Below is the next in a series of Guest Blogs on BRHP. The opinions expressed in this Guest Blog are of Arthur Firstenberg himself. Publication of these opinions in BRHP does not imply that BRHP automatically agrees with or endorses these opinions. Publication of this, and other Guest Blogs, facilitates an open debate and free exchange of opinions on wireless technology and health.
Critique of Martin Pall’s VGCC Hypothesis
by Arthur Firstenberg
Santa Fe, New Mexico, June 30, 2019
1. General Critique
Martin Pall hypothesizes that electromagnetic fields (EMFs) act primarily via a highly sensitive effect on voltage gated calcium channels (VGCCs) located in the membranes of all cells. He published his theory in a 2013 paper titled “Electromagnetic fields act via activation of voltage-gated calcium channels to produce beneficial or adverse effects,” J. Cell. Mol. Med. Vol 17, No 8, 2013, pp. 958-965. In that paper and others Pall lists 28 studies that found that calcium channel blockers prevented a wide variety of biological effects caused by EMFs. He concluded that therefore the primary target of EMFs must be the calcium channels. I find his theory unconvincing.
Pall’s reasoning is faulty. Calcium is necessary for hundreds of physiological processes that are affected by EMFs. If you prevent calcium from coming into the cell by using a calcium channel blocker, you will stop all of those physiological processes and prevent the EMF effects. That does not tell you anything about the mechanism of action of EMFs. If EMFs act directly on any function that requires calcium, the calcium channel blocker will prevent it. If EMFs instead act on the calcium channel itself, the calcium channel blocker will also prevent it. There is no way to distinguish whether EMFs act directly on the end mechanism or on the supplier of calcium to the end mechanism. Pall points to the “instantaneous” action of EMFs (taking less than 5 seconds) found in one study (Pilla 2012). However Pilla’s study (See Study No. 25, below) also does not prove where the locus of action of the EMFs in that study is.
Some common examples will make this clear. Calcium channel blockers are used in medicine to treat a variety of conditions, including hypertension, coronary artery disease, angina, arrhythmia, Reynaud’s disease, migraine headaches, brain hemorrhage, and high cholesterol. That does not mean that those conditions are caused by the calcium channels. For example, a calcium channel blocker will prevent vasospasm after a subarachnoid hemorrhage That does not mean that the hemorrhage or vasospasm is caused by the calcium channel.
A further caution: calcium channel blockers are pharmaceuticals and all pharmaceuticals have multiple effects. If a pharmaceutical that is known as a calcium channel blocker stops an EMF effect, you do not necessarily know whether it accomplishes this by acting on the calcium channel or by some other mechanism entirely. For example, you can reduce cholesterol with the calcium channel blocker amlopidine, but it turns out that this is an independent effect of this drug that has nothing to do with its effects on calcium channels.
2. Critique of the 28 Specific Studies
Pall asserts that EMFs are biologically active at extremely low levels of exposure because VGCCs are exquisitely sensitive to EMFs. He asserts via various arguments that VGCCs are 7.2 million times more sensitive to EMFs than the aqueous parts of the cell. Only 1 of the 28 studies cited in his reviews was done at such minute levels of exposure, and none of the studies fully supports his hypothesis. A few of them contradict his hypothesis. Some of the studies required exposure to very high levels of EMFs for long periods of time to produce the effects found. I review the 28 studies here:
#1. Cadossi R et al., Lymphocytes and Pulsing Magnetic Fields, In: Marino EE, editor, Modern Bioelectricity, New York: Dekker 1998, pp. 451–96.
These authors used pulsed 2 – 2.8 mT magnetic fields for 72 hours, which is about 50 times as strong as the Earth’s magnetic field. Even at such high exposure levels, they wrote that “The effect of PEMFs could not be explained solely as a consequence of the increased Ca++ influx, so some other cellular targets had to be involved.”
#2. Papatheofanis FJ, Use of calcium channel antagonists as magnetoprotective agents, Radiat Res. 1990 Apr;122(1):24-8.
The exposure level was 0.1 Tesla, which is 2,000 times as strong as the Earth’s magnetic field, for one hour.
#3. Morgado-Valle C et al., The role of voltage-gated Ca2+ channels in neurite growth of cultured chromaffin cells induced by extremely low frequency (ELF) magnetic field stimulation, Cell Tissue Res (1998) 291:217±230.
The exposure level was 7 Gauss for six days. This is 15 times as strong as the Earth’s magnetic field. The authors noted that the cells had to be placed in acrylic rather than steel racks to prevent temperature increases from the powerful magnetic field.
#4. Lorich DG et al., Biochemical pathway mediating the response of bone cells to capacitive coupling, Clin Orthop Relat Res. 1998 May;(350):246-56.
Bone cells were stimulated by EMFs. This was prevented by a calcium channel blocker. The exposure level was a 20 mV/cm (= 2 V/m) electric field. This study provides some support for Pall’s hypothesis, but the exposure level was not tiny.
#5. Gobba F et al., Effects of 50 Hz magnetic fields on fMLP-induced shape changes in invertebrate immunocytes: The role of calcium ion channels, Bioelectromagnetics2003 May;24(4):277-82.
The exposure was to a 50 Hz magnetic field at 300 microTesla, which is 10,000 times as strong as fields commonly found in homes. The authors reported that the magnetic field damaged, rather than stimulated, the VGCCs, so that calcium transport was prevented by the magnetic field. That is the opposite of Pall’s hypothesis.
#6. Lisi A. et al., Extremely low frequency electromagnetic field exposure promotes differentiation of pituitary corticotrope-derived AtT20 D16V cells, Bioelectromagnetics 2006 Dec;27(8):641-51.
EMFs promoted cell differentiation and this was prevented by calcium channel blockers. The cells were exposed to a 50 Hz magnetic field at 2 mT, which is 100,000 times as strong as fields commonly found in homes.
#7. Piacentini R et al., Extremely low-frequency electromagnetic fields promote in vitro neurogenesis via upregulation of Ca(v)1-channel activity, J Cell Physiol. 2008 Apr;215(1):129-39.
Neurogenesis was increased by EMFs and this was prevented by a calcium channel blocker. Again, the level of exposure was extremely high: 50 Hz magnetic field at 1 mT.
#8. Morris CE and Skalak TC, Acute exposure to a moderate strength static magnetic field reduces edema formation in rats, Am J Physiol Heart Circ Physiol 294:H50-H57, 2008.
In this experiment, a static magnetic field of strength 10 to 70 mT for 15 to 30 minutes reduced edema, while higher strengths did not reduce edema. This is not only a very high exposure level but contradicts Pall’s hypothesis that EMFs act on VGCCs in a dose-related manner.
#9. Ghibelli L et al., NMR exposure sensitizes tumor cells to apoptosis, Apoptosis 2006; 11: 359–365.
NMR caused apoptosis (cell death), and the effect was prevented by a calcium channel blocker. This provides some support for Pall’s hypothesis, but the levels of exposure were quite high: a static magnetic field of 0.3 – 66 mT.
#10. Fanelli C et al., Magnetic fields increase cell survival by inhibiting apoptosis via modulation of Ca2/ influx, FASEB J 13:95-102 (1999).
Static magnetic fields of 6 Gauss and higher (15 times stronger than the Earth’s field) prevented apoptosis (cell death). Fields of lower strength were without effect. It required one hour of exposure to have any effect.
#11. Jeong JH et al., Extremely low frequency magnetic field induces hyperalgesia in mice modulated by nitric oxide synthesis, Life Sci. 2006;78(13):1407-12.
EMFs lowered pain threshold. This was prevented by a calcium channel blocker. Exposure was to a 60 Hz magnetic field at 1.5 mT, again a very high exposure level.
#12. Vernier PT, Nanosecond electric pulse-induced calcium entry into chromaffin cells, Bioelectrochemistry 73(1): 1-4 (2008).
Nanosecond pulses of 2 MV/m (2 million volts per meter!) up to 8 MV/m induced calcium entry into adrenal cells.
#13. Kim IS et al., Novel Effect of Biphasic Electric Current on In Vitro Osteogenesis and Cytokine Production in Human Mesenchymal Stromal Cells, Tissue Engineering: Part A 15: 2411-22 (2009).
Bone formation was stimulated by a 100 Hz magnetic field at a strength of 1.5 or 15 microAmps per square centimeter for 250 or 25 microseconds at a time for 5 days. Cell proliferation was increased during stimulation, but calcium deposition did not occur until 7 days after electrical stimulation.
#14. Höjevik P et al., Ca2+ ion transport through patch-clamped cells exposed to magnetic fields, Bioelectromagnetics 1995;16(1):33-40.
Calcium transport across cell membranes has been shown in many studies to be enhanced by AC fields at particular frequencies, which have been hypothesized to be cyclotron resonances. This experiment showed that the VGCCs did not show any resonant behavior in the frequency range studied, indicating that the VGCCs are not involved in this phenomenon.
#15. E. Barbier et al., Stimulation of Ca2+ influx in rat pituitary cells under exposure to a 50 Hz magnetic field, Bioelectromagnetics 17(4): 303-311 (1996).
Exposure was to 50 Hz, 50 microTesla, for 30 minutes. Calcium influx caused by the magnetic fields was not completely blocked by calcium channel blockers, leading the investigators to suspect a direct effect on mitochondrial processes.
#16. C. Grassi et al., Effects of 50 Hz electromagnetic fields on voltage-gated Ca2+ channels and their role in modulation of neuroendocrine cell proliferation and death, Cell Calcium. 2004 Apr;35(4):307-15.
Exposure was to 50 Hz electric fields. Increased calcium transport into cells was proven not to be due to stimulation of the calcium channels, but rather to an increase in the number of calcium channels.
#17. GL Craviso et al., Nanosecond electric pulses: a novel stimulus for triggering Ca2+ influx into chromaffin cells via voltage-gated Ca2+ channels, Cell Mol Neurobiol. 2010 Nov;30(8):1259-65.
5 nanosecond, 5 MV/m (5 million volts per meter) electric pulses stimulated calcium influx. But calcium influx was not stimulated if the extracellular potassium concentration was reduced or the cells were in a sodium-free medium.
#18. I. Marchionni et al., Comparison between low-level 50 Hz and 900 MHz electromagnetic stimulation on single channel ionic currents and on firing frequency in dorsal root ganglion isolated neurons, Biochimica et Biophysica Acta 1758 (2006) 597–605.
Reviewing the literature on EMF exposure, these authors state: “Changes in transmembrane voltages are probably responsible for the mobilization of intracellular calcium described in some previous studies but not confirmed in others.” They conclude that there must be more than one mechanism for the effects of EMFs. In their own experiments they found that 50 or 60 Hz altered the firing rate of rat sensory neurons while 900 MHz did not alter the rate. They found that at 50 Hz, a field intensity of 125 microT (3 times as strong as the Earth’s field) was the most effective power level.
#19. Rao VS et al., Nonthermal effects of radiofrequency-field exposure on calcium dynamics in stem cell-derived neuronal cells: elucidation of calcium pathways, Radiat Res. 2008; 169: 319–29.
Exposure was to radio frequency radiation at frequencies of 700 to 1100 MHz and SAR levels of 0.5 to 5 W/kg. 5 W/kg is a thermal level, causing heat. Spikes in intracellular calcium were dependent on frequency and not on power level, again failing to provide support for Pall’s hypothesis.
#20. RK Adair et al., Detection of weak electric fields by sharks, rays, and skates, Chaos 8(3):576-587 (1998).
These authors theorize that detection of ultra-weak electric fields by sharks occurs via VGCCs. This is a theoretical model only and is not based on any actual experiments.
#21. PA Constable, Nifedipine alters the light-rise of the electro-oculogram in man, Graefes Arch Clin Exp Ophthalmol. 2011 May;249(5):677-84.
This is not a study on EMFs, but rather a study on the effect of light on the human eye. Light does not act on the eye or on any other part of the human body via voltage-gated calcium channels. See Banghart M, Light-activated ion channels for remote control of neuronal firing, Nat Neurosci, 2004 Dec; 7(12): 1381–1386 (“Neurons have ion channels that are directly gated by voltage, ligands and temperature but not by light).” Light-gated ion channels have been discovered only in some algae and bacteria, and none of them are calcium channels.
This study nevertheless asked what effect a calcium channel blocker has on the eye. The results did not shed much light on the question. In one-third of the subjects the eye’s response to light increased in the presence of a calcium channel blocker, in one-third of the subjects the response to light decreased, and in one-third of the subjects there was no change.
#22. J. Gmitrov and C. Ohkubo, Verapamil protective effect on natural and artificial magnetic field cardiovascular impact, Bioelectromagnetics 2002 Oct;23(7):531-41.
These authors investigated the effects of magnetic fields on the response of blood pressure and heart rate to certain drugs. They found that an artificial magnetic field had the opposite effect from the natural geomagnetic field, and that calcium channel blockers blocked both effects.
#23. Andrei L. Kindzelskii et al, Ion channel clustering enhances weak electric field detection by neutrophils: apparent roles of SKF96365-sensitive cation channels and myeloperoxidase trafficking in cellular responses, Eur Biophys J (2005) 35: 1–26.
Exposure was to 200 ms pulses of square wave DC electric fields. The minimum effective field strength was 0.0001 V/m. This is the only one of the 28 studies that was done at the kinds of minute exposure levels consistent with Pall’s hypothesis. However, even this study does not provide complete support for the hypothesis that calcium channels are the main locus for EMF effects in animals, because the electric field effects on neutrophils in this study were blocked not only by calcium channel blockers but also by potassium channel blockers.
#24. J. Xu et al, Signal transduction in electrically stimulated articular chondrocytes involves translocation of extracellular calcium through voltage-gated channels, Osteoarthritis and Cartilage 17: 397-405 (2009).
This is a study of gene induction and gene suppression by electric fields. Exposure was to 60 Hz at 20 mV/cm (= 2 V/m), which is not tiny, for 1 or 6 hours. Calcium channel blockers prevented the effects, providing some support for Pall’s hypothesis.
#25. Arthur A. Pilla, Electromagnetic fields instantaneously modulate nitric oxide signaling in challenged biological systems, Biochemical and Biophysical Research Communications 426: 330-333 (2012).
The author wrote: “The Ca/CaM-dependent NO cascade is an important and early response to physical, chemical or thermal injury.” In other words, nitric oxide release from cells is a response to injury. EMFs (27.12 MHz, 31-51 V/m, pulse modulated at 2 Hz) caused nitric oxide release in this study, which was blocked by a calcium channel blocker. All this proves is that EMFs at very high levels of exposure cause injury. It does not tell us the nature or the mechanism of the injury. Thermal injury causes the same nitric oxide release and is blocked by the same calcium channel blocker, but we do not conclude that the VGCC is the mechanism of thermal injury, it is only part of the response to the injury.
#26. T. Takieh et al., Effects of electromagnetic field exposure on conduction and concentration of voltage gated calcium channels: A Brownian dynamics study, Brain Research 1646: 560-569 (2016).
Takieh’s paper is based on a computer simulation and is not a result of any actual experiments.
#27. Lu XW et al., Effects of moderate static magnetic fields on the voltage-gated sodium and calcium channels currents in trigeminal ganglion neurons, Electromagn Bio. Med 34, 285–292 (2015).
Neurons were exposed to 125 mT and 12.5 mT magnetic fields. Both sodium and calcium channels were examined. The activation threshold, inactivation threshold, and velocity of the ion currents were altered, but not the magnitude of the current. No change in calcium or sodium current density occurred when the cells were exposed to these extremely high fields.
#28. Zhang J et al., Electrical stimulation of adipose-derived mesenchymal stem cells in conductive scaffolds and the roles of voltage-gated ion channels, Acta Biomater 32, 46–56 (2016).
Human stem cells were stimulated with 200 microamperes of direct current for 4 hours per days. After 21 days of stimulation, the amount of calcium deposited by the cells doubled. This effect was completely blocked by a calcium channel blocker, and partially blocked by a sodium channel blocker, a potassium channel blocker, and a chloride channel blocker.