Review Article A NEUROBIOLOGICAL BASIS FOR ELF GUIDELINES Richard D. Saunders* and John G. R. Jefferys† established literature describing these effects (reviewed, Abstract—It is well understood that electric currents applied for example, by Reilly 1998), mostly in relation to directly to the body can stimulate peripheral nerve and muscle tissue; such effects can be fatal if breathing is inhibited or electric current passing through the body as a result of ventricular fibrillation is induced. Exposure to extremely low inadvertent contact with a “live” conductor. Regulations frequency electric and magnetic fields will also induce electric which seek to prevent or minimize the effects of such fields and currents within the body, but these are almost contact have long been accepted world-wide. Exposure always much lower than those that can stimulate peripheral nerve tissue. Guidance on exposure to such fields is based on to extremely low frequency (ELF) electric and magnetic the avoidance of acute effects in the central nervous system. fields will also induce electric fields and currents within This paper reviews the physiological processes involved in the body, but these are almost always much lower than nerve cell excitability in the peripheral and central nervous those that can stimulate peripheral nerve tissue. Guidance system, and the experimental evidence for physiologically weak electric field effects. It is concluded that the integrative on exposure to such fields is published by ICNIRP properties of the synapses and neural networks of the central (1998) and IEEE (2002) and is based on the avoidance of nervous system render cognitive function sensitive to the acute effects in the central nervous system (CNS). This effects of physiologically weak electric fields, below the thresh- review briefly describes the physiological processes in- old for peripheral nerve stimulation. However, the only direct evidence of these weak field interactions within the central volved in nerve cell excitability in the peripheral and nervous system is the induction of phosphenes in humans—the central nervous system and the experimental evidence for perception of faint flickering light in the periphery of the physiologically weak electric field effects, reviewed at an visual field, by magnetic field exposure. Other tissues are ICNIRP/WHO workshop (McKinlay and Repacholi potentially sensitive to induced electric fields through effects on voltage-gated ion channels, but the sensitivity of these ion 2003), along with data from more recent studies. The channels is likely to be lower than those of nerve and muscle evidence for other possible health effects resulting from cells specialized for rapid electrical signaling. In addition, such EMF exposure have been reviewed elsewhere (e.g., tissues lack the integrative properties of synapses and neuronal ICNIRP 2003; McKinlay et al. 2004; WHO in press) and networks that render the central nervous system potentially more vulnerable. are not considered here. Health Phys. 92(6):596–603; 2007 Key words: electromagnetic fields; radiation, non-ionizing; VOLTAGE-GATED ION CHANNELS health effects; radiation protection Voltage-gated ion channels in cell membranes allow passage of particular ionic species across the cell mem- INTRODUCTION brane in response to the opening of a “gate,” which is ITISwell understood that electric currents applied di- sensitive to the transmembrane voltage (e.g., Catterall rectly to the body can stimulate peripheral nerve and 1995; Bezanilla 2000; Hille 2001; Mathie et al. 2003). It muscle tissue; such effects can be fatal if breathing is is well established that electric fields induced in the body inhibited or ventricular fibrillation is induced. There is an either by direct contact with external electrodes, or by exposure to low frequency magnetic fields, will, if of * Health Protection Agency, Centre for Radiation, Chemical and sufficient magnitude, excite nerve tissue through their Environmental Hazards Radiation Protection Division, Chilton, Did- interaction with these voltage-gated ion channels. The cot, Oxfordshire, OX11 0RQ, United Kingdom; † Division of Neuro- science (Neurophysiology), School of Medicine, The University of probability of an ion channel being open is regulated by Birmingham, Birmingham, B15 2TT, United Kingdom. the transmembrane voltage or membrane potential. This For correspondence contact: R. D. Saunders, Health Protection is achieved through the action of a voltage sensor, an Agency, Centre for Radiation, Chemical and Environmental Hazards Radiation Protection Division, Chilton, Didcot, Oxfordshire, OX11 electric dipole reorientation or charge movement within 0RQ, United Kingdom, or email at [email protected]. the ion channel protein, which induces a conformational (Manuscript accepted 21 December 2006) 0017-9078/07/0 change in the ion channel molecule favoring an open Copyright © 2007 Health Physics Society conformation or two distinct closed conformations, one 596 A neurobiological basis for ELF guidelines ● R. D. SAUNDERS AND J. G. R. JEFFERYS 597 capable of opening and the other being inactivated. in humans. Reilly (1998, 1999) calculated induced elec- Sensitivity is therefore primarily to the transmembrane tric field threshold values for peripheral nerve stimula- electric field but varies widely between different ion tion based on the changes in sodium and potassium channels (Hille 2001; Saunders and Jefferys 2002; conductance originally described by Hodgkin and Huxley Mathie et al. 2003). Many voltage-gated ion channels are (1952) and Frankenhaeuser and Huxley (1964). Mini- associated with electrical excitability and electrical sig- mum, orientation-dependent stimulus thresholds for large naling. Such electrically excitable cells not only com- diameter (20 ␮m) myelinated nerve axons were esti- Ϫ1 prise neurons, glial and muscle cells, but also gametes mated to lie around 6pk-pk Vm at frequencies up to and endocrine cells of the anterior pituitary, adrenal about 1–3 kHz. Electric field thresholds were estimated medulla, and pancreas (Hille 2001). to be larger for smaller diameter neurons. Above this All these cells generally express voltage-gated so- range, thresholds rise as the effective stimulus becomes dium and calcium channels. Both of these ion channels shorter than the membrane time-constant. The time- are involved in electrical signaling and calcium ions constant results from the structure of biological mem- activate a number of crucial cellular processes including branes: the thin lipid membrane behaves as a capacitance neurotransmitter release, excitation-contraction coupling while the ion channels provide a parallel resistance. At in muscle cells and gene expression (Catterall 2000; frequencies below around 10 Hz, accommodation to a Hille 2001). Some ion channels, for example voltage- slowly changing stimulus, which results from the slow gated potassium and chloride ion channels, also exist in inactivation of sodium channels, will also raise thresh- other, non-excitable tissues such as those in the kidney olds. In MRI, nerve stimulation is an unwanted side and liver and show slow electric potential changes, but effect of a procedure used to derive cross-sectional their voltage sensitivity is likely to be lower (e.g., Jan and images of the body for clinical diagnosis. Threshold rates Jan 1989; Begenisich and Melvin 1998; Catterall 2000; of change of the switched gradient magnetic fields used Cahalan et al. 2001; Nilius and Droogmans 2001). in MRI for perception, discomfort, and pain resulting from peripheral nerve stimulation have been exten- sively reviewed by Nyenhuis et al. (2001). Generally, PERIPHERAL NERVOUS SYSTEM median, minimum threshold rates of change of magnetic field (during periods of Ͻ1 ms) for perception were Peripheral nerves comprise neurons whose cell bod- 15–25 T sϪ1 depending on orientation and showed ies are located within the CNS with extended processes considerable individual variation (Bourland et al. 1999). (axons) that lie outside the CNS. They conduct action These values were somewhat lower than previously potentials (impulses) towards (sensory nerves) or from estimated by Reilly (1998, 1999), possibly due to the (motor nerves) the spinal cord, and nerve stimulation constriction of eddy current flow by high impedance shows an all-or-nothing threshold behavior. An action tissue such as bone (Nyenhuis et al. 2001). Thresholds potential is a brief, self-sustaining wave of electrical rose as the pulse width of the current induced by the depolarization that passes along the nerve axon and is switched gradient field decreased; the median pulse caused by an influx of sodium ions following the opening width (the chronaxie) corresponding to a doubling of the of transient voltage-gated sodium channels. This is rap- minimum threshold (the rheobase) ranged between 360 idly followed by a slower, longer lasting increase in and 380 ␮s but again showing considerable individual potassium ion conductance, which repolarizes the nerve variation (Bourland et al. 1999). Numerical calculations membrane and results in a short refractory period during of the electric field induced by pulses in the 84 subjects which further stimulation is either not possible or is tested by Nyenhuis et al. (2001) have been used to difficult. At power frequencies (50/60 Hz) for example, estimate the median threshold for peripheral nerve stim- excitation results from a membrane depolarization of ulation at 60 Hz as 48 mT (Bailey and Nyenhuis 2005).