Occupational asthma can be defined as a disease characterized by airflow limitation and/or airway hyper responsiveness due to causes and conditions attributable to a particular occupational environment and not to stimuli encountered outside the workplace (Bernstein et al., 1993). In most industrialized countries, the most common occupational lung disease is occupational asthma and it was reported by Mantyjarvi et al., 1992 that close to 200 agents are known to induce occupational asthma. Chemical-induced occupational asthma is mainly determined by the level and mode of exposure to such chemicals. Close to 15% of asthmatic patients are regarded as work-related and there is an increase in its occurrence year by year (Bernstein, 1996; Sastre et al., 2003). Occupational asthma was identified in early 460B.C. Basically, occupational asthma are classified into two types, chronic occupational asthma which involves subsequent exposure to OA inducing agents. This type of OA is also known or regarded as OA with latency period. The second type is simply regarded as acute occupational asthma (no latency period) which involves short exposure to a high concentration of OA inducing agent. Acute OA is sometimes referred to as reactive-airway dysfunction syndrome (RADS) or irritant induced asthma. Compounds that cause occupational asthma can be classified into high molecular and low molecular weight compounds. The mechanisms by which chemicals causes occupational asthma are not fully understood and it is possible for common pathways to be shared. Some of the postulated mechanisms by which chemicals cause occupational asthma include immunological and non-immunological mechanisms. The immunological mechanism is not fully clear but it can occur either through immunoglobulin E (IgE) dependent mechanism or non-IgE dependent mechanism. It was also established from studies that occupational asthma can be caused by more than one mechanism. Other postulated mechanisms include genetic mechanism, pharmacological mechanism, neurogenic and airway inflammation (Mapp et al., 1994).
MECHANISM BY WHICH CHEMICALS CAUSE OCCUPATIONAL ASTHMA.
Mechanisms such as immunological and non-immunological will be discussed in this essay.
Immunological Mechanism
Both high molecular and low molecular weight agents could mediate the immunological mechanism. Examples of low molecular weight compounds include metals (chromium, nickel, zinc and platinum), acid anhydrides, diisocyanate, plicatic acid, amines and so on (Chang-Yeung and Malo, 1994, Mapp et al., 1994). Examples of high molecular weight compounds include animal products, plant proteins of polysaccharide such as flour, pharmaceutical products, gums, fish and seafood protein and enzymes (M. Chang-Yeung and J.Malo, 1994).
Patients with occupational asthma are known to have activated T-lymphocytes, eosinophils and metachromatic cells in their immune system. For an immune response to be generated, T-cells require activation by antigen recognition. The antigens are located on the exterior part of accessory cells or antigen presenting cells (APCs). The APCs include B-cells, macrophages and dendritic cells. The dendritic cells are found in the airway wall and lungs and are known to be involved in presenting the antigens to T-cells. The APCs are involved in processing the antigens for recognition by T-cells. The processed antigen becomes soluble so as to be easily recognised by T-cell receptors known as clonotypic T-cell receptors (TCR). T-cell receptors identify soluble antigens joined to major histocompatibility complex (MHC) molecules and are presented on the exterior part of the cell. MHC molecule has two main classes namely; MHC -I which are involved in recognising or identifying only suppressor CD8+ cells and MHC-II which are involved in identifying only CD4+ helper cells (Larch et al., 2002; Mapp et al., 1994).
After T-cells are activated, certain lymphokines are released and function mainly in differentiating and proliferating certain leucocytes. The T -helper cells produced are classified based on the cytokine produced. T-helper 1 (Th1) cells are mainly involved in secreting interferon-y (IFN-y) and IL-2 unlike the T-helper 2 (Th2) cells which are involved in secreting IL-4 and IL-5. IL-3 and granulocyte/macrophage colony-stimulating factor (GM-CSF) are produced by Th1 and Th2 cells. A chemotactic cytokine IL-8 is secreted upon activation of T-cells and functions by secreting IL-5 and GM-CSF. GM-CSF initiates eosinophils production and are involved in increasing the inflammation caused as a result of eosinophils. B-cells are stimulated by IL-4 and are involved in secreting specific immunoglobulins such as IgE and IgG.
Di- (2-ethylhexyl) phthalate (DHEP) is an example of compounds that acts using the immunological mechanism. DHEP are used in the manufacture of polyvinyl chloride (PVC) where it serves as a plasticizer and a good example of phthalate ester. It undergoes enzymatic hydrolysis forming MHEP metabolite which is caused as a result of increased effect of DHEP. When DHEP are inhaled, it enhances antibody IgE production. The antibody IgE produced then binds covalently to phthalates resulting in a conformational change which makes them antigenic and causes hapten formation on surfaces of mast cells. Inflammatory molecules such as PGF2alpha, PGD2 and thromboxanes are produced when mast cells are stimulated resulting in bronchospasm and secretion of mucus (Mapp et al., 1994).
Acid anhydrides are also examples of compounds that act via immunological mechanism. They are used in epoxy and alkyd resins such as hexahydrophthalic, trimellitic, phthalic and tetrachlorophthalic anhydrides results in hypersensitivity reactions in exposed workers. They tend to bind with endogenous proteins to form conjugates with antibodies and also act as haptens with the antibodies detecting the haptens (Zeiss et al., 1993). "They can also combine with self-proteins to generate new, carrier-dependent antigenic determinants with antibody combining sites being directed against a conformational change in self-proteins" (Zeiss et al., 1993). When trimellitic anhydride are coupled with proteins, new determinants are induced which are antigenic in nature. This is very similar to when trimellitic anhydride induces specific IgE, IgM, IgG and IgA antibodies against hapten. Lung diseases such as asthma, pulmonary disease-anaemia syndrome, and rhinitis are caused as a result of high level of exposure to trimellitic anhydride. High exposure to Tetrachlorophthalate anhydride (TCPA) at workplace has been reported to induce occupational asthma. Workers exposed to TCPA-conjugate showed a high increase in specific IgE antibodies in a survey carried out by Chang-Yeung et al., 1994. The level of exposure to TCPA is very important as workers removed from exposure showed a decrease in IgE antibodies level (Chang-Yeung et al., 1994). It was also reported by Chang-Yeung et al that airway hyper responsiveness was absent but several types of hypersensitivity reactions were induced.
Non-Immunological Mechanism
This type of mechanism does not require immune response sensitization neither does it require a latency period. Re-exposure to OA inducing agents does not cause similar symptoms or response to be generated from exposed workers. There are different types of occupational asthma which uses this mechanism such as potroom asthma and reactive airways dysfunction syndrome (RADS).
Reactive Airway Dysfunction Syndrome (RADS)
In 1985, Brooks and his co-workers coined this syndrome (Brooks SM et al., 1985). This syndrome is also known as "irritant-induced asthma". This mechanism is not fully understood, but it was postulated that exposure to high concentration of OA inducing agents such as toluene diisocyanate, formaldehyde, ammonia, machining fluid, and so on causes damage to the bronchial epithelium resulting in neurogenic inflammation and activation of non-adrenergic non-cholinergic (NANC) mechanisms (Brooks SM et al., 1993). The NANC mechanism involves secreting neuropeptides of the sensory nerves located in the basal membrane. Furthermore, irritant agents cause neutral endopeptidases (NEP) to become suppressed alongside neuropeptide secretion. Neuropeptidase binds to cell receptors on the lungs controlled by the enzyme neutral endopeptidase (NEP). When NEP is not activated, inflammation results due to neuropeptides binding to cell receptors.
Toluene diisocyanate (TDI) is an example of a compound which uses the RADS mechanism to cause OA. Diisocyanates are compounds which have N, C and O group. These groups are attached to a radical and react with compounds such as polyglycols to form polyurethranes. They are extensively used in industries and are known to be the most common agent that causes OA. They are low molecular weight compounds synthesised when there is a reaction between amines and phosgene. They interact covalently with cellular proteins and cause sensitization which implies that they are strong electrophiles. TDI targets glutathione in the epithelial fluid of the lungs. Reaction between TDI and glutathione causes glutathione depletion in the cell resulting in oxidative damage and cell death. Also, this reaction leads to bis(S-glutathionyl) adduct formation (Redlich and Karol, 2002). Furthermore, intracellular glutathione deficiency can be induced by diisocyanates which in turns lead to the activation of mitogen-activated protein kinase. The levels of intracellular peroxide increases in workers exposed to diisocyanates and adhesion molecule in monocytic cell lines are expressed (Elms J et al., 2001).
Plicatic acid is also an example of compounds which acts via non-immunological mechanism. They are present in woods and are known to cause red cedar asthma (Harris MG et al., 1977). The molecular weight of plicatic acid is 440 k Da. Allergen is formed when there is a conjugation between plicatic acid and human serum albumin. Patients with red cedar asthma have been reported to involved in histamine release but recent studies indicates that specific IgE antibodies are not responsible for the histamine release. Further studies are required as the mechanism by which PA-induced asthma is not fully understood.
http://upload.wikimedia.org/wikipedia/commons/thumb/3/34/Plicatic_acid.svg/200px-Plicatic_acid.svg.png
Structure of Plicatic acid
Other postulated mechanisms by which chemicals cause occupational asthma are genetic mechanism, pharmacological mechanism, neurological and airway inflammation (Mapp et al., 1994).
CONCLUSION
The nature of the irritant agent and level of exposure could cause the different mechanisms involved in asthma induction. Immunological mechanism are IgE dependent while the non-immunological mechanism are non-IgE dependent. The high molecular weight compounds acts mostly using the immunological mechanism while the low molecular weight compounds acts via non-immunological mechanism. Although, recent findings suggested that there are certain low molecular weight compounds that are IgE dependent. Exposure level at work place should therefore be minimised so as to avoid OA.
