Interaction mechanisms for radio frequency radiation
A distinction that is often used with regard to exposure to higher frequency EM fields is that between thermal and nonthermal effects. However, this division is imprecise since interaction with the EM field always includes energy transfer and therewith usually a local temperature rise. Figure 2.4 shows the two separate paths for thermal and nonthermal effects.
Thermal mechanisms have been known since investigations into therapeutic applications of electricity were carried out based on studies in electromagnetism by Faraday, Ampere, Gauss, and Maxwell, and the
Figure 2.4 Two separate paths for thermal and nonthermal effects.
development of AC sources by d'Arsonval and Tesla. Heating is the primary interaction of EM fields at high frequencies. Excessive heating may lead to biological effects that may cause health implications or may be used in therapy. AT ELF fields, the induction of electric currents in the body, is the dominant action of EM fields.
Temperature is a macroscopic, average parameter of a system in mutual interaction and can be related to the average kinetic energy of the particles. Thermal effects result from the fact that EM fields with high frequencies may be partly absorbed by materials containing water, such as biological tissues, and be converted into heat. Heat resulting from the absorption of EM energy depends on the electrical conductivity of the tissues. The electrical conductivity is only partly due to the translational motion of charged particles, ions. The other main contribution arises from
Figure 2.5 The orientation of permanent electric dipoles.
the hindered rotation of molecules, principally water. The water molecule has a large permanent dipole moment (Figure 2.5), which is randomly oriented in the absence of an applied electric field, which partially orients the dipole moments along the direction of the field. Because of the viscosity of water, the field has to do work to rotate the dipoles, resulting in energy transfer into the liquid as heat. This dissipation mechanism is most effective over a broad range of frequencies .
Nonthermal effects have been increasingly becoming the norm of the current EM research. Occasionally, complaints are made that these nonthermal effects due to low-level RFR are not being considered in the analysis of the scientific information, because they are not used as a basis for establishing EM exposure limits. The second meaning is that intermediate RFR may cause biological effects, without the involvement of heat. This is sometimes referred to as an "athermal effect". In this case, the thermoregulatory system maintains the irradiated body at its normal temperature. Meanwhile, the macroscopic behavior of the body emerges out of quantum dynamics, producing the physics of living matter to a point where biochemistry has to be considered .
Controversy surrounds this matter, especially with intermediate- and low-level RFR. The controversy may be not only scientific, but to a certain extent regulatory and commercial. First, whether RFR at such low levels can cause harmful biological changes in the absence of demonstrable thermal effects. Second, whether effects can occur from RFR when thermoregulation maintains the body temperature at the normal level despite the EM energy deposition, or when thermoregulation is not challenged and there is no significant temperature change. Third, whether effects are considered short- or long-term. In response to the first issue, investigations on the extremely low-level RFR have been conducted and some results confirmed, but the information is yet inconclusive. Regarding the second issue, there can be two meanings in regard to biological effect. It may mean an effect when there is no evident change in temperature or when the exposure level is low enough not to trigger thermoregulation in the biological body under irradiation, suggesting that physiological mechanisms maintain the exposed body at a constant temperature. Such a case is related to the nonthermal effect where the effect occurs through mechanisms other than those due to macroscopic heating. In response to the third issue, short-term effects occur during or shortly after exposure, while long-term effects may not become obvious until long time later. Of course, every long-term effect is always the result of a short-term effect. At a certain point in time, there should have been an interaction between the EM fields and biological tissue.
Thermal and nonthermal effects develop simultaneously, and it is impossible to reach strong enough nonthermal effects with those field strengths which do not cause substantial heating. This old sentence of Schwan should be a slogan of any "nonthermal" research and application. Adair  clearly showed, using biophysical criteria, that continuous RFR with intensity of less than 10 mW/cm2 is unlikely to affect physiology significantly through athermal mechanisms because biological systems are basically noisy both on molecular scale and macroscopically; therefore, the direct physiologically significant effect of EM fields must be greater than that from the pervasive endogenous noise.
Thermal- or nonthermal-based exposure limits?
The existing's EM exposure safety guidelines are based on thermal standards. The idea is that if nonionizing EM fields do not heat the human body, then they cannot possibly cause health implications, even though there is evidence that nonthermal EM fields may cause biological damage. The reason is historical and goes back to the 1950s, after the development of microwave radar technology during World War II, where the military and industrial applications of microwave technology were seen as a greater priority than any potential health effects. During the 1960s and 1970s, economic growth was much more important than the possibility of people's sickness in the future. However, the scientists and regulatory bodies making those decisions during those times could have never envisioned that several decades later, society would be experiencing this enormous escalation in wireless technology that is happening now. Today, we have a situation where the growth in consumer wireless services has created some of the biggest and most profitable companies in the world. Accordingly, addiction to EM technology has quickly become an integral part of our economy and, lately, one of the few reliable driving forces of growth.
With this trend in mind, the thermal-dependent exposure limits elaborated several decades ago are not considered to be enough and should be replaced by new standards based on the nonthermal effects. However, it should be stated that the use of the nonthermal effects are still debatable for many reasons, and lots of development may happen in this direction especially with the advancement of 5G technologies.
By increasing the frequency toward MMWs as is the case for 5G technologies, most of the energy will be absorbed within the human skin and by the shell of the cornea. Since skin contains blood vessels and nerve endings in its dermis layer, effects may be transferred through molecular mechanisms or through the nerves. A review of the research  noted that a number of cellular studies have indicated that MMWs may alter structural and functional properties of membranes and affect the plasma membrane either by modifying ion channel activity or by modifying the phospholipid bilayer. Skin nerve endings are a likely target of MMWs and the possible starting point of numerous biological effects. Also, MMWs may trigger the immune system through stimulation of the peripheral neural system.
Cell membrane and the chemical link
The great puzzle, in regard to interaction of EM fields with biological systems, is that these fields are comprised of low-energy photons, those with insufficient energy to individually influence the chemistry of the cell, raising the question of how nonthermal effects of such EM fields can possibly occur .
The role of cell membranes
Many life scientists, through a series of findings [24-29], believe the cell membrane plays a principal role in the EM interaction mechanisms with biological systems. Indications point to cell membrane receptors as the probable site of initial tissue interactions with EM fields for many neurotransmitters, growth-regulating enzyme expressions, and cancer-promoting chemicals.
Scientists theorizing this mechanism conclude that biological cells are bioelectrochemical structures, which interact with their environment in various ways, including physically, chemically, biochemically, and electrically. According to Dr William Ross Adey at the University of California, Riverside , "The ions, especially calcium ions could play the role of a chemical link between EM fields and life processes. The electrical properties and ion distribution around cells are perfect for establishing effects with external steady oscillating EM fields". He presented a three-step model involving calcium ions, which could explain observed EM-induced bioeffects. Key to the model is the activation of intracellular messenger systems (adenylate cyclase and protein kinase) by calcium in a stimulus amplification process across the cell membrane.
According to Foster ,
Low-frequency electric fields can excite membranes, causing shock or other effects. At power line frequencies, the threshold current density required to produce shock is around 10 A/m2, which corresponds to electric field of 100 V/m in the tissue.
However, electric fields can create pores in cell membranes by inducing electric breakdown. This requires potential differences across the membranes at levels between 0.1 and 1 V, which, in turn, requires electric field in the medium surrounding the cell of at least 105 V/m.
The impact of EM fields may also be understood in terms of amplification and the cooperative sensing associated with simultaneous stimulation of all membrane receptors. Dr Litovitz and his team at the Catholic University of America  hypothesized that oscillating EM fields need to be steady for a certain period of time (approximately 1 s) for a biological response to occur. This allows cells to discriminate external fields from thermal noise fields, even though they might be smaller than the noise fields.
Schwan  indicates that the property of interest is the evoked membrane potential Vm or the evoked field strength in the membrane Em, which is by no means equal to the average tissue field Ea in the medium outside the cell.
where R is the cell radius and d is the membrane thickness. Typical ratios R/d are about 1,000. This means that the membrane field strength is about 1,000-fold stronger than the field in the medium surrounding the cell. Thus, modest field strength values in the medium are significantly amplified in the membrane and, therefore, may be of biological importance.
Voltage-gated calcium channels (VGCCs)
The role of increased intracellular calcium (Ca2+) following EM exposure is well documented in the literature, where Walleczek  reviewed the role of changes in calcium signaling that were produced in response to EM field exposure. The review shows that the L-type voltage-gated channel blocker verapamil could lower or block changes in response to EM fields.
According to Catterall , VGCCs are key transducers of cell surface membrane that allow intracellular Ca2+ in and out of cells and regulates calcium levels. They use electrical signaling and processes to allow certain amounts of calcium to pass through the membrane. They use this electricity to change membrane potentials and therefore cause ions to move through the membrane. VGCC mediate calcium influx in response to membrane depolarization and regulate intracellular processes such as contraction, secretion, neurotransmission, and gene expression in many different cell types. Therefore, VGCCs are the key signal transducers of electrical excitability, converting the electrical signal of the action potential in the cell surface membrane to an intracellular Ca2+ transient.
VGCCs are essential to the responses produced by ELF fields as well as RFR, with the implication that the L-type VGCCs where various L-type (one among many types) calcium channel blockers can block responses to
EM field exposure. L-type Ca2+ appear to be present in all excitable cells, as well as many types of non-excitable cells. In certain cells, L-type channels have been shown to be preferentially localized to specific subcellular regions. For example, the L-type channels responsible for skeletal muscle contraction are concentrated on the transverse tubule membrane, while neuronal L-type channels are located primarily on cell bodies and proximal dendrites. The L-type channel is the primary route for Ca2+ entry into cardiac, skeletal, and smooth muscles .
The current review provides support for a pathway for the biological action of ultralow frequency and microwaves, nanosecond pulses, and static electrical or magnetic fields: EM field activation of VGCCs leads to rapid elevation of intracellular Ca2+, nitric oxide and, in some cases at least, peroxynitrite. Potentially therapeutic effects may be mediated through the Ca2+/nitric oxide/cGMP/protein kinase G pathway. Pathophysiological effects may be mediated through the Ca2+/nitric oxide/peroxynitrite pathway. Other Ca2+-mediated effects may have roles as well, as suggested by Xu et al. .
In regard to establishing protection guidelines, Pall  calls for a paradigm shift away from only thermal effects toward VGCC activation and consequent downstream biological effects.