Review of the correlation between exposure to smoke or particles in the working environment, including passive smoking at work, and exposure to ultrafine particles, and the development of cardiovascular diseases

Introduction

Labour Market Insurance and the Occupational Diseases Committee have found that there is a need for two review projects on cardiovascular diseases as new knowledge is available.

One review project must focus on the mental stress / stress impacts etc. and the development of cardiovascular diseases,
and the other review project must focus on the exposure to smoke or particles in the working environment, including passive smoking at work, and the exposure to ultrafine particles, and the development of cardiovascular diseases (this notice).

Exposure to smoke or particles in the working environment and the development of cardiovascular diseases

Labour Market Insurance and the Occupational Diseases Committee find that there is a need for a review in the form of a scientific reference document assessing the possible causality between exposure to smoke or particles in the working environment, inclusive of passive smoking at work and exposure to ultrafine particles, and the development of cardiovascular diseases.

The scientific reference document is to present a knowledge update on the risk of developing cardiovascular diseases such as ischemic heart disease, acute coronary disease, high blood pressure, apoplexy (cerebral thrombosis or haemorrhage) following exposure to smoke or particles in the working environment, inclusive of passive smoking at work or exposure to ultrafine particles.

Documentation of a causal relation between the occupational exposure and the development of the diseases, including whether there is new knowledge about requirements in terms of the scope of exposure (type of exposure, scope and duration in years). The focus must be especially on the type and duration of the exposure as well as on a quantitative assessment of the correlation between exposure level and the development of diseases.

What is wanted is a description of how the exposure/exposure level may be measured/defined and what the minimum exposure requirement for causing a disease is. What is also needed is a description of the time correlation between exposure and disease (what is the latency between exposure and development of a disease).

What is wanted is also a description of the any competing diseases/conditions, e.g. heritage, weight, tobacco smoking, comorbidity (e.g. diabetes, hypertension, hypercolesterolemia) and how such factors impact on the onset and the development of the disease.

Background

Cardiovascular diseases generally have been discussed several times by the Occupational Diseases Committee. At a meeting in December 2023, the Occupational Diseases Committee and Labour Market Insurance discussed a review of literature on cardiovascular diseases. The literature review showed that there is a multitude of studies pointing to a causal relation between significant exposure to passive smoking and the development of heart diseases and perhaps vascular diseases.

The exposure to passive smoking at work and the development of heart diseases have not previously been discussed by the Committee. The review of the literature also showed that currently there is new knowledge on cardiovascular diseases and several types of impacts which the Committee has previously discussed, e.g. ischemic heart disease after exposure to welding fumes.

In 2014, the Occupational Diseases Committee discussed a review report from 2013 on the risk of developing a heart disease from welding work. This review report provided limited evidence of a causal relation. There was thus no basis for including ischemic heart disease in the List of Occupational Diseases, but the Occupational Diseases Committee decided to continue the practice of having claims involving ischemic heart disease as a result of long-term and significant exposure to welding fumes submitted to the Committee for a specific assessment of whether the disease is caused solely or mainly by the special nature of work.

Project framework

Against the background of a primarily epidemiologically based examination of the most substantial Danish and international research results in the relevant field, the scientific reference document will elucidate in detail, summarise and assess knowledge of the risk of developing cardiovascular diseases as the result of various occupational exposures. Against the background of the nature and duration of the exposure (the stress criteria) and competing factors, the document will include a description of the statistical correlation and evidence assessment. Particular emphasis should be placed on the dose-response correlations, latency and type of exposure.

What is wanted is a specific comparison of surveys across various research designs, including longitudinal surveys, case-control surveys as well as various types of measures to exposure.

Applicants must give an account of how, in their review, they will consider all the questions raised. In the event that the applicant finds it impossible to answer as required all the questions raised, they must instead describe an alternative method to be used in the review or perhaps in a subsequent survey (not comprised by the review).

For possibly work-related cardiovascular disease, the following information is required:

About the disease

Diagnostic delimitation and specification of the cardiovascular diseases: ischemic heart disease, acute coronary disease (heart thrombosis and angina pectoris), high blood pressure, apoplexy (cerebral thrombosis or haemorrhage)
Information about how the diagnosis was made
An assessment of the validity of the survey results
Information about the severity of the disease/symptoms

About the exposure

The general nature of the exposures (the types of work in question)
The more specific nature and intensity/scope of the exposures, compared with an assessment of the size of the risk
The total exposure duration over time (accumulated exposure, latency and possible aggravation after the exposure has ended)
A description of the nature and scope as well as duration of the occupational exposures
Correlation between the nature, scope and duration of the exposure and the risk of developing cardiovascular diseases

About dose-response correlation and latency

A summarising description and assessment of dose-response correlations
A description and assessment of onset time in relation to exposure
An assessment of the disease prognosis and the significance of the exposure for the prognosis

About competing and pre-existing diseases/factors

Description of the significance of competing and pre-existing diseases for the current disease development
Description of the significance of non-occupational, including private exposures, exposures in the person’s spare time, from smoking or exposures which are not work-related (private air pollution because of traffic and wood stoves etc.)
Descriptions of the significance of other, non-occupational factors (for instance inheritance, gender, age and other diseases)
A quantitative assessment of the role played by occupational exposures in the development of the disease, in relation to non-occupational diseases/factors

Summary

Description and assessment of the reliability of the exposure and disease documentation in the individual article
A summarised and graduated assessment of the evidence (see special guidelines for reviews of occupational diseases)
The project report will include an explanatory summary in Danish, addressed to lay persons

If the available literature is inadequate for the elucidation of the requested causalities, this will be stated, substantiated and specified.

If, in this connection, it is found that additional research should be initiated, the relevant efforts and goals for further research should be pointed out, substantiated and included in the overall conclusion of the project.

Special guidelines

The preparation of the review must follow the special guidelines for preparation and quality approval of reviews in the form of reference documents in the field of occupational diseases. The current edition of the guidelines is found below.

Special guidelines for preparation and quality approval of reviews in the form of reference documents in the field of occupational diseases

(Labour Market Insurance)

The objective of preparing a reference document in the field of occupational diseases is to provide the best evidence-based answers to questions regarding possible causalities between various types of work-related exposures and the development of various types of diseases/complaints.

Therefore, with a view to ensuring the highest possible targeted quality of the required scientific literature examination, the following special guidelines have been set up for preparation and quality approval of a reference document in the field of occupational diseases.

In connection with carrying out the project, the applicant will point to three or four external specialists in the current research area as relevant and competent reviewers. The Working Environment Research Fund (Arbejdsmiljøforskningsfonden) quality approves all reviewers and finally appoints two of those reviewers for the further process. All costs deriving from the work of the two reviewers will form part of the overall financial budget of the project, cf. the guide to application for subsidies from the Working Environment Research Fund. Budgets must be kept within an overall frame of DKK 50,000 for the reviewers’ work. Once the reviewers have been finally appointed by the Fund, a detailed budget for the project will be determined and approved by the Fund.
The reference document must be prepared according to the requirement specifications of the notice and will also, in addition to the budget, include a detailed plan for time consumption and deadlines for each phase of the project, including for the reviewing phase.
Within one month after receiving the applicant’s first final draft, the two reviewers will prepare and deliver to the applicant their written comments on the document.
The subsidy recipient will write the final conclusion of the manuscript, in accordance with the comments received, and the revised work will be forwarded to the reviewers for any new comments. If needed, there may be one or more rounds of changes and comments in this conclusive part of the process. If it is not possible to reach a final agreement on the evidence basis and conclusions in connection with the conclusive evaluation of the work, such disagreement, and the specific origin of it, will appear explicitly from the final document. Any disagreement will be set out separately in the document.
The final document with incorporated contributions from reviewers will be delivered to the Fund within the agreed time limit for conclusion of the project.
The reference document will be delivered in an English version, including an exhaustive Danish summary. The summary will focus in particular on answering the most substantial, overall questions of the notice, including in particular a summary of conclusions regarding causalities between exposures and disease(s) and the respective evidence levels.
In connection with the assessment of the evidence, the subsidy recipient will apply the recognised evidence model seen below – Guidelines for establishing reference documents on the causal relation between an occupational exposure and a disease outcome. In the event of the exceptional application of any other evidence model, such a model is required to give a presentation of evidence which is just as clear and transparent, based on equivalent principles.
The subsidy recipient will be under an obligation to personally present the results of the project, including the main conclusions of the reference document and the work method applied, to the Occupational Diseases Committee. Detailed arrangements will be made with Labour Market Insurance. The presentation will in principle be made not later than two to four months after conclusion of the project.
As soon as Labour Market Insurance and the Occupational Diseases Committee have finalised their negotiations on the review, Labour Market Insurance, in connection with publishing the results of the negotiations, will also publish the reference document on their website www.aes.dk. This will also appear from any press release.
The subsidy recipient must hold back his/her own publication of the reference document and its results, including part results, until Labour Market Insurance has reported back to the subsidy recipient that negotiations have been concluded and that the document may be released for own publication. The time of publication/release of the document and its results, including part results, cannot be determined in detail, this depending on the course of the negotiations.
In connection with any own publication of the reference document and its results after release by Labour Market Insurance, the subsidy recipient must state that the document was written on the initiative of Labour Market Insurance and the Occupational Diseases Committee and that the reference document can also be found on the website of Labour Market Insurance www.aes.dk.
In the event of an own publication of the reference document and its results after release by Labour Market Insurance, Labour Market Insurance will receive a copy of the subsidy recipient’s own published versions of the document and its results.
The subsidy recipient and reviewers must not be 1) members of the Occupational Diseases Committee, 2) employees of wage-earner or employer organisations, or 3) Labour Market Insurance employees. However, such persons (1, 2 and 3) are allowed to temporarily take part in a research group behind a review. If a Committee member or a Labour Market Insurance employee has taken part in the review work, they cannot participate in the Committee’s discussions of the same.

Further reference is made to the current standard terms for subsidies from the Working Environment Research Fund. These standard terms also apply to the preparation of reference documents.

Guidelines for establishing a reference document on the causal association between an occupational exposure and a disease outcome

(The Working Environment Research Fund)

Guidelines for manuscripts of reference documents

The aim of establishing a reference document is to provide the best evidence-based answers to questions on the causal relations between an occupational exposure and a disease outcome.

The reference document should be written in English and should be supplied with an extended popular summary. The text part of this summary will be translated to Danish. The reference document, tables and appendices will not be translated.

The reference document should be written in a form, which is suitable for publication in a peer-reviewed international journal. The word count of the main text should not exceed 8000 words. If the requirements outlined below (e.g. text summaries of key studies) imply that the review becomes too long for such a publication, some of the detailed information may be put in an appendix and only summarized in the main text.

The manuscript should be organised as follows:

1. Background and delimitations of the task to specific diagnoses and exposures

2. The outcome under study

Clinical diagnosis and proxy-measures used in epidemiological studies.
Exclusions of certain conditions from the study.
Risk factors for the outcome (excluding the exposure under study).
Descriptive epidemiology, incidences and prevalences of the outcome.

Preferably, literature references in this section should be to high quality reviews rather than original papers, since this introductory section is not based on a separate literature review by the authors.

This section should be oriented towards problems to be discussed in subsequent sections.

3. The exposure under study

Definition of the exposure.
Measurement of the exposure.
Distribution in the general population and occupational groups.

Preferably, literature references in this section should be to high quality reviews for the reasons given above.

This section should be oriented towards problems to be discussed in subsequent sections.

4. Literature search

Description of search terms, databases searched, date of final search and number of references.
Description of the procedure followed to arrive at the studies that are considered in the document (inclusion and exclusion criteria and the methods used to apply them).
If the final set of references includes a large number of studies (e.g. more than 25-30 studies per outcome) it is recommended to include only the studies that are most informative with respect to the issue (key studies). The procedure used to get to these studies must be described and documented.
A flow-diagram of the literature selection should be included.

5. Literature review

The final set of references from the literature search should be described in text and tables, study by study. The text should shortly present essential details of the study and provide the reader with a good impression of its distinguishing features, strengths and limitations, and should include evaluative comments by the authors of the reference document. More important studies are presented with more detail than less important ones. Critical comments on the individual study should be given [in square brackets] in this section.

If there are more than 25-30 references per outcome, only the key studies on which the conclusion is based need to be described in the text. The remaining articles should be described in an independent table corresponding to the table of the more informative studies. The purpose of this selection is to move quickly to the more important studies and not having the presentation mixed up with detailed descriptions and results from less informative studies.

6. Quality assessment of a specific study

In addition to systematic assessments of study quality using formal scoring systems, the quality of studies reviewers are encouraged to qualitatively assess the results of each study with respect to the likelihood that they may reflect chance, bias or confounding, and to assess the external validity of the study results. Quality should not be assessed only by a formal scoring system since there is no ‘gold standard’ for the true validity of a study.

7. Other relevant data

Other relevant data from human or animal, observational or experimental studies should be referred to. The assessment of plausible disease mechanisms to support a cause-effect relation may typically rest on such contributing evidence. The description of contributing evidence may rely on good reviews rather than original studies.

8. Discussion

The discussion should consider the whole set of results from the studies included in the reference document, and especially consider the degree to which it may be assumed that bias or confounding could explain the overall results. The discussion should aim at clarifying the main arguments pertinent to the overall conclusion on causality based on the literature review.

The discussion should deal with the diagnostic entities used in the epidemiological studies in the review compared to diagnostic criteria in clinical practice, the reliability and validity of the outcome measures used in different studies.

The discussion should further deal with problems of exposure assessment relevant to the problem, including reliability and validity. Inaccuracies in diagnosis or exposure assessment should be discussed with respect to the direction and magnitude of the resulting bias of the exposure-outcome relation.

Furthermore, the discussion should consider the effects of potential confounding or effect modification which was not accounted for, and the degree to which the overall results may be influenced by such uncontrolled confounding or effect modification.

The different arguments relating to bias and confounding of the relation between outcome and exposure should be detailed and summed up in a manner that clearly explains and justifies the conclusion.

9. Conclusion

The conclusion should start by describing the premises on which it is made. It should be a natural extension of the discussion and shortly declare the degree of evidence for a causal association between the outcome and exposure under consideration. The degree of evidence is described with a view to the classification scheme on the last page of these guidelines, but must verbally reflect the opinions of the authors in sufficient detail. However, the conclusion should be short and to the point. If it is concluded that there is strong or moderate evidence of a causal exposure-effect relationship, the exposure-response pattern of this relationship should be described – and if possible translated to a practically useful exposure measure. If several outcomes or exposures are included in the review, there must be a conclusion for each specific relation.

10. Abstract

11. Extended popular summary

The extended summary must give an accurate account of the work and especially focus on an argued response to the questions raised in the task description. The language should be straight forward and technical terms should be avoided. The summary is aimed at informing the organisation that funded the work, decision makers and the public at large on the background, results and conclusions of the work. The extended popular summary will be translated to Danish.

Degree of evidence of a causal association between an exposure to a specific risk factor and a specific outcome

The following categories are used:

+++ Strong evidence of a causal association

++ Moderate evidence of a causal association

+ Limited evidence of a causal association

0 Insufficient evidence of a causal association

Evidence suggesting lack of a causal association

Description of categories:

Strong evidence of a causal association (+++):

A causal relationship is very likely. A positive relationship between exposure to the risk factor and the outcome has been observed in several epidemiological studies. It can be ruled out with reasonable confidence that this relationship is explained by chance, bias or confounding.

Moderate evidence of a causal association (++):

A causal relationship is likely. A positive relationship between exposure to the risk factor and the outcome has been observed in several epidemiological studies. It cannot be ruled out with reasonable confidence that this relationship can be explained by chance, bias or confounding, although this is not a very likely explanation.

Limited evidence of a causal association (+):

A causal relationship is possible. A positive relationship between exposure to the risk factor and the outcome has been observed in several epidemiological studies. It is not unlikely that this relationship can be explained by chance, bias or confounding.

Insufficient evidence of a causal association (0):

The available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of a causal association.

Evidence suggesting lack of a causal association (-):

Several studies of sufficient quality, consistency and statistical power indicate that the specific risk factor is not causally related to the specific outcome.

Comments:

The classification does not include a category for which a causal relation is considered as established beyond any doubt.

The key criterion is the epidemiological evidence.

The likelihood that chance, bias and confounding may explain observed associations are criteria that encompass criteria such as consistency, number of ‘high quality’ studies, types of design etc.

Biological plausibility and contributory information may add to the evidence of a causal association.