The promise of 5G is that the normal evolutionary cycle we have seen from 2G via 3G to 4G will be broken.
The introduction of 5G is expected to be a revolution by comparison, since it will not be simply an increase in the speed of a cellular connection.
At the highest level, 5G aims to provide users with a ‘mix and match’ of technologies, bands and bandwidths, licence types and any other available options which could give the user the experience required at the time.
But these efforts will never be seen by the user, who will simply experience an appropriate connection, regardless of whether his or her location or demands change within a service area.
Although there is no standard definition of 5G yet, several key aims began to be qualified and quantified during 2014, on a worldwide basis.
For example, from Korea, Figure a1 shows 5G aims with quantification at a high level.
By way of another example, from the Americas, Intel is supporting a significant amount of 5G research in US universities, such as New York and Texas via its Strategic Research Alliance, and is a partner in the European Union MiWEBA research project which has similar expectations of 5G.
Significant features of future 5G include speed and latency evolutions as might be expected. But also revolutions towards
- maintenance of high performance levels even with a high density of active users;
- the idea that the user is ‘followed’ by the desired service level in order to maintain the user experience;
- a decrease in energy per bit transmitted, if the solution is to achieve the scale required;
- a need for very much higher speeds, which implies working at higher frequencies, such as millimetre wave.
Past and current EU projects have been a useful focus for the convergence of the aims of 5G, and today progress is beginning to be made towards a more specific architecture for 5G, see for example Figure a2.
We do not need to examine every detail of Figure a2, but there are a number of technology enablers which are worthy of further attention with respect to higher frequencies for 5G.
Firstly, different carrier frequencies are envisaged for different types of 5G communication scenarios. Specifically, high frequencies (‘High CF’ in the diagram) are envisaged to provide high capacity, in conjunction with antenna arrays, for both users and backhaul.
In addition, ‘Super high carrier frequencies’ are expected for local capacity provision, such as millimetre wave. Figure a3 from Ericsson shows a simple representation of the frequency ranges likely to be needed to satisfy the whole 5G concept.
Secondly, the control and user (C/U) planes are separated for users with the highest data rates. There are a number of reasons for this. For example, with such a split, users have the most efficient data connection to the backhaul, since control packets are no longer interspersed.
Equally important is that the umbrella macro cell can control the connection of user equipment, via a constantly present network discovery and management function. This reduces the demands on the mmW link considerably.
Thirdly, it is clear that a large number of diverse technology enablers are needed. For example, there needs to be provision for machine type networks (MTC), which need to be highly energy efficient and employ sleep cycles. Device to device (D2D) communication must be provided for, which is a further driver for a C/U plane split.
Higher up the architecture, Network Function Virtualisation (NFV) is required so that the network may be flexibly reconfigured and reduced in scope in order to save energy at times of low demand, via Software Defined Networking (SDN).
Finally, 5G is not a replacement network. Rather 2G, 3G and 4G will continue and will in fact be essential to remain in place as the 5G architecture encompasses these existing systems.
Our motivation for this study arises from the need for higher speeds, the wider bandwidths which this implies and hence likely operation at frequencies above 6 GHz.
Telecommunications companies worldwide, with the support of governments, are poised within the next two years to roll out the fifth-generation wireless network (5G).
This is set to deliver what is acknowledged to be unprecedented societal change on a global scale. We will have “smart” homes, “smart” businesses, “smart” highways, “smart” cities and self-driving cars.
Virtually everything we own and buy, from refrigerators and washing machines to milk cartons, hairbrushes and infants’ diapers, will contain antennas and microchips and will be connected wirelessly to the Internet.
Every person on Earth will have instant access to super-high-speed, low- latency wireless communications from any point on the planet, even in rainforests, mid-ocean and the Antarctic.
What is not widely acknowledged is that this will also result in unprecedented environmental change on a global scale. The planned density of radio frequency transmitters is impossible to envisage.
In addition to millions of new 5G base stations on Earth and 20,000 new satellites in space, 200 billion transmitting objects, according to estimates, will be part of the Internet of Things by 2020, and one trillion objects a few years later.
Importantly, 5G is not a new technology, but an evolution of already existing G1 to G4 technologies.
With the upcoming deployment of 5G mobile networks, significantly faster mobile broadband speeds and increasingly extensive mobile data usage will be ensured. This is made possible by the use of additional higher frequency bands. 5G is intended to be the intersection of communications, from virtual reality to autonomous vehicles to the industrial Internet and smart cities.
In addition, 5G is considered the base technology for the Internet of Things (IoT), where machines communicate with machines (M2M communication). At the same time, a change in the exposure to electromagnetic fields (EMF) of humans and the environment is expected (see, for example [1,2]).
The 5G networks will work with within several different frequency bands (Table 1), of which the lower frequencies are being proposed for the first phase of the 5G networks.
Several of these frequencies (principally below 1 GHz; Ultra-high frequencies, UHF) have actually been or are presently used for earlier mobile communication generations. Furthermore, much higher radio frequencies (RF) are also planned to be used at later stages of technology evolutions.
The new bands are well above the UHF ranges, having wavelengths in the centimeter (3–30 GHz) or the millimeter ranges (30–300 GHz; millimeter waves, MMW).
These latter bands have traditionally been used for radars and microwave links.
The introduction of wireless communication devices that operate in the high frequency parts of the electromagnetic spectrum has attracted considerable amounts of studies that focus on health concerns.
These studies encompass studies on humans (epidemiology as well as experimental studies), on animals, and on in vitro systems. Summaries and conclusions from such studies are regularly published by both national and international committees containing relevant experts (see e.g., [3–5].
The conclusions from these agencies and committees are that low level RF exposure does not cause symptoms (“Idiopathic Environmental Intolerance attributed to Electromagnetic Fields”, IEI-EMF), but that a “nocebo” effect (expectation of a negative outcome) can be at hand.
Some studies suggest that RF exposure can cause cancer, and thus the International Agency for Research on Cancer classified RF EMF as a “possibly carcinogenic to humans” (Group 2B) .
In a recent recommendation of a periodically working Advisory Group for IARC “to ensure that the Monographs evaluations reflect the current state of scientific evidence relevant to carcinogenicity” the group recommended radiofrequency exposure (among others) for re-evaluation “with high priority” .
There is further no scientific support for that effects on other health parameters occur at exposure levels that are below exposure guideline levels, even though some research groups have published non-carcinogen related findings after RF exposure at such levels (see [4,5]).
Environmental aspects of this technological development are much less investigated.
Frequencies in the MMW range are used in applications such as radar, and for some medical uses.
Occupational exposure to radars have been investigated in some epidemiological studies, and the overall conclusion is that this exposure does not constitute a health hazard for the exposed personnel .
This is due to that exposures for all practical purposes are below the guideline levels and thus not causing tissue heating. However, further studies are considered necessary concerning the possible cancer risk in exposed workers.
Medical use of MMW has been recently reviewed [8,9] suggesting a possibility for certain therapeutic applications, although the action mechanisms are unclear.
The 5G networks and the associated IoT will greatly increase the number of wireless devices compared to the present situation, necessitating a high density of infrastructure. Thus, a much higher mobile data volume per geographic area is to be created.
Consequently, it is necessary to build a higher network density because the higher frequencies have shorter ranges. The question that arises, is whether using the higher frequencies can cause health effects?
Exposure limits for both the general public and occupational exposure are available and recommended by the WHO in most countries, based on recommendations from ICNIRP  or IEEE  guidelines.
These limits, which have considerable safety factors included, are set so that exposure will not cause thermal damage to the biological material (thermal effects).
Thus, for 10 GHz to 300 GHz, 10 W/m2 is recommended as the basic restriction (no thermal effects), with reference values for 400 MHz to 2 GHz (2–10 W/m2) and >2 GHz (10 W/m2).
It should be pointed out that the present ICNIRP guidelines  are currently being revised, and new versions are to be expected in the near future.
In addition, ICNIRP proposes two categories of recommendations:
(1) the basic restriction values based on proven biological effects from the exposure and
(2) the reference levels given for the purpose of comparison with physical value measurements.
ICNIRP guidelines present no reference values above 10 GHz, only considering the basic restriction values.
This is due to that only surface heating occurs since the penetration depth is so small at these frequencies. Therefore any calculations of the Specific Absorption Rate (SAR) values, that take larger volumes into consideration, are not reasonable to perform.
The SAR is the measure of the absorption of electromagnetic fields in a material and is expressed as power per mass/volume (W/kg), where the penetration depth of the electromagnetic fields depends on the wavelength of the radiation and the type of matter.
The penetration depth of MMW is very shallow, hence the exposed surface area and not the volume is considered. The appropriate exposure metric for MMW is therefore the power density, power per area (W/m2).
It is of course too early to forecast the actual exposures to 5G networks. However, the antennas planned for 5G will have narrow antenna beams with direct alignment  to the receiving device.
This could possibly significantly reduce environmental exposure compared to the present exposure situation.
However, it is also argued that the addition of a very high number of 5G network components will increase the total EMF exposure in the environment, and that higher exposures to the higher frequencies can lead to adverse health effects.
Therefore, the question arises, what do we know so far about the effects on biological structures and on health due to exposure to the higher frequency bands (in this review we consider 6–100 GHz, since lower frequencies have been extensively investigated due to their use in already existing wireless communication networks)?
Do so-called “non-thermal” effects (effects that occur below the thermal e↵ect threshold) occur, that can lead to health effects?
Is there relevant health-oriented research using the 5G technology relevant frequencies?
Is there relevant research that can make a significant contribution to improving the risk assessment of exposure to the general population?
Answers to these questions are necessary for a rapid and safe implementation of a technology with great potential.
Overview of 5G Requirements
Many sources describe and analyse the services and related requirements that define a 5G network, including most notably ITU-R [Recommendation ITU-R M.2083-0].
We can distinguish among requirements most directly affecting:
- Transport capacity: throughput
- Network planning: traffic per area, that translates into site density (and MW/mmW link density)
- Networking: Latency, slicing, agility (SDN etc.)
- Areas not directly impacting MW/mmW transport: number of connected devices, mobility etc.
5G Mobile Transport Capacity Requirements
In order to determine the transport requirements across the network, we start from the capacity requirements of typical macro sites, and later combine this information with the network topology to get the transport requirements of the MW/mmW links in different segments of the network (tail links, aggregation links).
Four representative types of mobile base station site can be identified, as described in Table 1:
|Site Type||Mobile spectrum and type||Cell type||Backhaul Capacity|
|Dense Urban||LTE up to 50 MHz5G 200 MHz 16L MIMO ~4GHz5G ≥ 400 MHz 16L MIMO ~30GHz||Macro-cell: ~4GHz and ~30GHz Small-cell: ~4GHz or ~30GHz||>10 Gbps|
|Urban||LTE up to 50 MHz5G 100 MHz 8L MIMO ~4GHz5G 200 MHz 8L MIMO ~30GHz||Macro-cell: ~4GHz Small-cell: ~4GHz or ~30GHz||<10 Gbps|
|Sub Urban||LTE up to 50 MHz5G 100 MHz 8L MIMO ~4GHz||Macro-cell||<4 Gbps|
|Rural||LTE up to 50 MHz5G 50 MHz 4L MIMO ~2GHz5G 20 MHz 4L MIMO ~700MHz||Macro-cell||<2 Gbps|
Table 1 – Types of mobile site
Moreover the evolution of mmW technologies and the availability of new spectrum will allow supporting front-haul applications, with capacities ranging from 10 Gbps to 100 Gbps.
Microwave and mmW Transport Characteristics
The engineering of a MW or mmW link involves finding the optimal combination of link length, capacity, frequency band and availability.
MW and mmW Spectrum Overview
In the course of several decades increased transport capacity requirements and greater and greater site
density have promoted the use of ever higher frequency bands (see Figure 2).
The physics of radio waves propagation determine the relation among capacity, availability and link length.
Since the available spectrum is proportional to the centre frequency, the highest frequencies are also those that carry the most capacity, but also cover the comparatively shortest link lengths.
As a rule of thumb, frequencies below 13 GHz can be considered mostly unaffected by the intensity of rainfall and frequencies above are more and more influenced by the attenuation caused by rain, so that as a general principle higher frequencies are used for shorter links, as described in Figure 3.
BCA (multi-band aggregation), the combination of different frequency bands on the same radio link, allows combining the best of both worlds in terms of capacity, availability and link length, as depicted in Figure 4.
MW and mmW Transport Network Topology
The penetration of fibre to the edge of the network and the densification of sites have two main effects:
- Shortening of chains of cascaded radio links, approaching the limit of one radio link to the fibre
- Increase of the number of links originating from a hub site in a star-like topology
The tree topology of typical MW/mmW networks means we have to distinguish between tail links, connecting just one terminal mobile site, and aggregation links, which carry the traffic of different terminal sites.
A meshed topology can be used as well; in this case radio links are the fastest and most efficient way to assure the secondary connection, covering the requirements related to network slicing, per path and per service, and performing link protection with media differentiation over the shortest/fastest path between adjacent sites.
In general, these considerations lead us to define different network segments:
- Dense Urban and Urban scenarios: where previously the network was based on a hub-and-spoke kind of topology, there is a strong increase in fibre Points of Presence (PoP), from which a star topology of high capacity tail links originate; the fan-out of such hubs tends to be high. The depth of the MW/mmW network tends to become 1…1.5 hops from the fibre PoP.
- Sub-urban scenarios: the trend is the same, but here the MW/mmW network depth is going towards an average of 1.5…2 hops from the fibre PoP.
- Rural scenarios: here the variance will be greater due to the widely different geographical conditions, but it is expected that the average network depth should tend towards 2.5 hops from the fibre PoP.
- Mixed scenarios: in some places, it may happen that a small cluster of urban or suburban sites are situated at a certain distance from the fibre PoP, so that the MW/mmW link length for the aggregation link towards the PoP is not directly related to the cell radius.
MW and mmW Spectrum Availability
The availability of MW/mmW spectrum depends on both technological and regulatory factors.
Technology is available and under development to make full use of existing (6-86 GHz) and future (90-300 GHz) spectrum: E-band (80 GHz) has been commercially deployed for several years, W-band (100 GHz) and D-band (150 GHz) are the most promising upcoming bands, with trials already deployed for more than one year.
Wider channels (112MHz, even 224MHz where possible) in traditional frequency bands and raw availability of spectrum (10GHz in E-band, 18GHz in W-band and 30GHz in D-band) provide the main resources to expand the capacity of MW and mmW radio systems.
Apart from technological factors, the spectrum regulation and licensing, which is different country-by- country, is the key aspect:
- MW/mmW bands are not everywhere available to operators, including those that are considered “traditional” in most of the world (especially above 23 GHz)
- Lower frequency bands have been regulated many decades ago, based on transmission capacity and availability targets born in the TDM era, before features like adaptive modulation were even available. This complicates in some cases the regulation, planning and pricing of the MW/mmW backhaul network
- Techniques like XPIC (Cross Polar Interference Cancellation) and Line of Sight MIMO that address link spectrum efficiency should be made more attractive from license point of view
- Higher directivity antennas and new techniques for active interference cancellation should be encouraged with licensing schemes that incentivize geographical spectrum efficiency by a higher degree of channel reusability
MW/mmW technology is able to fulfil the challenge of 5G capacity and distance in all scenarios, as synthetically depicted in Figure 6.
Even if fibre penetration is increased, a very significant share of mobile and fixed access sites will still require a MW/mmW connection to the fibre infrastructure.
The MW/mmW industry is developing the solution along several dimensions:
- Expanding to new bands: the E, W, D-bands offer in total about 50GHz of new unused spectrum
- Increasing spectrum efficiency: MIMO, higher modulations, interference cancelling
- Working in close cooperation with standard bodies and all stakeholders to promote new, efficient and effective spectrum regulation and licensing
- Ultra-low, deterministic and guaranteed transmission delay
- New packet forwarding technologies
- Ultra-high precision time/phase packet-based synchronization
Operational agility and efficiency:
- Development and deployment of SDN across the whole network
- Support for current and future packet transmission protocols
Thermal biological effects of radiofrequency electromagnetic
In the following, health-related published scientific papers dealing with frequencies from 6 GHz to 100 GHz (using the term MMW for all the frequencies) are described in detail. It should be noted that there are no epidemiological studies dealing with wireless communication for this frequency range, thus, this review will cover studies performed in vivo and in vitro.
Thermal biological effects of radiofrequency electromagnetic fields occur when the SAR values exceed a certain limit, namely 4 W/kg (general population exposure limit: SAR 0.08 W/kg), which causes a tissue heating of 1 oC. However, in the literature, biological effects below 4 W/kg SAR values have been described. Since such effects are considered to be not due to warming, they are
termed non-thermal effects. In the present review, in some individual studies, the authors interpreted thermal effects as “no effect”. Those ones and studies without response/effect of MMW exposure were considered as “no response/effect” in our present analysis.
Grouping of Selected Parameters
For analysis, 94 publications were identified and selected from the accessible databases (in vivo and in vitro) [16–109]. It should be noted that the total number of individual examinations is larger than the number of publications, since some authors investigated several physical and/or biological conditions in the same publication.
Various biological endpoints have been identified, which are referred to as “response” or effects when appropriate. Since the list of these endpoints is relatively long, we have not mentioned them in detail, but summarized them in groups: Physiological, neurological, histological changes, or in in vitro studies gene or protein expression, cytotoxic effects, genotoxic changes, and also temperature- related reactions.
For a detailed analysis, a “Master-table” (Table S1) was prepared in which all parameters considered in the studies were included. The table contains the following information: frequency, in vivo or in vitro study (the latter distinguishes between primary cells and cell lines), power density, exposure duration, biological endpoints, and response. Some studies lack information on individual parameters.
For example, a publication had to be excluded completely because there was no information about the frequency. In nine studies the power density data were absent and in seven studies the calculated SAR values were provided instead of the power density. In ten studies, the exposure time was not given.
The 45 in vivo studies were mainly conducted on mammals (mouse, rat, rabbit) and a few on humans.
In some studies, bacteria, fungi, and other living material were also used for the experiments. 80% of all in vivo studies showed exposure-related reactions.
Primary cells (n = 24) or cell lines (n = 29) were used in the 53 in vitro studies, with approximately 70% of the primary cell studies and 40% of the cell line investigations showing exposure-related responses (Table 2).
All identified studies were analyzed as a function of frequency. For this purpose, frequency domains (groups) have been created (Figure 1) to analyze and illustrate the results. The frequency groups from 30 to 60 GHz were grouped in ten-GHz increments (up to 30, 30.1–40, 40.1–50, 50.1–60 GHz).
The frequency range 60–65 GHz was extra analyzed as in this group a larger number of publications was identified (in comparison to the other groups). Due to the low number of publications above 65.0 GHz, data was merged into the groups of “65.1–90” and “above 90 GHz”. As shown in Figure 1, the majority of studies show a frequency-independent response after MMW exposure.
All data regarding the individual papers are found in Table S1.
Up to 30 GHz
The first group “up to 30 GHz” was introduced since some of the 5G frequencies fall within this frequency range. Unfortunately, there are only two publications in this group, both showing responses to the MMW exposure.
A study that was conducted on bacteria and fungi showed an increase in cell growth . The other in vitro study was performed on fibroblasts (25 GHz, 0.80 mW/cm2, 20 min), with genotoxic effects observed at high SAR levels (20 W/kg) . A graphical presentation of the outcomes is presented in Figure 1 for this and all other frequency domains.
Frequency Group 30.1–40 GHz
As shown in Figure 1, responses were detected in approximately 95% of the 19 studies. In all in vivo studies responses were described after exposure [25,27,36,37,55,56,78,79,87,91,103,104].
Endpoints ranged from recorded footpad edema, which is a frequent endpoint for the measurement of inflammatory responses, to morphological changes, changes in skin temperature, blood pressure, heart rate, body temperature, neuronal electrical activity, and EEG analyses.
Protein expression studies, oxidative stress marker measurements, histological investigations, and induction of cell death (apoptosis) were performed. Only one study used lower power densities (0.01 mW/cm2, 0.1 mW/cm2; SAR: 0.15, 1.5 W/kg; 20 min, 40 min) to study inflammatory responses .
The authors determined the frequency-dependent anti-inflammatory effect as a function of power density and exposure duration and did not rule out temperature-related effects. The power densities of the other in vivo studies were extremely high (10, 75, 500–5000 mW/cm2), so the induced effects were likely temperature dependent.
Eight in vitro studies were performed [18,20,47,91,97,99,101,102] of which seven reported responses. In one study , human blood cells (ex vivo) were exposed to MMW for 5, 15 and 30 min (32.9–39.6 GHz, 10 mW/cm2).
The activation of the cells was examined in the presence or absence of bacteria. It was shown that in the presence of bacterial activation and after 15 min of exposure, the cells were activated to release free radicals.
These results were similar to the heated samples (positive controls), so a temperature effect is plausible. The induction of differentiation of bone marrow cells in to neuronal phenotype cells was also demonstrated (36.11 GHz, 10 mW/cm2, 3 ⇥ 10 min every 2 h for 24 h) .
In two studies, temperature-related reactions were described at the protein level [18,91]. When the cell cultures were cooled during exposure to prevent the induced temperature increase, no responses were detected.
In three publications, a research group described cell cycle changes, induction of cell death and activation of differentiation processes in primary cells (rat bone cells and mesenchymal stem cells) after exposure to 30–40 GHz (4 mW/cm2, different exposure durations) [47,101,102]. Unfortunately, the minimum quality criteria were not fulfilled in any of the three studies, mainly because there were no temperature controls.
Frequency Group 40.1–50 GHz
In the 40.1–50 GHz frequency group, 26 studies were identified, 13 in vivo [16,17,26,48,49,51,53,65,69,74,80,84,98] and 13 in vitro [29–31,62,64,86,89,92,93,100,105,107] with nine studies showing responses.
A large number of studies have tested cell biology endpoints such as cell proliferation, gene or protein expression, and changes in oxidative stress. In addition, immunological, neurological, morphological and genotoxic effects were investigated.
The power densities used vary enormously, from 0.02 to 450 mW/cm2, and one publication gave no information.
In healthy volunteers, a double-blind study was performed to investigate the effects of MMW on experimentally induced cold pain (42.25 GHz, <17.2 mW/cm2, 30 min) . The authors found no difference from the placebo effect.
This study was a repeat of a previous study with volunteers and the results of the older study could not be confirmed. The other four in vivo studies with no detectable effects were investigating genotoxic effects or oxidative stress [17,48,49,98].
Five in vivo publications addressed the effects of MMW on the immune system of mice or rats, finding activation of the immune system at both the cellular and molecular levels (41.95 or 42.2 GHz,19.5 µW/cm2, 0, 1, 31.5 mW/cm2, 20 min or intermittently over 3 days) [26,48,51,53,84].
MMW exposure of frog isolated nerve cells, (41.34 GHz, 0.02, 0.1, 0.5, 2.6 mW/cm2, 10–23 min) lead to a reduction of the action potential frequency. Interestingly, the effects at higher power density (2.6 mW/cm2) were similar to conventional heating .
One study detected an increase in the motility of human spermatozoa after 15 min of exposure (42.25 GHz, 0.03 mW/cm2) . Additional in vitro tests have identified the formation of free radicals, the activation of calcium-dependent potassium ion channels (around 42 GHz, 100, 150, 240 µW/cm2, 20–40 min) as well as changes at the cell membrane in exposed cells [29,30,100].
No responses on cell biological endpoints (cell cycle changes, cell death, heat shock proteins) were detected in four additional in vitro studies.
Frequency Group 50.1–60 GHz
We identified 16 studies in the frequency group 50.1-60 GHz (six in vivo, ten in vitro) and 60% of the studies showed responses to MMW exposures [21,23,35,38,43,46,59,61,72,77,81,83,85,94,109].
In five of the in vivo studies very different responses were shown. In a study on healthy volunteers, the authors wanted to find out whether the human skin at a so-called acupuncture point has different dielectric properties during exposure to MMW. They found that these properties change during exposure to 50–61 GHz from the surrounding skin .
A pilot study on mice (60 GHz, 0.5 mW/cm2, lifelong exposure for 30 min/5 days a week) showed that MMW exposure affects cancer-induced cells and increases in motor activity of healthy mice .
In rats, the influence of 54 GHz, 150 mW/cm2, on an area of approximately 2 cm2 on the head was examined . This transcranial electromagnetic brain stimulation induced pain prevention and prevented the conditioned avoidance response to a pain stimulus in 50% of the animals. However, no changes were detected when serotonin inhibitors were previously administered.
Therefore, the authors concluded that transcranial electromagnetic brain stimulation promotes the synthesis of serotonin, a transmitter that changes the animals’ pain threshold.
The effects of MMW were also tested (60 GHz, 475 mW/cm2, 1.898 mW/cm2, 6, 30 min) on rabbit eyes, describing acute thermal injuries of various types .
The authors also pointed out that the higher temperature just below the eye surface could induce injury.
Neurological investigations were performed on leeches (60 GHz, 1 min, 1, 2, 4 mW/cm2)  and electrophysiological studies were performed on frog oocytes (60 GHz, up to 5 min) . In both experimental systems effects were described, which were induced by the temperature rise.
Cell biological and morphological changes after exposure to 0.7–1.0 µW/cm2 (intermittent) were reported in three in vitro studies [72,83,94], with two publications providing no information regarding power density or exposure duration. At the level of protein analysis and total genome analysis no changes were identified in four in vitro studies [35,46,59,109].
Frequency Group 60.1–65 GHz
The number of studies in the 60.1–65 GHz frequency group is 27. Of these, twelve reported effects from exposure to MMW, and no responses were found in 15 studies.
The in vivo studies investigated different topics [23,27,44,52,67,68,70,71,73,75,76]. Thus, two studies examined the effects on tumor development in mice injected with tumor cells [52,70]. In one of the studies it was reported that exposure to 61.22 GHz, 13.3 mW/cm2, inhibited the growth of melanoma cells (exposure 15 days after tumor cell injection, 15 min/day) .
Other publications from one research group investigated the potential of MMW for pain relief and the associated biological mechanisms of action [67,71,73,75,76]. Several of the studies were performed on mice skin exposed to 61.22 GHz for 15 min.
The most commonly used power density was 15 mW/cm2. Another study addressed the dose issue with no effect below 1.5 mW/cm2. The authors’ conclusion is that MMW can lower the hypoalgesia threshold, which is likely mediated by the release of opioids.
The effects of 61.22 GHz exposure of mice were examined also with respect to the immune system . The animals were exposed on three consecutive days for 30 min per day. The exposure caused peak SAR values of 885 W/kg on the nose of the animals where the exposure took place.
The power density was 31 mW/cm2 and the measured temperature rise reached 1 oC. It was found that
MMW modulates the effects of the cancer drug cyclophosamide. In particular, the T-cell system of the immune system was activated and various other immune system relevant parameters affected.
The similar exposure condition was used in a study on gastrointestinal function, however no effects were identified .
A single exposure for eight hours (61 GHz, 10 mW/cm2), or five times four hours, did not cause eye damage to rabbits and rhesus monkeys .
It should be emphasized that several of the mentioned studies come from the same laboratory, and all criteria for the study quality are met.
However, the authors were able to replicate their own findings on pain relief whereas other laboratories have not replicated this work. In the in vitro studies, various biological endpoints were examined [28,32–4,42,45,50,59,60,66,83,88,94,95,108].
In one study, neurons of snails (Lymnea) were exposed at 60.22–62.22 GHz and no non-thermal responses on the ion currents were identified .
In a series of investigations with nerve cell-relevant cell lines, the dopamine transmission properties, stress, pain and membrane protein expression were investigated (60.4 GHz, 10 mW/cm2, 24 h) and no responses were detected [32–34,59,60,108].
The same exposure setup has also been used in studies examining different stress response related genes (0.14–20 mW/cm2) . No effects were found at the gene expression level. Interestingly, the overall genome impact was influenced when the exposure (60.4 GHz, 20 mW/cm2, 3 h) of the primary human keratinocytes was combined with 2-deoxyglucose, a glucose-6- phosphatase inhibitor.
This co-exposure caused a change in the amount of six different transcription factors, the effect differing from the effect of 2-deoxyglucose alone and 60.4 GHz alone (both factors alone induced no changes).
Other studies also examined human keratinocytes and astrocytoma glial cells after exposure to 60 GHz (0.54, 1 and 5.4 mW/cm2) [60,108]. Various parameters such as cell survival, intracellular protein homeostasis, and stress-sensitive gene expression were investigated.
Also, in these studies, no effects were observed. In contrast, in one publication, the elevation of an inflammatory marker (IL1-[3) was observed in human keratinocytes after exposure (61.2 GHz, 29 mW/cm2, 15, 30 min), while other inflammatory markers (chemotaxis, adhesion and proliferation) have remained unchanged .
Another type of study was performed on rat brain cortical slices . The brain slices were exposed to a field of 60.125 GHz (1 µW/cm2) for 1 min, and then specific electrophysiological parameters were measured. In many slices, transient responses on membrane characteristics and action potential
amplitude and duration were observed. The exposure caused a temperature rise of the medium (of 3 oC) in which the sections were stored. Interestingly, a chronically induced Ca2+ blockade did not affect the MMW response.
Frequency Group 65.1–90 GHz
The studies in the frequency group of 65.1 to 90 GHz were performed both in vivo and in vitro in a total of 14 articles (four in vivo and 11 in vitro investigations). The studies vary widely, based on different hypotheses, biological endpoints, power densities, and exposure durations.
In addition, some studies have used biological materials to identify physical properties such as dielectric properties and skin reflection coefficient. The latter studies are discussed in Section 4.2.
Four in vivo studies reported responses after MMW exposure. One study examined the dose of eye damage (especially damage to the corneal epithelium) . The dose was calculated as DD50 (based on the results for which the probability of eye damage was 50%). The experiments were carried out on rats with an exposure of 75 GHz, the DD50 value being 143 mW/cm2.
Other in vivo studies were performed on rats and mice as well as on insects [27,42,57]. The study on mice used different frequencies of 37.5 to 70 GHz, with power densities of 0.01 and 0.3 mW/cm2 for 20 to 40 min.
A single whole-body exposure of the animals reduced both the footpad edema and local hyperthermia on average by 20% at the frequencies of 42.2, 51.8, and 65 GHz. Other frequencies had no influence.
The study on insects (Chironomidae) focused on DNA effects of giant chromosomes of the salivary glands of the animals with different frequencies (64.1–69.1, 67.2, 68.2 GHz) . All frequencies, using power densities <6 mW/cm2, caused a reduction in the size of a particular area of the chromosome. This in turn led to the expression of certain secretory proteins of the salivary gland.
Different aspects were studied in the in vitro studies [18,28,39,50,64,72,83,89,94,106], where nerve cell function was investigated in three studies. Two studies used nerve cells from the snail Lymnea that were exposed at 75 GHz for a few minutes at very high SAR levels (up to 4200 W/kg, power density was not reported) [28,39].
The authors observed thermal effects on the ion currents and the firing rate of the action potentials. Another study also described thermal effects on transmembrane currents and ionic conductivity of the cell membrane. Again, the exposure was at very high SAR levels (2000 W/kg), and the authors emphasized the temperature dependence of the reaction.
Broadband frequencies (52–78 GHz) have been used in several publications, mainly investigating the effects on cell growth and cell morphology as well as the ultrastructure of different cell lines [50,72,83,94].
The values for the power densities were not given consistently but appear to have been very low (not higher than 1 µW/cm2). The results indicated the inhibition of cell growth, accompanied by changes in cell morphology.
Another group of studies used hamster fibroblasts, BHK cells, and exposed the cells at 65 to 75 GHz, with the power density reaching 450 mW/cm2 [18,64,89]. The authors noted the inhibition of protein synthesis and cell proliferation as well as cell death at higher power densities.
In a study using human dermal fibroblasts and human glioblastoma cells, no effects at the protein level (proliferation or cytotoxicity markers) were detected (70 GHz and higher, in 1 GHz increments; 3, 70 or 94 h) .
Power densities varied across frequencies, ranging from 1.27 µW/cm2 in the lower frequency range to 0.38 µW/cm2 at higher frequencies.
The in vitro studies in this group are similar to the in vivo studies in their diversity. The majority of studies in which responses were reported are thermal-effects due to MMW exposure.
In three studies, responses at low power densities were described, but all results were from the same laboratory, and were not replicated by others. Moreover, the quality of these studies is questionable, as the quality criteria were not met.
Frequency Group 90.1–100 GHz
Eight out of eleven studies in the 90.1–100 GHz frequency group are in vitro studies [22,41,57,82, 90,96,106]. The three in vivo investigations addressed a variety of issues including acute effects on muscle contraction, skin-reflection properties (which are more of a dose-related than health-related issue), and skin cancer [19,54,57].
The rat skin cancer study (one to two weekly, short-term exposures at 94 GHz, 1 W/kg; DMBA-initiated animals) did not show any positive outcome . Another study examined the muscle contraction of mice and described some responses . Again, 94 GHz was used, but power density or SAR values were not reported.
Seven of the eight in vitro studies showed responses after MMW exposure. In some studies, primary neurons were used to study the cytoskeleton (94 GHz, 31 mW/cm2)  or specific electrophysiological parameters (90–160 GHz) .
In the latter study it was found that the observed responses were more likely due to interactions with the cell culture medium than with the cells, although the mechanisms of action were not clear.
Other studies identified responses on the DNA integrity (100 GHz and higher)  or described changes in intracellular signaling pathways (94 GHz, 90–160 GHz) using different cell types [57,96]. The exposure time ranged from minutes to 24 h for partially unknown exposure values. In one study no cytotoxic influence at power density levels of a few µW/cm2 was detected in either normal or in tumor cells.
All identified studies were analyzed as a function of the used power densities. The studies were grouped depending on the power density as follows: below 1; 1.1–10; 10.1 to 50; 50.1–100, and 100.1 mW/cm2 or higher.
Studies that do not provide information on power density or SAR values are not displayed in these groups. As shown in Figure 2, the vast majority of studies show responses regardless of the power density used.
Exposure duration of the studies was also grouped for data analysis (Figure 3). The time groups were selected as seconds to 10 min; 10–30 min; 30–60 min; over 60 min-days and alternately/ intermittently.
The groups were selected so that the used exposure times and the number of studies are meaningfully summarized. Here, too, it becomes clear that the majority of all studies show responses regardless of the exposure time.
Interestingly, longer exposure times (over 60 min—days) seemingly lead to fewer reactions than in the other groups.
Studies without Responses
Table 3 shows the number of studies in which no responses were detected after or during MMW exposure. As “no response” also such investigations were referred to, which were considered by the authors themselves as such.
This means that in some cases the observed effects were described as temperature-related and not as a non-thermal MMW effect.
Few in vivo studies have shown no response at all. Noticeable is the frequency group 40.1–50 GHz, in which 6 studies were identified. These studies investigated immunosuppression, genotoxic effects, changes in pain sensitivity, and changes in enzyme activity. One study was carried out on bacteria and fungi.
There are a variety of in vitro studies in which no responses were detected. Interestingly, studies on protein or gene expression levels often failed to detect any changes after MMW exposure. This could be due to the fact that in in vitro studies the possibility of non-thermal effects were specifically investigated, where cooling was used to counteract the temperature increase.
We analyzed the quality of the selected studies according to specific criteria . The studies were categorized by the presence of sham/control, dosimetry, positive control, temperature control, and whether the study was blinded.
The presence of these five criteria while performing an MMW study is the minimum requirement for qualifying as a study with sufficient technical quality.
Of the 45 in vivo studies, 78% (35) demonstrated biological responses after exposure to MMW. Of all studies, 73% were performed with sham/controls, 76% employed appropriate dosimetry, 44% used positive control, and 67% were done under temperature control conditions (Figure 4).
Unfortunately, only 16% of the studies were performed according to protocols that ensured blinding and only three publications were identified that met all five criteria [26,51,53]. If the blinding criterion was excluded, 13 studies could be identified that met the remaining four criteria.
Considering three criteria only, namely sham, dosimetry, and temperature control, 40% (20 papers) were identified. Thus, the quality of the in vivo studies is unsatisfactory.
Out of the 53 in vitro studies, 31 showed biological responses. Only in 13 studies (42%) were three of the five quality criteria satisfied, namely the presence of sham/control, dosimetry, and temperature control (Figure 4).
Positive controls were used in 47% and only one study was performed with blinded protocol (2%).
These results show that the number of examinations and the quality criteria are insuicient for a statistical analysis.
It should be stressed that this quality analysis covers all publications dealing with the responses/effects of exposure to 6 to 100 GHz MMW, irrespective of the endpoints tested. To perform a correlation analysis, a larger number of comparable studies (e.g., identical endpoints in a frequency group) would be required.
- Chávez-Santiago, R.; Szydełko, M.; Kliks, A.; Foukalas, F.; Haddad, Y.; Nolan, K.E.; Kelly, M.Y.; Masonta, M.T.; Balasingham, I. 5G: The Convergence of Wireless Communications. Wirel. Pers. Commun. 2015, 83, 1617–1642. [CrossRef] [PubMed]
- Chih-Lin, I.; Han, S.; Xu, Z.; Sun, Q.; Pan, Z. 5G: Rethink mobile communications for 2020+. Philos. Trans. R. Soc. A Math. Phys. Eng. Sci. 2016, 374, 20140432. [CrossRef] [PubMed]
- International Agency for Research on Cancer. Non-Ionizing Radiation, Part. 2: Radiofrequency Electromagnetic Fields; International Agency for Research on Cancer: Lyon, France, 2013; Volume 102, pp. 1–460.
- Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). Opinion on: Potential health effects of exposure to electromagnetic fields. Bioelectromagnetics 2015, 36, 480–484. [CrossRef] [PubMed]
- SSM’s Scientific Council on Electromagnetic Fields. Recent Research on EMF and Health Risk: Eleventh report from SSM’S Scientific Council on Electromagnetic Fields; Swedish Radiation Safety Authority: Stockholm, Sweden, 2016.
- Marques, M.M.; Berrington de Gonzalez, A.; Beland, F.A.; Browne, P.; Demers, P.A.; Lachenmeier, D.W.; Bahadori, T.; Barupal, D.K.; Belpoggi, F.; Comba, P.; et al. Advisory Group recommendations on priorities for the IARC Monographs. Lancet Oncol. 2019, 20, 763–764. [CrossRef]
- WHO. Available online: https://www.who.int/peh-emf/publications/facts/fs226/en/ (accessed on 8 August 2019).
- Mattsson, M.O.; Zeni, O.; Simkó, M. Is there a Biological Basis for Therapeutic Applications of Millimetre Waves and THz Waves? J. Infrared Millim. Terahertz Waves 2018, 39, 863–878. [CrossRef]
- Ziskin, M.C. Millimeter waves: Acoustic and electromagnetic. Bioelectromagnetics 2013, 34, 3–14. [CrossRef] [PubMed]
- International Commission on Non-Ionizing Radiation Protection (ICNIRP). Guidelines for limiting exposure to time-varying electric, magnetic, and electromagnetic fields (Up to 300 GHz). Health Phys. 1998, 74, 494–522.
- IEEE Standards Coordinating Committee. IEEE Standard for Safety Levels with Respect to Human Exposure to Radio Frequency Electromagnetic Fields, 3kHz to 300 GHz; Technical report No. C95.1-2005; IEEE: Piscataway, NJ, USA, 2006; pp. 1–1991.
- IEEE. Available online: https://spectrum.ieee.org/video/telecom/wireless/everything-you-need-to-know- about-5g (accessed on 8 August 2019).
- Zeni, O.; Scarfì, M.R. Experimental requirements for in vitro studies aimed to evaluate the biological effects of radiofrequency radiation. In Microwave Materials Characterization; InTech: Rijeka, Croatia, 2012; pp. 121–138.
- Simkó, M.; Remondini, D.; Zeni, O.; Scarfi, M.R. Quality Matters: Systematic Analysis of Endpoints Related to ‘Cellular Life’ in Vitro Data of Radiofrequency Electromagnetic Field Exposure. Int. J. Environ. Res. Public Health 2016, 13, 701. [CrossRef]
- SCHEER–Scientific Committee on Health Environmental and Emerging Risks. Memorandum on Weight of Evidence and Uncertainties; European Comission: Brussels, Belgium, 2018.
- Alekseev, S.I.; Gordiienko, O.V.; Radzievsky, A.A.; Ziskin, M.C. Millimeter wave effects on electrical responses of the sural nerve in vivo. Bioelectromagnetics 2010, 31, 180–190. [CrossRef]
- Alekseev, S.I.; Radzievsky, A.A.; Szabo, I.; Ziskin, M.C. Local heating of human skin by millimeter waves: Effect of blood flow. Bioelectromagnetics 2005, 26, 489–501. [CrossRef]
- Bush, L.G.; Hill, D.W.; Riazi, A.; Stensaas, L.J.; Partlow, L.M.; Gandhi, O.P. Effects of millimeter-wave radiation on monolayer cell cultures. III. A search for frequency-specific athermal biological effects on protein synthesis. Bioelectromagnetics 1981, 2, 151–159. [CrossRef] [PubMed]
- Chatterjee, I.; Yoon, J.; Wiese, R. Millimeter wave bioeffects at 94 GHz on skeletal muscle contraction. In Proceedings of the 2013 IEEE Topical Conference on Biomedical Wireless Technologies, Networks, and Sensing Systems, Austin, TX, USA, 20–23 January 2013; pp. 67–69.
- Chen, Q.; Zeng, Q.L.; Lu, D.Q.; Chiang, H. Millimeter Wave Exposure Reverses TPA Suppression of Gap Junction Intercellular Communication in HaCaT Human Keratinocytes. Bioelectromagnetics 2004, 25, 1–4. [CrossRef] [PubMed]
- D’Agostino, S.; Della Monica, C.; Palizzi, E.; Di Pietrantonio, F.; Benetti, M.; Cannatà, D.; Cavagnaro, M.; Sardari, D.; Stano, P.; Ramundo-Orlando, A. Extremely High Frequency Electromagnetic Fields Facilitate Electrical Signal Propagation by Increasing Transmembrane Potassium E✏ux in an Artificial Axon Model. Sci. Rep. 2018, 8, 9299. [CrossRef] [PubMed]
- Deghoyan, A.; Heqimyan, A.; Nikoghosyan, A.; Dadasyan, E.; Ayrapetyan, S. Cell bathing medium as a target for non thermal effect of millimeter waves. Electromagn. Biol. Med. 2012, 31, 132–142. [CrossRef] [PubMed]
- Egot-Lemaire, S.J.-P.; Ziskin, M.C. Dielectric properties of human skin at an acupuncture point in the 50–75 GHz frequency range: A pilot study. Bioelectromagnetics 2011, 32, 360–366. [CrossRef] [PubMed]
- Franchini, V.; Franchini, V.; Regalbuto, E.; De Amicis, A.; De Sanctis, S.; Di Cristofaro, S.; Coluzzi, E.; Marinaccio, J.; Sgura, A.; Ceccuzzi, S.; et al. Genotoxic Effects in Human Fibroblasts Exposed to Microwave Radiation. Health Phys. 2018, 115, 126–139. [CrossRef] [PubMed]
- Frei, M.R.; Ryan, K.L.; Berger, R.E.; Jauchem, J.R. Sustained 35-GHz radiofrequency irradiation induces circulatory failure. Shock 1995, 4, 289–293. [CrossRef]
- Gapeyev, A.B.; Kulagina, T.P.; Aripovsky, A.V.; Chemeris, N.K. The role of fatty acids in anti-inflammatory effects of low-intensity extremely high-frequency electromagnetic radiation. Bioelectromagnetics 2011, 32, 388–395. [CrossRef]
- Gapeyev, A.B.; Gapeyev, A.B.; Mikhailik, E.N.; Mikhailik, E.N.; Chemeris, N.K. Anti-inflammatory effects of low-intensity extremely high-frequency electromagnetic radiation: Frequency and power dependence. Bioelectromagnetics 2008, 29, 197–206. [CrossRef]
- Alekseev, S.I.; Ziskin, M.C. Effects of millimeter waves on ionic currents of Lymnaea neurons.
Bioelectromagnetics 1999, 20, 24–33. [CrossRef]
- Gapeyev, A.B.; Safronova, V.G.; Chemeris, N.K.; Fesenko, E.E. Inhibition of the production of reactive oxygen species in mouse peritoneal neutrophils by millimeter wave radiation in the near and far field zones of the radiator. Bioelectrochem. Bioenerg. 1997, 43, 217–220. [CrossRef]
- Geletyuk, V.; Kazachenko, V. Dual effects of microwaves on single Ca 2+-activated K+ channels in cultured
kidney cells Vero. FEBS Lett. 1995, 359, 85–88. [CrossRef]
- Grundier, W.; Keilmann, F. Nonthermal Effects of Millimeter Microwaves on Yeast Growth. Z. Naturforsch. C
1978, 33, 15–22. [CrossRef]
- Haas, A.J.; Le Page, Y.; Zhadobov, M.; Boriskin, A.; Sauleau, R.; Le Dréan, Y. Impact of 60-GHz millimeter waves on stress and pain-related protein expression in differentiating neuron-like cells. Bioelectromagnetics 2016, 37, 444–454. [CrossRef] [PubMed]
- Haas, A.J.; Le Page, Y.; Zhadobov, M.; Sauleau, R.; Le Dréan, Y.; Saligaut, C. Effect of acute millimeter wave exposure on dopamine metabolism of NGF-treated PC12 cells. J. Radiat. Res. 2017, 58, 439–445. [CrossRef] [PubMed]
- Haas, A.J.; Le Page, Y.; Zhadobov, M.; Sauleau, R.; Le Dréan, Y. Effects of 60-GHz millimeter waves on neurite outgrowth in PC12 cells using high-content screening. Neurosci. Lett. 2016, 618, 58–65. [CrossRef] [PubMed]
- Habauzit, D.; Le Quément, C.; Zhadobov, M.; Martin, C.; Aubry, M.; Sauleau, R.; Le Dréan, Y. Transcriptome analysis reveals the contribution of thermal and the specific effects in cellular response to millimeter wave exposure. PLoS ONE 2014, 9, e109435. [CrossRef]
- Ivanov, V.B.; Subbotina, T.I.; Khadartsev, A.A.; Yashin, M.A.; Yashin, A.A. Exposure to low-intensive superhigh frequency electromagnetic field as a factor of carcinogenesis in experimental animals. Bull. Exp. Biol. Med. 2005, 139, 241–244. [CrossRef]
- Jauchem, J.R.; Ryan, K.L.; Walters, T.J. Pathophysiological alterations induced by sustained 35-GHz radio-frequency energy heating. J. Basic Clin. Physiol. Pharmacol. 2016, 27, 79–89. [CrossRef]
- Kojima, M.; Hanazawa, M.; Yamashiro, Y.; Sasaki, H.; Watanabe, S.; Taki, M.; Suzuki, Y.; Hirata, A.; Kamimura, Y.; Sasaki, K. Acute ocular injuries caused by 60-GHZ millimeter-wave exposure. Heal. Phys. 2009, 97, 212–218. [CrossRef]
- Alekseev, S.I.; Ziskin, M.C.; Kochetkova, N.V.; Bolshakov, M.A. Millimeter waves thermally alter the firing rate of the Lymnaea pacemaker neuron. Bioelectromagnetics 1997, 18, 89–98. [CrossRef]
- Kojima, M.; Kojima, M.; Suzuki, Y.; Sasaki, K.; Taki, M.; Wake, K.; Watanabe, S.; Mizuno, M.; Tasaki, T.; Sasaki, H. Ocular Effects of Exposure to 40, 75, and 95 GHz Millimeter Waves. J. Infrared Millim. Terahertz Waves 2018, 39, 912–925. [CrossRef]
- Korenstein-Ilan, A.; Barbul, A.; Hasin, P.; Eliran, A.; Gover, A.; Korenstein, R. Terahertz Radiation Increases Genomic Instability in Human Lymphocytes. Radiat. Res. 2008, 170, 224–234. [CrossRef]
- Koschnitzke, C.; Kremer, F.; Santo, L.; Quick, P.; Poglitsch, A. A Non-Thermal Effect of Millimeter Wave Radiation on the Puing of Giant Chromosomes. Zeitschrift für Naturforsch C 1983, 38, 883–886. [CrossRef]
- Koyama, S.; Narita, E.; Shimizu, Y.; Suzuki, Y.; Shiina, T.; Taki, M.; Shinohara, M.; Miyakoshi, J. Effects of long-term exposure to 60 GHz millimeter-wavelength radiation on the genotoxicity and heat shock protein (HSP) expression of cells derived from human eye. Int. J. Environ. Res. Public Health 2016, 13, 802. [CrossRef]
- Kues, H.A.; Anna, S.A.D.; Osiander, R.; Green, W.R.; Monahan, J.C. Absence of Ocular Effects After Either Single or Repeated Exposure to 10 mW/cm2 from a 60 GHz CW Source. Bioelectromagnetics 1999, 473, 463–473. [CrossRef]
- Le Quément, C.; Nicolas Nicolaz, C.; Zhadobov, M.; Desmots, F.; Sauleau, R.; Aubry, M.; Michel, D.; Le Dréan, Y. Whole-genome expression analysis in primary human keratinocyte cell cultures exposed to 60 GHz radiation. Bioelectromagnetics 2012, 33, 147–158.
- LeQuément, C.; Nicolaz, C.N.; Habauzit, D.; Zhadobov, M.; Sauleau, R.; Le Dréan, Y. Impact of 60-GHz millimeter waves and corresponding heat effect on endoplasmic reticulum stress sensor gene expression. Bioelectromagnetics 2014, 35, 444–451. [CrossRef]
- Li, X.; Ye, H.; Yu, F.; Cai, L.; Li, H.; Chen, J.; Wu, M.; Chen, W.; Lin, R.; Li, Z.; et al. Millimeter wave treatment promotes chondrocyte proliferation via G 1/S cell cycle transition. Int. J. Mol. Med. 2012, 29, 823–831. [CrossRef]
- Logani, M.K.; Agelan, A.; Ziskin, M.C. Effect of millimeter wave radiation on catalase activity. Electromagn. Biol. Med. 2002, 21, 303–308. [CrossRef]
- Logani, M.K.; Anga, A.; Szabo, I.; Agelan, A.; Irizarry, A.R.; Ziskin, M.C. Effect of millimeter waves on cyclophosphamide induced suppression of the immune system. Bioelectromagnetics 2002, 23, 614–621. [CrossRef]
- Alekseev, S.I.; Ziskin, M.C. Millimeter microwave effect on ion transport across lipid bilayer membranes.
Bioelectromagnetics 1995, 16, 124–131. [CrossRef]
- Makar, V.; Logani, M.; Szabo, I.; Zlskin, M. Effect of Millimeter Waves on Cyclophosphamide Induced Suppression of T Cell Functions. Bioelectromagnetics 2003, 24, 356–365. [CrossRef]
- Makar, V.R.; Logani, M.K.; Bhanushali, A.; Alekseev, S.I.; Ziskin, M.C. Effect of cyclophosphamide and
61.22 GHz millimeter waves on T-cell, B-cell, and macrophage functions. Bioelectromagnetics 2006, 27, 458–466. [CrossRef]
- Makar, V.R.; Logani, M.K.; Bhanushali, A.; Kataoka, M.; Ziskin, M.C. Effect of millimeter waves on natural killer cell activation. Bioelectromagnetics 2005, 26, 10–19. [CrossRef]
- Mason, P.A.; Walters, T.J.; DiGiovanni, J.; Beason, C.W.; Jauchem, J.R.; Dick, E.J., Jr.; Mahajan, K.; Dusch, S.J.; Shields, B.A.; Merritt, J.H.; et al. Lack of effect of 94 GHz radio frequency radiation exposure in an animal model of skin carcinogenesis in the radio frequency radiation (RFR) band is mutagenic, as either a promoter or co-promoter in some animal models of carcinogenesis. Recent develop. Carcinogenesis 2001, 22, 1701–1708. [CrossRef]
- Millenbaugh, N.J.; Kiel, J.L.; Ryan, K.L.; Blystone, R.V.; Kalns, J.E.; Brott, B.J.; Cerna, C.Z.; Lawrence, W.S.; Soza, L.L.; Mason, P.A. Comparison of blood pressure and thermal responses in rats exposed to millimeter wave energy or environmental heat. Shock 2006, 25, 625–632. [CrossRef]
- Millenbaugh, N.J.; Roth, C.; Sypniewska, R.; Chan, V.; Eggers, J.S.; Kiel, J.L.; Blystone, R.V.; Mason, P.A. Gene expression changes in the skin of rats induced by prolonged 35 GHz millimeter-wave exposure. Radiat. Res. 2008, 169, 288–300. [CrossRef]
- Narinyan, L.; Ayrapetyan, S. Cyclic AMP-dependent signaling system is a primary metabolic target for non-thermal effect of microwaves on heart muscle hydration. Electromagn. Biol. Med. 2017, 36, 182–191. [CrossRef]
- Nguyen, T.H.; Pham, V.T.; Nguyen, S.H.; Baulin, V.; Croft, R.J.; Phillips, B.; Crawford, R.J.; Ivanova, E.P. The bioeffects resulting from prokaryotic cells and yeast being exposed to an 18 GHz electromagnetic field. PLoS ONE 2016, 11, e0158135. [CrossRef]
- Nicolaz, C.N.; Zhadobov, M.; Desmots, F.; Ansart, A.; Sauleau, R.; Thouroude, D.; Michel, D.; Le Drean, Y. Study of narrow band millimeter-wave potential interactions with endoplasmic reticulum stress sensor genes. Bioelectromagnetics 2009, 30, 365–373. [CrossRef]
- Nicolas Nicolaz, C.; Zhadobov, M.; Desmots, F.; Sauleau, R.; Thouroude, D.; Michel, D.; Le Drean, Y. Absence of direct effect of low-power millimeter-wave radiation at 60.4 GHz on endoplasmic reticulum stress. Cell Biol. Toxicol. 2009, 25, 471–478. [CrossRef]
- Bellossi, A.; Dubost, G.; Moulinoux, J.P.; Himdi, M.; Ruelloux, M.; Rocher, C. Biological Effects of Millimeter-Wave Irradiation on Mice—Preliminary Results. IEEE Trans. Microw. Theory Tech. 2000, 48, 2104–2110.
- Pakhomov, A.G.; Prol, H.K.; Mathur, S.P.; Akyel, Y.; Campbell, C.B.G.B.G. Role of field intensity in the biological effectiveness of millimeter waves at a resonance frequency. Bioelectrochem. Bioenerg. 1997, 43, 27–33. [CrossRef]
- Pakhomov, A.G.; Prol, H.K.; Mathur, S.P.; Akyel, Y.; Campbell, C.B. Search for frequency-specific effects of millimeter-wave radiation on isolated nerve function. Bioelectromagnetics 1997, 18, 324–334. [CrossRef]
- Partlow, L.M.; Bush, L.G.; Stensaas, L.J.; Hill, D.W.; Riazi, A.; Gandhi, O.P. Effects of millimeter-wave radiation on monolayer cell cultures. I. Design and validation of a novel exposure system. Bioelectromagnetics 1981, 2, 123–140. [CrossRef]
- Partyla, T.; Hacker, H.; Edinger, H.; Leutzow, B.; Lange, J.; Usichenko, T. Remote Effects of Electromagnetic Millimeter Waves on Experimentally Induced Cold Pain: A Double-Blinded Crossover Investigation in Healthy Volunteers. Anesth. Analg. 2017, 124, 980–985. [CrossRef]
- Pikov, V.; Arakaki, X.; Harrington, M.; Fraser, S.E.; Siegel, P.H. Modulation of neuronal activity and plasma membrane properties with low-power millimeter waves in organotypic cortical slices. J. Neural Eng. 2010, 7, 045003. [CrossRef]
- Radzievsky, A.; Gordiienko, O.; Cowan, A.; Alekseev, S.; Ziskin, M. Millimeter-Wave-Induced Hypoalgesia in Mice: Dependence on Type of Experimental Pain. IEEE Trans. Plasma Sci. 2004, 32, 1634–1643. [CrossRef]
- Radzievsky, A.A.; Cowan, A.; Byrd, C.; Radzievsky, A.A.; Ziskin, M.C. Single millimeter wave treatment does not impair gastrointestinal transit in mice. Life Sci. 2002, 71, 1763–1770. [CrossRef]
- Radzievsky, A.A.; Gordiienko, O.V.; Alekseev, S.; Szabo, I.; Cowan, A.; Ziskin, M.C. Electromagnetic millimeter wave induced hypoalgesia: Frequency dependence and involvement of endogenous opioids. Bioelectromagnetics 2008, 29, 284–295. [CrossRef]
- Radzievsky, A.; Gordiienko, O.; Szabo, I.; Alekseev, S.I.; Ziskin, M.C. Millimeter wave-induced suppression of B16 F10 melanoma growth in mice: Involvement of endogenous opioids. Bioelectromagnetics 2004, 25, 466–473. [CrossRef]
- Radzievsky, A.A.; Rojavin, M.A.; Cowan, A.; Alekseev, S.I.; Radzievsky, A.A.; Ziskin, M.C. Peripheral neural system involvement in hypoalgesic effect of electromagnetic millimeter waves. Life Sci. 2001, 62, 1143–1151. [CrossRef]
- Beneduci, A.; Chidichimo, G.; De Rose, R.; Filippelli, L.; Straface, S.V.; Venuta, S. Frequency and irradiation time-dependant antiproliferative effect of low-power millimeter waves on RPMI 7932 human melanoma cell line. Anticancer Res. 2005, 25, 1023–1028.
- Radzievsky, A.A.; Rojavin, M.A.; Cowan, A.; Alekseev, S.I.; Ziskin, M.C. Hypoalgesic effect of millimeter waves in mice: Dependence on the site of exposure. Life Sci. 2000, 66, 2101–2111. [CrossRef]
- Radzievsky, A.A.; Rojavin, M.A.; Cowan, A.; Ziskin, M.C. Suppression of pain sensation caused by millimeter waves: A double-blinded, cross-over, prospective human volunteer study. Anesth. Analg. 1999, 88, 836–840. [CrossRef]
- Rojavin, M.A.; Cowan, A.; Radzievsky, A.A.; Ziskin, M.C. Antipruritic effect of millimeter waves in mice: Evidence for opioid involvement. Life Sci. 1998, 63, 251–257. [CrossRef]
- Rojavin, M.A.; Radzievsky, A.A.; Cowan, A.; Ziskin, M.C. Pain relief caused by millimeter waves in mice: Results of cold water tail flick tests. Int. J. Radiat. Biol. 2000, 76, 575–579.
- Romanenko, S.; Siegel, P.H.; Wagenaar, D.A.; Pikov, V. Effects of millimeter wave irradiation and equivalent thermal heating on the activity of individual neurons in the leech ganglion. J. Neurophysiol. 2014, 112, 2423–2431. [CrossRef]
- Ryan, K.L.; Frei, M.R.; Berger, R.E.; Jauchem, J.R. Does nitric oxide mediate circulatory failure induced by 35-GHz microwave heating? Shock 1996, 6, 71–76. [CrossRef]
- Ryan, K.L.; Frei, M.R.; Jauchem, J.R. Circulatory failure induced by 35 GHz microwave heating: Effects of chronic nitric oxide synthesis inhibition. Shock 1997, 7, 70–76. [CrossRef]
- Safronova, V.G.; Gabdoulkhakova, A.G.; Santalov, B.F. Immunomodulating Action of Low Intensity Millimeter Waves on Primed Neutrophils. Bioelectromagnetics 2002, 23, 599–606. [CrossRef]
- Samoilov, V.O.; Shadrin, E.B.; Filippova, E.B.; Katsnelson, Y.; Backhoff, H.; Eventov, M. The effect of transcranial electromagnetic brain stimulation on the acquisition of the conditioned response in rats. Biophysics 2015, 60, 303–308. [CrossRef]
- Samsonov, A.; Popov, S.V. The effect of a 94 GHz electromagnetic field on neuronal microtubules.
Bioelectromagnetics 2013, 34, 133–144. [CrossRef]
- Beneduci, A.; Chidichimo, G.; Tripepi, S.; Perrotta, E. Transmission electron microscopy study of the effects produced by wide-band low-power millimeter waves on MCF-7 human breast cancer cells in culture. Anticancer Res. 2005, 25, 1009–1013.
- Shanin, S.N.; Rybakina, E.G.; Novikova, N.N.; Kozinets, I.A.; Rogers, V.J.; Korneva, E.A. Natural killer cell cytotoxic activity and c-Fos protein synthesis in rat hypothalamic cells after painful electric stimulation of the hind limbs and EHF irradiation of the skin. Med. Sci Monit. 2005, 11, BR309–BR315.
- Shapiro, M.G.; Priest, M.F.; Siegel, P.H.; Bezanilla, F. Thermal Mechanisms of Millimeter Wave Stimulation of Excitable Cells. Biophys. J. 2013, 104, 2622–2628. [CrossRef]
- Shckorbatov, Y.G.; Grigoryeva, N.N.; Shakhbazov, V.G.; Grabina, V.A.; Bogoslavsky, A.M. Microwave irradiation influences on the state of human cell nuclei. Bioelectromagnetics 1998, 19, 414–419. [CrossRef]
- Sivachenko, I.B.; Medvedev, D.S.; Molodtsova, I.D.; Panteleev, S.S.; Sokolov, A.Y.; Lyubashina, O.A. Effects of Millimeter-Wave Electromagnetic Radiation on the Experimental Model of Migraine. Bull. Exp. Biol. Med. 2016, 160, 425–428. [CrossRef]
- Soubere Mahamoud, Y.; Aite, M.; Martin, C.; Zhadobov, M.; Sauleau, R.; Le Dréan, Y.; Habauzit, D. Additive Effects of Millimeter Waves and 2-Deoxyglucose Co-Exposure on the Human Keratinocyte Transcriptome. PLoS ONE 2016, 11, e0160810. [CrossRef]
- Stensaas, L.J.; Partlow, L.M.; Bush, L.G.; Iversen, P.L.; Hill, D.W.; Hagmann, M.J.; Gandhi, O.P. Effects of millimeter-wave radiation on monolayer cell cultures. II. Scanning and transmission electron microscopy. Bioelectromagnetics 1981, 2, 141–150. [CrossRef] [PubMed]
- Sun, S.; Titushkin, I.; Varner, J.; Cho, M. Millimeter Wave-induced Modulation of Calcium Dynamics in an Engineered Skin Co-culture Model: Role of Secreted ATP on Calcium Spiking. J. Radiat. Res. 2012, 53, 159–167. [CrossRef] [PubMed]
- Sypniewska, R.K.; Millenbaugh, N.J.; Kiel, J.L.; Blystone, R.V.; Ringham, H.N.; Mason, P.A.; Witzmann, F.A. Protein changes in macrophages induced by plasma from rats exposed to 35 GHz millimeter waves. Bioelectromagnetics 2010, 31, 656–663. [CrossRef] [PubMed]
- Szabo, I.; Kappelmayer, J.; Alekseev, S.I.; Ziskin, M.C. Millimeter wave induced reversible externalization of phosphatidylserine molecules in cells exposed in vitro. Bioelectromagnetics 2006, 27, 233–244. [CrossRef] [PubMed]
- Szabo, I.; Manning, M.R.; Radzlevsky, A.A.; Wetzel, M.A.; Rogers, T.J.; Ziskin, M.C. Low Power Millimeter Wave Irradiation Exerts No Harmful Effect on Human Keratinocytes In Vitro. Bioelectromagnetics 2003, 24, 165–173. [CrossRef]
- Beneduci, A.; Chidichimo, G.; Tripepi, S.; Perrotta, E.; Cufone, F. Antiproliferative effect of millimeter radiation on human erythromyeloid leukemia cell line K562 in culture: Ultrastructural and metabolic-induced changes. Bioelectrochemistry 2007, 70, 214–220. [CrossRef]
- Szabo, I.; Rojavin, M.A.; Rogers, T.J.; Ziskin, M.C. Reactions of keratinocytes to in vitro millimeter wave exposure. Bioelectromagnetics 2001, 22, 358–364. [CrossRef]
- Titushkin, I.A.; Rao, V.S.; Pickard, W.F.; Moros, E.G.; Shafirstein, G.; Cho, M.R. Altered Calcium Dynamics Mediates P19-Derived Neuron-Like Cell Responses to Millimeter-Wave Radiation. Radiat. Res. 2009, 172, 725–763. [CrossRef]
- Tong, Y.; Yang, Z.; Yang, D.; Chu, H.; Qu, M.; Liu, G.; Wu, Y.; Liu, S. Millimeter-wave exposure promotes the differentiation of bone marrow stromal cells into cells with a neural phenotype. J. Huazhong Univ. Sci. Technolog. Med. Sci. 2009, 29, 409–412. [CrossRef]
- Logani, M.K.; Bhanushali, A.; Ziskin, M.C.; Prihoda, T.J. Micronuclei in peripheral blood and bone marrow cells of mice exposed to 42 GHz electromagnetic millimeter waves. Radiat. Res. 2004, 161, 341–345. [CrossRef]
- Vlasova, I.I.; Mikhalchik, E.V.; Gusev, A.A.; Balabushevich, N.G.; Gusev, S.A.; Kazarinov, K.D. Extremely high-frequency electromagnetic radiation enhances neutrophil response to particulate agonists. Bioelectromagnetics 2018, 39, 144–155. [CrossRef] [PubMed]
- Volkova, N.A.; Pavlovich, E.V.; Gapon, A.A.; Nikolov, O.T. Effects of millimeter-wave electromagnetic exposure on the morphology and function of human cryopreserved spermatozoa. Bull. Exp. Biol. Med. 2014, 157, 574–576. [CrossRef] [PubMed]
- Wu, G.; Sferra, T.; Chen, X.; Chen, Y.; Wu, M.; Xu, H.; Peng, J.; Liu, X. Millimeter wave treatment inhibits the mitochondrion-dependent apoptosis pathway in chondrocytes. Mol. Med. Rep. 2011, 4, 1001–1006. [PubMed]
- Wu, G.W.; Liu, X.X.; Wu, M.X.; Zhao, J.Y.; Chen, W.L.; Lin, R.H.; Lin, J.M. Experimental study of millimeter wave-induced differentiation of bone marrow mesenchymal stem cells into chondrocytes. Int. J. Mol. Med. 2009, 23, 461–467. [PubMed]
- Xia, L.; Luo, Q.-L.; Lin, H.-D.; Zhang, J.-L.; Guo, H.; He, C.-Q. The effect of different treatment time of millimeter wave on chondrocyte apoptosis, caspase-3, caspase-8, and MMP-13 expression in rabbit surgically induced model of knee osteoarthritis. Rheumatol. Int. 2012, 32, 2847–2856. [CrossRef] [PubMed]
- Xie, T.; Pei, J.; Cui, Y.; Zhang, J.; Qi, H.; Chen, S.; Qiao, D. EEG changes as heat stress reactions in rats irradiated by high intensity 35 GHZ millimeter waves. Health Phys. 2011, 100, 632–640. [CrossRef]
- Beneduci, A. Evaluation of the Potential In Vitro Antiproliferative Effects of Millimeter Waves at Some Therapeutic Frequencies on RPMI 7932 Human Skin Malignant Melanoma Cells. Cell Biochem. Biophys. 2009, 55, 25–32. [CrossRef] [PubMed]
- Yaekashiwa, N.; Otsuki, S.; Hayashi, S.; Kawase, K. Investigation of the non-thermal effects of exposing cells to 70-300 GHz irradiation using a widely tunable source. J. Radiat. Res. 2018, 59, 116–121. [CrossRef]
- Yu, G.; Coln, E.A.; Schoenbach, K.H.; Gellerman, M.; Fox, P.; Rec, L.; Beebe, S.J.; Liu, S. A study on biological effects of low-intensity millimeter waves. IEEE Trans. Plasma Sci. 2002, 30, 1489–1496.
- Zhadobov, M.; Desmots, F.; Thouroude, D.; Michel, D.; Drean, Y. Evaluation of the potential biological effects of the 60-GHz millimeter waves upon human cells. IEEE Trans. Antennas Propag. 2009, 57, 2949–2956. [CrossRef]
- Zhadobov, M.; Sauleau, R.; Le Coq, L.; Debure, L.; Thouroude, D.; Michel, D.; Le Dréan, Y. Low-power millimeter wave radiations do not alter stress-sensitive gene expression of chaperone proteins. Bioelectromagnetics 2007, 28, 188–196. [CrossRef] [PubMed]
- Aminzadeh, R.; Thielens, A.; Bamba, A.; Kone, L.; Gaillot, D.P.; Lienard, M.; Martens, L.; Joseph, W. On-body calibration and measurements using personal radiofrequency exposimeters in indoor diffuse and specular environments. Bioelectromagnetics 2016, 37, 298–309. [CrossRef] [PubMed]
- Colombi, D.; Thors, B.; Tornevik, C.; Balzano, Q. RF Energy Absorption by Biological Tissues in Close Proximity to Millimeter-Wave 5G Wireless Equipment. IEEE Access 2018, 6, 4974–4981. [CrossRef]
- Neufeld, E.; Carrasco, E.; Murbach, M.; Balzano, Q.; Christ, A.; Kuster, N. Theoretical and numerical assessment of maximally allowable power-density averaging area for conservative electromagnetic exposure assessment above 6 GHz. Bioelectromagnetics 2018, 39, 617–630. [CrossRef] [PubMed]
- Foster, K.R.; Ziskin, M.C.; Balzano, Q. Thermal modeling for the next generation of radiofrequency exposure limits: Commentary. Health Phys. 2017, 113, 41–53. [CrossRef]
- Foster, K.R.; Ziskin, M.C.; Balzano, Q. Thermal Response of Human Skin to Microwave Energy: A Critical Review. Health Phys. 2016, 111, 528–541. [CrossRef]
- Zhadobov, M.; Alekseev, S.I.; Sauleau, R.; Le Page, Y.; Le Drean, Y.; Fesenko, E.E. Microscale temperature and SAR measurements in cell monolayer models exposed to millimeter waves. Bioelectromagnetics 2017, 38, 11–21. [CrossRef]
- Alekseev, S.I.; Gordiienko, O.V.; Ziskin, M.C. Reflection and penetration depth of millimeter waves in murine skin. Bioelectromagnetics 2008, 29, 340–344. [CrossRef]
- Alekseev, S.I.; Radzievsky, A.A.; Logani, M.K.; Ziskin, M.C. Millimeter wave dosimetry of human skin.
Bioelectromagnetics 2008, 29, 65–70. [CrossRef]
- Alekseev, S.I.; Ziskin, M.C.; Fesenko, E.E. Frequency dependence of heating of human skin exposed to millimeter waves. Biophysics 2012, 57, 90–93. [CrossRef]
- Laakso, I.; Morimoto, R.; Heinonen, J.; Jokela, K.; Hirata, A. Human exposure to pulsed fields in the frequency range from 6 to 100 GHz. Phys. Med. Biol. 2017, 62, 6980–6992. [CrossRef]
- Feldman, Y.; Puzenko, A.; Ben Ishai, P.; Caduff, A.; Agranat, A.J. Human skin as arrays of helical antennas in the millimeter and submillimeter wave range. In Proceedings of the 2008 33rd International Conference on Infrared, Millimeter and Terahertz Waves, Pasadena, CA, USA, 27 March 2008; pp. 1–2.
- Shafirstein, G.; Moros, E.G. Modelling millimetre wave propagation and absorption in a high resolution skin model: The effect of sweat glands. Phys. Med. Biol. 2011, 56, 1329. [CrossRef]
- Alekseev, S.I.; Ziskin, M.C. Enhanced absorption of millimeter wave energy in murine subcutaneous blood vessels. Bioelectromagnetics 2011, 32, 423–433. [CrossRef]
- Sasaki, K.; Wake, K.; Watanabe, S. Measurement of the dielectric properties of the epidermis and dermis at frequencies from 0.5 GHz to 110 GHz. Phys. Med. Biol. 2014, 59, 4739–4747. [CrossRef] [PubMed]
- Federal Communications Commission (FCC). Available online: https://www.fcc.gov/general/radio-frequency- safety-0 (accessed on 8 August 2019).
- Foster, K.R.; Morrissey, J.J. Thermal aspects of exposure to radiofrequency energy: Report of a workshop.
Int. J. Hyperth. 2011, 27, 307–319. [CrossRef]