NextGEM: Next-Generation Integrated Sensing and Analytical System for Monitoring and Assessing Radiofrequency Electromagnetic Field Exposure and Health.

The evolution of emerging technologies that use Radio Frequency Electromagnetic Field (RF-EMF) has increased the interest of the scientific community and society regarding the possible adverse effects on human health and the environment. This article provides NextGEM's vision to assure safety for EU citizens when employing existing and future EMF-based telecommunication technologies. This is accomplished by generating relevant knowledge that ascertains appropriate prevention and control/actuation actions regarding RF-EMF exposure in residential, public, and occupational settings. Fulfilling this vision, NextGEM commits to the need for a healthy living and working environment under safe RF-EMF exposure conditions that can be trusted by people and be in line with the regulations and laws developed by public authorities. NextGEM provides a framework for generating health-relevant scientific knowledge and data on new scenarios of exposure to RF-EMF in multiple frequency bands and developing and validating tools for evidence-based risk assessment. Finally, NextGEM's Innovation and Knowledge Hub (NIKH) will offer a standardized way for European regulatory authorities and the scientific community to store and assess project outcomes and provide access to findable, accessible, interoperable, and reusable (FAIR) data.

Special Issue: "Electric, Magnetic, and Electromagnetic Fields in Biology and Medicine: From Mechanisms to Biomedical Applications".

The last decades have seen a huge increase in applications and devices using and emitting non-ionizing radiation, otherwise referred to as "electromagnetic fields" (EMF) [...].

Emerging medical applications based on non-ionizing electromagnetic fields from 0 Hz to 10 THz.

The potential for using non-ionizing electromagnetic fields (EMF; at frequencies from 0 Hz up to the THz range) for medical purposes has been of interest since many decades. A number of established and familiar methods are in use all over the world. This review, however, provides an overview of applications that already play some clinical role or are in earlier stages of development. The covered methods include modalities used for bone healing, cancer treatment, neurological conditions, and diathermy. In addition, certain other potential clinical areas are touched upon. Most of the reviewed technologies deal with therapy, whereas just a few diagnostic approaches are mentioned. None of the discussed methods are having such a strong impact in their field of use that they would be expected to replace conventional methods. Partly this is due to a knowledge base that lacks mechanistic explanations for EMF effects at low-intensity levels, which often are used in the applications. Thus, the possible optimal use of EMF approaches is restricted. Other reasons for the limited impact include a scarcity of well-performed randomized clinical trials that convincingly show the efficacy of the methods and that standardized user protocols are mostly lacking. Presently, it seems that some EMF-based methods can have a niche role in treatment and diagnostics of certain conditions, mostly as a complement to or in combination with other, more established, methods. Further development and a stronger impact of these technologies need a better understanding of the interaction mechanisms between EMF and biological systems at lower intensity levels. The importance of the different physical parameters of the EMF exposure needs also further investigations.

5G Wireless Communication and Health Effects-A Pragmatic Review Based on Available Studies Regarding 6 to 100 GHz.

The introduction of the fifth generation (5G) of wireless communication will increase the number of high-frequency-powered base stations and other devices. The question is if such higher frequencies (in this review, 6-100 GHz, millimeter waves, MMW) can have a health impact. This review analyzed 94 relevant publications performing in vivo or in vitro investigations. Each study was characterized for: study type (in vivo, in vitro), biological material (species, cell type, etc.), biological endpoint, exposure (frequency, exposure duration, power density), results, and certain quality criteria. Eighty percent of the in vivo studies showed responses to exposure, while 58% of the in vitro studies demonstrated effects. The responses affected all biological endpoints studied. There was no consistent relationship between power density, exposure duration, or frequency, and exposure effects. The available studies do not provide adequate and sufficient information for a meaningful safety assessment, or for the question about non-thermal effects. There is a need for research regarding local heat developments on small surfaces, e.g., skin or the eye, and on any environmental impact. Our quality analysis shows that for future studies to be useful for safety assessment, design and implementation need to be significantly improved.

Activation of the intracellular temperature and ROS sensor membrane protein STIM1 as a mechanism underpinning biological effects of low-level low frequency magnetic fields.

The biological effects of low frequency magnetic fields (LF MF) at high flux densities are well known and the underlying mechanism is established. In contrast, health associated effects at lower flux densities, which can be found in the human environment, are controversial, and no accepted interaction mechanism has been presented. Here we present a hypothesis regarding the biological aspect of interaction between LF MF and cells. We suggest that the endoplasmic reticulum (ER) membrane protein STIM1, which functions as a sensor for several cellular conditions (low Ca2+ levels, temperature increase, increased levels of oxygen radicals, hypoxia), is a candidate LF MF sensor. Such a sensor function can be either direct (via local temperature increase caused by intracellularly induced electric fields), or indirect due to responses to increased reactive oxygen species (ROS) levels. Activated STIM1 leads to downstream effects by activation of signal transduction processes and changes in gene expression leading to secondary events. The nature of these changes would be dependent on both cell type and the particular physiological state the cell displays at the time of STIM1 activation. Results from testing of this hypothesis, as suggested in this paper, would greatly assist in understanding of the possible health-related effects of low-level LF MF. This would benefit both safety assessments regarding MF exposure as well as possible use of MF in medicine. A better understanding of the biological mechanisms underpinning MF exposure effects of living matter allows the targeted use of the fields in medical applications. There are several examples already in use based on empiric and not on mechanistic knowledge. Knowledge generated from our hypothesis testing makes it possible for MF based medical applications to be optimized.

Immune-Modulating Perspectives for Low Frequency Electromagnetic Fields in Innate Immunity.

In recent years, the effects of electromagnetic fields (EMFs) on the immune system have received a considerable interest, not only to investigate possible negative health impact but also to explore the possibility to favorably modulate immune responses. To generate beneficial responses, the immune system should eradicate pathogens while "respecting" the organism and tolerating irrelevant antigens. According to the current view, damage-associated molecules released by infected or injured cells, or secreted by innate immune cells generate danger signals activating an immune response. These signals are also relevant to the subsequent activation of homeostatic mechanisms that control the immune response in pro- or anti-inflammatory reactions, a feature that allows modulation by therapeutic treatments. In the present review, we describe and discuss the effects of extremely low frequency (ELF)-EMF and pulsed EMF on cell signals and factors relevant to the activation of danger signals and innate immunity cells. By discussing the EMF modulating effects on cell functions, we envisage the use of EMF as a therapeutic agent to regulate immune responses associated with wound healing.

Cellular Response to ELF-MF and Heat: Evidence for a Common Involvement of Heat Shock Proteins?

It has been shown that magnetic fields in the extremely low frequency range (ELF-MF) can act as a stressor in various in vivo or in vitro systems, at flux density levels below those inducing excitation of nerve and muscle cells, which are setting the limits used by most generally accepted exposure guidelines, such as the ones published by the International Commission on Non-Ionizing Radiation Protection. In response to a variety of physiological and environmental factors, including heat, cells activate an ancient signaling pathway leading to the transient expression of heat shock proteins (HSPs), which exhibit sophisticated protection mechanisms. A number of studies suggest that also ELF-MF exposure can activate the cellular stress response and cause increased HSPs expression, both on the mRNA and the protein levels. In this review, we provide some of the presently available data on cellular responses, especially regarding HSP expression, due to single and combined exposure to ELF-MF and heat, with the aim to compare the induced effects and to detect possible common modes of action. Some evidence suggest that MF and heat can act as costressors inducing a kind of thermotolerance in cell cultures and in organisms. The MF exposure might produce a potentiated or synergistic biological response such as an increase in HSPs expression, in combination with a well-defined stress, and in turn exert beneficial effects during certain circumstances.

The changing face of nanomaterials: Risk assessment challenges along the value chain.

Risk assessment (RA) of manufactured nanomaterials (MNM) is essential for regulatory purposes and risk management activities. Similar to RA of "classical" chemicals, MNM RA requires knowledge about exposure as well as of hazard potential and dose response relationships. What makes MNM RA especially challenging is the multitude of materials (which is expected to increase substantially in the future), the complexity of MNM value chains and life cycles, the accompanying possible changes in material properties over time and in contact with various environmental and organismal milieus, and the difficulties to obtain proper exposure data and to consider the proper dose metric. This article discusses these challenges and also critically overviews the current state of the art regarding MNM RA approaches.

Quality Matters: Systematic Analysis of Endpoints Related to "Cellular Life" in Vitro Data of Radiofrequency Electromagnetic Field Exposure.

Possible hazardous effects of radiofrequency electromagnetic fields (RF-EMF) at low exposure levels are controversially discussed due to inconsistent study findings. Therefore, the main focus of the present study is to detect if any statistical association exists between RF-EMF and cellular responses, considering cell proliferation and apoptosis endpoints separately and with both combined as a group of "cellular life" to increase the statistical power of the analysis. We searched for publications regarding RF-EMF in vitro studies in the PubMed database for the period 1995-2014 and extracted the data to the relevant parameters, such as cell culture type, frequency, exposure duration, SAR, and five exposure-related quality criteria. These parameters were used for an association study with the experimental outcome in terms of the defined endpoints. We identified 104 published articles, from which 483 different experiments were extracted and analyzed. Cellular responses after exposure to RF-EMF were significantly associated to cell lines rather than to primary cells. No other experimental parameter was significantly associated with cellular responses. A highly significant negative association with exposure condition-quality and cellular responses was detected, showing that the more the quality criteria requirements were satisfied, the smaller the number of detected cellular responses. According to our knowledge, this is the first systematic analysis of specific RF-EMF bio-effects in association to exposure quality, highlighting the need for more stringent quality procedures for the exposure conditions.

Pooling and Analysis of Published in Vitro Data: A Proof of Concept Study for the Grouping of Nanoparticles.

The study aim was to test the applicability of pooling of nanomaterials-induced in vitro data for identifying the toxic capacity of specific (SiO2, TiO2, ZnO, CuO, CeO2 and carbon nanotubes, [CNT]) nanoparticles (NP) and to test the usefulness for grouping purposes. Publication selection was based on specific criteria regarding experimental conditions. Two relevant biological endpoints were selected; generation of intracellular reactive oxygen species (ROS) and viability above 90%. The correlations of the ROS ratios with the NP parameters' size, concentration, and exposure time were analysed. The obtained data sets were then analysed with multiple regression analysis of variance (ANOVA) and the Tukey post-hoc test. The results show that this method is applicable for the selected metal oxide NP, but might need reconsideration and a larger data set for CNT. Several statistically significant correlations and results were obtained, thus validating the method. Furthermore, the relevance of the combination of ROS release with a cell viability test was shown. The data also show that it is advisable to compare ROS production of professional phagocytic with non-phagocytic cells. In conclusion, this is the first systematic analysis showing that pooling of available data into groups is a useful method for evaluation of data regarding NP induced toxicity in vitro.

Grouping of Experimental Conditions as an Approach to Evaluate Effects of Extremely Low-Frequency Magnetic Fields on Oxidative Response in in vitro Studies.

A large body of literature deals with biological effects of extremely low-frequency magnetic fields (ELF MFs) studied in vitro. Despite the multitude of studies, no coherent picture has evolved regarding the plausibility of effects at low-flux densities or regarding the interaction mechanisms. Here, we propose that ELF MF exposure in vitro causes changes in oxidative status as an early response. We tested this hypothesis by scrutinizing the literature and applying a grouping approach for analyzing relevant biological properties and exposure conditions. A total of 41 scientific original publications were analyzed for this purpose. The conclusion from the work is that ELF MF (modulated or unmodulated) consistently can influence the oxidative status, at or above 1 mT, in a broad range of cell types and independent of exposure duration. A response at lower flux densities is seen in certain studies, although not consistently. Further studies with stringent protocols for sham exposure, blinding, and statistical analysis as well as appropriate positive controls are needed to establish if true dose-relationships for effects on oxidative status exist.

Metrics, dose, and dose concept: the need for a proper dose concept in the risk assessment of nanoparticles.

In order to calculate the dose for nanoparticles (NP), (i) relevant information about the dose metrics and (ii) a proper dose concept are crucial. Since the appropriate metrics for NP toxicity are yet to be elaborated, a general dose calculation model for nanomaterials is not available. Here we propose how to develop a dose assessment model for NP in analogy to the radiation protection dose calculation, introducing the so-called "deposited and the equivalent dose". As a dose metric we propose the total deposited NP surface area (SA), which has been shown frequently to determine toxicological responses e.g. of lung tissue. The deposited NP dose is proportional to the total surface area of deposited NP per tissue mass, and takes into account primary and agglomerated NP. By using several weighting factors the equivalent dose additionally takes into account various physico-chemical properties of the NP which are influencing the biological responses. These weighting factors consider the specific surface area, the surface textures, the zeta-potential as a measure for surface charge, the particle morphology such as the shape and the length-to-diameter ratio (aspect ratio), the band gap energy levels of metal and metal oxide NP, and the particle dissolution rate. Furthermore, we discuss how these weighting factors influence the equivalent dose of the deposited NP.

Is there a relation between extremely low frequency magnetic field exposure, inflammation and neurodegenerative diseases? A review of in vivo and in vitro experimental evidence.

Possible health consequences of exposure to extremely low frequency magnetic fields (ELF-MF) have received considerable interest during the last decades. One area of concern is neurodegenerative diseases (NDD), where epidemiological evidence suggests a correlation between MF exposure and Alzheimer's disease (AD). This review is focussing on animal and in vitro studies employing ELF-MF exposures to see if there is mechanistic support for any causal connection between NDD and MF-exposure. The hypothesis is that ELF-MF exposure can promote inflammation processes and thus influence the progression of NDD. A firm conclusion regarding this hypothesis is difficult to draw based on available studies, since there is a lack of experimental studies that have addressed the question of ELF-MF exposure and NDD. Furthermore, the heterogeneity of the performed studies regarding, e.g., the exposure duration, the flux density, the biological endpoint and the cell type and the time point of investigation is substantial and makes conclusions difficult to draw. Nevertheless, the investigated evidence from in vivo and in vitro studies suggest that short-term MF-exposure causes mild oxidative stress (modest ROS increases and changes in antioxidant levels) and possibly activates anti-inflammatory processes (decrease in pro-inflammatory and increase in anti-inflammatory cytokines). The few studies that specifically have investigated NDDs or NDD relevant end-points show that effects of exposure are either lacking or indicating positive effects on neuronal viability and differentiation. In both immune and NDD relevant studies, experiments with realistic long-term exposures are lacking. Importantly, consequences of a possible long-lasting mild oxidative stress are thus not investigated. In summary, the existing experimental studies are not adequate in answering if there is a causal relationship between MF-exposure and AD, as suggested in epidemiological studies.

Risks from accidental exposures to engineered nanoparticles and neurological health effects: a critical review.

There are certain concerns regarding the safety for the environment and human health from the use of engineered nanoparticles (ENPs) which leads to unintended exposures, as opposed to the use of ENPs for medical purposes. This review focuses on the unintended human exposure of ENPs. In particular, possible effects in the brain are discussed and an attempt to assess risks is performed.Animal experiments have shown that investigated ENPs (metallic nanoparticles, quantum dots, carbon nanotubes) can translocate to the brain from different entry points (skin, blood, respiratory pathways). After inhalation or instillation into parts of the respiratory tract a very small fraction of the inhaled or instilled ENPs reaches the blood and subsequently secondary organs, including the CNS, at a low translocation rate. Experimental in vivo and in vitro studies have shown that several types of ENPs can have various biological effects in the nervous system. Some of these effects could also imply that ENPs can cause hazards, both acutely and in the long term. The relevance of these data for risk assessment is far from clear. There are at present very few data on exposure of the general public to either acute high dose exposure or on chronic exposure to low levels of air-borne ENPs. It is furthermore unlikely that acute high dose exposures would occur. The risk from such exposures for damaging CNS effects is thus probably very low, irrespective of any biological hazard associated with ENPs.The situation is more complicated regarding chronic exposures, at low doses. The long term accumulation of ENPs can not be excluded. However, we do not have exposure data for the general public regarding ENPs. Although translocation to the brain via respiratory organs and the circulation appears to be very low, there remains a possibility that chronic exposures, and/or biopersistent ENPs, can influence processes within the brain that are triggering or aggravating pathological processes.In general, the present state of knowledge is unsatisfactory for a proper risk assessment in this area. Crucial deficits include lack of exposure data, the absence of a proper dose concept, and that studies often fail in adequate description of the investigated ENPs.

Effects of 50-Hz magnetic field exposure on superoxide radical anion formation and HSP70 induction in human K562 cells.

Epidemiological studies suggest a correlation between exposure to low-level extremely low-frequency (ELF) magnetic fields (MF) and certain cancers and neurodegenerative diseases. Experimental studies have not provided any mechanism for such effects, although at flux density levels significantly higher than the ones encountered in epidemiological studies, radical homoeostasis and levels of stress response proteins can be affected. Here, we report on the influence of MF exposure (50-Hz sine wave; 1 h; 0.025-0.10 mT; vertical or horizontal MF exposure direction) on different cellular parameters (proliferation, cell cycle distribution, superoxide radical anion, and HSP70 protein levels) in the human leukaemia cell line K562. The positive control heat treatment (42°C, 1 h) did not affect either cell proliferation or superoxide radical anion production but caused accumulation of cells in the G2 phase and increased the stress protein HSP70. MF exposure (0.10 mT, 1 h) did not affect either cell cycle kinetics or proliferation. Both vertical and horizontal MF exposures for 1 h caused significantly and transiently increased HSP70 levels (>twofold), at several flux densities, compared to sham controls and also compared to heat treatment. This exposure also increased (30-40%) the levels of the superoxide radical anion, comparable to the positive control PMA. Addition of free radical scavengers (melatonin or 1,10-phenantroline) inhibited the MF-induced increase in HSP70. In conclusion, an early response to ELF MF in K562 cells seems to be an increased amount of oxygen radicals, leading to HSP70 induction. Furthermore, the results suggest that there is a flux density threshold where 50-Hz MF exerts its effects on K562 cells, at or below 0.025 mT, and also that it is the MF, and not the induced electric field, which is the active parameter.

Exposure to ELF magnetic fields modulate redox related protein expression in mouse macrophages.

The interaction of extremely low frequency (ELF) magnetic fields (MF) with cells can induce alterations in various cell physiological processes. Here, we present evidence that exposure of mouse macrophages to 50 Hz, 1.0 mT MF lead to immune cell activation seen as increased production of reactive oxygen species (ROS), and also to modulation on the expression level of important proteins acting in redox regulatory processes and thus explaining the noted changes in ROS levels seen after exposure. The MF exposure caused slight and transient decreases after short term exposures (2h or less) of clathrin, adaptin, PI3-kinase, protein kinase B (PKB) and PP2A, whereas longer exposures had no effect. The levels of the NAD(P)H oxidase subunit gp91phox oscillated between increased and normal levels compared to controls. The stress proteins Hsp70 and Hsp110 exhibited increased levels at certain time points, but not generally. The effects of MF on protein levels are different from the effects exerted by 12-O-tetradecanolyphobol-13-acetate (TPA) or LPS, although all three factors cause increases in ROS release. This suggests that ELF MF interacts with other cellular constituents than these chemicals, although induced pathways at least partially converge.

Background ELF magnetic fields in incubators: a factor of importance in cell culture work.

Extremely low frequency (ELF) magnetic fields in cell culture incubators have been measured. Values of the order of tens of muT were found which is in sharp contrast to the values found in our normal environment (0.05-0.1microT). There are numerous examples of biological effects found after exposure to MF at these levels, such as changes in gene expression, blocked cell differentiation, inhibition of the effect of tamoxifen, effects on chick embryo development, etc. We therefore recommend that people working with cell culture incubators check for the background magnetic field and take this into account in performing their experiments, since this could be an unrecognised factor of importance contributing to the variability in the results from work with cell cultures.