"The extent to which particular scientific results constitute progress in knowledge or contribute to societal well-being is often contested. This is especially the case when scientific findings are uncertain or controversial and when they can be interpreted to support controversial policy choices....Assessing science, no matter how rigorous the methods that may be used, is ultimately a matter of interpretation. The possibility of competing interpretations of evidence is ever-present when using science indicators or applying any other analytic method for measuring the progress and impact of science." (4)
(1) National Toxicology Program. Handbook for Conducting Systematic Reviews for Health Effects Evaluations. https://ntp.niehs.nih.gov/
(2) National Toxicology Program. Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration (March 4, 2019): https://ntp.niehs.nih.gov/ntp/
(3) National Toxicology Program. 2019 OHAT Handbook Update and Clarification Summary Document (March 4, 2019). https://ntp.niehs.nih.gov/ntp/
ohat/pubs/ handbookclarificationmarch2019 _508.pdf(4) National Research Council. 2007. A Strategy for Assessing Science: Behavioral and Social Research on Aging. Washington, DC: The National Academies Press. https://doi.org/10.17226/11788 .
Research Protocols for Radiofrequency EHC Reviews
Susanna Lagorio, Maria Blettner, Dan Baaken, Maria Feychting, Ken Karipidis, Tom Loney, Nicola Orsini, Martin Röösli, Marilia Silva Paulo, Mark Elwood. The effect of exposure to radiofrequency fields on cancer risk in the general and working population: A protocol for a systematic review of human observational studies. Environ Int. 2021 Aug 22;157:106828. doi: 10.1016/j.envint.2021.106828.
• A systematic review of all subject-relevant epidemiological studies is now needed.
• A detailed protocol ensures the review's transparency, utility and credibility.
• Original study validity will be evaluated with a customized OHAT risk of bias tool.
• Internal coherence and external plausibility will inform conclusions.
Background: The World Health Organization (WHO) has an ongoing project to assess potential health effects of exposure to radiofrequency electromagnetic fields (RF-EMF) in the general and working population. Here we present the protocol for a systematic review of the scientific literature on cancer hazards from exposure to RF-EMF in humans, commissioned by the WHO as part of that project.
Objective: To assess the quality and strength of the evidence provided by human observational studies for a causal association between exposure to RF-EMF and risk of neoplastic diseases.
Eligibility criteria: We will include cohort and case-control studies investigating neoplasia risks in relation to three types of exposure to RF-EMF: near-field, head-localized, exposure from wireless phone use (SR-A); far-field, whole body, environmental exposure from fixed-site transmitters (SR-B); near/far-field occupational exposures from use of handheld transceivers or RF-emitting equipment in the workplace (SR-C). While no restriction on tumour type will be applied, we will focus on selected neoplasms of the central nervous system (brain, meninges, pituitary gland, acoustic nerve) and salivary gland tumours (SR-A); brain tumours and leukaemias (SR-B, SR-C).
Information sources: Eligible studies will be identified through Medline, Embase, and EMF-Portal.
Risk-of-bias assessment: We will use a tailored version of the OHAT's tool to evaluate the study's internal validity.
Data synthesis: We will consider separately studies on different tumours, neoplasm-specific risks from different exposure sources, and a given exposure-outcome pair in adults and children. When a quantitative synthesis of findings can be envisaged, the main aims of the meta-analysis will be to assess the strength of association and the shape of the exposure-response relationship; to quantify the degree of heterogeneity across studies; and explore the sources of inconsistency (if any). When a meta-analysis is judged inappropriate, we will perform a narrative synthesis, complemented by a structured tabulation of results and appropriate visual displays.
Evidence assessment: Confidence in evidence will be assessed in line with the GRADE approach.
Funding: This project is supported by the World Health Organization. Co-financing was provided by the New Zealand Ministry of Health; the Istituto Superiore di Sanità in its capacity as a WHO Collaborating Centre for Radiation and Health; ARPANSA as a WHO Collaborating Centre for Radiation Protection.
Registration: PROSPERO CRD42021236798.
Ryan P.W. Kenny, Evelyn Barron Millar, Adenike Adesanya, Catherine Richmond, Fiona Beyer, Carolina Calderon, Judith Rankin, Mireille Toledano, Maria Feychting, Mark S Pearce, Dawn Craig, Fiona Pearson. The effects of radiofrequency exposure on male fertility and adverse reproductive outcomes: A protocol for two systematic reviews of human observational studies with meta-analysis. Environ Int. 158, 2022, 106968. doi: 10.1016/j.envint.2021.106968.
Background The World Health Organization (WHO) is bringing together evidence on radiofrequency electromagnetic field (RF-EMF) exposure in relation to health outcomes, previously identified as priorities for evaluation by experts in the field, to inform exposure guidelines. A suite of systematic reviews are being undertaken by a network of topic experts and methodologists in order to collect, assess and synthesise data relevant to these guidelines. Here, we present the protocol for the systematic review on the effect of exposure to RF on adverse reproductive outcomes (human observational studies), also referred to as Systematic Review (SR) 3 within the series of systematic reviews currently being commissioned.
Objectives Following the WHO handbook for guideline development and the COSTER conduct guidelines, we will systematically review the effect of RF-EMF exposure on both male fertility (SR3A) and adverse pregnancy outcomes (SR3B) in human observational studies. Herein we adhere to the PRISMA-P reporting guidelines.
Data sources We will conduct a broad search for potentially relevant records relevant for both reviews within the following bibliographic databases: MEDLINE; Embase; and EMF Portal. We will also conduct searches of grey literature through relevant databases and organisational websites. RF-EMF experts will also be consulted. We will hand search citation and reference lists of included study records.
Study eligibility criteria We will include quantitative human observational studies on the effect of RF-EMF exposure: (in SR3A) in adult male participants on infertility, sperm morphology, concentration or total sperm count or motility; and (in SR3B) in preconception adults or pregnant women on preterm birth, small for gestational age (associated with intrauterine growth restriction), miscarriage, stillbirth and congenital anomalies.
Study appraisal and synthesis methods Titles, abstracts and then full texts will be screened in blinded duplicate against eligibility criteria with input from a third reviewer as required. Data extraction from included studies will be completed by two reviewers as will risk of bias assessment using the Office of Health Assessment and Translation (OHAT) tool. If appropriate we will undertake meta-analysis to pool effect measures and explore heterogeneity using sub-group analyses or meta-regression as feasible. We will conduct sensitivity analysis to assess the impact of any assumptions made throughout the review process. The OHAT methodology, based on the GRADE guidelines for evidence assessment, will be used to evaluate the certainty of evidence per outcome and to conclude the level of evidence of a health effect.
Conclusion This manuscript details the protocols for two systematic reviews. The aims of publishing details of both protocols are to: pre-specify their scope and methods; reduce the impact of reviewer bias; promote transparency and replicability; and improve the review process.
Prospero registration CRD42021265401 (SR3A), CRD42021266268 (SR3B).
Declaration of Competing Interest
Open access paper: https://www.sciencedirect.com/science/article/pii/S0160412021005936
• Male infertility and adverse pregnancy outcomes are relevant human health problems.
• Radiofrequency electromagnetic fields are widespread in the human environment.
• A link between radiofrequency and adverse reproductive outcomes is controversial.
• This is the protocol of WHO-funded systematic review and meta-analysis on this issue.
Background Radiofrequency Electromagnetic Fields (RF-EMF) at environmental level have been reported to induce adverse effects on the male reproductive system and developing embryos. However, despite the number of experiments conducted since the 1970s, the diversity of testing approaches and exposure conditions, inconsistencies among results, and dosimetric flaws have not yet permitted a solid assessment of the relationship between RF-EMF exposure and such effects, warranting a more systematic and methodologically rigorous approach to the evaluation of available data.
Objectives This study aims at evaluating the effects of RF-EMF exposure on male fertility and pregnancy outcomes by a systematic review (SR) of experimental studies, conducted in compliance with international guidelines. The evidence will be organized into three streams: 1) Studies evaluating the impact of RF-EMF on the male reproductive system of experimental mammals; 2) studies evaluating the impact of RF-EMF on human sperm exposed in vitro; 3) studies evaluating the impact of RF-EMF on adverse pregnancy, birth outcomes and delayed effects in experimental mammals exposed in utero.
Study eligibility and criteria Eligible studies will include peer-reviewed articles reporting of original results about effects of controlled exposures to RF-EMF in the frequency range 100 kHz–300 GHz on the selected outcomes without any language or year-of-publication restrictions. Eligible studies will be retrieved by calibrated search strings applied to three electronic databases, PubMed, Scopus and EMF Portal and by manual search of the list of references of included papers and published reviews.
Study appraisal and synthesis method The internal validity of the studies will be evaluated using the Risk of Bias (RoB) Rating Tool developed by National Toxicology Program/Office of Health Assessment and Translation (NTP/OHAT) integrated with input from the SYRCLE RoB tool. Given sufficient commensurate data, meta-analyses will be performed, otherwise narrative syntheses will be produced. Finally, the certainty of the effects of RF-EMF exposure on male fertility and pregnancy and birth outcomes will be established following GRADE.
Funding The study is financially supported by the World Health Organization.
Registration OSF Registration DOI https://doi.org/10.17605/OSF.
• This protocol outlines the steps required for a systematic review of the effect of long-term radiofrequency exposure on cognition in human observational studies.
Background: The long term effects of exposure to radiofrequency (RF) electromagnetic fields (EMF) for frequencies from 100 kHz to 300 GHz on cognitive performance are best assessed using observational studies. In recent years, the use of mobile (cell) phones has been the main source of RF EMF exposure to the brain, although other sources of exposure may be significant. Cognitive function includes various mental and psychological abilities, which can be measured in a range of domains, such as learning, memory, reasoning, problem solving, decision making and attention. Although effects on cognitive function may be most evident later in life, in the experimental setting acute and immediate effects can only be studied. Observational studies are needed when effects are observed after months or years following short or long-term exposure. The importance of the effects of exposure on children has also been recently identified.
Objectives: To assess the long-term effects of RF EMF local and whole-body exposure compared to no or a lower level of exposure on indicators of cognition, including complex attention, executive function, learning and memory, perceptual motor ability and social cognition, but excluding cognitive effects caused by neurodegenerative diseases or neurodevelopmental disorders, and to assess if there is evidence of a dose response relationship.
Study eligibility and criteria: We will include observational studies that have evaluated cognitive effects of RF energy including a comparator group with a different level of exposure. Studies must report at least one validated measure of cognitive function, including global or domain specific measures, or cognitive impairment, with a minimum follow-up of 6 months. Cohort or case-control studies published in the peer review literature in any language are eligible. We will exclude cross-sectional studies and any that only report brain structure or biomarkers.
Study appraisal and synthesis method: We will conduct searches of PubMed, Embase, PsycINFO and the EMF-Portal. At least two authors will independently screen the titles/abstracts of all records, with any conflicts resolved by a third reviewer. Full-text screening will also be conducted independently by two authors with conflicts resolved by consensus. Data will be extracted from the studies included, such as identifiers and characteristics of the study design, exposure and comparator groups, participants, outcomes assessed and results. Risk of bias will be assessed with the Office of Health Assessment and Translation (OHAT) tool. We will conduct a meta-analysis of similar studies with a random effects model in STATA or similar software, if two or more studies are available for a given exposure-outcome combination. Confidence in the body evidence will be judged using GRADE methods as adapted by OHAT for reviews of environmental exposures.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Blanka Pophof, Jacob Burns, Heidi Danker-Hopfe, Hans Dorn, Cornelia Egblomassé-Roidl, Torsten Eggert, Kateryna Fuks, Bernd Henschenmacher, Jens Kuhne, Cornelia Sauter, Gernot Schmid. The effect of exposure to radiofrequency electromagnetic fields on cognitive performance in human experimental studies: A protocol for a systematic review. Environ Int. 2021 Jul 29;157:106783. doi: 10.1016/j.envint.2021.106783.
Background: The World Health Organization (WHO) is currently assessing the potential health effects of exposure to radiofrequency electromagnetic fields (RF-EMFs) in the general and working population. Related to one such health effect, there is a concern that RF-EMFs may affect cognitive performance in humans. The systematic review (SR) aims to identify, summarize and synthesize the evidence base related to this question. Here, we present the protocol for the planned SR.
Objectives: The main objective is to present a protocol for a SR which will evaluate the associations between short-term exposure to RF-EMFs and cognitive performance in human experimental studies.
Data sources: We will search the following databases: PubMed, Embase, Web of Science, Scopus, and the EMF-Portal. The reference lists of included studies and retrieved review articles will be manually searched.
Study eligibility and criteria: We will include randomized human experimental studies that assess the effects of RF-EMFs on cognitive performance compared to no exposure or lower exposure. We will include peer-reviewed articles of any publication date in any language that report primary data.
Data extraction and analysis: Data will be extracted according to a pre-defined set of forms developed and piloted by the review author team. To assess the risk of bias, we will apply the Rating Tool for Human and Animal Studies developed by NTP/OHAT, supplemented with additional questions relevant for cross-over studies. Where sufficiently similar studies are identified (e.g. the heterogeneity concerning population, exposure and outcome is low and the studies can be combined), we will conduct random-effects meta-analysis; otherwise, we will conduct a narrative synthesis.
Assessment of certainty of evidence: The certainty of evidence for each identified outcome will be assessed according to Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Performing the review according to this protocol will allow the identification of possible effects of RF-EMFs on cognitive performance in humans. The protocol has been registered in PROSPERO, an open-source protocol registration system, to foster transparency.
Registration PROSPERO CRD42021236168.
• No up to date comprehensive systematic review is available.
• Priority outcomes for head exposure are tinnitus, migraine, and headaches.
• Further priority outcomes are sleep disturbances and composite symptom scores.
Background Applications emitting radiofrequency electromagnetic fields (RF-EMF; 100 kHz to 300 GHz) are widely used for communication (e.g. mobile phones), in medicine (diathermy) and in industry (RF heaters). Concern has been raised that RF-EMF exposure affects health related quality of life, because a part of the population reports to experience a variety of symptoms related to low exposure levels below regulatory limits.
Objectives To systematically review the effects of longer-term or repeated local and whole human body RF-EMF exposure on the occurrence of symptoms evaluating migraine, tinnitus, headaches, sleep disturbances and composite symptom scores as primary outcomes.
Methods We will follow the WHO handbook for guideline development. For the development of the systematic review protocol we considered handbook for conducting systematic reviews for health effects evaluations from the National Toxicology Program-Office of Health Assessment and Translation (NTP-OHAT) and COSTER (Recommendations for the conduct of systematic reviews in toxicology and environmental health research).
Eligibility criteria Peer-reviewed epidemiological studies in the general population or workers aiming to investigate the association between local or whole-body RF-EMF exposure for at least one week and symptoms are eligible for inclusion. Only cohort, case-control and panel studies will be included.
Information sources We will search the scientific literature databases Medline, Web of Science, PsycInfo, Cochrane Library, Epistemonikos and Embase, using a predefined search strategy. This search will be supplemented by a search in the EMF-Portal and checks of reference lists of relevant papers and reviews.
Study appraisal and synthesis method Data from included papers will be extracted according to predefined forms. Findings will be summarized in tables, graphical displays and in a narrative synthesis of the available evidence, complemented with meta-analyses. We will separately review effects of local, far field and occupational exposure.
Risk of bias The internal validity of included studies will be assessed using the NTP-OHAT Risk of Bias Rating Tool for Human and Animal Studies, elaborated to observational RF-EMF studies.
Evidence appraisal To rate certainty of the evidence, we will use the OHAT GRADE-based approach for epidemiological studies.
Framework and funding This protocol concerns one of the ten different systematic reviews considered in a larger systematic review of the World Health Organization to assess potential health effects of exposure to RF-EMF in the general and working population.
Registration PROSPERO CRD42021239432.
Open access paper: https://www.sciencedirect.com/science/article/pii/S0160412021004773?via%3Dihub
Bernd Henschenmacher, Annette Bitsch, Tonia de las Heras Gala, Henry Jay Forman, Athanassios Fragoulis, Pietro Ghezzi, Rupert Kellner, Wolfgang Koch, Jens Kuhne, Dmitrij Sachno, Gernot Schmid, Katya Tsaioun, Jos Verbeek, Robert Wright. The effect of radiofrequency electromagnetic fields (RF-EMF) on biomarkers of oxidative stress in vivo and in vitro: A protocol for a systematic review. Environ Int. 158, 2022, 106932. doi: 10.1016/j.envint.2021.106932.
Background Oxidative stress is conjectured to be related to many diseases. Furthermore, it is hypothesized that radiofrequency fields may induce oxidative stress in various cell types and thereby compromise human and animal health. This systematic review (SR) aims to summarize and evaluate the literature related to this hypothesis.
Objectives The main objective of this SR is to evaluate the associations between the exposure to radiofrequency electromagnetic fields and oxidative stress in experimental models (in vivo and in vitro).
Methods The SR framework has been developed following the guidelines established in the WHO Handbook for Guideline Development and the Handbook for Conducting a Literature-Based Health Assessment). We will include controlled in vivo and in vitro laboratory studies that assess the effects of an exposure to RF-EMF on valid markers for oxidative stress compared to no or sham exposure. The protocol is registered in PROSPERO.
We will search the following databases: PubMed, Embase, Web of Science Core Collection, Scopus, and the EMF-Portal. The reference lists of included studies and retrieved review articles will also be manually searched.
Study appraisal and synthesis method Data will be extracted according to a pre-defined set of forms developed in the DistillerSR online software and synthesized in a meta-analysis when studies are judged sufficiently similar to be combined. If a meta-analysis is not possible, we will describe the effects of the exposure in a narrative way.
Risk of bias The risk of bias will be assessed with the NTP/OHAT risk of bias rating tool for human and animal studies.
We will use GRADE to assess the certainty of the conclusions (high, moderate, low, or inadequate) regarding the association between radiofrequency electromagnetic fields and oxidative stress.
Funding This work was funded by the World Health Organization (WHO).
Registration The protocol was registered on the PROSPERO webpage on July 8, 2021.
Open access paper: https://www.sciencedirect.com/science/article/pii/S0160412021005572
Jos Verbeek, Gunnhild Oftedal, Maria Feychting, Eric van Rongen, Maria Rosaria Scarfì, Simon Mann, Rachel Wong, Emilie van Deventer. Prioritizing health outcomes when assessing the effects of exposure to radiofrequency electromagnetic fields: A survey among experts. Environ Int. 146, 2021. 106300. doi:10.1016/j.envint.2020.106300.
• RF EMF may lead to other than heat-related health effects by yet unknown mechanisms
• Prioritizing health effects is needed for review utility and resource efficiency.
• RF EMF experts prioritized all peer-reviewed published biological and health outcomes.
• Cancer, heat-related effects, and adverse birth outcomes were rated most critical.
• WHO commissioned ten systematic reviews of the most critical health outcomes.
Exposure to radiofrequency (RF) electromagnetic fields (EMF) (frequencies of 100 kHz to 300 GHz) has been steadily increasing. In addition to heat-related effects of RF EMF, other yet-unspecified biological effects, might exist which could possibly lead to health effects. Given the large number of health endpoints that have been studied, we wanted to prioritize those that would merit systematic reviews.
We developed a survey listing of all health endpoints reported in the literature and we asked 300 RF EMF experts and researchers to prioritize these health effects for systematic review as critical, important or unimportant. We also asked the experts to provide the rationale for their prioritization.
Of the 300 RF EMF experts queried, 164 (54%) responded. They rated cancer, heat-related effects, adverse birth outcomes, electromagnetic hypersensitivity, cognitive impairment, adverse pregnancy outcomes and oxidative stress as outcomes most critical regarding RF EMF exposure. For these outcomes, systematic reviews are needed. For heat-related outcomes, the experts based their ranking of the critical outcomes on what is known from human or animal studies, and for cancer and other outcomes, they based their rating also on public concern.
Stephanie M. Eick, Dana E. Goin, Nicholas Chartres, Juleen Lam, Tracey J. Woodruff. Assessing risk of bias in human environmental epidemiology studies using three tools: different conclusions from different tools. Syst Rev 9, 249 (2020). doi: 10.1186/
Background Systematic reviews are increasingly prevalent in environmental health due to their ability to synthesize evidence while reducing bias. Different systematic review methods have been developed by the US National Toxicology Program’s Office of Health Assessment and Translation (OHAT), the US Environmental Protection Agency’s (EPA) Integrated Risk Information System (IRIS), and by the US EPA under the Toxic Substances Control Act (TSCA), including the approach to assess risk of bias (ROB), one of the most vital steps which is used to evaluate internal validity of the studies. Our objective was to compare the performance of three tools (OHAT, IRIS, TSCA) in assessing ROB.
Methods We selected a systematic review on polybrominated diphenyl ethers and intelligence quotient and/or attention deficit hyperactivity disorder because it had been endorsed by the National Academy of Sciences. Two reviewers followed verbatim instructions from the tools and independently applied each tool to assess ROB in 15 studies previously identified. We documented the time to apply each tool and the impact the ROB ratings for each tool had on the final rating of the quality of the overall body of evidence.
Results The time to complete the ROB assessments varied widely (mean = 20, 32, and 40 min per study for the OHAT, IRIS, and TSCA tools, respectively). All studies were rated overall “low” or “uninformative” using IRIS, due to “deficient” or “critically deficient” ratings in one or two domains. Similarly, all studies were rated “unacceptable” using the TSCA tool because of one “unacceptable” rating in a metric related to statistical power. Approximately half of the studies had “low” or “probably low ROB” ratings across all domains with the OHAT and Navigation Guide tools.
Conclusions Tools that use overall ROB or study quality ratings, such as IRIS and TSCA, may reduce the available evidence to assess the harms of environmental exposures by erroneously excluding studies, which leads to inaccurate conclusions about the quality of the body of evidence. We recommend using ROB tools that circumvent these issues, such as OHAT and Navigation Guide.
"Following on the publication of the INTERPHONE study (May 2010) and the IARC classification of RF fields (May 2011), the health risk assessment of radiofrequency fields by WHO was started with a kick-off meeting in January 2012. A core group of 6 experts has been gathered to help with the development of the monograph. They, in turn, have enlisted the help of close to 30 experts to develop different sections of the first draft. Monthly conference calls have been held over the past year. A face-to-face meeting was convened in Istanbul in May 2015.A number of systematic reviews have been performed based on published peer-reviewed data. Search strategies, inclusion/exclusion criteria and quality criteria have been developed for the different types of studies. A first draft was uploaded on the WHO website in the Fall of 2014. Over 90 entries were filed electronically through the consultation providing around 700 comments to different chapters and section of the draft. Over 300 missing papers were identified through this useful step. Each submission has been carefully considered by the Core Group and the draft has been revised to take account of relevant comments and of papers published since December 2012. As a result of the consultation, a new chapter on biochemical and biological effects was added.The drawing of conclusions from the literature and the drafting of these chapters is the remit of a formal Task Group that will be convened by WHO following due process. The meeting of the Task Group is currently slated to be held in the Fall of 2016."
In March 1993, almost 30 years ago, the WHO published the last EHC monograph on radiofrequency radiation:
Electromagnetic fields (300 Hz to 300 GHz)
Environmental Health Criteria Monograph No.137
"WHO's assessment of any health risks produced by EMF emitting technologies falls within the responsibilities of the International EMF Project. One of the goals of the International EMF Project is therefore to carry out health risk assessments of RF, ELF and static fields, published in the Environmental Health Criteria.
The health risk assessments are
the result of in-depth critical reviews conducted through independent,
scientific peer-review groups. The are usually undertaken if new data
are available that would substantially change the evaluation, if there
is public concern for health or environmental effects of the agent
because of greater exposure, or if an appreciable time period has
elapsed since the last evaluation."