Review of the correlation between pesticides in the working environment and the development of Parkinson’s disease

Review of the correlation between pesticides in the working environment and the development of Parkinson’s disease

Introduction

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 on Parkinson’s disease after exposure to pesticides as new knowledge may be available.

The scientific reference document is to provide an update on the risk of developing Parkinson’s disease after exposure to pesticides. Pesticides mean insecticides (chemicals for fighting insects), herbicides (chemicals for fighting plants) and fungicides (chemicals for fighting fungi). 

An assessment is requested of whether there is any documentation of a causal relation between the occupational exposure to pesticides and the development of the disease, including whether there is new knowledge about the requirements in terms 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 development of the disease. There must be an assessment of the dose-response correlation, latency period and exposure type (what pesticides do specifically result in the disease, if this is the case?). If it is impossible to describe the dose-response correlation, the reasons why are to be specified and elaborated on in the review.

A description of how the exposure/level of exposure can be defined is requested as well as a description of what the minimum exposure requirement is for such exposure to cause the disease. What is also needed is a description of the time correlation between exposure and disease (how long may the latency period between exposure and development of the disease last?).

Moreover, a description of any competing diseases/conditions is also requested, for example hereditary factors (PARK1-PARK20), age, environmental factors, neuroleptics and other medicines taken as well as exposure to other chemical substances such as manganese and a description of such factors/conditions affect the onset and the course of the disease.

Background

In 2009, Labour Market Insurance (at that time, the National Board of Industrial Injuries (Arbejdsskadestyrelsen)) and the Occupational Diseases Committee were aware that there might be a causal relation between exposure to the pesticides and Parkinson’s disease. The Occupational Diseases Committee was of the opinion that, throughout the years, research had generally provided growing evidence of a correlation between the exposure to pesticides and the development of Parkinson’s disease. The Occupational Diseases Committee members therefore agreed that Labour Market Insurance is to submit claims to the Occupational Diseases Committee for a specific assessment of whether or not the disease is caused solely or mainly by the special nature of the work.

At a meeting in March 2019, Labour Market Insurance and the Occupational Diseases Committee discussed Parkinson’s disease after working with pesticides on the basis of a Swedish systematic review that had looked into the existing knowledge about and research into correlations between the exposure to pesticides and the development of Parkinson’s disease.

The review showed an increased risk of developing Parkinson’s disease after working with pesticides, but the medical documentation requirements had not been sufficiently fulfilled. The literature review failed to provide an assessment of any dose-response correlations. The disease did therefore not qualify for inclusion in the list of occupational diseases, but Labour Market Insurance and the Occupational Diseases Committee decided that claims relating to Parkinson’s disease after working with pesticides are still to be submitted to the Committee for a specific assessment of whether or not the disease is solely or mainly caused the by special nature of the work involved.

According to the guidelines on occupational diseases, farmers and people holding horticulture jobs are particularly exposed to pesticides in connection with their work. Exposure typically occurs in connection with the preparation of pesticides prior to spraying and subsequently when the tools are to be cleaned etc. Pesticides are absorbed either through skin or through breathing. This means that a person must have been in direct contact with the pesticides to a not insignificant extent. The assessment of the exposure will therefore take into account whether or not sufficient protective equipment has been used, including also whether such equipment has been used throughout the entire process or only during part of the process and whether, for example, the mixing of pesticides took place indoors in constricted facilities or outdoors. As pesticides are used only during the spraying season and depend on the size of the field and type crop involved, no specific number of years during which spraying must have been performed can be specified. Instead, a specific assessment is made in each single claim.

In 2023/2024, a literature review/report was worked out in Germany, and on the basis of the conclusions herein, the decision was made to recognize Parkinson’s diseases as an occupational disease after long-term and significant exposure to pesticides. In the report in question – like in the Swedish review – no dose-exposure correlation, if any, was assessed.

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 must elucidate in detail, summarise and assess knowledge of the risk of developing Parkinson’s disease after exposure to pesticides. Against the background of the nature and duration of the exposure 

(exposure criteria) and competing factors, the document must include a description of the statistical 
correlation and evidence assessment. Particular emphasis should be placed on the dose-response correlations, latency period and type of exposure (what pesticides, if any, do specifically cause the disease?). 

What is required is a specific comparison of surveys across various research designs, including longitudinal surveys, case-control surveys as well as various types of measures of 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, the applicant is asked to 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 Parkinson’s diseases
•    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 
Parkinson’s disease

About dose-response correlation and latency
•    Summarising description and assessment of dose-response correlations
•    Description and assessment of onset time in relation to exposure
•    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 disease development in question
•    Description of the significance of non-occupational, including private exposures
•    Descriptions of the significance of other, non-occupational factors (for instance inheritance, gender, age and any consumption of pharmaceuticals)
•    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 
•    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 is to 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.

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 procedures 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 on 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 the quality of the study by using formal scoring systems, 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 funding 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.