Objective

Since the publication of the meta-analysis on occupational exposure to magnetic fields and neurodegenerative diseases by Vergara et al. (2013), there have been several new publications. The planned literature study should provide a summarised risk assessment of all the studies that are now available.

Assessment of the current data situation for the meta-analysis

The current state of the evidence is briefly summarised below. A scientific opinion can be found in the article Do low-frequency magnetic fields cause diseases of the nervous system? (only available as a German version).

1. Amyotrophic lateral sclerosis (ALS)

Three new meta-analyses reported a correlation between occupational exposure to low-frequency magnetic fields and an increased risk of ALS (Huss et al. 2018; Gunnarsson und Bodin 2019; Jalilian et al. 2020). These findings are consistent with the older meta-analysis by Vergara et al. (2013). The only meta-analysis on domestic exposure to low-frequency magnetic fields and an increased risk of ALS conducted to date provided no evidence of such a correlation (Röösli 2018). A pooled study on magnetic field exposure and ALS was tendered in a separate research project (“1.2 Pooled analysis on ALS and exposure to magnetic fields”).

2. Alzheimer’s dementia

Three new meta-analyses report a correlation between occupational exposure to magnetic fields and an increased risk of developing Alzheimer’s dementia (Jalilian et al. 2018; Gunnarsson und Bodin 2019). The new results confirm findings from the meta-analysis by Vergara et al. (2013). There are currently only two studies on domestic exposure. A meta-analysis is therefore not yet feasible.

3. Other neurodegenerative diseases

A new meta-analysis found no evidence of an increased risk of Parkinson’s dementia in connection with exposure to magnetic fields (Gunnarsson und Bodin 2019). This is consistent with the older meta-analysis by Vergara et al. (2013). For other diseases (e.g. multiple sclerosis or other types of dementia), no renewed meta-analysis was carried out. In the meta-analysis by Vergara et al. (2013), no risk increase was shown for occupational exposure to magnetic fields. The study situation on these diseases and a potential correlation with exposure to magnetic fields does not yet allow for a meta-analysis.

Summary

• The newly published meta-analyses (2018–2020) bring the evidence up to date. Therefore, no gain in knowledge is to be expected from a renewed meta-analysis. The project has therefore been cancelled.
• However, the evidence reported in the new meta-analyses for increased risks of ALS and Alzheimer's dementia in connection with occupational exposure to magnetic fields has limited informative value. There was evidence of publication bias (Gunnarsson und Bodin 2019; Jalilian et al. 2020). Possible misclassification of exposure and confounding were also identified as reasons for a possible systematic bias of the results (Jalilian et al. 2018; Huss et al. 2018).
• Within the framework of the research programme "Radiation protection in power grid expansion", a parallel project was started to investigate Associations between ALS and exposure to magnetic fields. In this project, a joint analysis of high-quality epidemiological studies should reduce scientific uncertainties. The study will be announced shortly.

Literature

Gunnarsson, L.-G. and L. Bodin (2019). "Occupational Exposures and Neurodegenerative Diseases—A Systematic Literature Review and Meta-Analyses." Int J Environ Res Public Health 16(3): 337.

Huss, A., et al. (2018). "Occupational exposure to extremely low-frequency magnetic fields and the risk of ALS: A systematic review and meta-analysis." Bioelectromagnetics 39(2): 156-163.

Jalilian, H., et al. (2018). "Occupational exposure to extremely low frequency magnetic fields and risk of Alzheimer disease: A systematic review and meta-analysis." Neurotoxicology 69: 242-252.

Jalilian H., et al. (2020). "Amyotrophic lateral sclerosis, occupational exposure to extremely low frequency magnetic fields and electric shocks: a systematic review and meta-analysis." Rev Environ Health: 36(1): 129–142.

Röösli, M. and H. Jalilian (2018). "A meta-analysis on residential exposure to magnetic fields and the risk of amyotrophic lateral sclerosis." Rev Environ Health 33(3): 309–313.

Vergara, X., et al. (2013). "Occupational exposure to extremely low-frequency magnetic fields and neurodegenerative disease: a meta-analysis." J Occup Environ Med 55(2): 135-146.

1.2.a Feasibility study of a pooled analysis of an association between amyotrophic lateral sclerosis (ALS) and exposure to magnetic fields (MF)

Project management: Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) of the University Medical Center of the Johannes Gutenberg University, Mainz
Start: 1 September 2018
End: 31 August 2019

Background

Several epidemiological studies with study populations occupationally exposed to relatively high levels of magnetic fields, suggest a connection between exposure to magnetic fields and the risk of developing ALS. However, the data situation is inconsistent, and animal studies do not yet support the assumption of an association. A recent meta-analysis (Huss et al. 2018) suggests that the quality of the exposure assessment plays an important role in the outcome of the studies. In addition, the role of other risk factors such as electric shocks, which are relatively common in occupations with higher exposure to magnetic fields, is unclear. The joint analysis of high-quality studies is suitable for reducing scientific uncertainty in this area.

Objective

In the present project, the feasibility of a joint analysis (pooling study) of epidemiological studies on ALS and exposure to magnetic fields was examined. It was also investigated whether and to what extent a joint analysis of high-quality studies contributes to clarifying open research questions.

Implementation

The relevant epidemiological publications were identified by means of a systematic literature search. The qualitatively convincing studies were selected using a formalised protocol and checked for their suitability for a pooled study. The individual studies were assessed with regard to the possibility of harmonising the exposure categories, the comparability of the study design, and the definition of the endpoints as well as the consideration of possible confounders. Power calculations were carried out taking into account various scenarios. The study centres responsible for carrying out the individual studies were contacted and asked about their willingness to participate in the pooling. Based on this, specific recommendations regarding a pooled analysis were made.

Results of the Feasibility study

The systematic literature search yielded 21 publications on occupational exposure to low-frequency magnetic fields (LF-MF) and five publications on domestic LF-MF exposure regarding the risk of ALS. In the five publications on the association between domestic exposure to magnetic fields and the risk of ALS, there was no evidence of an association between the two. Based on these results, and because exposure assessment in occupational and domestic settings differ greatly, the contractors recommended that only the studies on occupational LF-EMF exposure should be pooled in the main study.

Based on the quality of the exposure assessment, the contractors rated 18 of the 21 publications on occupational exposure to magnetic fields as suitable for a joint analysis. Five of these were case-control studies. The remaining 13 publications refer to 10 cohort studies. With respect to the harmonisation of exposure data for pooling, the contractors recommended limiting the exposure period to 1950 onwards for the cohort studies. The exposure categories used in the selected studies were comparable. This allows a uniform definition of the exposure categories in a pooled analysis.

The role of electric shocks, the most important potential confounder in studies on occupational exposure to magnetic fields, was investigated in only seven studies. The confounding variables for which the adjustment could be made across studies are age and sex.

The sample size calculations resulted in a total sample size of 2,044,121 people in order to determine a risk increase of 14 % with a statistical test power of 80 %.

Recommendation of the contractors

The contractors concluded that a pooling study would be feasible. They recommended the inclusion of only studies on occupational exposure. They also recommended to only consider the cohort studies for the pooled analysis because they provided a sufficiently homogenous exposure assessment.

The final report of the project is available in DORIS, the online repository of the Federal Office for Radiation Protection. The results of the feasibility study were also published (Baaken et al. 2021).

Further procedure

Conducting a main study as a pooling of original data is not possible due to data protection regulations. The previous plan of pooling original data has therefore been abandoned. This decision was presented in the expert workshop held on 25 January 2021 regarding epidemiological studies in the context of power grid expansion and was supported by the experts present. As an alternative approach, it was decided to develop a standardised analysis protocol to calculate study-specific effect estimates. The estimates are then summarised as a pooled effect estimate (meta-estimate). The research project is to be tendered promptly as "1.2b Meta-analysis of studies on the association between exposure to low-frequency magnetic fields and amyotrophic lateral sclerosis: main study".

1.2.b Meta-analysis of studies on the connection between exposure to extremely low frequency magnetic fields and amyotrophic lateral sclerosis: main study

Project management: Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) of the University Medical Center of the Johannes Gutenberg University, Mainz
Start: 01.04.2022
End: 31.03.2024

Background

Joint evaluations of existing epidemiological studies by means of meta-analyses have repeatedly provided evidence for an increased risk of amyotrophic lateral sclerosis (ALS) in connection with occupational exposure to extremely low frequency magnetic fields (ELF-MF) (Gunnarsson und Bodin 2018; Gunnarsson und Bodin 2019; Jalilian et al. 2020; Vergara et al. 2013). However, one meta-analysis with five studies found no evidence of an increased risk from domestic exposure to ELF-MF (Röösli und Jalilian 2018).

The literature available is inconsistent, and the results are limited in their significance because of publication bias. Animal studies also do not support the assumed connection. A meta-analysis from 2018 suggests that the quality of the exposure assessment plays an important role in the outcome of the studies (Huss et al. 2018). The role of other risk factors such as electric shocks, which are relatively common in occupations with higher exposure to magnetic fields, is also unclear (Huss et al. 2015; Koeman et al. 2017; Peters et al. 2019).

In order to obtain more meaningful findings on the association between extremely low frequency magnetic fields and ALS, it had been planned to pool original data from epidemiological studies on occupational exposure to ELF-MF. For data protection reasons, the investigators had to refrain from conducting the main study as a pooling of original data. Instead, a meta-analysis was initiated.

Objective

The aim of this research project is to gain meaningful insight into the relationship between extremely low frequency magnetic fields and the risk of ALS. The role of other risk factors, such as electric shocks, will also be investigated.

Implementation

The main study will be conducted as a meta-analysis. For this purpose, cooperations with the data holders of the original studies are to be contractually defined. Moreover, a study protocol and a standardised analysis protocol is to be developed. With the help of this, study-specific effect estimators in the respective original study will be calculated. These individual estimators are then to be combined centrally into a pooled effect estimator (meta-estimator). In this context, the role of electric shocks will also be investigated by using a so-called job exposure matrix.

In addition, an evaluation of the final results as well as the identification and assessment of new findings in the field of extremely low frequency magnetic fields with regard to the objectives of the project will be conducted.

Literature

Gunnarsson L-G und Bodin L (2018): Amyotrophic Lateral Sclerosis and Occupational Exposures: A Systematic Literature Review and Meta-Analyses. International Journal of Environmental Research and Public Health 15:2371.

Gunnarsson L-G und Bodin L (2019): Occupational Exposures and Neurodegenerative Diseases - A Systematic Literature Review and Meta-Analyses. International Journal of Environmental Research and Public Health 16:337.

Huss A, Peters S, Vermeulen R (2018): Occupational exposure to extremely low-frequency magnetic fields and the risk of ALS: A systematic review and meta-analysis. Bioelectromagnetics 39:156-163.

Huss A, Spoerri A, Egger M, Kromhout H, Vermeulen R (2015): Occupational exposure to magnetic fields and electric shocks and risk of ALS: the Swiss National Cohort. Amyotrophic lateral sclerosis & frontotemporal degeneration 16:80-85.

Jalilian H, Najafi K, Khosravi Y, Roosli M (2020): Amyotrophic lateral sclerosis, occupational exposure to extremely low frequency magnetic fields and electric shocks: a systematic review and meta-analysis. Rev Environ Health.

Koeman T et al. (2017): Occupational exposure and amyotrophic lateral sclerosis in a prospective cohort. Occupational and environmental medicine 74:578-585.

Peters S et al. (2019): Electric Shock and Extremely Low-Frequency Magnetic Field Exposure and the Risk of ALS: Euro-MOTOR. American journal of epidemiology.

Röösli M und Jalilian H (2018): A meta-analysis on residential exposure to magnetic fields and the risk of amyotrophic lateral sclerosis. Rev Environ Health.

Vergara X, Kheifets L, Greenland S, Oksuzyan S, Cho YS, Mezei G (2013): Occupational exposure to extremely low-frequency magnetic fields and neurodegenerative disease: a meta-analysis. J Occup Environ Med 55:135-146.

Project management: Federal Office for Radiation Protection
Start: 12 December 2017
End: 14 December 2017

Background

Studies of occupational exposure to high levels of alternating magnetic fields show a statistical correlation to an increase in some neurodegenerative diseases, most notably Alzheimer’s dementia (AD) and amyotrophic lateral sclerosis (ALS). Because neurodegenerative diseases are increasing in society in connection with increasing life expectancy, the question arises whether magnetic fields can additionally influence the development of these diseases – even at low field strengths.

Objective

In order to get an overview of the latest research and to identify new approaches on the basis of which further research can be initiated, an international workshop was organised. This took place in Munich from 12–14 December 2017.

Implementation

Experts from all over the world were invited to discuss the different aspects and problems as well as to jointly give an overview of the viewpoints of these different areas. Twenty-one international speakers were invited to present different disciplines and research areas in order to shape the programme items. Participants included medical doctors, biologists, epidemiologists, physicists, and electrical engineers. In total, 57 people from 15 different countries participated in the workshop.

The following points were discussed in eight sessions:

• Introduction to neurodegenerative diseases: what we know and what we don’t know
• Exposure determination
• Epidemiology: Low-frequency magnetic fields as potential risk factors for neurodegenerative diseases
• Aetiology of ALS: New insights from animal models
• Aetiology of Alzheimer’s dementia
• Molecular basis of ALS
• Molecular basis of Alzheimer’s dementia
• Molecular effects of low-frequency magnetic fields in animal models and cell cultures

Results

The workshop provided a comprehensive overview of the current state of research on the molecular and genetic basis of neurodegenerative diseases as well as on the correlation with low-frequency magnetic fields and potential mechanisms of action. Overall, it became apparent that the results of current epidemiological research first need to be updated in the form of meta-analyses or pooled analyses (Research projects 1.1 and 1.2). If a potential correlation between the diseases mentioned and magnetic fields is confirmed, it will be examined whether the molecular signatures of the diseases presented at the workshop and the new animal models are suitable for the further investigation of the influence of exposure to magnetic fields in animal models or in cells (Research projects 1.4–1.7).

Following the workshop, a joint report with the input of the speakers will be prepared and published. Based on this, further research projects will be initiated if necessary. The report on the results of the workshops with the agenda and the abstracts of the individual contributions has been published in DORIS, the Digital Online Repository and Information System of the BfS.

If current epidemiological studies as well as the planned meta-analysis (Research project 1.1.) and the currently ongoing pooled analysis (Research project 1.2.) confirm the correlation between low-frequency magnetic fields and ALS, suitable animal models and endpoints to be investigated will be selected. Those will be based on the results of the workshop (Research project 1.3.).Furthermore animal experiments involving exposure to low-frequency magnetic fields will be conducted.

If current epidemiological studies as well as the planned meta-analysis (Research project 1.1.) and the currently ongoing pooled analysis (Research project 1.2.) confirm the correlation between low-frequency magnetic fields and ALS, suitable animal models and endpoints to be investigated will be selected. Those will be based on the results of the workshop (Research project 1.3.). Furthermore animal experiments involving exposure to low-frequency magnetic fields will be conducted.

If current epidemiological studies as well as the planned meta-analysis (Research project 1.1) and the currently ongoing pooled analysis (Research project 1.2) confirm the correlation between low-frequency magnetic fields and ALS, the endpoints to be investigated and suitable cell lines will be selected based on the results of the workshop (Research project 1.3). Laboratory studies will be conducted using these cells (or sample material from the in vivo studies) involving exposure to low-frequency magnetic fields.

Research or contracting company: Neurobiology Laboratory – Clinical Neurobiology, Charité - Universitätsmedizin Berlin
Project management: PD Dr. Julian Hellmann-Regen
Beginn: 01.11.2022
End: 31.10.2025

Background

Since the late 1990s, epidemiological studies have provided evidence of a possible link between occupational exposure to low frequency magnetic fields (LF-MF) and an increased incidence of Alzheimer’s disease. Laboratory studies investigating this relationship have yielded highly inconsistent results: In addition to negative effects, both protective or even therapeutic effects of LF-MF in Alzheimer’s dementia have been shown – and no effects of these fields on Alzheimer’s disease. Furthermore, a potential mechanism of action that could explain how LF-MF could influence the onset and development of Alzheimer’s dementia is lacking.

Objective

In this research project, it will be investigated on a cellular level whether LF-MF influence processes of nervous system cells (i.e. neurons, astrocytes, glial cells) that play a role in the development and progression of Alzheimer’s disease. A distinction is to be made between the direct effect of the magnetic field on biological target structures and the effect of electric currents on the cell.

Implementation

Human nerve and nerve tissue cells are exposed for 2–120 h with magnetic fields in the frequency range from 16 Hz (overhead railway lines) to 50 Hz (power grid) and in the field strength range from 0.04 µT to the reference value of 200 µT (at 50 Hz) recommended by the International Commission on Non-Ionising Radiation Protection (ICNIRP) as well as a sham exposure under controlled laboratory conditions. The exposure will be blinded (i.e. it will not be known during the experiment whether the cells were exposed to the fields).

After exposure, it will be measured whether there are changes in the conversion of genetic information into proteins as well as the concentration of proteins that are important for the development and progression of Alzheimer’s disease (including amyloid precursor protein (APP), β-amyloid, tau protein). In addition, changes in oxidative stress in the cells will be analysed because this is frequently mentioned as a possible contributing factor to the disease.

Project management: Competence Center of Sleep Medicine, Charité – Universitätsmedizin Berlin
Start: 1 January 2022
End: 31 December 2024

Background

A connection between disturbed sleep and neurodegenerative diseases is known from the specialist literature; typical sleep disturbances are among the symptoms of many neurodegenerative diseases. Sleep disorders are also considered a risk factor and one of the possible causes of Alzheimer’s dementia (AD). An important finding in AD is deposits of the peptide β-amyloid. These deposits are influenced by disturbances in the sleep–wake rhythm. After a night of disturbed sleep, the β-amyloid concentration in test subjects increases. The connection between low-frequency magnetic fields and sleep is poorly studied. Only a few experimental studies reported impaired sleep during nocturnal exposure to magnetic fields. Sleep disturbances as a result of exposure to magnetic fields could be a mechanism of action that explains the statistical correlation between magnetic fields and AD.

Objective

The aim is to use the sleep EEG to test whether exposure to magnetic fields can influence the sleep parameters of humans. In addition, the influence of magnetic fields on the concentrations of β-amyloid and the hormone melatonin, which promotes sleep, will be determined, and the subjective quality of sleep will be assessed. Because poor sleep has a negative effect on memory consolidation, it will be tested whether exposure to magnetic fields impairs memory. The results will show whether magnetic fields affect sleep and have physiological effects that could promote AD.

Implementation

20 men and 20 women aged 55 to 75 years will be included in the study. Inclusion criteria: healthy right-handed individuals, non-smokers, post-menopausal women. Exclusion criteria: Use of substances that affect sleep, sleep disorders, implants. Each test person will be subjected to one adaptation night, one sham exposure, and two exposure levels at one-week intervals.

The study participants will be exposed by means of a coil arrangement. This will allow the continuous night-time exposure of lying persons during sleep but will not interfere with getting out of bed. The test persons will be subjected to one exposure with low frequency magnetic fields at 50 Hz and two intensities (high and low; in the range 1–30 microtesla) as well as a sham exposure. The exposure will be blinded (it will not be known when subjects are exposed to the fields).

During sleep, the EEG will be recorded, and the sleep structure (sleep stages, latency to fall asleep, sleep efficiency, sleep duration, and wake-up events) will be analysed. Standardised evening and morning logs will be filled out in order to record special daily events that can influence sleep as well as the state of health in the morning after the study night. Before and after each exposure night, biomarkers for sleep and AD (melatonin, β-amyloid, tau protein) will be determined in the plasma. In order to test whether the magnetic fields had an effect on nocturnal memory consolidation, memory tasks will be used in the evening and in the morning after sleep.