Genotoxic, carcinogenic and teratogenic effects of electromagnetic fields. Introduction and overview

Mutation Research 387 Ž1997. 165–171

Genotoxic, carcinogenic and teratogenic effects of electromagnetic fields. Introduction and overview J. Juutilainen ) , S. Lang Department of EnÕironmental Sciences, UniÕersity of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland Received 30 August 1997; accepted 16 September 1997

1. Background The people of industrialized societies are continuously exposed to increasing levels of electromagnetic fields ŽEMF. emitted by various electrical installations and telecommunication systems. The articles w1–3x included in this issue of Mutation Research review different aspects of the possible genotoxic, carcinogenic and teratogenic effects of EMFs. The recent discussion on EMFs has focused on the possible health hazards of radiofrequency ŽRF. radiation and extremely low frequency ŽELF. magnetic fields ŽMF., with much less attention on ELF electric fields. ELF magnetic fields are emitted by electric appliances and all conductors carrying alternating current. The public concerns on ELF MFs have focused mainly on the 50–60 Hz fields from powerlines, but many other sources of ELF fields exist in occupational and residential environments. RF radiation was previously mainly considered an occupational health hazard. The most important sources of exposure were radar equipment and industrial or medical devices using RF energy for heating conductive or dielectric materials. However, the exposure of the general public is now rapidly increasing due to the growing use of mobile telephones. The high number of people exposed has recently acti-

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vated new research projects on the biological effects of RF radiation. Relatively few studies have addressed the possible effects of EMFs in the very low frequency ŽVLF. range, located between the ELF and RF bands. Some concerns have been expressed that the VLF emissions of video display units might increase the risk of adverse pregnancy outcome. The focus areas of research described above guided the selection of articles into this collection. Two articles review the carcinogenic w2x and teratogenicrreproductive w1x effects of ELF magnetic fields. The latter article also includes studies on the effects of VLF fields on reproductive health. No separate article on the genotoxic effects of ELF MFs was included, since the subject has been covered in two relatively recent reviews published in Mutation Research w4,5x. This overview, however, gives a brief review of the genotoxicology of ELF fields published after the two more complete reviews. The literature on RF radiation is somewhat sparser than that on ELF fields, so a single article covers the genotoxic, carcinogenic and teratogenic effects of RF radiation w3x.

2. Definitions and physical characteristics of EMFs EMF. The term ‘‘electromagnetic field’’ is here used to refer to electric, magnetic or combined elec-

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tric and magnetic fields with frequencies from ) 0 Hz to 300 GHz. A figure showing the included range of frequencies and its relationship to the rest of the electromagnetic spectrum is given in the article by Verschaeve and Maes w3x. Electric field. A physical field that surrounds electrically charged objects. Electric fields can be either static Žset up by fixed charges. or time-varying Žset up by alternating voltage.. The intensity of an electric field is measured by a quantity called the electric field strength Ž E . in volts per meter ŽVrm.. Magnetic field. A physical field that surrounds conductors carrying electric current, moving charged objects and magnetized bodies Žpermanent magnets.. Magnetic fields can be either static Žset up by direct current or a permanent magnet. or time-varying Žset up by alternating current.. Two quantities — the magnetic field strength Ž H . in amperes per meter ŽArm., or the magnetic flux density Ž B . in Tesla ŽT. — can be used to describe the intensity of a magnetic field. Due to different traditions, literature on RF uses H, but most researchers use B at ELF. American literature still often uses the non-SI unit gauss ŽG s 0.1 mT. for B. Electromagnetic radiation. Electromagnetic waves consisting of coupled electric and magnetic fields. The intensity of electromagnetic radiation can be described by a quantity called the power density ŽS. in watts per square meter ŽWrm2 .. Electromagnetic fields exist in the form of electromagnetic waves only in the far field, i.e. far enough from the source. In the near field the electric and magnetic fields must be characterized separately. The limit between far and near fields is in most cases approximately one wavelength. Because the wavelengths of ELF fields are thousands of kilometers, the ELF electric and magnetic fields are always evaluated separately. At the highest microwave frequencies, on the other hand, the wavelength is so short that human exposure always occurs in the far field and there is no need to consider electric and magnetic fields separately. ELF. Frequencies below 300 Hz. VLF. Frequencies from 300 Hz to 100 kHz. RF. Frequencies from 100 kHz to 300 GHz. MicrowaÕes. RF radiation with frequencies from 300 MHz to 300 GHz. WaÕeform. Describes the change with time of a

time-varying electric or magnetic fields. Most ELF, VLF and RF sources produce fields with a sinusoidal waveform, but some sources emit EMFs with, e.g., triangular or rectangular waveforms. Waveforms with a high rate of change — in field strength units per unit of time, e.g. mTrs — induce strong currents in tissues and may therefore be biologically more active than waveforms with low rate of change. Modulation. RF radiation is often modulated by another, lower frequency signal to make it, for example, carry information or to save energy. The most common forms of modulation used for telecommunication are amplitude modulation ŽAM. and frequency modulation ŽFM.. In AM, the amplitude of the carrier waÕe is modulated by the low frequency signal, e.g. voice ŽFig. 1.. Similarly, FM involves modulation of the frequency so that it varies in a narrow band around the basic frequency. A form of AM is pulse modulation. Pulse-modulated radiation with very high-intensity, short-duration pulses is emitted by radars. Pulse modulation is also used in digital mobile phones, such as the European GSM system. Analog mobile phones, in contrast, are based on FM signals. Amplitude modulation may be important for the biological effects of RF radiation. Several in vitro and animal studies suggest that weak RF radiation, if amplitude-modulated at low frequencies, might have specific effects similar to the reported effects of ELF fields w6–8x.

Fig. 1. Schematic representation of an unmodulated Žcontinuous. wave ŽA. and two forms of amplitude modulation: waves modulated with a smoothly varying ŽB. or a pulsed ŽC. signal.

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3. Interaction of electric and magnetic fields with biological matter Possible biological and biochemical processes leading to the reported carcinogenesis-, teratogenesis- and mutagenesis-related effects of EMFs are discussed in the other articles of this issue w1–3x. The three articles, however, do not discuss the primary biophysical interaction that must occur before EMFs can produce any biological changes. A brief overview of the biophysical interaction mechanisms is given here. More complete descriptions can be found elsewhere w9–13x. 3.1. Penetration of EMFs into tissues At frequencies below about 10 MHz, the penetration of electric fields into tissues increases with increasing frequency. At 50 Hz, for example, the internal electric field of a person standing under a powerline is approximately 10y6 -times weaker compared with the external field strength. The low internal electric field at ELF is one of the reasons why the research on ELF health effects has focused on magnetic fields. Low-frequency magnetic fields, in contrast, are not attenuated by biological tissues, so the internal and external MF intensities are identical. Absorption of EMF energy into the human body is highest at about 30 MHz to 300 MHz, the resonance range for the whole body. Above the resonance range, EMFs penetrate into the body as electromagnetic waves rather than as separate electric and magnetic fields. In the microwave range, the penetration depth of electromagnetic waves decreases with increasing frequency.

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3.3. Heat generation The flow of induced currents in biological tissues generates heat. The main aim of the RF exposure limits recommended by international standard setting bodies and national authorities is to protect exposed persons from excessive general or local heating. Specific absorption rate ŽSAR. is a quantity that describes absorption of power from EMFs into tissues, in watts per kilogram ŽWrkg.. Because of the stronger induced currents, heat absorption is more important in the RF than in the low frequency ranges. Biological effects of RF radiation based on increased tissue temperatures are called thermal effects. Athermal effects refer to situations when there is a heat load, but the thermoregulatory system is able to maintain the organism at its nominal temperature, or a cooling system is used to compensate the RF heating, e.g. in cell culture experiments. Nonthermal effects are based on mechanisms other than heat absorption. The existence of nonthermal effect of RF radiation is a subject of debate, and there are no generally accepted mechanisms for explaining such effects. 3.4. Stimulation of excitable cells If the currents induced in tissues are strong enough, the voltage induced over the cell membrane can cause stimulation of nerve and muscle cells. The threshold field strength needed for stimulation increases with increasing frequency. At low frequencies, the threshold for electrical stimulation is lower than that for significant tissue heating, but heating is the predominant effect at RF frequencies above about 10–100 kHz.

3.2. Induction of electric currents 3.5. Effects of weak EMFs Both electric and magnetic fields induce electric currents in conducting materials, including biological tissues. The magnitude of the induced currents increases with increasing frequency and depends in a complex way on several other variables, such as size and shape of the biological organism, its orientation in relation to the lines of force of the electric and magnetic fields, and the size and location of the EMF source.

Biological effects of EMFs have been reported at such low field intensities that they cannot be explained by heat absorption or stimulation of excitable cells. One of the arguments against the plausibility of the reported health effects of ELF fields is that the internal electric fields induced by environmental ELF fields are weaker than electrical ‘‘noise’’ present in the tissues w14,15x. Several hypothetical mechanisms

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have been proposed to explain the observed effects of weak ELF fields w9–12,15x. None of these mechanisms, however, have been generally accepted w16x.

4. Carcinogenic effects of ELF magnetic fields The discussion on the possible cancer-related effects of ELF magnetic fields was initiated by epidemiological studies suggesting that residential or occupational MF exposure may be associated with increased risk for certain types of cancer, including leukemia, brain tumors and breast cancer. Several reviews of the epidemiological literature are available w17–19x. The paper by Loscher and Liburdy w2x ¨ is a thorough review of the experimental evidence on the possible role of ELF magnetic fields in carcinogenesis. The review covers both the laboratory animal studies conducted and a wide spectrum of in vitro studies that could shed light on the cell physiological and biochemical mechanisms of the carcinogenic effects of MFs. According to the authors, there is not much evidence for cancer initiation by MFs alone. However, accumulating evidence suggests that they could act as co-carcinogens if given in combination with known genotoxic andror non-genotoxic carcinogens. The interpretation of the experimental studies is complicated by the fact that most studies have used magnetic flux densities far above the levels occurring in human exposure situations. The in vitro studies also suggest that MFs affect several cellular processes that could plausibly explain their co-carcinogenic effects. Loscher and Liburdy con¨ clude that although the existing evidence is still insufficient for discerning a causal relationship between MF exposure and human disease, there is a need for further laboratory research under well-defined exposure conditions.

5. Teratogenic and reproductive effects of ELF and VLF magnetic fields The paper by Huuskonen et al. w1x reviews both epidemiological and experimental evidence on the possible role of ELF and VLF magnetic fields in teratogenesis and reproductive outcome. The reviewed studies indicate that exposure to low fre-

quency MFs during pregnancy does not exert strong effects on embryonic development. No gross malformations were found in animal studies and epidemiological studies did not show evidence of increased birth defects. Slight effects on, for example, fetal loss, minor skeleton anomalies or changes in postnatal development cannot be ruled out. No consistent biological effects were seen after paternal exposure. The authors conclude that further epidemiological studies should involve sufficient numbers of subjects exposed to high MF levels. Further experimental studies should address effects on early embryonic development, postnatal effects of prenatal exposure and possible ‘‘co-teratogenic’’ effects with known teratogenic agents.

6. Genotoxic effects of ELF magnetic fields Recent reviews in this journal w4,5x concluded that ELF MFs are probably not able to cause directly genotoxic effects. Only a small minority of the reported studies indicate potential of ELF MFs to cause genetic changes in biological systems. The few studies published after the two reviews will be briefly reviewed here. Miyakoshi and co-workers w20,21x found mutations in the hypoxanthine–guanine phosphoribosyl transferase gene ŽHGPT. of human melanoma MeWo cells exposed to a 400 mT 50 Hz field. Such extremely strong 50-Hz MFs are not found in occupational or residential environments. In a human study chromosomal aberrations, sister chromatid exchanges ŽSCEs., replication indices and micronuclei in peripheral blood lymphocytes were analyzed among nonsmoking power linesmen with considerable long-term exposure to 50-Hz electromagnetic fields w22x. No genotoxic effects were observed. Only a slight increase in the mean rate of lymphocytes with chromatid-type breaks among power linesmen was found, but this finding may be explained by the previous smoking history of the workers. A slight increase in chromosomal aberrations was observed in human amniotic cells exposed to 50-Hz fields at a relatively low flux density of 30 mT w23x. However, no genotoxic alterations were found in human peripheral lymphocytes exposed to 50-Hz sinusoidal MFs at up to 1 mT w24x. Lai and Singh w25x reported

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that acute exposure of rats to 60-Hz magnetic fields of up to 0.5 mT increases DNA strand breaks in brain cells. A few studies have addressed the possibility that ELF MFs could enhance the action of known genotoxic chemicals or ionizing radiation. There is some evidence that ELF MFs might enhance the genotoxic potential of g-radiation w26x, X-rays w20x or mutagenic chemicals w27x. Overall, the majority of the published results are still consistent with the conclusions of the two reviews published in 1993 w4,5x. The few positive findings should be followed up in independent, well-controlled experiments.

7. Effects of RF radiation The paper by Verschaeve and Maes w3x reviews the literature on the genotoxic, carcinogenic and teratogenic effects of RF radiation. The majority of studies suggest that low-level, nonthermal exposure to RF radiation is not genotoxic or teratogenic and does not induce cancer. There are, however, some provocative results that motivate further research. The authors emphasize the need of studies on the possible mechanisms and on synergistic effects with other physical or chemical agents.

8. Possible biological mechanisms that could explain carcinogenic and reproductive effects of EMFs 8.1. Gene mutations Based on biophysical considerations, it is unlikely that the relatively weak environmental RF or ELF electromagnetic fields exert direct genotoxic effects. The quantum energies of these EMFs Žsee Fig. 1 of the review by Verschaeve and Maes w3x. are far too low to damage DNA. Also the majority of the experimental data reviewed in the three reviews of this issue indicate that ELF or RF electromagnetic fields are not directly genotoxic Žexcluding the effects due to tissue heating in very intense RF fields.. However, the possibility that EMFs are able to cause direct damage in the DNA molecule cannot be entirely

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rejected. For example, recent theoretical studies by Bohr et al. w28x suggest that the eigenfrequency of collective twist excitations in chain molecules can be in the megahertz and gigahertz range. Thus, exposure to EMFs at these frequencies may alter the conformation of the molecules and their ability to function, and a breaking of the chain can result. This hypothesis is interesting but very difficult to test experimentally. Studies by Miyakoshi et al. w20,21x indicate that mutations induced by ELF MFs might be cell cycle-dependent. They suggest that DNA replication errors andror disturbance of the mismatch repair systems may occur during exposure of cells at the S-phase. Lai and Singh w25x suggest that ELF MFs affect enzymatic processes involved in DNA repair, leading to an accumulation of DNA strand breaks. More experimental research is needed to confirm or refute these hypotheses. 8.2. Non-genotoxic mechanisms According to the three reviews of this issue, the majority of animal and cellular studies suggest that, if the relatively weak environmental EMFs exert any cancer- or teratogenesis-related effects, they act via non-genotoxic pathways. Carcinogenesis is a complex multistage process, and even if EMFs do not cause direct DNA damage, there are several other steps in carcinogenesis on which EMFs may act Žsee Fig. 1 in the review by Loscher and Liburdy w2x.. In their article, Loscher ¨ ¨ and Liburdy discuss EMF effects on signal transduction and intracellular calcium, gene expression and protein synthesis, ornithine decarboxylase ŽODC. activity, cell proliferation, and intercellular communication. All these cellular and molecular events are linked to the cell cycle machinery and might increase the probability that a DNA damage, induced by, e.g., a genotoxic agent, is ‘‘cloned’’ to the next cell generations. The authors also discuss the possibility that EMFs could increase the risk of DNA changes through their interactions with free radicals. They also review studies suggesting that EMFs might decrease the circulating levels of the pineal hormone melatonin, discuss the possible role of melatonin as an anticarcinogen and present in vitro data indicating that EMFs may modify melatonin’s oncostatic action.

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As pointed out by Huuskonen et al. w1x, the cellular and systemic mechanisms discussed by Loscher and Liburdy could also lead to alterations in ¨ reproduction and development. 8.3. Effects of amplitude-modulated RF fields Carcinogenesis-, mutagenesis- and teratogenesisrelated effects have been reported at both ELF and RF electromagnetic fields w1–3x. In spite of the similarity of the reported bioeffects, the primary biophysical interaction mechanisms may be different at ELF and RF because of the large difference in frequency and wavelength. As mentioned in the introductory part of this overview, it has been hypothesized that amplitude modulated RF fields could have specific bioeffects based on the ELF modulation signal. From this point of view, it is of interest to note that the studies reviewed by Verschaeve and Maes w3x do not clearly indicate that the bioeffects of RF fields would depend on the presence of amplitude modulation.

ments may be, in part, due to the fact that all experimental details have not been exactly duplicated in different laboratories w1,32,33x. The difficulties in replicating, nevertheless, indicate that the possible EMF effects are subtle; strong effects would not be sensitive to small variations in experimental details. The subtlety of the effects does not necessarily mean that they are insignificant. Because of the high number of exposed persons, even subtle effects may be important for public health. The authors of the three reviews included in this issue stress the importance of understanding the interaction mechanisms, further laboratory research in well-defined conditions, and epidemiological studies with good exposure assessment and a high number of subjects exposed to strong EMFs. It is worth noting that interactions with other agents, the possible co-carcinogenic and co-teratogenic effects of EMFs, are mentioned in the conclusions of all three reviews.

References 9. Concluding remarks A large number of experimental and epidemiological studies have been carried out to elucidate the possible health hazards associated with human exposure to ELF or RF electromagnetic fields. There is no convincing evidence supporting direct DNAdamaging effect of EMFs. Many studies have, however, provided evidence suggesting that EMFs with relatively low Ženvironmental. intensity are capable of interacting with many molecular, cellular and systemic processes associated with carcinogenesis, mutagenesis and teratogenesis. It is still unclear how these studies should be interpreted in terms of human risk assessment. One of the main problems is the lack of a generally accepted biophysical interaction mechanism that could explain the reported bioeffects of weak EMFs without violating basic physical principles. Evaluation of the present data is also difficult due to the use of varying study designs and the relatively small number of replication studies. Also, attempts to replicate some of the key findings in independent laboratories have often been unsuccessful w29–32x. Difficulties in replicating EMF experi-

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