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Minireview biological effects of magnetic fields
Life Sciences, Vol. 49, pp. 85-92 Printed in the U.S.A.
Pergamon Press
MINIREVIEW BIOLOGICAL EFFECTS OF MAGNETIC FIELDS Marco Villa (a), Piercarlo Mustarelli (a) and Marco Caprotti (b) (a) Laboratorio NMR c/o Dip. Chimica Fisica, Via Taramelli 16, 27100 Pavia, Italy (b) Fondazione Clinica del Lavoro, Via Severino Boezio 26, 27100 Pavia, Italy (Received in final form April 23, 1991)
Summary The literature about the biological effects of magnetic fields is reviewed. We begin by discussing the weak and/or time variable fields, responsible for subtle changes in the circadian rhythms of superior animals, which are believed to be induced by same sort of "resonant mechanism". The safety issues related with the strong magnetic fields and gradients generated by clinical NMR magnets are then considered. The last portion summarizes the debate about the biological effects of strong and uniform magnetic fields. Today, a growing number of researchers are accepting the notion that subtle interactions exist between magnetic fields (B) and biological systems; a new discipline is taking shape which may be called magneto-biology. However, as the most recent overviews of the subject imply (1, 2, 3), there is still very little understanding of the interaction mechanisms between B-fields and living matter, and it is still quite difficult to organize the experimental findings into a coherent phenomenological picture; in addition, poorly performed or documented experiments and bitter contentions, both in the scientific literature and in public policy discussions about safety regulation, have certainly not helped the image of the discipline, or contributed to the authority of its researchers. On the positive side, the quality of the experimental work seems now to improve rapidly, as journals specialize in this topic and entire research teams give the matter continued attention. Furthermore, the spreading of magnetic resonance imaging (MRI) and spectroscopy (MRS) equipments in clinical environments add urgency to the need of defining meaningful guidelines for exposure to magnetic fields (4). A short catalogue of the three sets of items which define most experimental activities, i.e. stimulus, system and response, may give an idea of the complexity of magneto-biology. i) The stimulus. A large variety of experimental protocols have been explored, with static or time-varying magnetic fields, with weak geomagnetic-type of fields (10-3-10 -5 Tesla) or with the strong fields of NMR magnets (10-1-10 Tesla), with uniform or inhomogeneous fields with large gradients, with prolonged (more than few hours), short or intermittent exposure of either stationary or mobile systems. ii) The system may be an specially designed model system (a membrane, an artificial artery, etc), a simple organism, a tissue, an egg, an organ, an insect, a vertebrate.
0024-3205/91 $3.00 +.00 Copyright (c) 1991 Pergamon Press plc
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iii)
The system response may be evaluated with biochemical, physiological or behavioural indicators, or with parameters describing morphology, growth, development, reproductive rates, population statistics, etc. With the assistance of well established concepts about the interaction of electromagnetic fields and matter, we will now present a critical review of the most recent results, which have been ordered according to the type of exposure protocol.
Time-varvina fields v
For characteristic rates of change above v>105 Hz, the most energetic coupling between biological matter and electromagnetic radiation is likely to be the interaction between ionic charges and the electric field, E, associated with the derivative of the magnetic field, B, with respect to the time (dB/dt). It follows that the question of radiofrequency power deposition does not belong to magneto-biology, although it is a major safety issue for clinical MRI & MRS applications, and it has often been reviewed together with true magneto-biologic effects (3, 5). While the effects of fast switched B-field of the type used in neurology as a convenient substitute of an electric stimulus (dB/dt up to 105 Tesla/s) should obviously not enter a review of magnetobiologic effects, we are unable to make any statement about the relative importance of the electric and magnetic interaction for many of the experiments with pulsed magnetic field reported in the literature. As examples, we may quote i) the recent work of Peeling et al. (6) which found that pulsed magnetic fields and gradients (103 Tesla/s, with 1 Hz repetition rate) inhibit the growth of a nematode; ii) reviews (5,7) describing range of phenomena, including resonant and "windowed" interactions, observed when an electromagnetic stimulus is periodically applied to the biological matter, iii) the devices commonly used by orthopedists in "electromagnetic therapies", which are believed to assist fracture-healing and tissue-regeneration processes (8). On the other hand, if the B-field varies slowly enough to warrant that the associated electric and heating effects are negligible, we should have true magneto-biologic effects. An early behavioural study of Persinger (9) has been repeated by Rudolph et al. (10) and Thomas et al. (11), who found that exposure of rats to weak oscillating (typically 50 Hz) B-field modifies their open field response, in particular by increasing the rearing activity. Kavaliers and Ossenkopp (12, 13, 14) found that slowly changing (0.5 Hz) and weak (0.15-9 mTesla) magnetic fields have significant and differential inhibitory influences on various opioid systems in rodents and snails.
Magnetic field ~radients We distinguish three different interactions which, in order of increasing importance, are i) displacement of a magnetic dipole in a Bx--dB/dx gradient. For free particles with a dipole of g=9.3.10 -24 J/Tesla (electronic magnetic moment) and an elementary electronic charge e=l.6.10 -19 C, this interaction is equivalent to that of an electric field IXBx/e, or about 60 mV/cm for an enormous 101 Tesla/cm gradient. As long as the biological structures do not carry a permanent magnetic dipole orders of magnitude larger than the electronic magnetic moment, as is possibly the case of hemoglobin in sickled red cells (15), the interaction is expected to be negligible. ii) Displacing with a velocity, v, a material of conductivity, a, in a gradient B x = dB/dx causes a Faraday current of density proportional to ~.vx-B x, or about 1 mA/cm 2 in the tissues of a man (a - 0.5 Siemens/m) walking (v = 1 m/s) near a magnet with B x = 2 Tesla/m. People
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working near an experimental 4 Tesla whole body magnet (16, 17) experiences sensorial perceptions (vision flash, metallic taste), which we believe are due to the Faraday currents, but which produce no apparent harm. Paramagnetic structures acquire a magnetization proportional to B, and experience a force proportional to B-B x. The blood flow in large vessels may be distorted by the combination of strong gradients and strong B-fields. A simple model system has been set up by Okazaki et al. (18) which studied the flow of different blood cocktails in a B gradient (B = 0.6 Tesla, B x = 0.5 Tesla/cm, for a B.B x = 0.3 T2/cm). The expected magnetohydrodynamic effects are observed, which predictably increase with the hematocrit level.
$~a~i¢ and uniform maenetic fields a) Weak fields Under this heading we cover studies of the effects of static field of the order of (or smaller than) 10-4 Tesla, i.e. comparable with the earth field (2.10 -5 Tesla). The matter has been recently reviewed in (2). In a series of reports, different groups of researchers have shown that exposure to weak magnetic fields depresses the pineal gland activity in rodents and pigeons. In particular, inversion for one hour during the night of the horizontal component of the geomagnetic field substantially lowers the levels of melatonin and of enzymes associated with its synthesis (e.g. serotonin-Nacetyltransferase), as well as the levels of cyclic adenosine monophosphate (19,20,21, 22, 23, 24). Similar experiments with much stronger fields (B =0.14 Tesla, (25)) and in an artificial field exactly compensating the earth field 03 = 0, (26)) did not revealed any alteration of the pineal circadian rhythm; these findings point to the existence of a "magnetic window", i.e. to a range of B-intensities to which the pineal gland responds (2). Detection of geomagnetic fields seems to involve the visual system. While it was known that photic stimuli alter the pineal function (27), the hypothesis is strongly supported by recent experiments: blind mice, or mice kept in total darkness, do not respond to inversion of the geomagnetic field, while mice in dim light do (2, 23, 25). Many researchers have hypothesized that some species use detection of the earth's field as an aid to navigation. Behavioural data collected by Mather and Baker (28) suggest that the European wood mouse resorts to magnetic cues for direction finding when visual and olfactory stimuli are withdrawn or give conflicting information. In another behavioural experiment (29), the rates of homing were measured for pigeons released in places with different magnetic declinations after being exposed for few minutes to a "demagnetizing" field (B = 0.1 Tesla). Both local geomagnetic irregularities and the demagnetization procedure appears to slightly hinder the homing, and the effect is more evident in young (less experienced ?) pigeons. However, the behavioural response seems to be weak or ambiguous, since other researchers have apparently been unable to reproduce the Mather and Baker results (2). Different mechanisms have been invoked to explain the results of these findings: Mather and Baker (28) tried to test the hypothesis of the existence of ferromagnetic structures, while Kalmijn (30) suggests a mechanism based upon magnetic induction. Leask (31) invokes the presence of magnetized particles and an optical pumping mechanism at the level of photoreceptors, which would naturally explains the absence of a response in exposed blind mice (2) and the changes of catecholamine levels of retina in mice exposed to B-fields at night (23). Beers (3) has recently reviewed an interesting class of experiments which may be listed under the heading of "Magnetic Resonance" and may eventually provide a clue of the mechanism
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on which the magnetoreceptors are based: combined exposure to a weak B-field and to an oscillating E-field with frequency related to the B-intensity induces a substantial enhancement of the Ca ++ efflux from cells in culture. It has been suggested that this phenomenon is related to the cyclotron frequency of the ions (32) (v = q.B/m, or about 102 Hz for the earth field and the Ca ++ ion), but no generally accepted explanation has been developed yet. The motion of an ion in a viscous medium under the influence of static and oscillating magnetic fields has been studied by Durney et al. (33) and by Halle (34) which conclude that cyclotron resonance is unlikely to be the mechanism for the resonant response of a biological system. b) Strong fields It is well known that strong magnetic fields may have harmful effects on humans through interaction with implanted devices containing ferromagnetic parts, such as pace-makers and surgical clips. However, this matter is a safety issue and does not pertain to magneto-biology. A uniform magnetic field is expected to deflect a moving charge (Lorentz force) and to align the magnetic moments within the biological matter. The electric field associated with the Lorentz force is proportional to the charge velocity (v) and to B; when charges are moved by an electric potential, v is expected to be extremely small, and, as far as we known, only one research group has succeeded in measuring the Lorentz force potential (Hall effect) in an ionic system (a solid electrolyte). The situation is different when a charged fluid like blood is mechanically displaced in a B-field; the potential difference generated across the aorta can be large enough to be observed in an electrocardiogram, and also a small increase in blood pressure is expected (1). No permanent harm or permanent effect is expect from such magnetohydrodynamic interaction. The energy of interaction between the magnetic moment of an electron and the largest Bfields ever produced (about 30Tesla) is a fraction (-0.1) of the thermal energy at room temperature ( k T = - 4 - 1 0 -21 J). For these reason, most MRI people do not even consider the possibility that exposure to their static and homogeneous B fields may affect the biological functions of patients or animals; when they do, a statement is usually included about the absence of any observable biological consequence of the exposure (35). Others (e.g. (36)) study the response of experimental animals to the full NMR-imaging procedure (which involves also rf power deposition and exposure to magnetic gradients switching at audio frequencies), and conclude that no harmful or permanent effect is due to MRI. Some NMR specialists (37, 38) have performed long-term exposure experiments with rodents to demonstrate how safe the MRI fields are. The absence of observable effects of strong B-fields on behaviour, growth, circadian rhythms, immune response, reproduction and survival rates, of rodents has been reviewed by Miller (1). Recently, Peeling et al. (6) found that continuous exposure to a 2 Tesla field, or to a 6 Tesla/m gradient, does not modify the 4-days long development cycle of the nematode Panagrellus redivivus. Also NGO et al (39) found that DNA synthesis in Chinese hamster V79 cells is not affected by prolonged exposure to a 0.75 Tesla field. An opposite conclusion is reached by Barnothy (40, 41) and Laforge et al. (42, 43) which reported weight reduction, organ anomalies, and behavioural modifications in mice and rats exposed to strong static fields. In a number of reports that appeared in 1986, a Polish research group found that intermittent exposure (1 hour per day per several weeks) to static fields (0.005 to 0.3 Tesla) disturbs the respiration of mitochondria in liver cells of rats (44), accelerate the thrombolytic process in rabbits (45), increases the fibrinogen degradation products in the serum of rabbits with thrombosis (46), and decreases the activity of glutamic pyruvic transaminase in the serum of guinea pigs (47). These changes are apparently unrelated to the field intensity, and observable, or even most evident, at the lowest fields.
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No one of all the effects reviewed so far has proven to be permanent; weeks or months after exposure, the animals show no longer significant differences relative to their control. Our studies of behavior of weaning mice exposed for one week to strong fields according to different protocols (fields from 1 to 8.5 Tesla, continuous or intermittent exposure) agree with this conclusion. At the end of treatment, the exposed mice showed generic stress-like effects: reduced exploratory activity in the open field, sometimes accompanied by reduced body weight. However, control and exposed animals behaved the same way after one month. Several reports on the effects of short time (up to few hours) exposure to B fields are byproducts of NMR studies: the MRI fields apparently increase the free calcium concentration in HL60 promyelocytic cells (48), and predentin formation in rodents (49). The skin and body temperature of patients increases by fractions of a degree in a 1.5 Tesla imager (50); since thermocouple readings may be affected by B, and details of air convection within the magnet bore are not given, we may wonder what the temperature readings would be when a phantom is used in place of the patients. Rosen and Lubowsky (51) measured the visual evoked response in cats exposed to a 0.12 Tesla field; an exposure longer than 50 s significantly reduces the cortical excitability, and the effect persists few minutes after the field has been turned off. The action of the B field on the synapse, rather than on axonal conduction, is believed to provide the mechanism of the effect. These studies seldom attempt to determine whether the exposure effects are proportional to a "dose" (product of B-intensity and exposure time) or if some threshold exists. An exception is the work by Hong et al. (52) which exposed rats to fields up to 1 Tesla for short intervals (up to 60 s) before measuring the compound muscle action potential following tail nerve excitation. They found a substantial and dose-related increase in the submaximally evoked potential for exposures longer than 15 s and fields above 0.5 Tesla. No changes in latency or maximally evoked muscle can be observed for all explored magnetic doses. Early in vitro studies (53, 54) failed to detect any effect. A very complex picture of the combined effects of magnetic field exposure, temperature and environment of system upon the radioisotopically detected activity of thymidine kinase (TdRK) results from a work of Feinendegen and Muhlensiepen (55). The enzyme activity temporarily increases, by an amount proportional to B, in the bone marrow cells of mice kept immobile in fields of the order of 1 Tesla at 27-29°C, while it decreases at 37°C. No effects are observed with moving mice, cell suspensions, or TdR-K solutions. The findings of both Hong and Feinendegen point to the existence of magnetic structures, possibly located within the cell membranes, which relax in minutes under the influence of strong B-fields. This relaxation process is hindered either by the Brownian motion, or by the animal motion. Indirect evidence of a magnetic field-induced orientational order of biochemical complexes has been discussed by Shungu et al. (56). They observed that the displacement of the 23Na NMR signal of sodium in gramicidin from a reference does not scale with the magnetic field when B is in the 1-10 Tesla range. If the observed phenomenon is really a "chemical shift effect", as these authors believe, it implies that the magnetic susceptibility of gramicidin changes with the field, or that the distribution of sodium ions is somehow modified by B. A full account of these experiments should include a discussion of nuclear interactions such as the quadrupolar couplings and the chemical exchange mechanism, and give the temperature dependence of the 23Na shifts.
Conclusion~ The field of magneto-biology is making rapid progresses on the experimental side, most notably in the area of resonant effects, and of the biochemical modifications induced by weak
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static fields, but the nature of the magnetoreceptors and their interaction path with biochemical processes still elude us. A working hypothesis seems to be that geomagnetic field interaction is performed with a resonant mechanism, which would explain the absence of dose-related effects and the sensitivity to a small range of field intensities. While evidence is growing that "strong" fields affect the living matter through mechanisms well separated from those operating at low B-intensities, the number of negative reports still balances that of the positive ones. In a sense the situation is paradoxical because the resonant phenomena are certainly more difficult to evidence experimentally, and to explain theoretically, than the interactions with strong B-fields. The time has certainly arrived to give the matter of the biological effects of strong B-fields some attention, and to chart a program of research in this field based upon the following working hypothesis: 1) a number of large magnetic structures exists in living organisms which may be temporarily oriented by a B-field. Both natural (lipid tubules, (57)) and model systems (magnetic particles in ceils, (58, 59)) have recently been discussed. By short term exposure to static B-fields we need to estimate characteristic relaxation rates and saturation fields for these structures. Our expectation, confirmed by data collected so far, is that polarization of magnetic structures by short term exposure is a fully reversible phenomenon, with subtle and non-permanent effects on living matter, and that no simple dose-effect relationship holds. 2) The most important practical question is whether continuous exposure to a polarizing B-field coupled with the reproduction and growth of an organism gives permanent or semi-permanent effects. Organisms of increased complexity should be continuously monitored while developing in fields of different intensities. 3) Sensory stimuli are induced in moving animals by a strong field. Their effect should be evaluated and discounted by carefully designed experiments. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
17.
G. MILLER, Am. Ind. Hyg. Assoc. J. 48 957-968 (1987). J. OLCESE, S. REUSS and P. SEMM, Life Sci. 42 605-613 (1988). G.J. BEERS, Magnetic Reson. Imag. ~ 309-331 (1989). U.S. DEPARTMENT OF ENERGY, Memorandum EP 32, Nov. 1981. W.R. ADEY, Physiol. Rev. 61 435-515 (1981). J. PEELING, J.S. LEWIS, M. SAMOILOFF, E. BOCK and E. TOMCHUK, Magn. Reson. Imaging 6 655-660 (1988). W.R. ADEY, Nature 333 401 (1988). C.A.L. BASSETr, Bio Essays 6 36-42 (1987). M.A. PERSINGER, Dev. Psychobiol. 2 168-171 (1969). K. RUDOLPH, K. KRAUCHI, A. WIRZ-JUSTICE and H. FEER, Physiol. Behav. 35 505508 (1985). J.R. THOMAS, J. SCHROT and A.R. LIBOFF, Bioelectromagnetics Z 349-357 (1986). M. KAVALIERS and K.P. OSSENKOPP, Peptides 7 449-453 (1986). M. KAVALIERS and K.P. OSSENKOPP, Physiol. Behav. 40 559-562 (1987). M. KAVALIERS and K.P. OSSENKOPP, J. Comp. Physiol. 162 551-558 (1988). T.F. BUDINGER, J. Comput. Assisted Tomography ~ 800-811 (1981). R.W. REDINGTON, C.L. DUMOULIN, J.F. SCHENCK, P.B. ROEMER and S.P. SOUZA, Book of Abstract, Society of Magnetic Resonance in Medicine (SMRM) VII Annual Meeting, San Francisco (1988), p. 20. J.F. SCHENCK, C.L. DUMOULIN, S.P. SOUZA, O.M. MUELLER and H.Y. KRESSEL, Book of Abstract, SMRM IX Annual Meeting, New York (1990), p. 277.
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18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53.
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M. OKAZAKI, K. KON, N. MAEDA and T. SHIGA, Physiol. Chem. Phys. Med. NMR 20 3-14 (1988). H.A. WELKER, P. SEMM, R.P. WlLLIG, J.C. COMMENTZ, W. WlLTSCHKO and L. VOLLRATH, Exp. Brain Res. 50 426-432 (1983). P. SEMM, Comp. Biochem. Physiol. 7~iA 683-689 (1983). C. DEMAINE and P. SEMM, Neurosci. Lett. 62 119-122 (1985). C. DEMAINE and P. SEMM, Neurosci. Lett. 72 158-162 (1986). J. OLCESE, Neurosci. Lett. 64 97-99 (1986). K. RUDOLPH, A. WIRZ-JUSTICE, K. KRAUCHI and H. FEER, Brain Res. 446 159-160 (1988). S. REUSS, IRCS Med. Sci. 13 471-474 (1985). R. KHOORY, Neurosci. Lett. 76 (1987) 215-220. H. ILLNEROVA and J. VANECEK, Brain Res. 167 431-434 (1979). J.C. MATHER and R.R. BAKER, Nature 291 152-155 (1981). C. WALCOTr, J.L. GOULD and A.J. LEDNOR, J. Exp. Biol. 134 27-41 (1988). A.J. KALMIJN, Science 218 916-918 (1982). M.J.M. LEASK, Nature 267 144-145 (1977). R.F. SMITH, Bioelectromagnetics ~ 387-391 (1988). C.H. DURNEY, C.K. RUSHFORT, A.A. ANDERSON, Biolectromagnetics 9 315-336 (1988). B. HALLE, Biolectromagnetics 2 381-385 (1988). T.H. MARECI, L.J. GUILLETTE and W.W. BREY, Book of Abstract, SMRM VIII Annual Meeting, Amsterdam (1989), p. 1050. G.C. TESKEY, K.P. OSSENKOPP, F.S. PRATO and E. SESTINI, Physiol. Chem. Phys. 19 43-49 (1987). B. CHANCE, Invited lecturer in Symposium on magnetic resonance imaging and in vivo spectroscopy, IX Annual Bioelectromagnetic Society (BEMS) Meeting, Portland (1987). T.F. BUDINGER, in Symposium on magnetic resonance imaging and in vivo spectroscopy, IX BEMS Meeting, Portland (1987). F.Q. NGO, J.W. BLUE and W.K. ROBERTS, Magn. Reson. Med. 5 307-317 (1987). J.M. BARNOTHY, Nature 200 86-87 (1963). J.M. BARNOTHY and I. SUMEGI, Nature 221 270-271 (1969). H. LAFORGE, M. MOISAN, F. CHAMPAGNE and M.K. SEGUIN, J. Psychol. 98, 49 (1978). H. LAFORGE, M.R. SADEGHI and M.K. SEGUIN, J. Psychol. 120, 299 (1986). E. GORCZYNSKA, G. GALKA, R. WEGRZYNOWICZ and H. MIKOSZA, Physiol. Chem. Phys. Med. NMR 18 61-69 (1986). E. GORCZYNSKA, Clin. Phys. Physiol. Meas. Z 225-235 (1986). E. GORCZYNSKA, J. Hyg. Epidemiol. Microbiol. Immunol. 30 269-273 (1986). E. GORCZYNSKA and R. WEGRZYNOWlCZ, J. Hyg. Epidemiol. Microbiol. Immunol. 30 275-281 (1986). J.J.L. CARSON, F.S. PRATO, L.D. DIESBOURG, D.J. DROST, S.J. DIXON, Book of Abstract, SMRM VIII Annual Meeting, Amsterdam (1989) p. 293. A. KWONG-HING, H. SANDHU, F.S. PRATO, J.R.H. FRAPPIER and M. KAVALIERS, Book of Abstract, SMRM VII Annual Meeting, San Francisco (1988), p. 1075. F.G. SHELLOCK, D.J. SCHAEFER and J.V. CRUES, Book of Abstract, SMRM VII Annual Meeting, San Francisco (1988), p. 1073. A.D. ROSEN and J. LUBOWSKY, Exp. Neurol. 95 679-687 (1987). C.-Z. HONG, D. HARMON and B. YU, Arch. Phys. Med. Rehabil. 67 746-749 (1986). J.-L. SCHWARTZ, IEEE Trans. Biomed. Eng. 25 467-473 (1978).
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54. 55. 56. 57. 58. 59.
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J,-L. SCHWARTZ, IEEE Trans. Biomed. Eng. 26 238-243 (1979). L.E. FEINENDEGEN and H. MUHLENSIEPEN, Int. J. Radiat. Biol. 52 469-479 (1987). D.C. SHUNGU, P.T. MASIAKOS, J.F. HINTON and R.W. BRIGGS, Book of Abstract, SMRM VIII Annual Meeting, Amsterdam (1989), p. 1110. C. ROSENBLATT, P. YAGER and P.E. SCHOEN, Biophys. J. 52 295-301 (1987). P.A. VALBERG and J.P. BUTLER, Biophys. J. 52 537-550 (1987). P.A. VALBERG and H.A. FELDMAN, Biophys. J. 52 551-561 (1987).
Pergamon Press
MINIREVIEW BIOLOGICAL EFFECTS OF MAGNETIC FIELDS Marco Villa (a), Piercarlo Mustarelli (a) and Marco Caprotti (b) (a) Laboratorio NMR c/o Dip. Chimica Fisica, Via Taramelli 16, 27100 Pavia, Italy (b) Fondazione Clinica del Lavoro, Via Severino Boezio 26, 27100 Pavia, Italy (Received in final form April 23, 1991)
Summary The literature about the biological effects of magnetic fields is reviewed. We begin by discussing the weak and/or time variable fields, responsible for subtle changes in the circadian rhythms of superior animals, which are believed to be induced by same sort of "resonant mechanism". The safety issues related with the strong magnetic fields and gradients generated by clinical NMR magnets are then considered. The last portion summarizes the debate about the biological effects of strong and uniform magnetic fields. Today, a growing number of researchers are accepting the notion that subtle interactions exist between magnetic fields (B) and biological systems; a new discipline is taking shape which may be called magneto-biology. However, as the most recent overviews of the subject imply (1, 2, 3), there is still very little understanding of the interaction mechanisms between B-fields and living matter, and it is still quite difficult to organize the experimental findings into a coherent phenomenological picture; in addition, poorly performed or documented experiments and bitter contentions, both in the scientific literature and in public policy discussions about safety regulation, have certainly not helped the image of the discipline, or contributed to the authority of its researchers. On the positive side, the quality of the experimental work seems now to improve rapidly, as journals specialize in this topic and entire research teams give the matter continued attention. Furthermore, the spreading of magnetic resonance imaging (MRI) and spectroscopy (MRS) equipments in clinical environments add urgency to the need of defining meaningful guidelines for exposure to magnetic fields (4). A short catalogue of the three sets of items which define most experimental activities, i.e. stimulus, system and response, may give an idea of the complexity of magneto-biology. i) The stimulus. A large variety of experimental protocols have been explored, with static or time-varying magnetic fields, with weak geomagnetic-type of fields (10-3-10 -5 Tesla) or with the strong fields of NMR magnets (10-1-10 Tesla), with uniform or inhomogeneous fields with large gradients, with prolonged (more than few hours), short or intermittent exposure of either stationary or mobile systems. ii) The system may be an specially designed model system (a membrane, an artificial artery, etc), a simple organism, a tissue, an egg, an organ, an insect, a vertebrate.
0024-3205/91 $3.00 +.00 Copyright (c) 1991 Pergamon Press plc
86
Biological Effects of Magnetic Fields
Vol. 49, No. 2, 1991
iii)
The system response may be evaluated with biochemical, physiological or behavioural indicators, or with parameters describing morphology, growth, development, reproductive rates, population statistics, etc. With the assistance of well established concepts about the interaction of electromagnetic fields and matter, we will now present a critical review of the most recent results, which have been ordered according to the type of exposure protocol.
Time-varvina fields v
For characteristic rates of change above v>105 Hz, the most energetic coupling between biological matter and electromagnetic radiation is likely to be the interaction between ionic charges and the electric field, E, associated with the derivative of the magnetic field, B, with respect to the time (dB/dt). It follows that the question of radiofrequency power deposition does not belong to magneto-biology, although it is a major safety issue for clinical MRI & MRS applications, and it has often been reviewed together with true magneto-biologic effects (3, 5). While the effects of fast switched B-field of the type used in neurology as a convenient substitute of an electric stimulus (dB/dt up to 105 Tesla/s) should obviously not enter a review of magnetobiologic effects, we are unable to make any statement about the relative importance of the electric and magnetic interaction for many of the experiments with pulsed magnetic field reported in the literature. As examples, we may quote i) the recent work of Peeling et al. (6) which found that pulsed magnetic fields and gradients (103 Tesla/s, with 1 Hz repetition rate) inhibit the growth of a nematode; ii) reviews (5,7) describing range of phenomena, including resonant and "windowed" interactions, observed when an electromagnetic stimulus is periodically applied to the biological matter, iii) the devices commonly used by orthopedists in "electromagnetic therapies", which are believed to assist fracture-healing and tissue-regeneration processes (8). On the other hand, if the B-field varies slowly enough to warrant that the associated electric and heating effects are negligible, we should have true magneto-biologic effects. An early behavioural study of Persinger (9) has been repeated by Rudolph et al. (10) and Thomas et al. (11), who found that exposure of rats to weak oscillating (typically 50 Hz) B-field modifies their open field response, in particular by increasing the rearing activity. Kavaliers and Ossenkopp (12, 13, 14) found that slowly changing (0.5 Hz) and weak (0.15-9 mTesla) magnetic fields have significant and differential inhibitory influences on various opioid systems in rodents and snails.
Magnetic field ~radients We distinguish three different interactions which, in order of increasing importance, are i) displacement of a magnetic dipole in a Bx--dB/dx gradient. For free particles with a dipole of g=9.3.10 -24 J/Tesla (electronic magnetic moment) and an elementary electronic charge e=l.6.10 -19 C, this interaction is equivalent to that of an electric field IXBx/e, or about 60 mV/cm for an enormous 101 Tesla/cm gradient. As long as the biological structures do not carry a permanent magnetic dipole orders of magnitude larger than the electronic magnetic moment, as is possibly the case of hemoglobin in sickled red cells (15), the interaction is expected to be negligible. ii) Displacing with a velocity, v, a material of conductivity, a, in a gradient B x = dB/dx causes a Faraday current of density proportional to ~.vx-B x, or about 1 mA/cm 2 in the tissues of a man (a - 0.5 Siemens/m) walking (v = 1 m/s) near a magnet with B x = 2 Tesla/m. People
Vol. 49, No. 2, 1991
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working near an experimental 4 Tesla whole body magnet (16, 17) experiences sensorial perceptions (vision flash, metallic taste), which we believe are due to the Faraday currents, but which produce no apparent harm. Paramagnetic structures acquire a magnetization proportional to B, and experience a force proportional to B-B x. The blood flow in large vessels may be distorted by the combination of strong gradients and strong B-fields. A simple model system has been set up by Okazaki et al. (18) which studied the flow of different blood cocktails in a B gradient (B = 0.6 Tesla, B x = 0.5 Tesla/cm, for a B.B x = 0.3 T2/cm). The expected magnetohydrodynamic effects are observed, which predictably increase with the hematocrit level.
$~a~i¢ and uniform maenetic fields a) Weak fields Under this heading we cover studies of the effects of static field of the order of (or smaller than) 10-4 Tesla, i.e. comparable with the earth field (2.10 -5 Tesla). The matter has been recently reviewed in (2). In a series of reports, different groups of researchers have shown that exposure to weak magnetic fields depresses the pineal gland activity in rodents and pigeons. In particular, inversion for one hour during the night of the horizontal component of the geomagnetic field substantially lowers the levels of melatonin and of enzymes associated with its synthesis (e.g. serotonin-Nacetyltransferase), as well as the levels of cyclic adenosine monophosphate (19,20,21, 22, 23, 24). Similar experiments with much stronger fields (B =0.14 Tesla, (25)) and in an artificial field exactly compensating the earth field 03 = 0, (26)) did not revealed any alteration of the pineal circadian rhythm; these findings point to the existence of a "magnetic window", i.e. to a range of B-intensities to which the pineal gland responds (2). Detection of geomagnetic fields seems to involve the visual system. While it was known that photic stimuli alter the pineal function (27), the hypothesis is strongly supported by recent experiments: blind mice, or mice kept in total darkness, do not respond to inversion of the geomagnetic field, while mice in dim light do (2, 23, 25). Many researchers have hypothesized that some species use detection of the earth's field as an aid to navigation. Behavioural data collected by Mather and Baker (28) suggest that the European wood mouse resorts to magnetic cues for direction finding when visual and olfactory stimuli are withdrawn or give conflicting information. In another behavioural experiment (29), the rates of homing were measured for pigeons released in places with different magnetic declinations after being exposed for few minutes to a "demagnetizing" field (B = 0.1 Tesla). Both local geomagnetic irregularities and the demagnetization procedure appears to slightly hinder the homing, and the effect is more evident in young (less experienced ?) pigeons. However, the behavioural response seems to be weak or ambiguous, since other researchers have apparently been unable to reproduce the Mather and Baker results (2). Different mechanisms have been invoked to explain the results of these findings: Mather and Baker (28) tried to test the hypothesis of the existence of ferromagnetic structures, while Kalmijn (30) suggests a mechanism based upon magnetic induction. Leask (31) invokes the presence of magnetized particles and an optical pumping mechanism at the level of photoreceptors, which would naturally explains the absence of a response in exposed blind mice (2) and the changes of catecholamine levels of retina in mice exposed to B-fields at night (23). Beers (3) has recently reviewed an interesting class of experiments which may be listed under the heading of "Magnetic Resonance" and may eventually provide a clue of the mechanism
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on which the magnetoreceptors are based: combined exposure to a weak B-field and to an oscillating E-field with frequency related to the B-intensity induces a substantial enhancement of the Ca ++ efflux from cells in culture. It has been suggested that this phenomenon is related to the cyclotron frequency of the ions (32) (v = q.B/m, or about 102 Hz for the earth field and the Ca ++ ion), but no generally accepted explanation has been developed yet. The motion of an ion in a viscous medium under the influence of static and oscillating magnetic fields has been studied by Durney et al. (33) and by Halle (34) which conclude that cyclotron resonance is unlikely to be the mechanism for the resonant response of a biological system. b) Strong fields It is well known that strong magnetic fields may have harmful effects on humans through interaction with implanted devices containing ferromagnetic parts, such as pace-makers and surgical clips. However, this matter is a safety issue and does not pertain to magneto-biology. A uniform magnetic field is expected to deflect a moving charge (Lorentz force) and to align the magnetic moments within the biological matter. The electric field associated with the Lorentz force is proportional to the charge velocity (v) and to B; when charges are moved by an electric potential, v is expected to be extremely small, and, as far as we known, only one research group has succeeded in measuring the Lorentz force potential (Hall effect) in an ionic system (a solid electrolyte). The situation is different when a charged fluid like blood is mechanically displaced in a B-field; the potential difference generated across the aorta can be large enough to be observed in an electrocardiogram, and also a small increase in blood pressure is expected (1). No permanent harm or permanent effect is expect from such magnetohydrodynamic interaction. The energy of interaction between the magnetic moment of an electron and the largest Bfields ever produced (about 30Tesla) is a fraction (-0.1) of the thermal energy at room temperature ( k T = - 4 - 1 0 -21 J). For these reason, most MRI people do not even consider the possibility that exposure to their static and homogeneous B fields may affect the biological functions of patients or animals; when they do, a statement is usually included about the absence of any observable biological consequence of the exposure (35). Others (e.g. (36)) study the response of experimental animals to the full NMR-imaging procedure (which involves also rf power deposition and exposure to magnetic gradients switching at audio frequencies), and conclude that no harmful or permanent effect is due to MRI. Some NMR specialists (37, 38) have performed long-term exposure experiments with rodents to demonstrate how safe the MRI fields are. The absence of observable effects of strong B-fields on behaviour, growth, circadian rhythms, immune response, reproduction and survival rates, of rodents has been reviewed by Miller (1). Recently, Peeling et al. (6) found that continuous exposure to a 2 Tesla field, or to a 6 Tesla/m gradient, does not modify the 4-days long development cycle of the nematode Panagrellus redivivus. Also NGO et al (39) found that DNA synthesis in Chinese hamster V79 cells is not affected by prolonged exposure to a 0.75 Tesla field. An opposite conclusion is reached by Barnothy (40, 41) and Laforge et al. (42, 43) which reported weight reduction, organ anomalies, and behavioural modifications in mice and rats exposed to strong static fields. In a number of reports that appeared in 1986, a Polish research group found that intermittent exposure (1 hour per day per several weeks) to static fields (0.005 to 0.3 Tesla) disturbs the respiration of mitochondria in liver cells of rats (44), accelerate the thrombolytic process in rabbits (45), increases the fibrinogen degradation products in the serum of rabbits with thrombosis (46), and decreases the activity of glutamic pyruvic transaminase in the serum of guinea pigs (47). These changes are apparently unrelated to the field intensity, and observable, or even most evident, at the lowest fields.
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No one of all the effects reviewed so far has proven to be permanent; weeks or months after exposure, the animals show no longer significant differences relative to their control. Our studies of behavior of weaning mice exposed for one week to strong fields according to different protocols (fields from 1 to 8.5 Tesla, continuous or intermittent exposure) agree with this conclusion. At the end of treatment, the exposed mice showed generic stress-like effects: reduced exploratory activity in the open field, sometimes accompanied by reduced body weight. However, control and exposed animals behaved the same way after one month. Several reports on the effects of short time (up to few hours) exposure to B fields are byproducts of NMR studies: the MRI fields apparently increase the free calcium concentration in HL60 promyelocytic cells (48), and predentin formation in rodents (49). The skin and body temperature of patients increases by fractions of a degree in a 1.5 Tesla imager (50); since thermocouple readings may be affected by B, and details of air convection within the magnet bore are not given, we may wonder what the temperature readings would be when a phantom is used in place of the patients. Rosen and Lubowsky (51) measured the visual evoked response in cats exposed to a 0.12 Tesla field; an exposure longer than 50 s significantly reduces the cortical excitability, and the effect persists few minutes after the field has been turned off. The action of the B field on the synapse, rather than on axonal conduction, is believed to provide the mechanism of the effect. These studies seldom attempt to determine whether the exposure effects are proportional to a "dose" (product of B-intensity and exposure time) or if some threshold exists. An exception is the work by Hong et al. (52) which exposed rats to fields up to 1 Tesla for short intervals (up to 60 s) before measuring the compound muscle action potential following tail nerve excitation. They found a substantial and dose-related increase in the submaximally evoked potential for exposures longer than 15 s and fields above 0.5 Tesla. No changes in latency or maximally evoked muscle can be observed for all explored magnetic doses. Early in vitro studies (53, 54) failed to detect any effect. A very complex picture of the combined effects of magnetic field exposure, temperature and environment of system upon the radioisotopically detected activity of thymidine kinase (TdRK) results from a work of Feinendegen and Muhlensiepen (55). The enzyme activity temporarily increases, by an amount proportional to B, in the bone marrow cells of mice kept immobile in fields of the order of 1 Tesla at 27-29°C, while it decreases at 37°C. No effects are observed with moving mice, cell suspensions, or TdR-K solutions. The findings of both Hong and Feinendegen point to the existence of magnetic structures, possibly located within the cell membranes, which relax in minutes under the influence of strong B-fields. This relaxation process is hindered either by the Brownian motion, or by the animal motion. Indirect evidence of a magnetic field-induced orientational order of biochemical complexes has been discussed by Shungu et al. (56). They observed that the displacement of the 23Na NMR signal of sodium in gramicidin from a reference does not scale with the magnetic field when B is in the 1-10 Tesla range. If the observed phenomenon is really a "chemical shift effect", as these authors believe, it implies that the magnetic susceptibility of gramicidin changes with the field, or that the distribution of sodium ions is somehow modified by B. A full account of these experiments should include a discussion of nuclear interactions such as the quadrupolar couplings and the chemical exchange mechanism, and give the temperature dependence of the 23Na shifts.
Conclusion~ The field of magneto-biology is making rapid progresses on the experimental side, most notably in the area of resonant effects, and of the biochemical modifications induced by weak
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static fields, but the nature of the magnetoreceptors and their interaction path with biochemical processes still elude us. A working hypothesis seems to be that geomagnetic field interaction is performed with a resonant mechanism, which would explain the absence of dose-related effects and the sensitivity to a small range of field intensities. While evidence is growing that "strong" fields affect the living matter through mechanisms well separated from those operating at low B-intensities, the number of negative reports still balances that of the positive ones. In a sense the situation is paradoxical because the resonant phenomena are certainly more difficult to evidence experimentally, and to explain theoretically, than the interactions with strong B-fields. The time has certainly arrived to give the matter of the biological effects of strong B-fields some attention, and to chart a program of research in this field based upon the following working hypothesis: 1) a number of large magnetic structures exists in living organisms which may be temporarily oriented by a B-field. Both natural (lipid tubules, (57)) and model systems (magnetic particles in ceils, (58, 59)) have recently been discussed. By short term exposure to static B-fields we need to estimate characteristic relaxation rates and saturation fields for these structures. Our expectation, confirmed by data collected so far, is that polarization of magnetic structures by short term exposure is a fully reversible phenomenon, with subtle and non-permanent effects on living matter, and that no simple dose-effect relationship holds. 2) The most important practical question is whether continuous exposure to a polarizing B-field coupled with the reproduction and growth of an organism gives permanent or semi-permanent effects. Organisms of increased complexity should be continuously monitored while developing in fields of different intensities. 3) Sensory stimuli are induced in moving animals by a strong field. Their effect should be evaluated and discounted by carefully designed experiments. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
17.
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