Journal of Cellular Biochemistry 93:83–92 (2004)

Extremely Low Frequency Electromagnetic Fields asEffectors of Cellular Responses In Vitro:Possible Immune Cell Activation

Myrtill Simko1* and Mats-Olof Mattsson2

1Division of Environmental Physiology, Institute of Cell Biology and Biosystems Technology,University of Rostock, Albert-Einstein-Strasse 3, D-18059 Rostock, Germany2Cell Biology Laboratory, Department of Natural Sciences, Orebro University, SE-701 82 Orebro, Sweden

Abstract There is presently an intense discussion if electromagnetic field (EMF) exposure has consequences forhuman health. This include exposure to structures and appliances that emit in the extremely low frequency (ELF) range ofthe electromagnetic spectrum, as well as emission coming from communication devices using the radiofrequency partof the spectrum. Biological effects of such exposures have been noted frequently, although the implication for specifichealth effects is not that clear. The basic interaction mechanism(s) between such fields and living matter is unknown.Numerous hypotheses have been suggested, although none is convincingly supported by experimental data. Variouscellular components, processes, and systems can be affected by EMF exposure. Since it is unlikely that EMF can induceDNA damage directly, most studies have examined EMF effects on the cell membrane level, general and specific geneexpression, and signal transduction pathways. In addition, a large number of studies have been performed regarding cellproliferation, cell cycle regulation, cell differentiation, metabolism, and various physiological characteristics of cells.Although 50/60 Hz EMF do not directly lead to genotoxic effects, it is possible that certain cellular processes altered byexposure to EMF indirectly affect the structure of DNA causing strand breaks and other chromosomal aberrations. The aimof this article is to present a hypothesis of a possible initial cellular event affected by exposure to ELF EMF, an event which iscompatible with the multitude of effects observed after exposure. Based on an extensive literature review, we suggest thatELF EMF exposure is able to perform such activation by means of increasing levels of free radicals. Such a generalactivation is compatible with the diverse nature of observed effects. Free radicals are intermediates in natural processeslike mitochondrial metabolism and are also a key feature of phagocytosis. Free radical release is inducible by ionizingradiation or phorbol ester treatment, both leading to genomic instability. EMF might be a stimulus to induce an ‘‘activatedstate’’ of the cell such as phagocytosis, which then enhances the release of free radicals, in turn leading to genotoxicevents. We envisage that EMF exposure can cause both acute and chronic effects that are mediated by increased freeradical levels: (1) Direct activation of, for example macrophages (or other cells) by short-term exposure to EMF leads tophagocytosis (or other cell specific responses) and consequently, free radical production. This pathway may be utilized topositively influence certain aspects of the immune response, and could be useful for specific therapeutic applications.(2) EMF-induced macrophage (cell) activation includes direct stimulation of free radical production. (3) An increase in thelifetime of free radicals by EMF leads to persistently elevated free radical concentrations. In general, reactions in whichradicals are involved become more frequent, increasing the possibility of DNA damage. (4) Long-term EMF exposure leadsto a chronically increased level of free radicals, subsequently causing an inhibition of the effects of the pineal glandhormone melatonin. Taken together, these EMF induced reactions could lead to a higher incidence of DNA damage andtherefore, to an increased risk of tumour development. While the effects on melatonin and the extension of the lifetime ofradicals can explain the link between EMF exposure and the incidence of for example leukaemia, the two additionalmechanisms described here specifically for mouse macrophages, can explain the possible correlation between immunecell system stimulation and EMF exposure. J. Cell. Biochem. 93: 83–92, 2004. � 2004 Wiley-Liss, Inc.

Key words: ELF EMF; free radicals; melatonin

� 2004 Wiley-Liss, Inc.

Received 8 March 2004; Accepted 10 May 2004

DOI 10.1002/jcb.20198Published online 26 July 2004 in Wiley InterScience(www.interscience.wiley.com).

*Correspondence to: Myrtill Simko, Division of Environ-mental Physiology, Institute of Cell Biology and BiosystemsTechnology, University of Rostock, Albert-Einstein-Strasse3, D-18059 Rostock, Germany.E-mail: myrtill.simko@biologie.uni-rostock.de

The question whether electromagnetic fields(EMFs) induce biological effects which might beharmful to human health and the environmentremains a controversial issue. Of interest is theexposure to structures and appliances that emitin the extremely low frequency (ELF) range ofthe electromagnetic spectrum, such as powerlines and ordinary household appliances, aswell as the emission coming from communica-tion devices using the radiofrequency part of thespectrum (e.g., mobile phones and their basestations). Numerous investigations have shownthe presence of a multitude of biological effects,from whole organisms down to the sub-cellularlevel. However, the situation regarding morespecific health effects is not that clear.

Expert groups have recently classified ELFelectric and magnetic field exposure as apossible carcinogen, class 2B [NIEHS, 1998;IARC, 2002]. This is primarily based on the riskfor childhood cancer and living close to power-lines, and on occupational exposure and anincreased risk for leukemia and brain tumors.

Although a large number of reports have beenpublished regarding biological effects caused bypower line-frequency EMFs (50/60 Hz) duringthe last few years [NIEHS, 1998; IARC, 2002,for extensive reviews], there is still need formore basic research in this area, since knowl-edge of the underlying molecular mechanismswill allow an estimate of potential health risks.The question whether EMFs cause neoplasticdevelopment leading to carcinogenesis is ofspecial interest.

However, the basic interaction mechanismsbetween these relatively weak fields and livingmatter are presently unclear. Numerous hy-potheses have been put forward, although noneis convincingly supported by experimental data.There is, furthermore no model for the biologicalmechanism(s) involved, although our own work,among many others, support that molecules(yet unidentified) in or close to the plasma mem-brane are involved very early on in the biologicalresponse.

There are many observations of cellular re-sponses induced by EMFs in vitro. A largenumber of cellular components, cellular pro-cesses, and cellular systems can conceivably beaffected by EMF exposure. However, becauseevidence from theoretical and experimentalstudies suggest that EMFs are unlikely toinduce DNA damage directly, most studies havebeen conducted to examine EMF effects on the

cell membrane level, general and specific geneexpression, and signal transduction pathways.In addition, a large number of studies have beenperformed on processes such as cell prolifera-tion, cell cycle regulation, cell differentiation,metabolism, and various physiological char-acteristics of cells. In addition to studies withobserved effects after EMF exposure, it must betaken into account that several observationshave been difficult to replicate in other studies,and that many studies have reported no effectsdue to exposure.

It is generally accepted that 50/60 Hz EMFdo not transfer energy to cells in sufficientamounts to directly damage DNA leading togenotoxic effects. However, it is possible thatcertain cellular processes altered by exposure toEMF, such as free radicals, indirectly affect thestructure of DNA causing strand breaks andother chromosomal aberrations, includingsister chromatid exchange, micronucleus for-mation, effects on DNA repair, or leading tocytotoxic effects inducing cell death. Genotoxiceffects after EMF exposure, such as micronu-cleus formation in vitro [Simko et al., 1998a,b,2001a], chromosomal aberration [Nordensonet al., 1994] or sister chromatid exchange[Rosenthal and Obe, 1989; Khalil and Quassem,1991] and chromosomal breaks [D’Ambrosioet al., 1988] were reported by different authors.After using the comet assay, dose-dependentDNA strand breaks have been noted [Lai andSingh, 1997; Ivancsits et al., 2002]. In contrast,a number of other studies reported that EMFexposure does not induce chromosomal damagein vitro [Garcia-Sagredo et al., 1990; Livingstonet al., 1991; Scarfi et al., 1993; Fairbairn andO’Neill, 1994].

Numerous studies have addressed the inter-action between EMF and calcium fluxes, be-cause calcium is a principal regulator of severalcellular processes. Modulations in intracellularCa2þ concentrations during exposure to EMFwere reported by various investigators [Liburdyet al., 1993a; Lindstrom et al., 1993; Loschingeret al., 1999; Mattsson et al., 2001]. It has beenconcluded that modulation of intracellular Ca2þ

concentrations is possible only in stimulatedimmune cells [Walleczek, 1992].

In accordance, findings regarding effects onsignal transduction processes have also beenreported [Korzh-Sleptsova et al., 1995; Uckunet al., 1995; Dibirdik et al., 1998, among others].This also includes stimulation of activity of the

84 Simko and Mattsson

enzyme PKC, which plays a key role in trans-ferring external signals to the cells interior inorder to regulate proliferation and differentia-tion, as well as other processes. When PKC isactivated either naturally or synthetically (e.g.,with the phorbol ester TPA), the enzyme istranslocated from the cytosol to the cell mem-brane. Several studies with 50/60 Hz MF ondifferent human cells have shown that treat-ment with suboptimal TPA concentrations isaugmented by EMF exposure, whereas EMF initself do not cause PKC translocation [Tuinstraet al., 1998; Tao and Henderson, 1999; Richardet al., 2002]. A possible explanation for theseresults is that cells exposed to suboptimalconcentrations of TPA shift from a normal intoan activated state without saturating the phy-siological capacity to respond to TPA, so allow-ing an additional effect caused by magneticfield exposure.

Alterations in DNA and RNA synthesis rateswere found to be produced by EMF; effects onspecific gene transcription have also beenreported [cf. Lacy-Hulbert et al., 1998]. On theother hand, certain results have not beenpossible to reproduce at other laboratories,causing intense discussion about the generalityof the observations [Lacy-Hulbert et al., 1995;Saffer and Thurston, 1995].

Increases in ornithine decarboxylase (ODC)activity in cultured mammalian cells afterexposure to EMF, were reported by severalauthors [Litovitz et al., 1991; Valtersson et al.,1997; Mullins et al., 1999]. This is of interestsince this enzyme is the first and rate-limitingstep in the synthesis of polyamines, multi-charged low-molecular weight compounds in-volved in cell growth.

Altered proliferation of cells after EMF-exposure has been observed in a number ofstudies in vitro. An increase in cell cycleprogression of human lymphocytes exposed toa 5 mT (50 Hz) were shown [Rosenthal and Obe,1989; Antonopoulos et al., 1995] and Westet al. [1994] demonstrated increased colonygrowth in anchorage-independent JB6 cellsafter 10–14 days exposure to a 1.1 mT (60 Hz)MF. In a study by Katsir and Parola [1998], anincrease in cell proliferation with exposure overthe frequency range of 50–100 Hz and intensityrange of 0.1–0.7 mT was demonstrated. Bothfrequency- and intensity-dependent responseswere observed, with a maximum enhancementof proliferation of 70% seen with exposure to

100 Hz at 0.7 mT. Studies have shown theproliferative effect of EMF with regard tospecific cell cycle parameters. In general, thesedata are consistent with a small decrease in therate of progression through the early part of thecell cycle. Cridland et al. [1999] revealed thatexposure to weak MF (50 Hz, 20 and 200 mT)lead to a delay in the onset of DNA synthesisin synchronized normal human fibroblasts,which indicates a lengthening of the G1 phase.Schimmelpfeng and Dertinger [1993] reportedthat exposure to 50 Hz, 2 mT caused alterationsof several indicators of cell proliferation, includ-ing an accumulation of G1 phase cells. Langeet al. [2002] showed that exposure to EMFs(1 mT) modifies the passage of amniotic fluidcells through the cell cycle, leading to a retarda-tion of DNA synthesis, which was indicated by aless rapid increase in the rate of BrdU incor-poration. They also described alterations in theexpression of cell cycle relevant proteins(cyclins, cdks, p21, p16).

However, in other studies no or oppositeeffects were found. Zhao et al. [1999] failed todemonstrate any significant differences in therate of DNA synthesis after EMF exposure(60 Hz, 0.1–0.8 mT) in INIT/10T1/2 cells.Results of Wei et al. [2000] suggest that 60 Hzmagnetic fields at intensities of 90 and 120 mT,respectively, can increase [3H] thymidine incor-poration into DNA of astrocytoma cells in a timedependent manner, while 60 mT had no effect onthe DNA synthesis.

There are several studies concerning celldifferentiation under EMF-exposure conditions.Rodemann et al. [1989] described that long-termEMF exposure of fibroblasts in vitro induces thedifferentiation of mitotic to postmitotic cells thatare characterized by differentiation-specific pro-teins and differentiation-dependent enhancedmetabolic activities. Landry et al. [1997] showedthat EMFs can affect osteogenesis by increasingthe rate of differentiation, whereas Tao andHenderson [1999] reported that only co-expo-sure to EMF and a phorbol ester (TPA) influencethe time-schedule of differentiation in HL-60cells. A flux density dependent inhibition ofdifferentiation coupled with an increased pro-liferation rate in the undifferentiated Frienderythroleukemia cells was presented by Chenet al. [2000].

It has been suggested that cells respond toEMF as to an unspecific stressor, causing onsetof transcription, and subsequent translation, of

Possible Immune Cell Activation 85

inducible heat shock protein genes (includinghsp70) or of heat-shock transcription factor(hsf1) [Goodman and Blank, 1998; Lin et al.,1998; Junkersdorf et al., 2000].

Taken together, these and other studies haveshown that the wide variety of effects of EMFexposure on different cell types are dependenton cell age, differentiation status, activationand/or metabolic state, etc. [see also Eremenkoet al., 1997; Nindl et al., 1997; Simko et al.,1998a]. Moreover, the fact that most of theobserved effects are of a very small magnitude(often in the order of 20–30%) additionallycomplicates the evaluation of the controversialresults and the verification of published studies.

The aim of this article is to present a hypo-thesis of a possible initial cellular event affectedby exposure to ELF EMF, an event which iscompatible with the multitude of effects ob-served after exposure. The interaction of EMFwith the biological system must include activa-tion of a cellular process, which is generallyoccurring, and capable of activating signaltransduction pathways that are causing thepreviously mentioned observations. Based onseveral lines of investigations, we here suggestthat ELF EMF exposure is able to perform suchactivation by means of increasing levels of freeradicals. Such a general activation is compatiblewith the diverse nature of observed effects, andis furthermore not excluding other initial inter-action processes, possibly due to EMF withother physical characteristics. A considerableamount of the literature supporting this notionrelates to experiments on cells of the immunesystem, which is covered in the next section ofthis article.

IMMUNE CELL ACTIVATION

Cell regulatory processes, involving theinduction of free radical production, which areable to interact with DNA or other cellularcomponents, can lead to a potentiation of freeradical-dependent effects. Such processes cantherefore be likely targets of EMF-inducedcellular responses. In macrophages, physiologi-cal activation is associated with the onset ofphagocytosis and leads to increased formationof reactive oxygen species (ROS). EMF has beenshown to increase ROS levels in phorbol ester-activated neutrophils [Roy et al., 1995], but untilrecently it was unclear whether non-activatedmacrophages can be activated by short-termEMF stimulation. Thus, Simko et al. [2001b]

found that 1 mT MF for 45 min is able to activatemacrophages and to increase the internali-zation rate of latex beads with 35%. Particleuptake was measured as a function of fluxdensity, showing a significant increase at dosesas low as 0.5 mT. In a previous study [Flipo et al.,1998] using pre-stimulated cells, a decrease inphagocytic uptake of beads combined withincreased intracellular Ca2þ-levels wasreported. However, in this study cells wereexposed to static and much higher (25–106 mT)magnetic fields, as well as for prolonged periodsof time (24 h).

It is not known why various cell types respondto EMF with different efficacy, but it seems to beclear that several cell types are responsive toEMF by different mechanisms. The responsive-ness might depend on the number and thedistribution of cell-specific membrane recep-tors, which are variably expressed on differentcell types. It is known that TPA enhances thestimulation of macrophages for phagocytosisvia the phospholipid dependent protein kinaseC pathway. It is noteworthy that the TPA-effecton differentiation of HL-60 cells was reported tobe mimicked by EMF [Tao and Henderson,1999], similar to the TPA-effect on activation ofmacrophage phagocytosis in the study of Simkoet al. [2001b].

ROS are unstable reactive molecules pro-duced continuously in several cell types, and areinvolved in intracellular signal transductionpathways, regulation of gene expression deter-mining the anti-inflammatory response, cellgrowth, differentiation, proliferation and stressresponse. A significantly increased super oxideproduction in the absence of phagocytic activitywas detected after exposure to EMF in mousemacrophages [Simko et al., 2001b; Rollwitzet al., 2004] and also in human monocytes[Lupke et al., 2004], which is an indication ofcell activation processes. These investigationsdemonstrate a low, but significant induction ofsuper oxide production indicating a specificactivation of the NADH-oxidase after EMF-exposure. On the other hand, the activation ofNADPH-oxidase would result in a higher pro-duction of free radicals leading to an oxidativeburst. Interestingly, Roy et al. [1995] reportedan increased oxidative burst after exposure to0.1 mT MF in TPA-activated rat peritonealneutrophils; however the authors proposed anincreased lifetime of free radicals due to themagnetic fields as a possible mechanism.

86 Simko and Mattsson

SYNTHESIS AND PROPOSALOF A HYPOTHESIS

The experimental set-up of the exposure con-ditions to investigate the influence of EMF onbiological systems and its biological effective-ness, are extremely heterogeneous, regardingthe field strength, frequency, and the use ofpulsed or modulated fields. However, therapeuticapplication of EMF ranges from bone fracturehealing up to cancer treatments [Glaser, 1992]and, therefore the question whether EMFs arebiologically effective can be answered with yes.Nevertheless, the nature of the underlyingmechanism and their relevance to health riskhas to be revealed. It should be taken intoaccount that continuous environmental expo-sure to 50 Hz EMFs is well below 50 mT, whereasmost of the experimental work and all of themedical applications use field strengths beyond50 mT.

There are several reports published to eluci-date possible correlation between EMF andcancer or other diseases but no causal relation-ship is supported by the discussed mechanisms.Valberg et al. [1997] outlined five main physicalpossibilities of interaction: (1) energy transferby acceleration of ions and charged proteinsmodifies cell membranes and receptor proteins.However, 50 Hz EMF energies are far belowthose of biomolecules. (2) Electric fields inducedinside the body exert forces on electric chargesand electric moments, but these forces seem tobe smaller than biological forces. (3) Magneticmoments of ferromagnetic particles and freeradicals interact with EMF physically, butmagnetic field sensory cells have not been foundin humans and modification of radical recombi-nation rates in biological systems are veryproblematic. (4) Resonant interactions includeEMFs driving transitions in ion-biomoleculecomplexes. This mechanism conflicts withaccepted physics and experimental tests failedto find effects. (5) Temporal averaging or spatialsummation can improve the ratio of signal tonoise in any system but this requires structuresand processes having the capabilities of EMFdetection that have been not found in humans.

It seems that the interaction between EMFand cellular systems is not based on only one ofthe mentioned hypotheses. Moreover, multipletriggering events seem to amplify cellularreactions, causing different effects, dependingon the affected cell type. Externally applied

EMFs are able to shift the equilibrium distribu-tions of ions slightly, as described by Blank[1988] in his surface compartment model. Smalldeviation of the local concentrations nearmembrane associated enzymes and proteinsmay trigger their function and induce connectedcascades.

The combination of different biological condi-tions and physical parameters may result in‘‘multiple windows’’ which interact by second-ary mechanisms causing cellular responsesthat lead to, for example, genotoxicity or othercellular changes. The cell shape seems also to beof importance, for example, fibroblast cells arespindle-shaped whereas blood cells are round inshape. The induced electric fields can be focusedin different regions on the cell surface or withinthe cell causing ‘‘hot spots’’ with very highelectric field intensities. Depending on theorientation of exposed cells to the E-field, iden-tical physical parameters can induce differentcellular responses [Bernhardt, 1979].

The induced field densities or magnetic fieldscan influence enzymatic activities by mimickingreceptor binding, which affects proteins andother biomolecules to activate biochemical cas-cades and ‘‘out of schedule’’ cellular reactions.These induced physiological reactions causecellular effects through secondary or indirectmechanisms such as ‘‘cell activation’’ processes,for example, through the release of free radicalsand/or the out of schedule switching-on oftransduction pathways.

It has been hypothesized by Stevens [1987]that exposure to 50/60 Hz EMF may suppressthe nocturnal production of the pineal hormonemelatonin. A later report suggests that reducedlevels of melatonin could lead to an increasedrisk of breast cancer [Stevens and Davis, 1996].A number of studies have been done to elucidatethe role of melatonin and the mechanism of itsphysiological activity. Melatonin acts also as areceptor independent free radical scavengerand antioxidant, and is able to reduce theincidence of mutations and likelihood of devel-oping cancer. Moreover, melatonin inhibits thegrowth of different types of established tumours[Dubocovich, 1995; Reiter, 1997]. It seems thatmelatonin inhibits mammary tumour genesis inanimals and in vitro, and acts in an oncostaticmanner in different cancer cells [Reiter, 1997].Several studies described reduced levels ofmelatonin in EMF exposed animals [Katoet al., 1994; Yellon, 1994] as well as in vitro

Possible Immune Cell Activation 87

[Lerchl et al., 1991; Liburdy et al., 1993b;Loscher and Mevissen, 1994], but short-termexposure to human volunteers failed to pro-vide evidence for EMF-effects on melatonin[Graham et al., 1996; Selmaoui et al., 1996].However, epidemiological studies reported sup-pressed levels of melatonin in occupational orresidential EMF exposed humans [Pfluger andMinder, 1996; Burch et al., 1998]. It remains tobe determined whether EMF exposure is able toreduce the melatonin synthesis or its physiolo-gical effects to levels where an increased cancerincidence would be a consequence.

In order to clarify the question of a possiblecorrelation between cancer and EMF, reprodu-cible effects at the cellular level have to beobtained and the underlying mechanisms haveto be elucidated. It is important to note thatmost experimental designs of EMF exposureand hence investigations are focused only onsimple well defined questions. However, theinteraction of EMF with an organism is verycomplex. We, therefore set out to describemechanisms, which take into account the wholeorganism.

We have shown in previous studies that 50 HzEMF induce genotoxic effects in humanamniotic cells. However, it is obvious that EMFsare not able to induce genotoxic effects by directinteraction with DNA, but only due to an in-directly mediated mechanism. The shape,origin, and the amount of cell-specific mem-brane receptors seem to play a key role in theeffectiveness of EMF. Depending on the re-ceptors, cell specific responses can be induced,leading to cell specific activity.

We also studied the PKC mediated signaltransduction pathway in human amniotic fluidcells, in SCL II cells as well as in mouse bonemarrow derived macrophages and did not findany direct correlation between EMF-exposureand PKC activation [Simko et al., 2001b;Richard et al., 2002]. However, further studiesat the molecular level showed disturbances andchanges in the expression of cell cycle relatedproteins [Lange et al., 2002]. Therefore, weconclude that genotoxicity after exposure toEMF is due to secondary induced mechanisms,such as, the production of free radicals, whichmust be induced by different signal transduc-tion pathways.

Free radicals are important intermediates innatural processes and are released duringnatural cell metabolism. These intermediates

arise in mitochondrial respiration and are also akey feature of the phagocytic process. It is wellknown that the release of free radicals isinducible by ionizing radiation or TPA, bothleading to genomic instability. EMF might be astimulus to induce cell activating processescausing an ‘‘activated state’’ of the cell such asin phagocytic activity, which then enhances therelease of free radicals, which in turn can lead togenotoxic events.

Scaiano et al. [1994] proposed that MF isable to stabilize free radicals in such a way asto increase their lifetime and permit a widerdispersion rather than their return to the basallevel. The hypothesis of a prolonged lifetime offree radicals will increase the probability ofradical-mediated DNA damage and thereforethe overall amount of DNA damage, leadingto clastogenic damage. The suppression of theEMF enhanced cell proliferation in the presenceof radical scavengers, shown by Katsir andParola [1998], is another supportive finding forthis proposed model of interaction betweenEMF and biological systems.

Macrophages play an essential role in theimmune system. Activated macrophages pos-sess enhanced phagocytosis and elevated phy-siological production of toxic oxygen as well asnitrogen intermediates. In our studies, an in-creased phagocytic activity in mouse macro-phages after exposure to EMF was detectedin a dose-dependent manner [Simko et al.,2001b]. This cellular activation was shown inthe absence of any pre- or co-stimulation. We,furthermore showed increased super oxideradical production during exposure to 1 mTEMF in the absence of phagocytosis. This istaken for evidence of a direct activation ofmacrophages by EMF.

Tan et al. [1999] identified markedly elevatedlevels of melatonin in rat bone marrow, which isan endogenous free radical scavenger and animmune-enhancer. It has been suggested thatthe high level of melatonin may provide pro-tection by reducing oxidative damage and toenhance the immune capacity. Therefore, mel-atonin is supposed to be oncostatic as well. As ithas been hypothesized that EMF may suppressmelatonin synthesis [Stevens and Davis, 1996],reduced levels of melatonin could also lead to anincreased cancer risk. The following reactionmay be induced in an organism after chronicexposure to EMF: an increased ‘‘cell activation’’process concomitant with an increased free

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radical production including a prolonged life-time of radicals, coupled with a decrease of theradical scavenger melatonin leading to in-creased ROS levels in organs generally, butespecially in lymph nodes and in the bonemarrow including stem cells. Such changescould lead to an increased risk of cancers suchas lymphomas and leukemia, but also to breastcancer. On the other hand, short term ex-posure to EMF may have the beneficial effectof activating immune response cells such asmacrophages. These findings have potentialimplications for therapeutic applications.

The different pathways of free radical in-volvement in physiological and pathologicalreactions to EMF exposure are summarized inFigure 1. The hypothesis how cancer can beinduced or promoted in macrophages is oneexample of cell activation processes by EMF.Direct activation of macrophages (or other cells)by short-term exposure to EMF leads to phago-cytosis (or cell specific response) and conse-quently, free radical production (a). Thispathway may be utilized to positively influencecertain aspects of the immune response, andcould be useful for certain therapeutic applica-tions. An additional pathway in EMF-inducedmacrophage (cell) activation is the direct stimu-lation of free radical production (b). The docu-mented increase in the lifetime of free radicalsby magnetic fields [Walleczek, 1992; Harkinsand Grissom, 1994; Roy et al., 1995] leads toelevated free radical concentrations for ex-tended periods of time (c). In general, reactionsin which radicals are involved become more

frequent, increasing the possibility of DNAdamage. The fourth pathway (d) suggested,leading to an increase of free radical concen-tration, is the inhibitory potential of chronicEMF-exposure on the availability of the pinealgland hormone melatonin [Thun-Battersbyet al., 1999; Caplan et al., 2000], which acts asa radical scavenger. Such reduced melatoninlevels could be involved in amplification of DNAdamage.

Altogether, these EMF induced reactionscould lead to a higher incidence of DNA damageand therefore, to an increased risk of tumourdevelopment. While the effects on melatoninand the extension of the lifetime of radicals havebeen invoked to explain the link between EMFexposure and incidence of for example, leukae-mia and mammary gland tumours, the twoadditional mechanisms described here specifi-cally for mouse macrophages can well explainthe possible correlation between immune cellsystem stimulation and EMF-related tumourdevelopment. Thus, tumours developing fromtissues affected by chronic inflammatory dis-eases as well as leukaemias and lymphomashave in common that a higher number ofactivated radical-producing macrophages areresiding in the vicinity of their origin. On theother hand, the potential for employing short-term EMF exposure for therapeutic purposes isobvious and should be further explored.

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