Temporal Relationships Between Occupational Exposure to High Molecular Weight Allergens and Associated Short Latency Respiratory Health Outcomes: Laboratory Animal Allergens

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript from Mason et al. describes the occurrence of allergic diseases related to an occupational exposure to mice or rats in a laboratory setting. The approach is original and the fact that the study was performed over a long period of time improves the quality.

Major comments:

• The data of the allergens that were collected in the laboratory since 2005, the data on the number of animal procedures in Great Brittain over the same timeframe and the SWORD data on the number of reported cases of occupational asthma do not seem to have a direct correlation. The structure of the manuscript somehow suggests that this correlation exists. This point should be discussed in far more detail and where possible, the different factors should be correlated against each other.
• There is a relatively large number of papers on this subject from the past. This literature should be included in the discussion and introduction in more detail. Examples of this literature are: org/10.1111/j.1365-2222.2010.03609.x; doi.org/10.1258/00236779378074; doi.org/10.1164/ajrccm.155.2.9032195; doi.org/10.1093/annweh/wxy060  Moreover, it should be made clear in more detail what the novelty of the currently presented study is.
• In the discussion, the part on the other occupational allergic diseases can be omitted or strongly shortened.

 

Minor comments:

• There are quite a few typing errors (line 93: analyzed; line 251: there instead of they), double spacing (for example line 74, 114, 121) and missing commas (line 43 & 229: Therefore, ….) in the manuscript. These mistakes should all be removed (not only the ones given as examples above).
• If possible, Table 1 could be accomplished by a graph to provide more information to the reader.
• The abbreviation “Medn” is not explained in the table legend of table 1.

Author Response

Reviewer 1 comments:

 

The manuscript from Mason et al. describes the occurrence of allergic diseases related to an occupational exposure to mice or rats in a laboratory setting. The approach is original and the fact that the study was performed over a long period of time improves the quality.

Major comments:

We thank the reviewer for his comments and suggestions

• The data of the allergens that were collected in the laboratory since 2005, the data on the number of animal procedures in Great Britain over the same timeframe and the SWORD data on the number of reported cases of occupational asthma do not seem to have a direct correlation. The structure of the manuscript somehow suggests that this correlation exists. This point should be discussed in far more detail and where possible, the different factors should be correlated against each other.

The thrust of this paper is the examination of the relationship over-time between the SWORD health endpoint data and the atmospheric monitoring data measured in our laboratory has undertaken. The data on the number of animal procedures is added to inform the reader that, despite the 3Rs initiative to reduce the number of animal experiments and Covid, that significant numbers of animals (rodents) continue to be utilised and that use of mice predominates over rats. This latter finding may have relevance in terms of causative rodent species causing the health endpoints. 

• There is a relatively large number of papers on this subject from the past. This literature should be included in the discussion and introduction in more detail. Examples of this literature are: org/10.1111/j.1365-2222.2010.03609.x; doi.org/10.1258/00236779378074; doi.org/10.1164/ajrccm.155.2.9032195; doi.org/10.1093/annweh/wxy060  Moreover, it should be made clear in more detail what the novelty of the currently presented study is.

In hindsight we now recognise that the draft paper lacks a historical perspective on occupational exposure to rodent allergens and the research studies undertaken. We had presumed such knowledge.  We will certainly add to the introduction to cover this.  The novelty of this work is two-fold. Firstly that previous studies have been invariably cross-sectional, unlike our longitudinal  data, and secondly that most other prior studies have focussed on IgE sensitisation as surrogates of  potential health outcome in relation to exposure, whereas we have focussed on the real health outcomes of occupational asthma and rhinitis. We will change  the draft paper so that its novelties in relation to published work are better highlighted

• In the discussion, the part on the other occupational allergic diseases can be omitted or strongly shortened.

We will significantly shorten as suggested. The reason that it is included is to highlight that there are other more pressing occupational diseases where a similar laboratory-involved approach may pay dividends in reducing the disease burden.

Minor comments:

• There are quite a few typing errors (line 93: analyzed; line 251: there instead of they), double spacing (for example line 74, 114, 121) and missing commas (line 43 & 229: Therefore, ….) in the manuscript. These mistakes should all be removed (not only the ones given as examples above).

We will carefully proof read and amend such errors.

• If possible, Table 1 could be accomplished by a graph to provide more information to the reader.

In earlier drafts we originally presented the data as graphs , but it surprisingly was difficult to amalgamate the data and show in graph form the relationships between exposure and health outcomes. Therefore, we decided to  display all exposure and health outcome characteristics for the 3 yearly rolling data on a single table.  This allows readers to readily be able to explore the data in further analyses, if they wish.

• The abbreviation “Medn” is not explained in the table legend of table 1.

Abbreviation identified.

Reviewer 2 Report

Comments and Suggestions for Authors

The paper presents an update on similar studies resulting from reports of a large surveillance program. There were no recent papers on this subject found in my searches of Medline.

As reported the figures summarise what must be a very granular data from animal use under a diversity of conditions. They are nevertheless interesting and should be made widely available. The difference in the fall of asthma and rhinitis in recent years is potentially important for refining exposure limits and for the causation of the different manifestations of allergy.

The 2005-2022 paper reported that thirty-seven percent of submitted samples could be identified as derived from commercial pharmaceutical and contract toxicology laboratories, 30% from research institutes and 33% from universities. Has any of this changed in recent years especially post covid?

Although individually ventilated cages have been the norm for quite a few years (or is it in the UK) some comment on the possible increase in the last few years would be appreciated. As well as occupational health this could arise from changes in work practices to insulate the animals from infection and a increases in the use of immunodeficient mice

The methods section states the ELISAs were similar to those in references 3 and 4. It also should note if there have been changes in the air sampling.

Allergen nomenclature still uses a capital letter to start Mus m1 and Rat n 1.

Author Response

Reviewer 2 comments:

The paper presents an update on similar studies resulting from reports of a large surveillance program. There were no recent papers on this subject found in my searches of Medline.

As reported the figures summarise what must be a very granular data from animal use under a diversity of conditions. They are nevertheless interesting and should be made widely available. The difference in the fall of asthma and rhinitis in recent years is potentially important for refining exposure limits and for the causation of the different manifestations of allergy.

I would agree with the reviewers comments. The data is granular and potentially influenced by the nature of the study based on commercial sampling.  However, with caveats we believe the data and our analysis is an important contribution, and we know of no other longitudinal data that studies the important health outcomes of asthma and rhinitis.

The 2005-2022 paper reported that thirty-seven percent of submitted samples could be identified as derived from commercial pharmaceutical and contract toxicology laboratories, 30% from research institutes and 33% from universities. Has any of this changed in recent years especially post covid?

We know that within the “covid years” on 2020-2022, the commercial Pharma/contract toxicology sector appeared to keep going while there was a drop-off in research institutes and universities, but that has quickly adjusted. Without a detailed analysis, my impression is that the relative sectors submitted as back to previous.

Although individually ventilated cages have been the norm for quite a few years (or is it in the UK) some comment on the possible increase in the last few years would be appreciated. As well as occupational health this could arise from changes in work practices to insulate the animals from infection and a increases in the use of immunodeficient mice.

In the UK. individually ventilated cages (IVCs)  were taken up significantly in around 2010-2012 particularly in the Pharma sector.  Universities had been slower to take them up. The reviewer is right to highlight there have been other changes in the sector that may have implications, as stated immunodeficient mice, and also the increase in genetically modified mice as disease models that are treated as a very crucial and expensive commodity. These need careful protection and, where appropriate, specialised small scale breeding colonies to be established. It may be useful in the discussion to highlight some of these changes.

The methods section states the ELISAs were similar to those in references 3 and 4. It also should note if there have been changes in the air sampling.

The recommended sampling method has also not changed over the time, neither has the extraction of the allergens collected on the filters or the analytical method. We will ensure the paper reflects this.

Allergen nomenclature still uses a capital letter to start Mus m1 and Rat n 1.

Ooops, lack of proof reading. I will amend