers, their families, their employers, and government agencies. Sensitised workers must avoid exposure to the allergen both at work and outside the workplace in order to have the best chance of improvement or clearing of the allergic manifestations. This may be achieved by altering workplace tasks and duties, implementing engineering controls, or by providing workers with appropriate personal protective equipment. Most often, a sensitised worker would have to move to a completely different area or change to a different workplace or occupation to avoid further exposure to the offending allergen.

However, numerous approaches that integrate risk assessment and risk management strategies have been developed to control workplace exposures to occupational allergens.^58–61 In this context, it is imperative to establish an effective risk management strategy that is designed to prevent the induction of sensitisation in naïve individuals and inhibit elicitation of allergic responses in those that have become sensitised.² Such a strategy should include both primary and secondary prevention methods. Primary prevention methods are interventions used to prevent worker sensitisation and may include the following:

Modification of the allergen to inhibit exposure

Secondary prevention methods attempt to characterise workplace exposure, in addition to detecting and limiting the progression of allergic diseases. Examples of secondary preventive methods include medical monitoring^58,62,63 and workplace exposure monitoring.^2,58,61

Another important tool applied to characterise and aid in controlling workplace exposures to occupational hazards are occupational exposure limits (OELs). Despite their widespread use globally, few OELs are established on the basis of preventing sensitisation. The quantitative risk assessment approaches used to derive OELs have been developed primarily for non-immune-mediated effects, such as portal of entry effects, non-cancer systematic effects, or cancer. Application of these approaches to develop OELs for allergens has been inhibited because of data limitations and a lack of understanding of the biological processes that govern immune-mediated effects. The route of exposure, exposure intensity, and duration/ frequency of exposure have also been identified as factors complicating this process.² Research addressing these challenges along with a better understanding of allergic disease has direct implications in hazard identification, informing appropriate risk assessment, and management decisions to facilitate interventions and prevention of occupational allergies.