Abstract

AIM:
The biological mechanisms of work-related asthma induced by irritants remain unclear. We investigated the associations between occupational exposure to irritants and respiratory endotypes previously identified among never asthmatics (NA) and current asthmatics (CA) integrating clinical characteristics and biomarkers related to oxidative stress and inflammation.

METHODS:
We used cross-sectional data from 999 adults (mean 45 years old, 46% men) from the case-control and familial Epidemiological study on the Genetics and Environments of Asthma (EGEA) study. Five respiratory endotypes have been identified using a cluster-based approach: NA1 (n=463) asymptomatic, NA2 (n=169) with respiratory symptoms, CA1 (n=50) with active treated adult-onset asthma, poor lung function, high blood neutrophil counts and high fluorescent oxidation products level, CA2 (n=203) with mild middle-age asthma, rhinitis and low immunoglobulin E level, and CA3 (n=114) with inactive/mild untreated allergic childhood-onset asthma. Occupational exposure to irritants during the current or last held job was assessed by the updated occupational asthma-specific job-exposure matrix (levels of exposure: no/medium/high). Associations between irritants and each respiratory endotype (NA1 asymptomatic as reference) were studied using logistic regressions adjusted for age, sex and smoking status.

RESULTS:
Prevalence of high occupational exposure to irritants was 7% in NA1, 6% in NA2, 16% in CA1, 7% in CA2 and 10% in CA3. High exposure to irritants was associated with CA1 (adjusted OR aOR, (95% CI) 2.7 (1.0 to 7.3)). Exposure to irritants was not significantly associated with other endotypes (aOR range: 0.8 to 1.5).

CONCLUSION:
Occupational exposure to irritants was associated with a distinct respiratory endotype suggesting oxidative stress and neutrophilic inflammation as potential associated biological mechanisms.

Full Text

Comments

This paper defines a respiratory irritant very broadly to include most low molecular weight sensitisers (isocyanates, epoxy resins, amines, acrylates), as well as some possible high molecular weight allergens (moulds, wood) which most would not regard primarily as irritants. The paper groups asthmatics into 3 endotypes 1. symptomaric adult onset treated asthma with poor lung function, neutrophilia and incresaed fluorescent oxygenation products (a measure of damage due to oxidative stress). This group had more exposure to the list of "irritants". When broken down by category the risk was bighest for biocides 2. Asthma with rhinitis and low IgE 3. Atopic childhood-onset astma and high IgE

10/11/2021

This study of endotypes responsible for the development of irritant induced occupational asthma raises questions as to what is meant by a respiratory irritant [1]. Classifying an exposure as irritant usually implies that the effect is non-specific, i.e. all similar asthmatics would react to the exposure whether they have had previous exposure to the agent or not. For instance, sulphur dioxide is a respiratory irritant, the exposure needed to provoke asthma is correlated with the degree of preexisting non-specific reactivity, as measured with methacholine or histamine [2]. The paper by Andrianjafimasy [1] uses a JEM whose list of irritants includes the best known low molecular weight respiratory sensitisers, such as isocyanates, acrylates, epoxy resins and amines where there is no evidence of airflow obstruction in previously unexposed, or exposed asymptomatic workers induced by exposures that can cause severe reactions in sensitised individuals. Reactive low molecular weight chemicals may act as haptens, binding to body protein creating neoantigens [3]. The action of biocides denaturing proteins may have a similar effect again leading to specificity in the airway response [4]. The mechanisms, and perhaps susceptibility to reactions with specificity is likely to differ from agents which lack specificity. Labelling a chemical as a sensitiser should lead to better control than adding an irritant label, which risks degrading the significance of the exposure, similar to classifying an exposure as a “nuisance” dust. We believe that labelling a substance as an irritant needs as much evidence as labelling a chemical as a sensitiser. The potential for a low molecular weight chemical to act as a sensitiser can often be predicted from its chemical structure [5]. We may need an additional category where the mechanism awaits elucidation, such as exhaust fumes and textile dust [1] where there are studies appearing to show some specificity of the airway responses [6] 1. Andrianjafimasy MV, Febrissy M, Zerimech F, Dananché B, Kromhout H, Matran R, Nadif M, Oberson-Geneste D, Quinot C, Schlünssen V, Siroux V, Zock JP, Le Moual N, Nadif R, Dumas O, Association between occupational exposure to irritant agents and a distinct asthma endotype in adults., Occup Environ Med, 2021;:,doi.org/10.1136/oemed-2020-107065 2. Harries MG, Parkes PEG, Lessof ME, Orr TSC, Role of irritant receptors in asthma, Lancet, 1981;i:5-6 3. Tee RD, Cullinan P, Welch JA, Burge PS, Newman Taylor AJ, Specific Ige To Isocyanates: A Useful Diagnostic Role In Occupational Asthma, J Allergy Clin Immunol, 1998;101:709-715 4. Walters GI, Robertson AS, Moore VC, Burge PS, Occupational asthma caused by sensitization to a cleaning product containing triclosan, Antibac, (2,4,4’-trichloro-2’-hydroxydiphenyl ether), nurse, cleaner,, Ann Allergy Asthma Immunol, 2017;118:370-

3/7/2022

This study of endotypes responsible for the development of irritant induced occupational asthma raises questions as to what is meant by a respiratory irritant [1]. Classifying an exposure as irritant usually implies that the effect is non-specific, i.e. all similar asthmatics would react to the exposure whether they have had previous exposure to the agent or not. For instance, sulphur dioxide is a respiratory irritant, the exposure needed to provoke asthma is correlated with the degree of preexisting non-specific reactivity, as measured with methacholine or histamine [2]. The paper by Andrianjafimasy [1] uses a JEM whose list of irritants includes the best known low molecular weight respiratory sensitisers, such as isocyanates, acrylates, epoxy resins and amines where there is no evidence of airflow obstruction in previously unexposed, or exposed asymptomatic workers induced by exposures that can cause severe reactions in sensitised individuals. Reactive low molecular weight chemicals may act as haptens, binding to body protein creating neoantigens [3]. The action of biocides denaturing proteins may have a similar effect again leading to specificity in the airway response [4]. The mechanisms, and perhaps susceptibility to reactions with specificity is likely to differ from agents which lack specificity. Labelling a chemical as a sensitiser should lead to better control than adding an irritant label, which risks degrading the significance of the exposure, similar to classifying an exposure as a “nuisance” dust. We believe that labelling a substance as an irritant needs as much evidence as labelling a chemical as a sensitiser. The potential for a low molecular weight chemical to act as a sensitiser can often be predicted from its chemical structure [5]. We may need an additional category where the mechanism awaits elucidation, such as exhaust fumes and textile dust [1] where there are studies appearing to show some specificity of the airway responses [6] 1. Andrianjafimasy MV, Febrissy M, Zerimech F, Dananché B, Kromhout H, Matran R, Nadif M, Oberson-Geneste D, Quinot C, Schlünssen V, Siroux V, Zock JP, Le Moual N, Nadif R, Dumas O, Association between occupational exposure to irritant agents and a distinct asthma endotype in adults., Occup Environ Med, 2021;:,doi.org/10.1136/oemed-2020-107065 2. Harries MG, Parkes PEG, Lessof ME, Orr TSC, Role of irritant receptors in asthma, Lancet, 1981;i:5-6 3. Tee RD, Cullinan P, Welch JA, Burge PS, Newman Taylor AJ, Specific Ige To Isocyanates: A Useful Diagnostic Role In Occupational Asthma, J Allergy Clin Immunol, 1998;101:709-715 4. Walters GI, Robertson AS, Moore VC, Burge PS, Occupational asthma caused by sensitization to a cleaning product containing triclosan, Antibac, (2,4,4’-trichloro-2’-hydroxydiphenyl ether), nurse, cleaner,, Ann Allergy Asthma Immunol, 2017;118:370-

3/7/2022

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4/3/2022