Has Electromagnetic Energy in the Band 0.1–100 GHz Useful Medical Applications? A Review of...

1638 IEEE TRANSACTIONS ON PLASMA SCIENCE, VOL. 36, NO. 4, AUGUST 2008

Has Electromagnetic Energy in the Band0.1–100 GHz Useful Medical Applications?

A Review of Mechanisms and BiologicalDatabase Offers Dim Prospects

Mays Swicord, Senior Member, IEEE, and Quirino Balzano, Life Fellow, IEEE

Abstract—We now have a history of more than 50 years ofsearching for low-level nonthermal radio frequency (RF) effects onbiological systems. An analysis of this database and an evaluationof the proposed mechanism of interactions suggest that the prob-ability of finding such effects between the frequencies of 100 MHzand 150 GHz is vanishingly small and that most likely, such effectsdo not exist between 10 MHz and 200 GHz. However, studies usinglow-frequency fields with amplitude on the order of or exceedingendogenous fields, the development of terahertz spectroscopy, andmedical imaging at terahertz frequencies and RF fields that cancause temperature elevation have proven and are proving to befruitful areas of research.

Index Terms—Medical application of radio frequency (RF),nonthermal bioeffect inconsistency, research directions, state ofresearch.

I. INTRODUCTION

THIS PAPER reviews the state of the science of biologicaland biochemical responses to RF exposure, beginning

with a discussion of the proposed mechanisms. It is recognizedthat nonthermal effects do exist below a few megahertz andmaybe at frequencies ≥ 150 MHz. Those wishing to develop alow-level nonthermal (LLNT) medical application of RF energywill not find the frequencies between a few megahertz andabout 200 GHz fruitful. The majority of research funding in thisfrequency range has been driven by concerns for adverse healtheffects and not by inherent scientific interest or a search forbeneficial applications. This adverse-health-related objectivehas served the interest of health regulators and those inter-ested in developing standards but has not necessarily servedthe scientific community well. The prevalence of no-effector nonrepeatable findings may be useful for risk evaluationbut has not led to advancements in science and may havedriven or fostered dead-end research lacking original hypothe-ses. Historically, less expensive microwave sources have beenavailable at frequencies widely used by consumer products suchas microwave ovens, cell phones, etc., and have promoted theuse of selected frequencies for research. Available funds and

Manuscript received October 12, 2008; revised October 18, 2008.M. Swicord, retired, was with Motorola, Inc., Plantation, FL 33322 USA.Q. Balzano is currently with the Department of Electrical and Computer

Engineering, University of Maryland, College Park, MD 20742 USA.Digital Object Identifier 10.1109/TPS.2008.927165

RF sources are necessary ingredients for research but allowingsuch items to drive research turns the scientific process on itshead. The proper simile is given as follows: looking under thestreet lights for a lost coin because the illumination is better.

The areas of bioelectromagnetic research that have been orare fruitful include not only hyperthermia but also applied dc orlow-frequency fields that exceed endogenous fields, promotingbone and wound healing, high-peak short pulses that are onthe order of membrane potentials, and terahertz signals forspectroscopy and medical imaging. The physics behind theseapplications is sound, and investigations should lead to repeat-able findings, providing a fruitful body of data for building an-alytical and predictive theories. This sharply contrasts with thelack of theoretical or experimental support for LLNT biologicaleffects between about 0.1 and 150 GHz.

The denominations athermal and nonthermal have beenused to identify effects or mechanisms that might occur whenthe temperature increase during the exposure is insufficientto change biochemical reactions and the biological processesthey serve. There is no firm basis to distinguish these terms,both of which are widely understood to involve no measurabletemperature increase (athermal) or temperature changes of< 1 K (nonthermal). Biological effects have been reported [1]to occur from high-peak-energy pulses with low power aver-aged over the period of the pulse train. These responses arebriefly discussed in this document; however, we do not applythe term LLNT mechanisms or effects to the response fromhigh-peak-energy or high-field-strength exposures with low av-erage power. We recognize that thermal effects do occur at verylow levels. Cell metabolism is affected by small temperaturechanges of a few tenths of a degree [2], [3]. Thus, exposing cellsfor long periods of time, 24 h or more, with slight differencesin temperature will result in measurable responses. To eliminateboth these low-level thermal effects and short high-peak-powerpulse effects from our discussion, we use the term LLNT RFbiological effects.

II. PROPOSED MECHANISMS OF INTERACTION

The reader is referred to an extensive review of proposedmechanisms that we coauthored (Sheppard et al. [4]), whichwill be summarized here. We begin with the observation thatbiological systems have molecules held together by Coulombic

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SWICORD AND BALZANO: HAS ELECTROMAGNETIC ENERGY IN THE BAND 0.1–100 GHz MEDICAL APPLICATIONS 1639

forces; membrane potentials governing membrane processes;endogenous fields playing essential roles in growth, develop-ment, and wound and bone healing; nerve impulses provid-ing nervous system communication; and many other electricalproperties. In order to affect these processes with externalfields, we must either pump energy into existing molecular os-cillatory modes, causing a conformation and functional change,or impose fields large enough to affect the function of one ormore of the various endogenous fields. Elevation of the tem-perature by any means, including absorption of RF, distributesenergy to all available modes of the system. Thus, temperatureelevation will cause functional changes in the biological sys-tem as discussed further below. The principal mechanisms ofabsorption of RF energy resulting in increased temperature aredielectric relaxation and ohmic loss. This subject will not bediscussed here, and the reader is referred to [4].

Endogenous electric fields are dc or low frequency and rangein magnitude from 1 to 109 V/m. Physiological steady-statefields are on the order of 1–200 V/m, and embryonic develop-mental fields, which range in frequency from 0 to 100 Hz, areon the order of 10–150 V/m [5], [6]. Fields across membranesof thickness 7.5–10 nm [7] are about 106 to 107 V/m with apotential of about 70 mV [8]. Finally, chemical bonds involvefields ≥ 109 V/m. These fields govern biological processes,which can be disrupted or affected by the application of fieldson the same order of magnitude or higher but with the properdirection, timing, or frequency. For example, wounds inducedin animals exhibit current flow across the gap [5]. Appliedfields that enhance these currents promote wound healing, asdemonstrated by Borgens et al. [9], and fields that oppose theendogenous currents decrease the rate of healing. It should thusbe obvious that oscillating fields would provide little or nonet effect on this process. However, some processes may beaffected by extremely low frequency (ELF) fields, but biolog-ical mechanisms involving electric induction of ELF fields arenot relevant for exposures to unmodulated RF fields becausebiological structures capable of supporting induction at RFfrequencies are not known to exist. Induction of ELF amplitude-modulated RF fields would be of interest if there were ademodulation mechanism that produced ELF electric signalsof sufficient magnitude, but no such demodulation mecha-nism has been reported for frequencies above approximately10 MHz. Experiments by Barsoum and Pickard [10] in plantcells showed that nonlinear behavior at cell membranes doesnot occur above approximately 10 MHz in the absence of heat-ing. These observations were supported by theoretical analysis[11] and recent experimental work in humans by Silny [12], inwhich a single RF pulse up to 100 ms in duration was usedto determine the threshold of nerve stimulation. Silny variedthe carrier frequency up to about 10 MHz where the requiredamplitude of the RF signal for detection was so large thatthe pain threshold was reached before being able to observenerve stimulation indicative of demodulation. Thus, RF fieldsabove a few megahertz are not rectified by the biologicalsystems efficiently enough to affect endogenous dc or ELFfields, particularly by mechanisms involving electrical potentialchanges at the plasma membrane. The estimated applied fieldsby Silny [12] were about 100 V/m at 20 Hz and 20 kV/m at

500 kHz. Thus, it would seem more efficient to use the lowerfrequency if electrical stimulation were desirable for medicalapplication.

It is well known that a single RF photon is not energeticenough to cause ionization. Hydrogen bonds, considered theweakest of chemical bonds, are on the order of 1–5 Kcal/mole[13], which would be equivalent in energy to a 10-THz pho-ton. This is also on the order of magnitude of the frequencyof infrared photons with energy equivalent to 37 ◦C. Thus,some hydrogen bonds are not stable at body temperature,promoting continuous metabolic processes. Even though RFcannot directly contribute to the breaking of chemical bonds,one must consider the possibility of excitation of molecu-lar modes (e.g., vibration modes) that may exist in the RFrange. The excitation of such modes could lead to changesin biochemical processes with demonstrable biological conse-quences. Although experimental studies have reported resonantRF absorption in highly purified DNA [14], these studies werenot confirmed through independent replication [15], [16]. Sub-sequent theoretical analysis by Prohofsky [17] indicates thatwater damps all such modes below several hundred gigahertz.Prohofsky [17] discusses a unique vibrational mode in whicha large heme group resonates at the relatively low frequencyof 184 GHz because of the rotational freedom within a pocketof surrounding protein that effectively isolates the heme groupfrom the viscous damping by water. This observation leadsto a rather limited testable hypothesis but trumps speculationconcerning resonant absorption in the low-gigahertz range. Ingeneral, water damps all modes below a few hundred gigahertz,and thus, resonant absorption cannot occur. In 1977, Webband Stoneham [18] used Raman spectroscopic techniques andreported seeing Raman lines using B. megaterium. Attempts atreplication by Furia and Gandhi [19] failed to confirm theseresults, and Cooper and Amer [20] suggested that the timevariations reported by Webb et al. [21] were due to clumping ofthe synchronous cells, which produced changes in the total lightscattered (Mie scattering from clumped cells), and were notdue to specific frequency components. Spectroscopic studies todate support the theoretical analysis [17] and have revealed noactive modes of bimolecular systems below 150 GHz. Modesare likely absent below several hundred gigahertz.

In principle, multiple-photon processes could occur in alower RF region, thus upshifting incident energy to a regionwhere resonant interactions are known to occur. Generally, suchmultiphoton processes require intense incident beams such asthose from a laser so that there will be an appreciable numberof photons arriving virtually simultaneously or within onecycle time. The probability of m photons being simultaneouslyabsorbed varies as the mth power of transition probabilityfor one photon [22]. Thus, for a 10-GHz signal to pump the184-GHz mode described by Prohofsky [17], it would require ahighly improbable eighteenth-order transition. Most molecularvibrational modes are in the range above 20 cm−1, reflectingthe fact that molecular spectroscopy is typically conducted inthe range of 10–100 cm−1 (300–3000 GHz).

An overriding principle affecting all proposed nonthermalmechanisms is the background or thermal noise of the bio-logical system. Again, the reader is referred to [4] for a more


detailed discussion. For electromagnetic energy to affect bio-logical processes, it must first interact with and modify a mole-cular function. This must be accomplished by either “pumping”existing vibrational, rotational, or electronic modes of resonantabsorption (not likely to occur as discussed above) or affect-ing nonresonant energy absorption processes in a way thatovercomes the molecular noise level resulting from fluctuatingtemperature, concentration, mechanical stress, and backgroundelectric fields [23]. Background electromagnetic noise resultsfrom the random motion of atoms and molecules. Biologicalsystems generate additional noise [23]. The resulting noise isbroadband, covering a large frequency range. Thus, a nonres-onant absorption process such as an increase in temperaturemust compete with a background of thermodynamic noise overan unlimited spectrum. In contrast, for a resonant absorptionprocess, the relevant noise energy is confined to the bandwidthof the applied signal and is proportional to that bandwidth. Thisis the reason why nearly all proposed mechanisms for effects ofLLNT RF fields concern pumping energy into resonant modesfor which the in-band noise level is very much reduced from thesystem-wide noise level. There can be speculative exceptionsabout regions or molecular systems that might be isolated fromthe overall thermodynamic system and thus able to selectivelyabsorb energy and have a lower noise level. The noise spectrumin the RF band is featureless with no outstanding or dominantfrequency components. Any exogenous signal has to overcomethe in-band background signal given by the Rayleigh–Jeanslaw [24] if there is to be a plausible interference with ongoingbiological processes. A signal-to-noise ratio of less than 0.1 isconsidered a conservative threshold for RF to be effective inchanging a biochemical process [23].

A good example of the limitation imposed by noise was dis-cussed by Adair [25], who used dimensional analysis to showthe impossibility of overcoming thermal noise with an RF elec-tric field strength of 200 V/m. His calculations showed that thesignal-to-noise ratio would be about 2 × 10−13 for a field actingon a proton moving in water, 5.5 × 10−9 for a field acting toswitch a system molecular system from a lower to a high energystate with no significant energy lost to dissipative processes,and 10−7 for the case of electrostrictive forces on an objectwith the size of a large molecule. Electrostrive forces can bemuch larger for large objects such as a cell, but these forces arenot oscillatory and should be compared to other steady forces,for example, gravitational forces and body movement [26].Thus, in general, RF signals must add energy that exceeds thelocal thermal environment in order to deliver information to thebiological system.

In the discussion of physical mechanistic interactions, wegenerally emphasize responses to the electric field. However,there are three basic mechanisms for magnetic field sensing[26]: 1) Indirect sensing of magnetic fields up to 10 Hz byelectrosensitive animals. Marine animals may be able to senseELF electric fields because they are surrounded by conductingseawater [27]. 2) Some animals have developed a magnetite-based receptor such as an array of magnetite that may besensitive to static magnetic fields as low as 1–10 nT. Studies ofanimal behavior indicate the sensitivity of vertebrates, particu-larly birds, to static magnetic fields of 0.50–10 µT, comparable

to the geomagnetic field strength [28]. 3) Finally, radical pairmechanisms, which can affect biochemical reaction yields, canbe changed by both static and RF magnetic fields, dependingon the magnetic properties of the nuclei comprising the radicalpair [29]. Evidence suggests that some animals utilize theradical pair mechanism as well as magnetite-based receptors fornavigation [30], [31]. The evolutionary developments that haveutilized these magnetic field sensing systems have respondedto environmental dc or low-frequency fields. Significant RFsources did not exist in the natural environment, and thus, therewas no evolutionary need to develop RF sensing systems.

The only one of these three magnetic field detection systemsthat might be useful for RF biological interaction and couldhave possible interest in medical applications would be the radi-cal pair mechanism. Changes in a photochemical reaction yieldin solution have been observed at discrete frequencies in therange 1–80 MHz using a 300-µT RF magnetic field [32], [33].These experiments were done with no static magnetic fieldcomponent, which allowed isolation of effects on each mem-ber of the radical pair. Unusually large hyperfine couplingconstants associated with strongly magnetic nuclei could leadto effects above 100 MHz [32]. However, despite the greatnumber of biochemical reactions that can involve free radicals,several restrictive conditions make RF magnetic field effectson biochemistry uncommon. The molecular hyperfine couplingconstant sets the limit for energy level splitting of a radicalpair, causing RF resonance effects to be limited to frequenciesbelow approximately 100 MHz, although resonances in mostmolecules occur between 0.1 and 10 MHz [33]. In addition tothe frequency constraints, radical pair interactions are restrictedby the necessity for the creation of spin-correlated radicalpairs that remain in close proximity, radical lifetimes longenough to be affected by an oscillatory magnetic field, relax-ation processes slow enough to allow adequate radical lifetime,and static magnetic fields of appropriate field strength [29].Requirements on free radical lifetimes, spatial localization,relaxation processes, and hyperfine coupling constants indicatethat static and RF magnetic field effects on the radical pairmechanism are not a general feature of biological chemistryabove 10 MHz, particularly above approximately 100 MHz.

It seems reasonable to postulate that at some field strengthlevel, RF energy could affect molecular processes (e.g., chem-ical binding at ion transport channels, receptor sites, en-zymes, and other proteins). Calculations have been made thatdemonstrate this point. Apollonio et al. [34] used ab initiocomputational methods to obtain molecular potentials for thebinding/unbinding of CO to the active site of the heme group.However, their model showed that 108 V/m was the lowestlocal field strength that could affect the binding and unbind-ing energy barriers. Thus, it would require an unattainablystrong exogenous electric field to directly perturb the energysurface at the active site. Other examples include the work ofSuydam et al. [35], who showed that fields on the order of108 to 109 V/m were associated with functionally signifi-cant changes in the structure of the enzyme aldose reductase.English and Mooney [36] showed that changes in the secondarystructure of lysozymes in a frequency- and field-strength-dependent manner were possible at a specified constant


temperature of 298 K. Such change required field strengths inthe range 109 to 5 · 109 V/m at frequencies of 50–500 GHz.This nonthermal mechanism for protein denaturation was at-tributed to interactions with the overall protein molecular dipolemoment with further influences due to side-chain interactionswith solvent (water) molecules. The degree of denaturationwould have required temperatures of 400–500 K to be producedby heating. However, these theoretical observations may onlybe of academic interest because there are no technologicalmeans of achieving these large fields in the RF range.

There are several other speculative mechanisms that havebeen proposed such as microthermal effects and hot spots, in-teratomic molecular resonances, and electron tunneling, whichare discussed in more detail in [4]. In general, these all suf-fer from the omission of an important consideration such asthe ubiquitous presence of water or the signal-to-noise prob-lems in living systems at 37 ◦C. Thus, low-level RF energyonly increases the entropy (the state of molecular disorder)of the biological system without coupling to specific modesin molecules, cells, and tissues. An analysis of all proposedtheoretical mechanisms of interaction with biological systemsin the range of a few megahertz to several hundred gigahertzprovides no encouragement for theoretical research or any guid-ance for experimental research (no testable hypothesis). Thepossible exception is the investigation of biochemical changesbased on spin-coupled radical pairs at selected frequenciesbelow 100 MHz.

III. STATE OF BIOLOGICAL EFFECTS RESEARCH

Even though theoretical analysis provides no guidance forexperimental work, more than 1700 peer-reviewed publicationson biological responses to RF exposure have been produced inthe last 50 years, with a large portion searching for LLNT ef-fects. These studies are listed on the World Health Organization(WHO) research database [37] and include epidemiological,human, in vivo, and in vitro studies, as summarized in Table I.This WHO database comprehensively covers the peer-reviewedliterature on RF biological effects published in English. It doesnot cover nor will we review other-language-based literaturesuch as Russian publications. For a discussion of Russianliterature including medical applications, see the review byPakhomov and Murphy [38]. About 42% of the publicationshave occurred since 1990 with the ability to utilize betterdosimetry. Unfortunately, a number of researchers did not takeadvantage of these engineering advancements and producedvariable and nonrepeatable results. The question remains as tothe proper approach to evaluate this large database. Our searchis for indications of nonthermal effects that might indicate howRF could be used to control biological or biochemical pro-cesses. This implies that we need to find repeatable phenomena,which can be studied and provide sufficient information fora mechanistic explanation. Repeatability is vital to establishscientific certainty of a reported effect. The factors that causefalse experimental findings include statistical variation, honestmistakes, and poor techniques. If 100 biological studies areconducted and the results of each study compare the responseto some stimuli of an exposed group to that of an unexposed

TABLE IRF BIOEFFECTS: PEER-REVIEWED PUBLICATIONS SINCE 1950

group on a 95% confidence level, then five studies are mostlikely to yield incorrect results. This is independent of howwell the studies are conducted. There is a tendency in analyzinga body of literature such as the studies listed in Table I byevaluating each study and eliminating those that are consideredpoorly performed. It is, however, possible for a poorly donestudy to give the correct results and vice versa. Thus, we lookfor substantiation of reported findings through replication orcomplementary studies.

Our interest here is not to conduct a risk assessment butrather to determine whether there is a candidate effect in thedatabase that might be further studied for scientific interest andthe development of a basis for a mechanistic understanding.Results that need to be developed are a dose response orthreshold of response (if the response has a threshold) as afunction of frequency. For risk assessment, epidemiology andhuman studies are of primary importance. Animal studies areextremely useful when epidemiological and human studies areinconclusive. In vitro studies are only of value in defining amechanism of an established health effect. A large numberof the studies conducted before 1990 looked for thresholds ofthermal response, and the vast majority conducted after 1990looked for LLNT responses. This latter portion of the databasewill be our primary focus. A complete review of these studiesis not practical for this exercise; thus, we will select subareas ofresearch that exemplify that portion of the database. For a moredetailed review of the database up to 2004, see [39, Annex B].

A. Epidemiology

One hundred ninety nine of the epidemiological publicationslisted in Table I have been published since 1990, with a largenumber of these addressing the question of mobile phonesafety. The vast majorities are hypothesis-generating studiesand are not designed to provide definitive health answers. Themore recent and better studies attempt to use large numbersof subjects and are mobile telephony related. A large multi-center study supported by the European Union’s Fifth Frame-work Program and the industry, the INTERPHONE study, has


TABLE IIMETAANALYSIS OF MOBILE PHONE USE AND INTRACRANIAL TUMORS

institutions conducting studies in 13 countries using the sameprotocol to determine whether the use of mobile phones causesan increase in the occurrence of head and neck tumors. Insti-tutions are publishing results independently and collectively.The combined results from five countries [40] on the risk ofacoustic neuroma show no risk association with regular mobilephone use (OR = 0.9, 95% CI: 0.7−1.1) and no association ofrisk with the duration of use, the lifetime cumulative hours ofuse, or the number of calls, for phone use overall or for analogand digital phones separately with use for 10 years or longer.The data were collected by personal interview from 678 casesand 3553 controls. In a population-based case–control study[41], again a part of the INTERPHONE study, with 1522 glio-ma patients and 3301 controls, the authors reported no evi-dence of increased risk of glioma related to regular mobilephone use (OR = 0.78, 95% CI: 0.68, 0.91), and no significantassociation was found across categories with the duration ofuse, the years since the first use, the cumulative number ofcalls, or the cumulative hours of use. The authors conclude that“Although our results overall do not indicate an increased riskof glioma in relation to mobile phone use, the possible risk inthe most heavily exposed part of the brain with long-term use(≥ 10 years) needs to be explored further before firm con-clusions can be drawn.” There are other suggestions of tumorformation after 10 years in some of the other INTERPHONEstudies, but all constitute small numbers and would requirefurther study. The latest review of these reports can be foundin the September 25, 2007 INTERPHONE report [42].

Lahkola et al. [43] performed a metaanalysis of 12population-based case–control studies and estimated risk forindividuals using mobile phones for up to five years for gliomas,meningiomas, and acoustic neuromas. The odds ratios andconfidence limits are shown in Table II. They concluded thatthere is no evidence for risk of intracranial tumors from mobilephone exposure for at least five years.

It is not practical to completely review the large database ofepidemiological studies on RF exposure for this paper. Thereare a number of studies reporting effects, and some of those areincluded in the Lahkola et al. metaanalysis [43]. The negativeoverall findings by the three studies above are consistent withtrends of several studies [44]–[46] that examined trends intumor formation over 30-year periods. These studies showthat tumor incidence increased during the 1970s and early1980s, coinciding with improved diagnostic methods, and theoverall incidence has remained stable during the period after theintroduction and widespread use of mobile phones. One group[44] points out that such studies are limited in their ability to

TABLE IIITYPE AND NUMBER OF PUBLISHED IN HUMAN/PROVOCATION RF STUDIES

reveal potentially small increases in risk for diseases with a longlatency period.

In contrast, Hardell et al. [47] recently published a meta-analysis of studies reporting incidence of various types of headtumors for those using mobile phones for more than 10 years.Up to 10 studies were used for each tumor type with thestudies coming mostly from Hardell’s previous work and thosecompleted studies of the INTERPHONE project. With smallnumbers, an increase in the incidence of tumors was reportedfor almost all types of tumors. This result is inconsistent withthe long-term animal studies as well as in vitro studies discussedbelow and is without support of any mechanism. Neither dosuch reports aid in mechanistic studies.

Most analyses of the epidemiology database, particularly thecombined analysis discussed above, provides no support ofLLNT RF effects, and thus, this portion of the database providesno guidance for further studies of such effects.

B. Human Studies

Of the 211 human studies listed in Table III, 172 havebeen published since 1995. Those published before 1995mainly dealt with thermal responses and microwave hearing.Research on microwave hearing, a well-established phenom-enon, has been reviewed by Elder and Chou [48]. Microwavehearing involves short RF pulses in the frequency range of2.4–10 000 MHz, inducing pressure waves in the head that aretypically detected by the auditory system as clicks or a buzz.Absorbed energy results in rapid localized heating, resulting ina pressure wave. The threshold temperature is extremely small,for example, < 10−6 K for one typical set of conditions [49].


A relatively quiet environment is required for humans to hearthese microwave pulses, and this microwave response is gener-ally believed to be not harmful [40].

Studies on mobile phone use and headaches have generallybeen uncontrolled surveys or questionnaires, providing varyingresults. Three controlled laboratory provocation studies haveexamined the effects of RF exposure on headaches, reportingno effect [50]–[52].

More recent studies have focused on cognitive function, EEGand sleep disturbance, subjective symptoms, and, to a lesserdegree, the remaining items listed in Table III. Preece et al.[53] reported improved reaction time in testing subjects withstandardized computer programs. Koivisto et al. [54], [55]attempted follow-up studies that again showed a small (lessthan the normal variability among subjects) improvement inreaction time and cognitive function. However, the Preece et al.[53] studies did not necessarily agree with the Koivisto et al.[54] results in that different tests showed an increased reactiontime in each study—not a situation conducive to the studyof mechanisms. A subsequent study [56] attempting an exactreplication of [53] failed to support the original findings. Otherstudies, for example, that of Wilen et al. [57] and subsequentstudies by Preece et al. [58] and Haarala et al. [59] usingchildren as subjects, showed no effect.

The most difficult studies to assess are EEG provocationstudies due to the extensive variability in results. A largenumber of these studies have reported observing effects due toRF- or mobile-phone-type exposure. For example, Huber et al.have published papers in 2002 [60] and 2003 [61] reportingeffects on alpha rhythm. In both publications, the response wasan increase in different alpha frequency bands, which is nota candidate reliable effect for mechanistic study. Hamblin andWood [62] reviewed the subject of effects on brain activity in2002, and recently, Wood [63] has reviewed 21 studies on alpharhythm, of which 10 reported increases (in various bands),10 reported a decrease or no effect, and one reported bothincreases and decreases. Several factors could be responsiblefor this variability. A major potential source of the problem isthat subjects are exposed with electrodes in place, with analysisconducted either during exposure or following exposure. Thepotential for artifactual stimulation is great. Hamblin et al. [64]have conducted studies to show that the electrode cap doesaffect the fields within the skull. Those that consider theseresults to be indicative of LLNT effects need to address theseissues.

Alpha rhythm findings are inconsistent across the databaseand are exemplary of the RF human studies database.

C. Animal Studies

Listed in Table IV are the number of publications and typesof animal studies that have been conducted to determine the ef-fect of RF exposure on health. A large number of these studies,particularly those conducted before 1990, investigated thresh-olds of thermally related responses such as behavior. Theseprovided repeatable findings, establishing thermal thresholds ofresponse (failure to perform tasks for a reward) that could leada detrimental health condition. On the other hand, we find no

TABLE IVTYPE AND NUMBER OF PUBLISHED IN VIVO RF STUDIES

group of studies listed in Table IV that provides a repeatableLLNT response. This does not mean that there are no reports ofnonthermal effects. An example can be taken from the bloodbrain barrier (BBB) studies. Of the 56 publications listed inline 4 of Table IV, 52 are investigations of whether RF exposurecauses a disruption of the BBB. The majority (37) of these pub-lished papers show either no effect (16) or a response to thermalincrease (21), with the remaining 15 reporting a nonthermalresponse. There is a tendency for some particular laboratories toprovide multiple publications of results or additional research.Lumping multiple publications from the various laboratoriesdoes not seem to change the ratio of effects to no effects, with11 studies showing no effect, 10 reporting thermal effects, and8 reporting effects.

Two observations emerge from an examination of thesepapers. First, the numbers are large enough to attempt a com-parison, and second, there is a great deal of inconsistency. Themajority does not necessarily rule and determine the outcome.However, a number of investigators have proceeded further toinvestigate the role that temperature plays in BBB disruptions inan attempt to clarify the cause of positive reports. It was shownby Sutton and Carroll [65] that RF exposure to the rat headthat elevated the brain temperature to 40 ◦C or more caused


TABLE VCHRONIC RF ANIMAL STUDIES PUBLISHED SINCE 1990

increased permeation of the BBB. Perfusion of the brain withcooled blood prevented disruption during RF exposure. Studiesby Merritt et al. [66] also point to temperature increase asthe cause of BBB disruption under RF exposure by showingthat hot air or RF exposure resulted in similar effects. Others,including Fritz et al. [67] and Ohmoto et al. [68], have demon-strated that temperature increase is the most likely mechanismof BBB disruption from RF exposure.

A second important group of studies to be considered forLLNT effects are the chronic animal studies, the publicationslisted as cell line injection tumor bioassays, chemical radiationgenetically initiated bioassays, and long-term rodent bioassays.Forty of these studies have been published since 1990 and arelisted in Table V. The duration of these studies is from severalweeks to 25 months, and they utilize exposure frequenciesfrom a few hundred megahertz to 94 GHz. The vast majorityfalls within the frequency range of 900–2450 MHz, utilizingvarious frequency and amplitude modulation schemes. Sixteenof these studies exposed animals for 12–25 months, and sevenstudies exposed animals almost continuously (20–24 h/dayand 7 days/week for 10–25 months). Four studies exposedanimals 20–22 h/day and 7 days/week for 8–25 months. In twostudies, animals were exposed in utero and, after birth, were

exposed for two years. These studies were primarily looking forincreased tumor formation, but the length of these studies hadfar reaching implications for the general health of the animals.Thirty-seven of the 40 studies showed no significant changein tumor formation. In 1992, Chou et al. [69] reported aslight increase in overall tumor incidence in a two-year ratstudy. However, the authors did not consider this observationas biologically significant due to no clear or significant increasein any single tumor type or change in survival. This result isnot supported by any of the other studies listed in Table V.Repacholi et al. [70] reported increased formation of follicularlymphomas in transgenic mice (Pim-1) exposed to not well-defined levels of RF for 18 months. Follow-up studies byUtteridge et al. [71] and Oberto et al. [72] failed to confirmthese findings. The last of the three studies reporting effectswas conducted by Anghileri et al. [73], who concluded thatRF exposure caused tumors and increased early mortality.This study failed to report exposure levels and used a smallnumber of animals, making replication difficult and, perhaps,not worthwhile. Needless to say, these findings are inconsistentwith the remaining database.

An important observation for long-term studies is the factthat 23 of 24 studies reporting survival data going back to 1980observed no significant change due to RF exposure, and all24 studies reporting body weight observed no significantchange due to RF. Thus, one may conclude a lack of detrimentalor beneficial effects to animals for chronic exposure.

The two important examples of in vivo studies given aboveof biological responses to RF exposure, BBB studies, and long-term chronic studies exemplify all areas listed in Table IV.Each area has some publications reporting effects that are notsubstantiated by the remaining database. Thus, no reproduciblefindings exist, providing no basis for further directions inresearch. These additional areas are more extensively reviewedin Annex B of the IEEE safety standard [38] with referencesup to 2005. The additional reported studies since 2005 have notaltered the conclusions of that document.

D. In Vitro Studies

Epidemiological, human, and in vivo studies are of greatvalue in determining possible adverse health conditions, but theabsence of effects in these studies cannot lead us to concludethe total absence of LLNT adverse effects. In vitro studiescan explore this issue and are generally of most interest toresearchers because of the implication for the fundamentalunderstanding of biological processes. However, particularlyfor RF biological responses, they are very prone to false-positive outcomes. The principal reason for this variabilityis the inability to control the temperature between sham andexposed samples. Temperature differences may occur simplybecause sham and control samples are in slightly differentenvironments or unexpected heating may occur in the exposedsample. Small temperature differences of a few tenths of adegree can result in cellular metabolic differences, which canresult in the divergence of observed endpoints over a period oftime [2], [3]. An example of this problem is provided by thework of de Pomerai et al., who used a transgenic nematode to


TABLE VITYPE AND NUMBER OF PUBLISHED IN VITRO RF STUDIES

study possible genetic effects of RF exposure. Although, strictlyspeaking, this is an in vivo study, the experiments using thissmall worm parallel in vitro exposure conditions and biochemi-cal analysis techniques. The genome of the nematode is alteredwith a hsp16 stress-reporter gene, enhancing the expression ofb-galactosidase. Worms are placed in multiwell plates and areexposed in a TEM cell. Initially, sham controls were wrappedin aluminum foil and placed in the same incubator as theTEM cell. Five studies by de Pomerai et al. reported effectsof low-level (90 mW/kg or less) RF exposure [74]–[78]. Theinvestigators were able to receive funding for an improvedexposure system that provided better parallel treatment of ex-posed and sham exposed. This resulted in a final publication[79] reporting the inability to replicate previous experimentaloutcomes and suggesting that a temperature difference as littleas 0.2 ◦C could be responsible for the previously reportedfindings.

Examination of the in vitro RF database listed in Table VIreveals no consistent or reproducible reported effects acrossa large number of endpoints examined under various ex-posure conditions. Some examples are worth reviewing.Penafiel et al. [80] reported observing enhancement of 40% inornithine decarboxylase (ODC) activity in L929 cells following8 h of exposure to RF emitted by a digital mobile phone.An attempt to replicate this effect with a different exposuresystem by a group from the US Food and Drug Administration

TABLE VIIEXAMPLE IN VITRO STUDY RESULTS

[81] with close cooperation from the original group and withone member (A. Desta) playing a central role in both studiesfailed to show any change in ODC levels. A study performedby Diem et al. [82] reported DNA damage in cultured humanfibroblasts exposed to 1800-MHz RF at an SAR of 2 W/kg.Both continuous and intermittent exposure, with and withoutmodulations, was employed for 16 or 24 h of exposure. Bothalkaline and neutral versions of the comet assay were usedto assess DNA damage. In some cases, almost twice as muchdamage was reported in the exposed over the controls. Again,in an attempt of exact replication using the same cell line and anexposure system constructed by the same engineers, there wasan inability to replicate these effects by a group in Germany[83]. Criticism and explanations of possible sources of error inthe Diem et al. study [82] and a second study by the same groupreporting differences in cell line response [84] were publishedby Vijayalaxmi [85].

A third example can be taken from studies of micronucleiformation and chromosomal aberrations. The review of suchstudies can be found in [85]–[88]. In 2002, Tice et al. publishedfindings suggesting that RF exposure from mobile-phone-typesignals could cause enhanced micronuclei formation when ex-posed to 5 W/kg in vitro with cell temperature maintained at37 ◦C [89]. This study received a lot of publicity even though itwas inconsistent with studies published previously or at aboutthe same time [90]–[94]. Micronuclei formation is known tobe temperature sensitive, and issues were raised concerning theability to maintain a constant temperature in the sample duringRF exposure. Nevertheless, confirmation of the Tice et al. study[89] was necessary. Subsequent in vitro studies [95] by twoItalian laboratories and an in vivo study [96] failed to givesupport to these findings.

These areas of studies selected as examples are not with-out reports of effects. Table VII gives an indication of thenumbers reporting effects and those not reporting effects.A study may represent more than one publication. Again, aslight elevation of the temperature will affect cell metabolismand could be the cause of the large number of studies reportingeffects on gene and protein expression as well as affectingstudies on micronuclei formation. One would not expect smalltemperature changes to cause an increase in DNA damageor mutation. Examining the numbers in Table VII does notlead us to a conclusion concerning the presence or absence ofan LLNT effect but gives an indication of whether there aresufficient studies for scientific analysis. For science to progressand address this issue, one must find a reproducible effect. The


absence of such prevents the study of a possible mechanismand supports the conclusion of the theoretical analysis thatLLNT effects do not exist. In searching the literature containinga large number of biological endpoints with cells exposed tovarious frequencies and numerous modulation schemes, we findno independently reproducible effect. Attempts at independentreplication/confirmation have consistently failed, which is theonly consistent observation in this large multifarious ensembleof studies.

E. Conclusion of Biological Research Review

There is no consistent or repeatable observation of anLLNT biological or biochemical effect between 150 MHz and150 GHz and probably none between 10 MHz and 300 GHz.

The nonexistence of an effect cannot be proven, just as onecannot prove the null hypothesis. However, these observationssupport the theoretical analysis of no predictable effect. Thus,there is no guidance or encouragement for further experimentalwork in this frequency range.

IV. CONCLUSION AND SUGGESTED

RESEARCH DIRECTIONS

Selective examination of the large RF biological databasedeveloped over the last 50 years will lead to a biased conclusionconcerning the existence of LLNT biological effects. Exami-nation of the database as a whole, considering both proposedphysical theories and the results of more than 1700 peer-reviewed published papers, leads us to conclude that findingany LLNT effect between 150 MHz and 150 GHz is ex-tremely unlikely, and finding such effects between 10 MHz and300 GHz may not be possible.

We believe that there are more fruitful areas of bioelectro-magnetic research for those interested in medical applications,and guidance for such research can be found in the physicalprinciples stated above. In addition to the well-establishedmedical application of RF such as hyperthermia and MRI, theseareas of research include the following four categories:

1) ways of affecting growth and repair-related processes(applied fields on the order of or exceeding endogenousfields);

2) electroporation and supraelectroporation (large appliedfields on the order of or exceeding local membranepotentials);

3) the use of terahertz signals for imaging and spectroscopy;4) studies of the possible effects due to free radical for-

mation below a few megahertz (speculative but possiblemechanism with supporting data).

The effects of applied fields on growth and repair processeshave been studied for some time. The aspects of bone healinghave been reviewed by Spadaro [97] and Pilla [98]. Aftermore than 30 years of use, the underlying mechanism does notseem to be understood. We believe that a greater attention toestablishing the magnitude and direction of endogenous fieldsin vivo could aid in this regard, perhaps with the methodsdeveloped by Jaffe and Nuccitelli [99]. Pulsed magnetic fieldshave been used to induce internal electric fields in an efficient

manner. However, it appears that not a lot of attention hasbeen given to the magnitude and direction of exogenous fieldsin relation to the apparently nonfunctional endogenous fields.The support for this idea comes from studies of surface woundhealing experiments as reviewed by Nuccitelli [6]. Applied dcfields opposing endogenous fields inhibit healing, and thoseenhancing the endogenous fields promote wound healing. Littlesuccess has been recently reported by Walker et al. [100] inusing a “ramped” waveform to promote nerve regeneration.Was this signal asymmetric enough, in the proper directions,and of sufficient magnitude or do electric fields play little or norole in nerve regeneration? Similar questions have been raisedby Greenebaum and Sisken [101].

Electroporation employs pulses of 100 µs or longer with peakfield strengths between 10 and 100 kV m−1 and is utilized forenhanced delivery of macromolecules into cells [102], [103].Theoretical examination of this process has been performedby Gowrishankar et al. [104] and Stewart et al. [105]. Thesetheoretical examinations also provide a basis for supraelectro-poration, which employs much shorter and more intense pulses(1 to 30 MV m−1 and 1 µs or less) and has been utilized byNuccitelli et al. [1] to cause tumor regression. In particular, thefull utility and mechanistic understanding of supraelectropora-tion has not been fully explored and opens many avenues ofinvestigation.

The potential for studying basic biochemical processes us-ing terahertz spectroscopy should be of great interest, andthe potential with such studies is already under way [104].Furthermore, medical imaging using terahertz frequencies isunder development [106] and again opens the door for furtherresearch.

Finally, the biochemistry of the radical pair formation shouldbe evaluated in detail, specifically the rate changes of enzymaticreactions in vivo. The research should be targeted for potentialclinical use. Therefore, the physical parameters for specificradical pair formation should be quantified, e.g., field intensity,frequency, and best conditions of application. Also of interestis the determination of the frequency band of the biochemicalrelevance of this phenomenon.

A single observation in frequency and amplitude can gener-ate a hypothesis but is useless in developing an understandingand promoting scientific progress. Observations as a function offrequency and amplitude are vital to demonstrate consistencyand provide information for the development of a testablehypothesis. Once a repeatable phenomenon is obtained, one canthen move to areas of greater risk of failure but with guidancefrom the developed hypothesis.

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Mays Swicord (SM’80) was born in Chunju, Korea,in May 1938. In 1960, he received the B.A. degreein mathematics from King College, Bristol, TN, theM.S. degree in physics from the University of NorthCarolina, Chapel Hill, in 1963, and the Ph.D. degreein electrophysics with a minor in biophysics from theUniversity of Maryland, College Park, MD, in 1980.His doctoral research involved studies of microwaveabsorption by liquids and liquid solutions of biolog-ical materials.

He joined Motorola, Inc., Plantation, FL, in Fall1995 to direct their health effects research programs and retired in May 2006.He is currently an independent consultant. He has had 40 years of research andteaching experience in the government, the industry, and the academia. Duringhis 26 years of service in the Food and Drug Administration (FDA), he wasresponsible for building multidisciplinary research teams to address questionsof possible health effects from radio frequency exposure.

Dr. Swicord is a member of the Bioelectromagnetics Society (BEMS), wherehe served as the President from 1991 to 1992, and the European Bioelectromag-netics Association. He has served on various standard committees, includingthe American National Standard Institute’s Committee on Radiofrequency Ra-diation Hazards, the IEEE/G-TM Technical Committee on Radiation Hazards,IEEE SCC 28, and the International Commission on Non-Ionizing RadiationProtection.

QuirinoBalzano (S’63–M’72–SM’83–F’02–LF’06)was born in Rome, Italy, in December 1940. Hereceived the Ph.D. degree in electronics engineeringfrom the University of Rome, Rome, Italy, in 1965.

During 1966, he was with FIAT, SpA, Turin,Italy. From 1967 to 1974, he was with the Mis-sile Systems Division, Raytheon Corporation. Hewas involved in the research and development ofplanar and conformal phased arrays. In 1974, hejoined Motorola, Inc., Plantation, FL, where hewas the Corporate Vice President and the Direc-

tor of the Florida Research Laboratories. He retired from Motorola, Inc.,on February 2001, as a Consulting Scientist. Since August 2002, he hasbeen with the Department of Electrical and Computer Engineering, Uni-versity of Maryland, College Park, MD, where he is a Senior Staff Re-searcher and teaches a graduate course on antennas. His main interests in-clude electromagnetic fields, antenna design, and the biological effects ofhuman exposure to RF energy. He is the author or a coauthor of more than50 papers on RF dosimetry near electromagnetic sources and the biologicaleffects of RF energy and of more than 100 publications. He is the holder of27 patents in antenna and IC technology.

Prof. Balzano was on the Board of Directors of the BioelectromagneticsSociety, a scientific society dedicated to the research of the biological effectsof electromagnetic fields. He was the Chair of the Commission A of theInternational Union of Radio Science in 2005. He received the IEEE VehicularTechnology Society Paper Prize Award in 1978 and 1982 and a certificate ofmerit from the Radiological Society of North America in 1981 for ht treatmentof tumors with RF energy.

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