Sex- and Gender-Based Differences in Asthmatic Responses to Chemical Sensitizers, Particularly in Occupational Settings: A Scoping Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The review focused on the role of occupational exposure on asthma, considering the significant modifying effect of sex and gender. The review considers many aspects that thoroughly describe the complexity of this interrelationship.  However, the structure of the manuscript should be revised in some parts to make it more readable and fluent.

Major revisions

Lines 40-87: the introduction should be better balanced. The section on legislation should be shortened, considering that this is not the main objective of the manuscript.

Lines 111-118: Reading the introduction, it might seem that the effect of smoking habits will be explored in greater detail in the review. However, this is not the case. Therefore, I suggest exploring this aspect further or simply mentioning smoking as a potential risk factor to consider, along with for example air pollution or comorbidities.

Lines 139-141: in the aim of the review the mention of occupational exposure is missing.

Lines 226-229: this paragraph should be moved to section 3.1.2.

Section 3.2: I suggest using the same title as for section 3.1 “The gender:…”, otherwise the gender aspect is not clearly stated in the manuscript.

Furthermore, the epidemiological evidence addresses both gender and sex. The authors could use the epidemiological evidence on sex to support section 3.1 (or vice versa) and leave the epidemiological evidence on gender in this section. I believe 2 separate sections (3.1 for sex, with biological and epidemiological evidence, and 3.2 for gender) would make the review clearer. So, leaving in section 3.2 the paragraphs starting from line 367 (for example).

Line 336-337: the first sentence talks about gender and the following sentences on sex. Is this a typo?

Limitations: indeed, some of the studies described in section 3.3 don’t compare the different probability of having asthma between males and females, but only the higher percentages of women employed in specific occupational sectors. This is not sufficient to formulate hypothesis about the relationship between asthma-occupation-sex/gender. This limitation should be described in the limitations section. On the other hand, this lack of studies could be highlighted to reinforce the need for ad hoc studies that consider the important issue on gender/sex effect.

Author Response

REFEREE-1_ REPLY

Lines 40-87: the introduction should be better balanced. The section on legislation should be shortened, considering that this is not the main objective of the manuscript.

1. We agree with the reviewer, and the section on legislation has been partially shortened.

However, we consider it essential to provide a brief legislative introduction to clarify that the focus of our work is on chemical sensitizers, particularly respiratory sensitizers, as defined by Regulation (EC) No. 1272/2008 (CLP) and aligned with the UN Globally Harmonized System (GHS). While some reviewers noted that respiratory effects can also arise from allergens more generally and suggested that a clearer distinction between sensitizers and irritants should be included in the context of chemical exposure, we have maintained the CLP definition for sensitizers and added the CLP definition for respiratory irritants to highlight their different classification based on their distinct effects. For this reason, we also deemed it important to specify the mechanism of action of chemical sensitizers.

Finally, the discussion on certain chemical sensitizers included among VHC substances emphasizes the health risks associated with this class of substances (sensitizers) and the EU-level concerns that have led to restrictive measures, highlighting the relevance and timeliness of our paper for protecting both the general and working populations.

Lines 111-118: Reading the introduction, it might seem that the effect of smoking habits will be explored in greater detail in the review. However, this is not the case. Therefore, I suggest exploring this aspect further or simply mentioning smoking as a potential risk factor to consider, along with for example air pollution or comorbidities.

1. We agree with the reviewer and the sentences related the effect of tobacco smoke have been simplified as follows.

“Tobacco exposure should be recognized as an important potential confounding factor as is independently associated with airway sensitization, hyperresponsiveness, and inflammation, and may contribute to both atopic and non-atopic. While the effects of active or passive smoking are not the focus of this review, it should be considered alongside other potential risk factors (e.g. air pollution or comorbidities), when interpreting asthma outcomes.”

 

Lines 139-141: in the aim of the review the mention of occupational exposure is missing.

1. Thank you for highlighting it. Abstract, title and aim of the study have been revised.

 

Lines 226-229: this paragraph should be moved to section 3.1.2.

3. Thank you for your suggestion, now the phrase is moved in section 3.1.2.

 

Section 3.2: I suggest using the same title as for section 3.1 “The gender:…”, otherwise the gender aspect is not clearly stated in the manuscript.

1. We agree with the reviewer, and the titles of the subsections in Results and Discussion (now Section 4) have been updated:

4.1. Sex and gender: epidemiological evidence on general population

4.2. Sex and gender: epidemiological evidence in occupational settings

 

Furthermore, the epidemiological evidence addresses both gender and sex. The authors could use the epidemiological evidence on sex to support section 3.1 (or vice versa) and leave the epidemiological evidence on gender in this section. I believe 2 separate sections (3.1 for sex, with biological and epidemiological evidence, and 3.2 for gender) would make the review clearer. So, leaving in section 3.2 the paragraphs starting from line 367 (for example).

3. We apologize if the structure of the text was not sufficiently clear. Section 3.1 provides a description of possible biological mechanisms and therefore necessarily refers only to sex. In contrast, Section 3.2 presents epidemiological findings (from environmental and occupational exposure), which may include both sex and gender differences. We chose to keep these two aspects separate because, as stated in the Methods, the main aim of the scoping review was to consider exposure data involving sensitizing chemicals and the onset of asthma ranging from the general population to occupational settings. The description of biological mechanisms was, in our view, essential to support the epidemiological evidence and provide a better understanding of the topic.

To avoid any misunderstanding, we have moved paragraph 3.1 out of the Results and placed it into a specific section (3. Biological mechanisms underlying sex differences in asthma), where the biochemical mechanisms are presented as preliminary information and as background to support the findings of the scoping review.

Therefore, the article’s new structure is as follows:

3. Biological mechanism underlying sex differences in asthma

3.1. Biological and physiological differences linked with possible different health effects

3.1.1 Sex and anatomic factor’s role on asthma

3.1.2. Sex hormone’s role on asthma

3.1.3. Genetic and epigenetic mechanism’s role on asthma

4. Results and Discussion

4.1. Sex and gender: epidemiological evidence on general population

4.2. Sex and gender: epidemiological evidence in occupational settings

 

Line 336-337: the first sentence talks about gender and the following sentences on sex. Is this a typo?

Sorry it was a typo; the correct phrase is “The role of sex and gender…”.

 

Limitations: indeed, some of the studies described in section 3.3 don’t compare the different probability of having asthma between males and females, but only the higher percentages of women employed in specific occupational sectors. This is not sufficient to formulate hypothesis about the relationship between asthma-occupation-sex/gender. This limitation should be described in the limitations section. On the other hand, this lack of studies could be highlighted to reinforce the need for ad hoc studies that consider the important issue on gender/sex effect.

1. Thank you very much; this is indeed a very important issue. We have now added this limitation to the Conclusions, also highlighting the need for ad hoc studies.

“Additionally, some studies, while evaluating male and female working populations separately, do not properly investigate the differences in disease incidence between the two sexes. This should be acknowledged as a limitation of including these studies in the present discussion and further emphasizes the need for future research that consider the important issue on gender/sex effect.”

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This is a very comprehensive review covering a current and interesting topic. The introduction provides a brief yet complete and understandable overview of inter-sex/-gender differences in asthma prevalence as well as in chemicals exposure context. The sources’ selection as per PRISMA-ScR guidelines for this type of reviews is fine and no issues are to be raised here. Article screeining process is clearly described and well presented in chart, which needs to be underlined here.

Please find below my comments and remarks with regard to further parts of the manuscript.

MAJOR ISSUE:

Although the term “sensitizers” is used throughout the manuscript, the immunoglobulin E (IgE) are not mentioned at all, while their presence is an important hallmark of immunological reaction and sensitization. Maybe additional clear-cut delimitation between sensitizers and irritants should be included in the context of the exposure to chemicals. It should be emphasized and clearly indicated whether the review focises on sensitizaers (i.e., solely on immunological indices of exposure), or on irritants and sensitizers alike.

MINOR ISSUES

Lines 139-141: The goal of the review should be more precisely formulated in the context of chemical sensitizers.

Although the definition and reasons for differentiation between the notions of ‘sex’ and ‘gender’ has been provided, the terms look to be misused in some places in the manuscript (e.g., line 336 with regard to ‘gender’). Please check throughout to assure uniformity of terminology.

In line 359 – the reference should be provided in the correct format and receive a consecutive number, as per journal guidelines

Author Response

REFEREE-2_ REPLY

MAJOR ISSUE:

Although the term “sensitizers” is used throughout the manuscript, the immunoglobulin E (IgE) are not mentioned at all, while their presence is an important hallmark of immunological reaction and sensitization. Maybe additional clear-cut delimitation between sensitizers and irritants should be included in the context of the exposure to chemicals. It should be emphasized and clearly indicated whether the review focises on sensitizaers (i.e., solely on immunological indices of exposure), or on irritants and sensitizers alike.

1. As suggested by the reviewer, it was clarified in the Introduction that the focus of our work is on chemical sensitizers, particularly respiratory sensitizers, as defined by Regulation (EC) No. 1272/2008 (CLP) and aligned with the UN Globally Harmonized System (GHS). These differ from respiratory irritants, which have a distinct definition and classification under the CLP. In addition, we have provided a clearer description of how the chemical sensitization mechanism generally occurs from a physiological perspective. Introduction has therefore been modified as follows:

“According to CLP Regulation, a substance must be classified as a respiratory sensitizer (Category 1) if: (a) there is evidence in humans that the substance can induce specific respiratory hypersensitivity; and/or (b) there are positive results from an appropriate animal test. From a physiological perspective, the first contact with a chemical sensitizer usually does not produce noticeable symptoms but instead primes the body through the development of specialized memory cells. Subsequent exposures to the same substance, even at low levels, elicit an abnormal and exaggerated immune response, resulting in symptoms of varying severity [1,2]. In contrast, although inhaled chemical irritants can cause a range of effects on the respiratory system, they induce direct tissue damage through localized inflammation at the site of contact without triggering an allergic reaction. Therefore, they should not be confused with respiratory chemical sensitizers, as their mechanism of action is different. According to the CLP, a substance that “may cause respiratory irritation” is classified as “specific target organ toxicity after single exposure” (Category 3), causing transient effects that temporarily impair human function but from which recovery occurs without lasting structural or functional damage.”

 

Finally, the central role of the immunoglobulin E (IgE) in the immune response has been better underlined in the section 3.1.2. Sex hormone’s role on asthma:

 

“Notably, B lymphocytes are stimulated to produce immunoglobulin E (IgE) antibodies, which bind to receptors on the surface of mast cells and basophils, priming them for a more effective immune response upon subsequent exposure to the allergen or chemical sensitizers. When the allergen or chemical sensitizer reappears, it binds to the IgE antibodies already attached to the cells, triggering their degranulation and the release of pro-inflammatory mediators (histamine, prostaglandins, and leukotrienes) that contribute to bronchoconstriction, increased vascular permeability, and mucus secretion [45]. In asthma, IgE thus plays a central role in the immunological response leading to the airway inflammation and bronchoconstriction characteristic of the disease. IgE is also implicated in the late-phase response, chronic airway inflammation, and airway remodeling, making it a key target for therapies in severe allergic asthma.”

 

MINOR ISSUES

Lines 139-141: The goal of the review should be more precisely formulated in the context of chemical sensitizers.

1. Thank you for highlighting this. The abstract, title, and aim of the study have been revised to emphasize the role of respiratory sensitizers in the onset and progression of asthma, considering data from the general population to occupational settings, with a focus on sex and gender as key modifiers of risk, disease severity, and occupational outcomes.

 

Although the definition and reasons for differentiation between the notions of ‘sex’ and ‘gender’ has been provided, the terms look to be misused in some places in the manuscript (e.g., line 336 with regard to ‘gender’). Please check throughout to assure uniformity of terminology.

1. Thank you very much for your suggestion; the text has now been carefully checked regarding this.

 

In line 359 – the reference should be provided in the correct format and receive a consecutive number, as per journal guidelines

1. We apologize for the oversight. The reference citations have now been corrected and numbered consecutively in accordance with the journal guidelines.

 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Considering that asthma is characterized by highly heterogeneous pathophysiology and phenotypic manifestations, the topic of this paper is valuable.However, the formulation of 'chemical sensitizers' needs correction. Sensitization  is an immune reaction, chemicals irritants, and increase the inflammatory response on the bronchial tree, which consequently leads to asthma symptoms.It is not immunologically mediated reaction.

Author Response

REFEREE-3_ REPLY

Considering that asthma is characterized by highly heterogeneous pathophysiology and phenotypic manifestations, the topic of this paper is valuable. However, the formulation of 'chemical sensitizers' needs correction. Sensitization is an immune reaction, chemicals irritants, and increase the inflammatory response on the bronchial tree, which consequently leads to asthma symptoms. It is not immunologically mediated reaction.

1. Thank you for your suggestion. As suggested, it was clarified in the Introduction that the focus of our work is on chemical sensitizers, particularly respiratory sensitizers, as defined by Regulation (EC) No. 1272/2008 (CLP) and aligned with the UN Globally Harmonized System (GHS). These differ from respiratory irritants, which have a distinct definition and classification under the CLP. In addition, we have provided a clearer description of how the chemical sensitization mechanism generally occurs from a physiological perspective. Introduction has therefore been modified as follows:

“According to CLP Regulation, a substance must be classified as a respiratory sensitizer (Category 1) if: (a) there is evidence in humans that the substance can induce specific respiratory hypersensitivity; and/or (b) there are positive results from an appropriate animal test. From a physiological perspective, the first contact with a chemical sensitizer usually does not produce noticeable symptoms but instead primes the body through the development of specialized memory cells. Subsequent exposures to the same substance, even at low levels, elicit an abnormal and exaggerated immune response, resulting in symptoms of varying severity [1,2]. In contrast, although inhaled chemical irritants can cause a range of effects on the respiratory system, they induce direct tissue damage through localized inflammation at the site of contact without triggering an allergic reaction. Therefore, they should not be confused with respiratory chemical sensitizers, as their mechanism of action is different. According to the CLP, a substance that “may cause respiratory irritation” is classified as “specific target organ toxicity after single exposure” (Category 3), causing transient effects that temporarily impair human function but from which recovery occurs without lasting structural or functional damage.”

 

 

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

Asthma is a very prevalent chronic disease. It is well known that the disease is more prevalent in females. Most asthma cases begin in childhood or adolescents, fewer later in life. Among these late-onset cases, a large proportion already showed signs of respiratory allergies before and asthma developed by a kind of “stage shift” (from the nose to the bronchial system). Some “new” asthmatics might have had some less apparent form of asthma since many years. But when they got in contact with new allergens or irritants at their workplace, they developed a more severe form that interfered with there work capability.

Therefore, in my mind, it is most important to study causes of asthma in early childhood or even before birth. For example, when most of the asthma cases already develop in childhood, I do not understand how (active) smoking can be a relevant cause of asthma. I do agree that tobacco smoke contains a lot of different irritants so that smoking can increase asthma symptoms. Even passive smoking has grave adverse effects and very likely plays a role in asthma initiation. The problem with studies on early asthma origins is with the correct diagnosis in young age. The bronchial system has not many options how to react to multiple external stimuli: the bronchial muscles can contract, the mucus production can be enhanced, the connective tissue can develop signs of inflammation. The same symptoms can indicate a one-time and reversible infectious process, the effect of a single toxic or irritative result, or the first incidence of a chronic disease with episodes triggered by allergen contact. Another problem is this: Pneumologists are divided as to how define asthma. Besides a reluctance to call the first asthma episode by its true name (a verdict of chronic disease), they are also divided how to distinguish different types of asthma or how to distinguish asthma from chronic obstructive pulmonary disease (COPD). While in theory, asthma is characterized by distinct and reversible obstructive episodes, and COPD by a persistent obstruction, there is in practice a continuum between both entities. This also leads to the argument if there is really something like “neutrophilic asthma”, or if this name only describes either a kind of “intermittent COPD” or some combination of asthma and COPD. Again, in theory, although the reality again is blurred, “asthma” would be an atopic disease with reactions to specific allergens, indicated by an eosinophilic inflammation and high exhaled NO levels. In practice again, asthma-like episodes can also be triggered by a lot of different non-allergic stimuli, including mechanical and chemical agents. Irritating substances (often of low molecular weight), besides causing asthma-like symptoms themselves, might also damage the epithelium and thus enhance the likelihood of a true (allergic, atopic, eosinophilic) asthma development. The allergens then keeping up the disease process are often of higher molecular weight, although some smaller molecules can also act as haptens to turn human proteins into allergens. Therefore, while irritants and infectious agents “are meant to” cause a neutrophilic reaction, while allergens lead to an eosinophilic inflammation, mixed reactions and a broad grey zone between “true asthma” and “asthma-like” bronchial inflammation are rather the norm than the exception.

This paper sets out to scrutinize the literature to answer two questions, I think: “what causes asthma?”, focusing on external, environmental causes, not on genetic ones, and “why is there a sex/gender difference?” As outlined above, I find concentrating on occupational factors (or on active smoking) when seeking the main external causes of the disease rather pointless. And regarding sex differences, we only learn that they are really there and that they might be caused by “hormones”. Who would have expected that? Yes, there are also gender differences. Depending on the population and occupations under study, men and women will face different kinds of exposure that will also affect disease development. This is also not a very novel fact!

An interesting aspect about sex and gender differences is the reverse sex ratio before puberty. It seems the authors believe this might also be explained by “hormones”, but I do not really see why. I do not know the true reason. But I have a kind of theory that this difference is rather a gender difference than a sex difference: Boys are expected to be physical active, to play more aggressively outdoors, while girls are in many societies still expected to take it easy, help at home, etc. Therefore, in childhood, maybe first asthmatic symptoms just show more readily in boys? Differences in growth spurts also might play a role and also misguided spirometry norm values. These norm values are based on age and body height. But during rapid body growth, the long bones in the legs might lengthen very fast, while the chest volume does not catch up at once. The timing of these growth episodes does differ between sexes. And this might have an impact on asthma diagnosis.

To summarize: The authors ask: “What causes asthma?” And they look at the wrong time in life. And they ask: “Why do we see a sex and gender difference?” And they only confirm that this difference exists. Both outcomes are very disappointing.

In addition, I have also minor complaints. But since I suggest rejecting the paper, this would not really matter:

Regarding their methodology, the authors state: “Research on biological mechanisms of action, although not selected for formal inclusion in the scoping review, was used to illustrate the underlying mechanisms of observed effects and to support the interpretation of sex- and gender-stratified data.” I believe, this is important. And indeed, they do cite mechanistic studies. But then, in the discussion, they acknowledge not “using in vitro and in vivo surveys” as a limitation. Yes, I agree that focusing on experimental studies instead of on epidemiological studies might have helped them better to answer their questions. But at least, they should be consistent: is this a review of the prevalence and incidence of disease and of real-world causes and triggers, or is this a review of the causes and mechanisms?

The authors often state that they looked for “sensitizing” (occupational) substances. As discussed above (and as also confirmed by the authors), it is not only sensitizers that matter.

The introduction has a very strong focus on comparing international rules on allergens. This part has only very little relevance for the overall theme of the paper.

The authors use the term “chemical sensitizer” (e.g., in table 2). In my understanding, a “sensitizer” is an allergen. And I already wrote that allergens are only one side of the coin. But here, I am concerned about the meaning of “chemical”. Every substance is “chemical”, isn’t it? Or do you mean “synthetic chemicals”? but then, also biological and organic substances can act as allergens and are, among others, also listed in table 2.

In table 2, they also mention “hardwood dust (e.g., oak, beech)”. I know this dust to cause nasal cancer. As a relevant cause for asthma, this was new for me. As only evidence for their claim, they provide a reference that is a case study of a single worker exposed to chengal wood dust. Maybe the terpenes in chengal wood are highly allergenic. I do not know. But this is not proof that oak-wood is a relevant cause of asthma.

The whole chapter on “3.1. The sex: biological and physiological differences linked with possible different health effects” is long, but remains rather vague. It can be summarized by their sentence: “The underlying causes of these sex-based differences in asthma development are not yet fully understood.” Yes, anatomy might play a role as well as hormones and genes and their epigenetic regulation. We learn that “the number of alveoli per unit area and alveolar size do not differ significantly between the sexes”. But also, that boys exhibit “a greater alveolar surface area.” This sounds contradictory. But I guess, the sex differences vary across age stages. Still, what does this mean for asthma? Is a larger lung “good”, because it has a larger residual capacity, or is it “bad”, because a larger reactive area increases the risk that “something goes wrong”?

“In early life, female sex hormones appear to promote lung development and maturation, whereas androgens may exert inhibitory effects.” But in the previous paragraph we learned that boys have the larger lung!

Chapter 3.1.1, which is about anatomy according to its title, discusses hormonal effects on anatomy, while chapter 3.1.2, which is about sex hormones, really discusses the immune system. As I have explained, there is an issue about atypical or neutrophilic asthma. The issue is approached in chapter 3.1.2, but, in my mind, not in a very enlightening manner. We learn that there are type 2 and non-type-2 mechanisms and then type 2 is described in very much detail. The other type of inflammation is mentioned in passing and described in one short paragraph, but without much context. The chapter continues with considerations about the impact of hormones. The conclusion of this is best summarized by their sentence: “Similarly, the impact of progesterone on asthma is complex, exhibiting both pro-inflammatory and anti-inflammatory effects.”

Chapter 3.1.3 deals with genetic and epigenetic Here, I want mostly to point out that also men have an X-chromosome. Only genes on the Y-chromosome are specific to one sex only. Yes, epigenetics might switch on or off specific genes. But it does not matter if they are on the X-chromosome or on any other chromosome.

Chapter 3.2 is about epidemiological evidence. Yes, hormones play a role. But the evidence is still obscure demonstrating either protective or adverse effects. This is true for hormone replacement therapy, asthma severity changes with the hormonal cycle, and other observations.

According to line 356, Hansen et al. [71] is a large case-control study, while according to line 388, the same study is “a large prospective cohort study”. Also, another study ([Shah, 2021]) is mentioned, that is not listed in the references.

And how does the effect of surgery support the central role of hormones?

Pregnancies must cope with a growing foreign body in the womb. In my understanding, during pregnancy, immune responses should be suppressed. But anatomical changes and a larger demand for oxygen will likely augment asthma symptoms.

It does not come as a surprise that smoking affects lung function (line 384). According to the description of study [66], asthma is more prevalent in women (which we know), women smoke less, and have a better lung function. Is this because they smoke less or because their asthma is less severe? Is this only true for asthmatics or for healthy women compared to healthy men also?

Which “clinical trial findings” (line 397) investigate childhood prevalence? Clinical trials do not examine prevalence in the general population, but compare intervention and control groups.

Figure 5 is just a repetition of the text above. Only “obese neutrophilic asthma” is a new information. But without context and detail, this point has not much meaning.

Chapter 3.3. starts with the ground-braking information, that sensitizers (low- and high-molecular weight) increase the risk of asthma.

Figure 6 is again a (nearly word-by-word) repetition of the text before.

Line 469 tells us another unexpected fact: atopy increases the risk of asthma! Who would have expected that?

Line 486: “The data also confirmed that a significant proportion of women with asthma were employed in social or medical care roles”. Yes, right. But is this not also the case for non-asthmatic women? Yes, different gender roles lead to different exposures. These differences might even differ between societies and cultures. And yes, different exposures matter. What is the consequence?

Line 520: I doubt that cyanates are a problem! I am only concerned about isocyanates.

Author Response

REFEREE-4_ REPLY

Asthma is a very prevalent chronic disease. It is well known that the disease is more prevalent in females. Most asthma cases begin in childhood or adolescents, fewer later in life. Among these late-onset cases, a large proportion already showed signs of respiratory allergies before and asthma developed by a kind of “stage shift” (from the nose to the bronchial system). Some “new” asthmatics might have had some less apparent form of asthma since many years. But when they got in contact with new allergens or irritants at their workplace, they developed a more severe form that interfered with there work capability.

Therefore, in my mind, it is most important to study causes of asthma in early childhood or even before birth. For example, when most of the asthma cases already develop in childhood, I do not understand how (active) smoking can be a relevant cause of asthma.

1. We would like to clarify that we deliberately focused our work on Asthmatic Responses to Chemical Sensitizers due to environmental and occupational exposures, with the specific aim of investigating whether sex/gender differences could be observed. We decided to limit the scope of the paper to the role of chemical respiratory sensitizers in asthma manifestations, based on the CLP definition: ‘there is evidence in humans that the substance can induce specific respiratory hypersensitivity’ and the hazard statement H: ‘May cause allergy or asthma symptoms or breathing difficulties if inhaled’.

Chemical sensitizers can themselves induce asthma, but they can also exacerbate pre-existing or latent forms; however, such cases were not reported in the studies selected according to the criteria described in the ‘Materials and Methods’ section. Studying the causes of asthma in early childhood or even before birth is outside the scope of this work. While this is certainly an interesting aspect, it falls beyond the focus of our review. We fully acknowledge that asthma, like many other diseases, is multifactorial; however, the scope of this scoping review was to assess, through the available literature, the epidemiological evidence linking asthma with chemical respiratory sensitizers, and to explore the existence of possible sex/gender differences. Nevertheless, based on this comment, we have revised the title, the introduction, and further specified the aim of the work in both the abstract and the main text.

Finally, the sentences related the effect of tobacco smoke have been simplified as follows:

“Tobacco exposure should be recognized as an important potential confounding factor as is independently associated with airway sensitization, hyperresponsiveness, and inflammation, and may contribute to both atopic and non-atopic. While the effects of active or passive smoking are not the focus of this review, it should be considered alongside other potential risk factors (e.g. air pollution or comorbidities), when interpreting asthma outcomes.”.

 

I do agree that tobacco smoke contains a lot of different irritants so that smoking can increase asthma symptoms. Even passive smoking has grave adverse effects and very likely plays a role in asthma initiation.

1. We agree with the reviewer, and therefore the term ‘smoking’ has been replaced by ‘tobacco exposure’ to include both active and passive exposure. Tobacco smoke contains several hazardous chemical substances, including carcinogens, compounds with acute toxicity, specific target organ toxicity, sensitizers, irritants etc according to CLP classification. However, it is important to clarify that sensitizers differ from chemical irritants. Therefore, the definition of irritants (from CLP legislation) has also been added in the introduction.

The problem with studies on early asthma origins is with the correct diagnosis in young age. The bronchial system has not many options how to react to multiple external stimuli: the bronchial muscles can contract, the mucus production can be enhanced, the connective tissue can develop signs of inflammation. The same symptoms can indicate a one-time and reversible infectious process, the effect of a single toxic or irritative result, or the first incidence of a chronic disease with episodes triggered by allergen contact.

Another problem is this: Pneumologists are divided as to how define asthma. Besides a reluctance to call the first asthma episode by its true name (a verdict of chronic disease), they are also divided how to distinguish different types of asthma or how to distinguish asthma from chronic obstructive pulmonary disease (COPD). While in theory, asthma is characterized by distinct and reversible obstructive episodes, and COPD by a persistent obstruction, there is in practice a continuum between both entities. This also leads to the argument if there is really something like “neutrophilic asthma”, or if this name only describes either a kind of “intermittent COPD” or some combination of asthma and COPD. Again, in theory, although the reality again is blurred, “asthma” would be an atopic disease with reactions to specific allergens, indicated by an eosinophilic inflammation and high exhaled NO levels. In practice again, asthma-like episodes can also be triggered by a lot of different non-allergic stimuli, including mechanical and chemical agents. Irritating substances (often of low molecular weight), besides causing asthma-like symptoms themselves, might also damage the epithelium and thus enhance the likelihood of a true (allergic, atopic, eosinophilic) asthma development. The allergens then keeping up the disease process are often of higher molecular weight, although some smaller molecules can also act as haptens to turn human proteins into allergens. Therefore, while irritants and infectious agents “are meant to” cause a neutrophilic reaction, while allergens lead to an eosinophilic inflammation, mixed reactions and a broad grey zone between “true asthma” and “asthma-like” bronchial inflammation are rather the norm than the exception.

1. This review did not focus on asthma, its causes, or its diagnosis. Rather, it is a scoping review aimed at analysing asthmatic responses to chemical sensitizers in occupational settings, also considering sex and gender differences. Starting from the definition of respiratory sensitizers according to the CLP classification, we explored the literature to understand the correlation between chemical exposure to these chemicals and the development of occupational asthma.

We chose to consider the impact of sex and gender differences to evaluate the most appropriate prevention strategies, particularly during workplace health surveillance, which is one of our company’s objectives. Therefore, we analyzed studies reporting effects such as asthma. About the purpose of our study, we did not aim to consider the criteria for diagnosing asthma.

 

 

 

This paper sets out to scrutinize the literature to answer two questions, I think: “what causes asthma?”, focusing on external, environmental causes, not on genetic ones, and “why is there a sex/gender difference?”

1. We apologize for any misunderstanding. The primary question addressed by our review is clearly stated in the (now revised) introduction:

‘What does the scientific literature report regarding the role of sex and gender in the onset of asthma and its severity, particularly in occupational settings?’ with a specific focus on exposure to chemicals capable of eliciting an immunological response (chemical sensitizers).

We did not intend to illustrate all causes of asthma, as this would have required a different aim, a different literature search, a different article selection process, and the inclusion of numerous studies outside the scope of this review. Instead, our focus was to assess whether sex differences in the onset or severity of asthma are reported in epidemiological studies and workplace investigations, and whether these differences have been considered in terms of prevention and worker protection. This is particularly relevant because occupational exposure to sensitizing chemicals can represent a specific risk factor, as evidenced by restriction or authorization measures implemented at the European level (see Introduction).

It is therefore incorrect to suggest that we aimed to answer the question ‘why a gender difference is observed,’ as this would have required a separate, in-depth analysis of the literature and a different review altogether. We considered it necessary to outline, at least broadly, the mechanisms that could underlie the epidemiologically observed differences; however, as explicitly stated in the Methods section, this aspect is not the subject of the current scoping review.

 

As outlined above, I find concentrating on occupational factors (or on active smoking) when seeking the main external causes of the disease rather pointless.

1. Our interest is focused on occupational risk factors, in particular on exposure to sensitizers, from the general population to occupational settings, rather than on other risk factors. We apologize if the objective of the study was not fully understood.

 

And regarding sex differences, we only learn that they are really there and that they might be caused by “hormones”. Who would have expected that? Yes, there are also gender differences. Depending on the population and occupations under study, men and women will face different kinds of exposure that will also affect disease development. This is also not a very novel fact!

1. The purpose of a review is precisely to collect the available scientific literature on a particular topic, in our case, occupational exposure to sensitizing chemicals and their role in the onset of asthma in men and women. If no scientific evidence existed, it would be impossible to conduct a literature review, so the reviewer’s criticism appears rather incomprehensible to us.

This review aimed to gather studies that would allow us to understand whether, in occupational settings, the risk associated with professional exposure to sensitizing chemicals shows differences between sexes/genders in relation to asthma. The interest arises from the goal of informing those responsible for managing chemical risks in the workplace about the possibility of implementing prevention and protection measures that also consider the gender of the workforce, as the literature indicates that this aspect requires attention.

We considered it entirely appropriate to briefly illustrate the main biochemical mechanisms underlying the epidemiological evidence. From this perspective, it would have been inappropriate to exclude considerations regarding hormones. In occupational settings, sex and hormonal differences are not typically considered during health surveillance. The review aims to raise awareness on this point, likely less familiar to occupational physicians. Furthermore, gender considerations are increasingly important due to the convergence of male and female roles in the workplace, which calls for greater attention to potential sex- and gender-related differences.

 

An interesting aspect about sex and gender differences is the reverse sex ratio before puberty. It seems the authors believe this might also be explained by “hormones”, but I do not really see why. I do not know the true reason. But I have a kind of theory that this difference is rather a gender difference than a sex difference: Boys are expected to be physical active, to play more aggressively outdoors, while girls are in many societies still expected to take it easy, help at home, etc. Therefore, in childhood, maybe first asthmatic symptoms just show more readily in boys? Differences in growth spurts also might play a role and also misguided spirometry norm values. These norm values are based on age and body height. But during rapid body growth, the long bones in the legs might lengthen very fast, while the chest volume does not catch up at once. The timing of these growth episodes does differ between sexes. And thismight have an impact on asthma diagnosis.

 

1. Literature data showed that the reversal in asthma prevalence across the lifespan between female and male is around puberty, suggesting a significant impact of sex hormones on asthma pathophysiology. Hormones play a pivotal role in mediating the sex-based differences observed in asthma. Estrogen, progesterone, testosterone regulate immune responses, airway inflammation, and bronchial hyperresponsiveness, influencing asthma onset and severity at different life stages. Sex hormones control the reproductive system and have several immuno-modulatory effects affecting immune cells, including T and B cell development, antibody production, lymphoid organ size, and lymphocyte death. Moreover, studies have suggested that female sex hormones amplify memory immune responses, which may lead to an excessive immune response impacting the pathogenesis, airway hyperresponsiveness, inflammation of airways, and mucus production of allergic diseases (Gutierrez-Brito et al, 2025).

Finally, we would like to note that the sentence ‘Boys are expected to be physically active, to play more aggressively outdoors, while girls in many societies are still expected to take it easy, help at home’ does not reflect scientific evidence. It expresses an opinion and, importantly, is not universally applicable across all societies.

 

To summarize: The authors ask: “What causes asthma?” And they look at the wrong time in life. And they ask: “Why do we see a sex and gender difference?” And they only confirm that this difference exists. Both outcomes are very disappointing.

1. We apologize, but as already indicated previously, these are not the questions we intended to address. We regret any misunderstanding, but it seems that the reviewer may not have fully considered the actual aim of this study.

This is a scoping review aimed at collecting articles on this specific topic, with particular attention to worker exposure and exposure to sensitizing chemical substances. Any other aspects would require a different literature search, a different approach, and the selection of other articles—essentially constituting a separate study.

 

In addition, I have also minor complaints. But since I suggest rejecting the paper, this would not really matter:

Regarding their methodology, the authors state: “Research on biological mechanisms of action, although not selected for formal inclusion in the scoping review, was used to illustrate the underlying mechanisms of observed effects and to support the interpretation of sex- and gender-stratified data.” I believe, this is important. And indeed, they do cite mechanistic studies. But then, in the discussion, they acknowledge not “using in vitro and in vivo surveys” as a limitation. Yes, I agree that focusing on experimental studies instead of on epidemiological studies might have helped them better to answer their questions. But at least, they should be consistent: is this a review of the prevalence and incidence of disease and of real-world causes and triggers, or is this a review of the causes and mechanisms?

1. As discussed before, this review did not focus on asthma, its causes, or its diagnosis. Rather, it is a scoping review aimed at analyzing asthmatic responses to chemical sensitizers considering sex and gender differences.

Starting from the definition of respiratory sensitizers according to the CLP classification, we explored the literature to understand the correlation between exposure to chemicals and the onset of occupational asthma, ranging from the general population to occupational settings. We also considered the impact of sex and gender differences to evaluate the most appropriate prevention strategies, particularly in the context of workplace health surveillance, which is one of our company’s objectives.

The description of biological mechanisms was, in our view, essential to support the epidemiological evidence and provide a better understanding of the topic. To avoid any misunderstanding, we have now moved paragraph “3.1 The sex: biological and physiological differences linked with possible different health effects out” of the Results and placed it into a specific section (3. Biological mechanisms underlying sex differences in asthma), where the biochemical mechanisms are presented as preliminary information and as background to support the findings of the scoping review.

 

The authors often state that they looked for “sensitizing” (occupational) substances. As discussed above (and as also confirmed by the authors), it is not only sensitizers that matter.

We would like to clarify that we deliberately focused our work on Asthmatic Responses to Chemical Sensitizers (identified exclusively based on CLP and GHS legislation), with the specific aim of investigating whether sex/gender differences could be observed.

We fully acknowledge that asthma, like many other diseases, is multifactorial; however, the scope of this scoping review was to assess, through the available literature, the epidemiological evidence linking asthma with chemical respiratory sensitizers, and to explore the existence of possible sex/gender differences. Nevertheless, based on this comment, we have revised the title, the introduction, and further specified the aim of the work in both the abstract and the main text.

 

The introduction has a very strong focus on comparing international rules on allergens. This part has only very little relevance for the overall theme of the paper.

1. We partially agree with the reviewer and the section on legislation have been shortened and revised. However, we consider it essential to provide a legislative introduction (now more concise) to clarify that the focus of our work is not on allergens in general, but specifically on chemical sensitizers, particularly respiratory sensitizers, as defined by Regulation (EC) No. 1272/2008 (CLP) and aligned with the UN Globally Harmonized System (GHS). While some reviewers noted that respiratory effects can also arise from irritants, we considered it important to provide a clearer distinction between sensitizers and irritants in the context of chemical exposure. Therefore, we have maintained the CLP definition for sensitizers and added the CLP definition for respiratory irritants to highlight their different classification based on their distinct effects. For this reason, we also deemed it important to specify the mechanism of action of chemical sensitizers.

Finally, the discussion on certain chemical sensitizers included among VHC substances emphasizes the health risks associated with this class of compounds and the EU-level concerns that have led to restrictive measures, highlighting the relevance and timeliness of our paper for protecting both the general and working populations.

 

The authors use the term “chemical sensitizer” (e.g., in table 2). In my understanding, a “sensitizer” is an allergen. And I already wrote that allergens are only one side of the coin. But here, I am concerned about the meaning of “chemical”. Every substance is “chemical”, isn’t it? Or do you mean “synthetic chemicals”? but then, also biological and organic substances can act as allergens and are, among others, also listed in table 2.

1. This comment relates to our previous response. By ‘chemical sensitizers’ we mean to those identified based on CLP regulation and associated with widely recognized chemical identifiers, such as CAS numbers, EC numbers, IUPAC names, InChI, etc., for which we have reported the CLP definition. Enzymes are also assigned chemical identifiers. Nevertheless, taking this comment into account, we have decided to remove the row corresponding to hardwood dust from Table 2 due to the absence of an assigned chemical identifier, despite the well-established role of hardwood dust in the development of occupational diseases.

 

In table 2, they also mention “hardwood dust (e.g., oak, beech)”. I know this dust to cause nasal cancer. As a relevant cause for asthma, this was new for me. As only evidence for their claim, they provide a reference that is a case study of a single worker exposed to chengal wood dust. Maybe the terpenes in chengal wood are highly allergenic. I do not know. But this is not proof that oak-wood is a relevant cause of asthma.

Although the primary effect of hardwood dust is related to sinonasal cancer, there are studies that also investigate its role in asthma development, such as the following (which we apologize for not including in the text).

• M Pérez-Ríos et al. A meta-analysis on wood dust exposure and risk of asthma. Allergy. 2010 Apr;65(4):467-73. 
• Malo et al. Occupational asthma caused by oak wood dust. Chest. 1995 Sep;108(3):856-8.
• Pylkkänen et al. Wood dusts induce the production of reactive oxygen species and caspase-3 activity in human bronchial epithelial cells. Toxicology.Volume 262, Issue 3, 21 August 2009, Pages 265-270

This explains why this item was initially included in Table 2.  Nevertheless, for the reasons indicated above, we have decided to remove the row corresponding to hardwood dust from Table 2.

 

The whole chapter on “3.1. The sex: biological and physiological differences linked with possible different health effects” is long, but remains rather vague. It can be summarized by their sentence: “The underlying causes of these sex-based differences in asthma development are not yet fully understood.” Yes, anatomy might play a role as well as hormones and genes and their epigenetic regulation. We learn that “the number of alveoli per unit area and alveolar size do not differ significantly between the sexes”. But also, that boys exhibit “a greater alveolar surface area.” This sounds contradictory. But I guess, the sex differences vary across age stages. Still, what does this mean for asthma? Is a larger lung “good”, because it has a larger residual capacity, or is it “bad”, because a larger reactive area increases the risk that “something goes wrong”?

In early life, female sex hormones appear to promote lung development and maturation, whereas androgens may exert inhibitory effects.” But in the previous paragraph we learned that boys have the larger lung!

1. In our review, we reported literature data showing that sex differences in lung development and physiology resulting in different work of breathing. All statements reported are supported by the literature, and this analysis is essential to support the epidemiological evidence from environmental and occupational exposures and to provide a better understanding of the topic.

 

Chapter 3.1.1, which is about anatomy according to its title, discusses hormonal effects on anatomy, while chapter 3.1.2, which is about sex hormones, really discusses the immune system. As I have explained, there is an issue about atypical or neutrophilic asthma. The issue is approached in chapter 3.1.2, but, in my mind, not in a very enlightening manner. We learn that there are type 2 and non-type-2 mechanisms and then type 2 is described in very much detail. The other type of inflammation is mentioned in passing and described in one short paragraph, but without much context. The chapter continues with considerations about the impact of hormones. The conclusion of this is best summarized by their sentence: “Similarly, the impact of progesterone on asthma is complex, exhibiting both pro-inflammatory and anti-inflammatory effects.”

5288. The type 2 immune response mechanism refers to the most severe form of asthma, characterised by inflammation, remodelling and hyperreactivity of the airways, leading to recurrent symptoms and exacerbations. Literature data show that this inflammation mechanism is better known than the non-type 2 mechanism. The non-type 2 response, on the other hand, which is associated with increased oxidative stress, epithelial damage and mucus production, is less well defined (Borrelli et al. Sex-Based Differences in Asthma: Pathophysiology, Hormonal Influence, and Genetic Mechanisms. Int J Mol Sci. 2025; 26(11):5288.). For this reason, only the type 2 response has been described in detail and reported in Figure 3.

About considerations on the impact of hormones, in our study we have reported data from the literature, as explained above. 

 

Chapter 3.1.3 deals with genetic and epigenetic Here, I want mostly to point out that also men have an X-chromosome. Only genes on the Y-chromosome are specific to one sex only. Yes, epigenetics might switch on or off specific genes. But it does not matter if they are on the X-chromosome or on any other chromosome.

1. According to several studies, genetic factors are key contributors to sex-based differences in asthma, particularly through the effects of sex chromosomes and autosomal genes that regulate immune function and airway remodelling. The X chromosome contains many genes related to immune responses, which may help explain the higher prevalence and severity of asthma observed in females. Because of X chromosome inactivation, females have a distinct immune profile: some genes escape inactivation and are expressed at higher levels than in males. Notably, TLR7 and TLR8, which encode toll-like receptors involved in innate immunity, are more highly expressed in females and may enhance inflammatory responses in the airways.

As a reference, you can see Borrelli et al. Sex-Based Differences in Asthma: Pathophysiology, Hormonal Influence, and Genetic Mechanisms. Int J Mol Sci. 2025; 26(11):5288.

 

Chapter 3.2 is about epidemiological evidence. Yes, hormones play a role. But the evidence is still obscure demonstrating either protective or adverse effects. This is true for hormone replacement therapy, asthma severity changes with the hormonal cycle, and other observations.

3. In fact, this aspect is already highlighted in section 3.2; as examples:

The impact of sex and gender on asthma prevalence is well established [63], and research in this field is steadily increasing [64], although some controversies remain [65,66].

The role of sex hormones leads to clear epidemiological observations: male children show more frequent asthma onset, while after puberty the prevalence is higher in female population [56].

The association between severe asthma and female sex hormones has also been proposed by some authors [58,67], who observed a worsening of symptoms during specific phases of the menstrual cycle and pregnancy. In fact, 11–45% of women report experiencing “premenstrual asthma,” which is likely related to elevated estrogen and progesterone levels during the luteal phase. Additional evidence supporting a link between sex hormones and asthma has been reported by Nwaru et al. [68,69], who found that the use of hormonal contraceptives appears to reduce both asthma exacerbations and the incidence of new-onset asthma.

Although a definitive biochemical mechanism has not been identified, epidemiological evidence suggests that controlling fluctuations in estrogen and progesterone levels during the menstrual cycle may improve asthma management. Women in the menopausal period have been shown to experience more severe asthma and an increased risk of new-onset asthma [70]. Similar findings have been reported in women undergoing hormone replacement therapy (HRT), although variations in asthma risk appear to be associated with the specific type of HRT used.

In a large case-control study involving 379,649 participants, Hansen et al. [71] reported an increased asthma risk with combined estrogen–progesterone HRT, whereas a decreased risk was observed with progesterone-only therapy. However, these findings have not been consistently confirmed in other studies [72].

 

According to line 356, Hansen et al. [71] is a large case-control study, while according to line 388, the same study is “a large prospective cohort study”.

1. We thank the reviewer for noticing this. The correct reference for the second paper (also by Hansen, 2021) has now been added, and the reference numbering has been corrected.

 

Also, another study ([Shah, 2021]) is mentioned, that is not listed in the references.

1. We thank the reviewer for noticing this. It is now correctly added in the references.

 

And how does the effect of surgery support the central role of hormones?

1. In the text we are talking about surgery for people who decide to change sex, in these cases hormone therapy is administered both before and after the operations as you can read in numerous published articles like:

• Vin Tangpricha, Martin den Heijer. Oestrogen and anti-androgen therapy for transgender women Lancet Diabetes Endocrinol. 2017 Apr;5(4):291-300. doi: 10.1016/S2213-8587(16)30319-9.
• Dijkman BAM, Helder D, Boogers LS, Gieles NC, van Heesewijk JO, Slaa ST, Liberton NPTJ, Wiepjes CM, de Blok CJM, den Heijer M, Dreijerink KMA. Addition of progesterone to feminizing gender-affirming hormone therapy in transgender individuals for breast development: a randomized controlled trial. BMC Pharmacol Toxicol. 2023 Dec 20;24(1):80. doi: 10.1186/s40360-023-00724-4.

 

Pregnancies must cope with a growing foreign body in the womb. In my understanding, during pregnancy, immune responses should be suppressed. But anatomical changes and a larger demand for oxygen will likely augment asthma symptoms.

1. We have reported what has been published in the literature regarding pregnancy and asthma; this reflects the evidence, not our opinion. However, we have now added a consideration on the possible role of physiological changes in respiratory problems and included a new reference.

“Regarding pregnant women, it should be added that physiological changes can lead to an increase in respiratory problems which can contribute to the recording of more serious asthma symptoms”

Respiratory Failure and Mechanical Ventilation in the Pregnant Patient. David Schwaiberger et al. Crit Care Clin 32 (2016) 85–95. http://dx.doi.org/10.1016/j.ccc.2015.08.001)

 

It does not come as a surprise that smoking affects lung function (line 384).

1. We believe it is important to explicitly mention this, rather than omit it, as it represents a key aspect investigated in the article (Ricciardolo et al. Asthma in the real world: the relevance of gender). Given the focus on gender, it is particularly appropriate to consider it as a contributing factor.

According to the description of study [66], asthma is more prevalent in women (which we know), women smoke less, and have a better lung function. Is this because they smoke less or because their asthma is less severe? Is this only true for asthmatics or for healthy women compared to healthy men also?

1. We reported the findings from the published study: the authors observed 499 asthmatic patients, but they did not include healthy controls, so no information is available for that group. Among the recruited subjects, the authors observed a higher proportion of females; however, this sample exhibited lower asthma symptom severity (which may also be related to lower smoking prevalence). The sentence has now been revised for better clarity.

“These findings suggest that in the sample studied the severity of the pathology in the female population (although larger than the male population) was less problematic; this reminds us of the multifactorial nature of the etiology and the role of risk factors such as smoking.”

Of course, the underlying causes of asthma are multifactorial (the smoke is not the only risk factor), the risk factors can be very different.

 

Which “clinical trial findings” (line 397) investigate childhood prevalence? Clinical trials do not examine prevalence in the general population, but compare intervention and control groups.

1. The phrase in the text is: “Epidemiological studies in children support clinical trial findings indicating that, during the prepubertal period, males exhibit a higher prevalence and greater severity of asthma [84].”

We don’t have written that clinical trials investigate the prevalence of pathology, absolutely (!). We are referring to clinical studies that define, for example, the need for specific therapies for severe asthma and which record a greater presence of male child patients. The prevalence is investigating in the paper cited that is an epidemiological study, as written.

 

Figure 5 is just a repetition of the text above. Only “obese neutrophilic asthma” is a new information. But without context and detail, this point has not much meaning.

1. We agree and the figure has been deleted.

 

Chapter 3.3. starts with the ground-braking information, that sensitizers (low- and high-molecular weight) increase the risk of asthma.

1. This information is not so obvious; we are talking about chemical sensitizing agents for the respiratory tract used in occupation settings, which can produce different types of reactions, not necessarily asthma. Furthermore, this is a review, and we need to use the papers already published of course. What is the matter?

 

Figure 6 is again a (nearly word-by-word) repetition of the text before.

1. We agree and the figure has been deleted.

 

Line 469 tells us another unexpected fact: atopy increases the risk of asthma! Who would have expected that?

1. Again, we reported the findings of published papers. According to the reviewer, should we only include articles with previously unknown information? Do you consider that a review? A proper review methodology requires a rigorous selection of papers; we cannot exclude studies simply because the information is already known to the reviewer.

 

Line 486: “The data also confirmed that a significant proportion of women with asthma were employed in social or medical care roles”. Yes, right. But is this not also the case for non-asthmatic women? Yes, different gender roles lead to different exposures. These differences might even differ between societies and cultures. And yes, different exposures matter. What is the consequence?

1. The consequence is precisely what we aim to highlight with this study, namely that being a ‘woman’ can lead to experiencing different working conditions and exposures, which may result in different effects, what we have consistently emphasized throughout the text as gender differences.

We regret to say that this comment once again indicates that the reviewer has not fully understood the purpose of the work.

 

Line 520: I doubt that cyanates are a problem! I am only concerned about isocyanates.

1. Once again, we have reported what has been published in the literature. If you have doubts regarding the published experimental study, you may contact the authors of that study directly. If useful, the abstract of the paper is provided below.

ABSTRACT

Introduction : Les asthmes sont la cause la plus fréquente de maladie respiratoire professionnelle dans les pays industrialisés. Les données épidémiologiques sur la prédominance d’un genre au sein de la population de travailleurs atteints d’asthme en relation avec le travail (ART) sont contradictoires, les données les plus récentes suggérant toutefois une prédominance féminine. L’objectif de notre étude est de comparer par sexe, les expositions et les secteurs d’activités au sein d’une population française de travailleurs ayant consulté pour un ART.Méthodes : Nous avons recensé les cas d’ART (Codes J45, U05, J68 de la CIM-10) enregistrés entre 2001 et 2018 dans la base du RNV3P (Réseau national de vigilance et de prévention des pathologies professionnelles). Les paramètres étudiés étaient les données démographiques du patient, les expositions professionnelles, les postes de travail et le secteur d’activité. Seules les expositions avec une imputabilité jugée moyenne ou forte par le clinicien ont été retenues.Résultats : Entre 2001 et 2018, 8385 cas d’ART ont été enregistrés, majoritairement chez les hommes (54,5 %) ; 13,5 % étaient des asthmes aux irritants. Une tendance à la diminution du nombre d’ART a été constatée sur la période. Les femmes souffrant d’ART exerçaient significativement plus dans les secteurs de la coiffure, des activités hospitalières et étaient principalement exposées aux composés d’ammonium quaternaire, aux produits d’entretien et détergents pour locaux. Les hommes étaient significativement plus représentés dans la boulangerie et le secteur du bâtiment et travaux publics (BTP), et majoritairement exposés aux poussières de farines, aux cyanates et isocyanates.Conclusion : Notre étude confirme des différences en fonction du genre en termes d’expositions et de secteurs d’activités à l’origine d’ART. Il apparaît nécessaire de tenir compte des spécificités des ART dans les deux sexes afin d’établir rapidement le lien entre une exposition, un secteur d’activité et l’apparition ou l’aggravation d’un asthme.

 

Finally, although cyanates as a chemical group are not generally considered respiratory sensitizers, unlike diisocyanates, there are several cyanates that are classified as respiratory sensitizers according to the CLP (H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled). Some non-exhaustive examples include:

• Phenyl cyanate (CAS 1122-85-6)
• Tetrabutylammonium cyanate (CAS 39139-87-2)
• Potassium cyanate (CAS 590-28-3)
• 4,4'-Methylenebis(2,6-dimethylphenyl cyanate) (CAS 101657-77-6)
• 4,4'-Ethylidenediphenyl dicyanate (CAS 47073-92-7)

You can check the classification at Legislazione - ECHA

 

 

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I thank the Authors for addressing my concerns. In my opinion, the manuscript is suitable for publication.

Reviewer 2 Report

Comments and Suggestions for Authors

My comments have been addressed accordingly. Notably, the IgE role has been highlighted and underlined and the overall goal of the review has been clearly expressed. The only issue I have is the interchangeable use of either US or British spelling of "sensitizers" (or "sensitisers) - this should be checked during editorial processing and employed in a uniform way.

Otherwise, no issues to be raised.