The effects of radiofrequency electromagnetic field exposure on biomarkers of oxidative stress in vivo

Abstract

The effects of radiofrequency electromagnetic field exposure on biomarkers of oxidative stress in vivo and in vitro: A systematic review of experimental studies (WHO SR 9) My note: SR 9 is the eighth of the WHO SRs (systematic reviews) on RF-EMF effects to be published in Environment International. Like its predecessors, the authors of this SR systematically excluded most of the relevant research. Most of the meta-analyses in this paper suffered from high levels of heterogeneity with little effort to understand the source of the varied results. Some meta-analyses were unreliable as they violated a key assumption of the random effects model, namely, independence of observations. I think a critique of this SR could build a strong case for retraction of this paper. Meyer F, Bitsch A, Forman HJ, Fragoulis A, Ghezzi P, Henschenmacher B, Kellner R, Kuhne J, Ludwig T, Sachno D, Schmid G, Tsaioun K, Verbeek J, Wright R. The effects of radiofrequency electromagnetic field exposure on biomarkers of oxidative stress in vivo and in vitro: A systematic review of experimental studies. Environment International, 2024. doi: 10.1016/j.envint.2024.108940. Highlights The evidence for or against a relation between RF-EMF and biomarkers of oxidative stress is overall of very low certainty. Inconsistent overall study results. Need for drastic improvements of studies on RF-EMF and biomarkers of oxidative stress. Abstract Background Oxidative stress is thought to be related to many diseases. Furthermore, it is hypothesized that radiofrequency electromagnetic fields (RF-EMF) may induce excessive oxidative stress in various cell types and thereby have the potential to compromise human and animal health. The objective of this systematic review (SR) is to summarize and evaluate the literature on the relation between the exposure to RF-EMF in the frequency range from 100 kHz to 300 GHz and biomarkers of oxidative stress. Methods The SR framework was developed following the guidelines established in the WHO Handbook for Guideline Development and NTP/OHAT’s Handbook for Conducting a Literature-Based Health Assessment. We used the latter handbook’s methodology for implementing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for environmental health assessments. We searched the following databases up until June 30, 2023: PubMed, Embase, Web of Science Core Collection, Scopus, and the EMF-Portal. The reference lists of included studies and retrieved review articles were also manually searched. We rated Risk of Bias (RoB) using the OHAT RoB Rating Tool and assessed publication bias using funnel plots of included studies. We assessed the certainty of the evidence (high, moderate, low, or inadequate) for an association between RF-EMF and oxidative stress using an adapted version of the GRADE framework. Data were extracted according to a predefined set of forms developed in DistillerSR. Data were analysed after grouping them first as in vitro or in vivo and then according to outcome category, species category, and exposed tissue. We synthesized study results using a random effects meta-analysis when study characteristics were judged sufficiently similar to be combined and heterogeneity (I2) was lower than 75 %, otherwise we describe the findings narratively. Results Fifty-six (56) studies, 45 in vivo and 11 in vitro, exposed to frequencies in the range 800–2450 MHz, were included in the SR after eliminating 11,543 publications because they did not meet the criteria defined in the published protocol (Henschenmacher et al., 2022). Of 56 studies 51 studies with 168 individual results were included in the meta-analysis. Together, these studies examined six human in vitro samples and fifty animal samples, including rodents (mice, rats, hamsters, and guinea pigs, [n = 46]) and rabbits [n = 4]. RF-EMF were predominantly applied as continuous wave exposures in these studies. The outcome biomarkers for modified proteins and amino acids were measured in 30 studies, for oxidized DNA bases in 26 studies, for oxidized lipids in 2 studies and hydrogen peroxide production in 2 studies. Outcomes were mostly measured in the brain (n = 22), liver (n = 9), cells (n = 9), blood (n = 6), and testis (n = 2). RoB in studies was high, mainly due to biases in exposure and outcome assessment. In vivo studies Brain: The effect on biomarkers for oxidized DNA bases in the rodent brain (five studies, n = 98) had an inconsistent effect, varying from a large decrease with a standardized mean difference (SMD) of −3.40 (95 % CI [−5.15, −1.64]) to a large increase with an SMD of 2.2 (95 % CI [0.78, 3.62]). In the brain of rabbits (two studies, n = 44), the effect sizes also varied, from an SMD of −1.06 (95 % CI [−2.13, 0.00]) to an SMD of 5.94 (95 % CI [3.14, 8.73]). The effect on biomarkers for modified proteins and amino acids in the rodent brain (15 studies, n = 328) also varied from a large decrease with an SMD of −6.11 (95 % CI [−8.16, −4.06]) to a large increase with an SMD of 5.33 (95 % CI [2.49, 8.17]). The effect on biomarkers for oxidized lipids in the brain of rodents (one study, n = 56) also varied from a large decrease with SMD = −4.10 (95 % CI [−5.48, −2.73]) to SMD = 1.27 (95 % CI [0.45, 2.10]). Liver: The effect on biomarkers for oxidized DNA bases in the rodent liver (two studies, n = 26) was inconsistent with effect sizes in both directions: SMD = −0.71 (95 % CI [−1.80, 0.38]) and SMD = 1.56 (95 % CI [0.19, 2.92]). The effect on biomarkers for oxidized DNA bases in the rabbits’ liver (two studies, n = 60) was medium with a pooled SMD of 0.39 (95 % CI [−0.79, 1.56]). Biomarkers for modified proteins and amino acids in the liver of rodents (six studies, n = 159) increased with a pooled SMD of 0.55 (95 % CI [0.06, 1.05]). Blood: The effect of RF-EMF on biomarkers for oxidized DNA bases in rodent blood (four studies, n = 104) was inconsistent, with SMDs ranging from −1.14 (95 % CI [−2.23, −0.06]) to 1.71 (95 % CI [−0.10, 3.53]). RF-EMF had no effect on biomarkers for modified proteins and amino acids in rodent blood (three studies, n = 40), with a pooled SMD of −0.08 (95 % CI [−1.32, 1.16]). There was a large increase in biomarkers for oxidized DNA bases in rodent plasma (two studies, n = 38) with a pooled SMD of 2.25 (95 % CI [1.27, 3.24]). Gonads: There was an increase in biomarkers for oxidized DNA bases in the rodent testis (two studies, n = 24) with a pooled SMD of 1.60 (95 % CI [0.62, 2.59]). The effect of RF-EMF on biomarkers for modified proteins and amino acids in the ovary of rodents (two studies, n = 52) was inconsistent with a small effect, SMD = 0.24 (95 % CI [−0.74, 1.23])) and a large effect (SMD = 2.08 (95 % CI [1.22, 2.94])). Thymus: RF-EMF increased biomarkers for modified proteins and amino acids in the thymus of rodents (one study, n = 42) considerably with a pooled SMD of 6.16 (95 % CI [3.55, 8.76]). Cells: RF-EMF increased oxidized DNA bases in rodent cells with SMD of 2.49 (95 % CI [1.30, 3.67]) (one study, n = 27). There was a small effect in oxidized lipids (one study, n = 18) but not statistically significant with an SMD of 0.34 (95 % CI [−0.62, 1.29]). In vitro studies In in vitro studies in human cells (three studies, n = 112), there were inconsistent increases in biomarkers for oxidized DNA bases, where the SMDs varied between 0.01 (95 % CI [−0.59, 0.62]) and 7.74 (95 % CI [2.24, 13.24]) in 4 results (2 of them statistically significant). In rodent cells (three studies, n = 24), there was a not statistically significant large effect in biomarkers for oxidized DNA bases with SMD = 2.07 (95 % CI [−1.38, 5.52]). The RF-EMF biomarkers for modified proteins and amino acids in human cells (one study, n = 18) showed a large effect with SMD = 1.07 (95 % CI [−0.05, 2.19]). In rodent cells (two studies, n = 24) a medium effect of SMD = 0.56 (95 % CI [−0.29, 1.41]) was observed. Discussion The evidence on the relation between the exposure to RF-EMF and biomarkers of oxidative stress was of very low certainty, because a majority of the included studies were rated with a high RoB level and provided high heterogeneity. This is due to inaccurate measurements of exposure and/or of measurement of oxidative stress biomarkers and missing information on the blinding of the research personnel. There may be no or an inconsistent effect of RF-EMF on biomarkers of oxidative stress in the brain, liver, blood, plasma and serum, and in the female reproductive system in animal experiments but the evidence is of very low certainty. There may be an increase in biomarkers of oxidative stress in testes, serum and thymus of rodents but the evidence is of very low certainty. Future studies should improve experimental designs and characterization of exposure systems as well as the use of validated biomarker measurements with positive controls. Other: This review was partially funded by the World Health Organization. The protocol for this review is registered in PROSPERO (crd.york.ac.uk) and published in Environment International (doi.org) (Henschenmacher et al., 2022). 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. Open access paper: sciencedirect.com

AI evidence extraction

Main findings

This systematic review of experimental studies (56 total; 45 in vivo and 11 in vitro) on RF-EMF exposure (reported frequency range 800–2450 MHz within an intended scope of 100 kHz–300 GHz) found overall inconsistent results across oxidative stress biomarkers and tissues. Risk of bias was rated high in many studies and heterogeneity was high; the review judged the overall certainty of evidence as very low. The authors state there may be no or inconsistent effects in several tissues (e.g., brain, liver, blood, female reproductive system) and there may be increases in some outcomes/tissues (e.g., testes, serum, thymus), but all with very low-certainty evidence.

Outcomes measured

• Biomarkers of oxidative stress (modified proteins and amino acids)
• Oxidized DNA bases
• Oxidized lipids
• Hydrogen peroxide production

Limitations

• Overall certainty rated very low by the review (GRADE)
• High risk of bias in included studies, mainly in exposure and outcome assessment
• High heterogeneity across studies
• Missing information on blinding of research personnel
• Inaccurate measurements of exposure and/or oxidative stress biomarkers reported as contributors to uncertainty

{
    "publication_year": null,
    "study_type": "systematic_review",
    "exposure": {
        "band": "RF",
        "source": null,
        "frequency_mhz": null,
        "sar_wkg": null,
        "duration": null
    },
    "population": "Animal experiments (primarily rodents; some rabbits) and in vitro cell samples (including human cells).",
    "sample_size": null,
    "outcomes": [
        "Biomarkers of oxidative stress (modified proteins and amino acids)",
        "Oxidized DNA bases",
        "Oxidized lipids",
        "Hydrogen peroxide production"
    ],
    "main_findings": "This systematic review of experimental studies (56 total; 45 in vivo and 11 in vitro) on RF-EMF exposure (reported frequency range 800–2450 MHz within an intended scope of 100 kHz–300 GHz) found overall inconsistent results across oxidative stress biomarkers and tissues. Risk of bias was rated high in many studies and heterogeneity was high; the review judged the overall certainty of evidence as very low. The authors state there may be no or inconsistent effects in several tissues (e.g., brain, liver, blood, female reproductive system) and there may be increases in some outcomes/tissues (e.g., testes, serum, thymus), but all with very low-certainty evidence.",
    "effect_direction": "mixed",
    "limitations": [
        "Overall certainty rated very low by the review (GRADE)",
        "High risk of bias in included studies, mainly in exposure and outcome assessment",
        "High heterogeneity across studies",
        "Missing information on blinding of research personnel",
        "Inaccurate measurements of exposure and/or oxidative stress biomarkers reported as contributors to uncertainty"
    ],
    "evidence_strength": "high",
    "confidence": 0.7800000000000000266453525910037569701671600341796875,
    "peer_reviewed_likely": "yes",
    "stance": "neutral",
    "stance_confidence": 0.61999999999999999555910790149937383830547332763671875,
    "summary": "This WHO-linked systematic review evaluated experimental evidence on whether RF-EMF exposure is associated with biomarkers of oxidative stress. Across 56 included studies (mostly animal in vivo, plus in vitro studies including human cells), results were inconsistent across biomarkers and tissues, and many studies were judged to have high risk of bias and substantial heterogeneity. The authors conclude the overall certainty of evidence is very low and call for major improvements in exposure characterization and biomarker measurement.",
    "key_points": [
        "The review aimed to assess RF-EMF exposure (100 kHz–300 GHz scope) and oxidative stress biomarkers, with included studies reported at 800–2450 MHz.",
        "Fifty-six experimental studies were included (45 in vivo and 11 in vitro), with 51 studies contributing to meta-analyses (168 individual results).",
        "Most in vivo evidence came from rodents, with a smaller number of rabbit studies; in vitro evidence included human cell samples.",
        "Across brain, liver, blood, and reproductive tissues, reported effects often varied in direction and magnitude, indicating inconsistency.",
        "The review reports possible increases in some tissues (e.g., rodent testes and thymus) but emphasizes very low certainty.",
        "Risk of bias was frequently high, mainly due to exposure and outcome assessment issues and limited reporting on blinding.",
        "The authors used OHAT risk-of-bias methods and an adapted GRADE approach and assessed publication bias using funnel plots.",
        "The review recommends substantial methodological improvements in future RF-EMF oxidative stress studies."
    ],
    "categories": [
        "RF-EMF",
        "Oxidative Stress",
        "Animal Studies",
        "In Vitro Studies",
        "Systematic Reviews"
    ],
    "tags": [
        "Radiofrequency EMF",
        "Oxidative Stress Biomarkers",
        "Systematic Review",
        "WHO Review",
        "GRADE",
        "OHAT Risk Of Bias",
        "Animal Experiments",
        "Rodent Studies",
        "Rabbit Studies",
        "In Vitro",
        "Human Cells",
        "Meta-Analysis",
        "Heterogeneity",
        "Exposure Assessment",
        "Reactive Oxygen Species"
    ],
    "keywords": [
        "RF-EMF",
        "radiofrequency electromagnetic fields",
        "oxidative stress",
        "biomarkers",
        "oxidized DNA bases",
        "modified proteins",
        "amino acids",
        "oxidized lipids",
        "hydrogen peroxide",
        "in vivo",
        "in vitro",
        "random effects meta-analysis"
    ],
    "suggested_hubs": [],
    "social": {
        "tweet": "WHO-linked systematic review (56 experimental studies) on RF-EMF (mostly 800–2450 MHz) and oxidative stress biomarkers reports inconsistent findings and overall very low-certainty evidence due to high risk of bias and heterogeneity.",
        "facebook": "A systematic review of 56 experimental studies examined whether RF-EMF exposure is linked to oxidative stress biomarkers. The authors report inconsistent results across tissues and biomarkers and rate the overall certainty of evidence as very low, citing high risk of bias and heterogeneity.",
        "linkedin": "This Environment International systematic review (WHO SR 9) assessed experimental evidence on RF-EMF exposure and biomarkers of oxidative stress. Across 56 studies, findings were inconsistent and the overall certainty of evidence was rated very low, largely due to high risk of bias and substantial heterogeneity; the authors call for major improvements in study design and exposure/biomarker measurement."
    }
}

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