Introduction

We are continuously exposed in our environment to electromagnetic fields (EMF) which are either of natural origin (geomagnetic field, intense solar activity, thunderstorms) or manmade (factories, transmission lines, electric appliances at work and home), magnetic resonance imaging, medical treatment, etc. Electric and magnetic fields which exist wherever electricity is generated, transmitted, or distributed correspond to three frequency ranges: the extremely low frequency (ELF) range includes the frequencies (50 Hz in Europe, 60 Hz in North America) of the electric power supply and of electric and magnetic fields (EMF) generated by electricity power lines and electric/electronic appliances; intermediate frequency (IF, 300 Hz to <10 MHz) is used in computer monitors, industrial processes, and security systems; and finally, radiofrequency range (RF, 10 MHz to 300 GHz) includes radars, and radio and television broadcasts and telecommunications.

Biological effects of ELF-EMF and their consequences on human health have become the subject of important and recurrent public debate. The growth of electric power use in industrialized countries and the parallel increase of environmental exposure to ELF-EMF resulted in a widespread concern that ELF-EMF may have harmful effects in humans, a concern stimulated in the past decades by a number of epidemiologic studies reporting deleterious effects of ELF-EMF on human health. Wertheimer and Leeper1,2 published the first report, conducted in the Denver area, on the association between childhood cancer and exposure to ELF-EMF, with the conclusion of a higher risk of childhood leukemia at higher residential ELF-EMF exposure. Savitz et al3 gave support to this assertion with the publication of similar results in the same area (Denver). From then, several epidemiologic papers have reported a possible link, without any experimental evidence, however, between exposure of humans to ELF-EMF and diseases such as leukemia and other cancers,4-6 depression, and suicide,7 and neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis.8-11 All these results, though some of them were conflicting, resulted in a “melatonin hypothesis” as a tentative explanation, with the idea that those potential ELF-EMF deleterious effects might be a consequence of an inhibitory effect of ELF-EMF on the production of melatonin,12 a hormone whose secretion has been shown to be altered (concentration decline and/or alteration of its circadian rhythm) in some diseases including cancers (review in Hill et al, ref 13), depressive disorders,14-16 and disorders of the circadian time structure.17,18

The concern regarding public health resulted in reports on this matter of official organizations, the most recent reports being those of the International Agency for Research on Cancer (IARC) in 2002 and the World Health Organization in 2007.19 Of special interest, the IARC published in 2002 an evaluation of the carcinogenic risks of ELF to humans.20 The agency classified ELF electric fields into category 3, which in the classification corresponds to “inadequate evidence” of deleterious effects, and classified ELF magnetic fields into category 2B, corresponding to the category of agents that are “possibly carcinogenic to humans.” A classification into group 2B is “usually based on evidence in humans which is considered credible, but for which other explanations could not be ruled out.” It has to be noted that these extremely-low-frequency electric and magnetic fields are separate entities.

Whether or not ELF magnetic field exposure is causally related to increased health risks has led many scientists to examine the potential mechanisms by which ELF magnetic fields might affect human health. It is known that cancer and neurobehavioral alterations may be associated with circadian rhythm disruption and/or effect on melatonin secretion.21-24 Theoretically, melatonin could be a good mechanistic candidate to explain potentially deleterious effects of EMF since: i) its secretion is dramatically inhibited by light,25-28 which is the visible part of EMF; ii) the circadian pattern of the hormone is phase-advanced or -delayed by light according to the time of exposure, which is known as the phase response curve or PRC,29 and this property might occur with exposure to EMF; iii) the oncostatic properties of melatonin have been described,30-32 which resulted in the hypothesis that a decrease in the secretion of melatonin by the pineal gland might promote the development of breast cancer in humans12; iv) and last, its association with depressive, disorders has been put forward.14-16

Since both melatonin and cortisol are major markers of the circadian system, we reviewed data from the literature on these two marker rhythms, in search of deleterious effects of EMF on both their blood levels and abnormalities in their circadian profiles, eg, a phase-advance or a phase-delay which would point out a rhythm desynchronization of the organism, ie, a situation that occurs when the biological clock is no longer in step with its environment.17,33

Rationale for studying the effects of ELF-EMF on melatonin and cortisol secretions

Melatonin (N-acetyl 5- methoxytryptamine), a neurohormone produced by the pineal gland, is characterized by a prominent circadian rhythm with high levels at night and very low levels during the daytime, whatever the age.34,35 Its secretory pattern has a strong endogenous component and is physiologically controlled by light. Melatonin is therefore considered as a marker rhythm of the circadian temporal structure. A marker rhythm is a physiological rhythmic variable, whose circadian pattern is highly reproducible on an individual basis and as a group phenomenon, which thus allows characterization of the timing of the endogenous rhythmic time structure and provides information on the synchronization of individuals (Figure 1.).36 Besides melatonin, the most frequent marker rhythms used both in humans and animals are the core body temperature circadian pattern37 and the cortisol circadian rhythm, since they are also highly reproducible.36,17

Figure 1.
Figure 1. Reproducibility of the circadian patterns of plasma cortisol and melatonin in young healthy men. The circadian rhythms of the two hormones are highly reproducible from a day to another. Both are useful circadian markers of the time structure. Reproduced from ref 36: Selmaoui B, Touitou Y. Reproducibility of the circadian rhythms of serum cortisol and melatonin in healthy subjects. A study of three different 24-h cycles over six weeks. Life Sci. 2003;73:3339-3349. Copyright © Pergamon Press 2003

Cortisol also displays a robust and highly reproducible circadian rhythm that does not respond rapidly to minor and transient environmental changes, as they are part of daily life, which also makes it a good candidate as a marker rhythm.36 Since a relationship between the pineal gland and the adrenal gland has been documented in vitro,38 and considering the hypothesis of the alteration of melatonin by EMF, it can be useful to look at their potential effects on cortisol, another rhythm marker of the circadian system, and to obtain an additional argument for a circadian desynchronization of the organism.

ELF-EMF effects on melatonin

Animal studies

For the sake of clarity, we present in two different tables the reports on ELF-EMF effects on melatonin. Table Ia displays the reports showing an alteration of melatonin secretion in different animal species, mainly rodents, after exposure to ELF-EMF. Table Ib deals with all of the studies reporting no effect of ELF-EMF on melatonin secretion in the different species under study.

Magnetic field reports on the modification of melatonin secretion in different animal species. Mel, melatonin; Pl, plasma; Ser, serum; aMT6s, 6 sulfatoxymelatonin; MF, magnetic field; NAT: serotonin N-acetyl transferase

Reference of the studySpeciesExposure characteristicsTiming of exposureFluid or pinealSampling timeEffect on melatonin secretion
Wilson et al, 198139Adult rats60 Hz- 1.7-1.9 kV/m20 h/day for 30 daysPineal Mel and NAT activityDay/nightDecrease in pineal Mel and NAT activity
Wilson et al, 198640Adult rats60 Hz- 65 kV/m (39 kV/m effective)20 h/day for 3 weeksPineal Mel and NAT activityDay/nightDecrease in pineal Mel and NAT activity within 3 weeks
Reiter et al, 198841Adult rats50 Hz- 10, 65 or 130 kV/mDuring gestation and 23 days postnatallyPineal MelNighttimeDecreased and delayed nighttime peak
Martinez Soriano et al, 199252Adult rats50 Hz- 5 mT30 min during the morning for 1, 3, 7, 15 and 21 daysSer MelNighttimeDecrease in Ser Mel on day 15
Kato et al, 199348Adult rats50 Hz- 1, 5, 50 or 250 μT6 weeksPineal and Pl MelNighttimeDecrease in serum and pineal melatonin
Yellon, 1992, 199446Djungarian hamsters60 Hz- 100 μT18 h/ day for one weekPineal and Ser MelNighttimeDecreased and delayed nighttime peak
Grota et al, 199442Adult rats60 Hz- 10 or 65 kV/m20 h/day for 30 daysPineal Mel and NAT activity, Ser MelNighttimeDecrease in Ser Mel after exposure to 65 kV/m but no effect on nighttime pineal Mel and NAT
Kato et al, 199451Adult albino rats50 Hz- 1 μT, circularly polarized6 weeksPineal and Ser MelDay/nightDecrease in nighttime peneal and Ser Mel Recovery 1 week after cessation of exposure
Kato et al, 199450Adult pigmented rats50 Hz- 1 μT, circularly polarized6 weeksSer Mel12 h and 24 hDecrease at night
Löscher et al, 199453Adult rats50 Hz- 0.3-1 μT24 h/day, 7 days/ week 91 daysSer MelNighttimeDecrease in nocturnal Ser Mel
Rogers et al, 199576Baboons60 Hz- 6 kV/m and 50 μT or 30 kV/m and 100 μT irregular and intermittent sequence6 weeksSer MelNighttimeDecrease in Ser Mel
Selmaoui and Touitou, 199562Adult rats50 Hz- 1, 10 or 100 μT12 h, or 18 h per day for 30 daysSer Mel and pineal NAT activityNighttimeDecrease in Mel and NAT activity after 100 μT (acute) and 10 and 100 μT (chronic)
Truong et al, 199657Young Djungarian hamsters60 Hz- 100 μT15 min, 2 h before dark; over 3-weeksPineal and Ser MelNighttimeDecreased and delayed nighttime peak though not replicated in the same paper = inconclusive
Yellon, 199658Djungarian hamsters60 Hz- 100 μT15 min, 2 h before dark; over 3-weeksPineal and Ser MelNighttimeDecreased and delayed nighttime peak though not replicated in the second part of the paper = inconclusive
Mevissen et al, 199671Adult rats50 Hz- 10 μT24 h/day, 7 days/ wk, for 91 daysSer MelNighttimeDecreased Mel levels
Niehaus et al, 199759Djungarian hamsters50 Hz- 450 μT sinusoidal or 360 μT rectangular56 daysPineal and Ser MelNighttimeIncreased nighttime serum melatonin levels after rectangular field exposure
Reiter et al, 199883Adult rats0 Hz- Pulsed Magnetic field (1s off and on intervals) of 50 to 500 μT15 to 120 minPineal Mel and NAT activity, Ser MelNighttimeInconsistent results from 15 experiments
Lerchl et al, 199860teleost fish, the brook trout (Salvelinus fontinalis)1 Hz- maximum 40 μT (200 ms on, 800 ms off)45 min: exposure started at 22 h45Pineal and Ser MelAt 23:30Increase
Selmaoui and Touitou, 199963Aged rats50 Hz- 100 μT18 h per day for one weekSer Mel and Pineal NATNighttimeDecrease of Mel and NAT activity in young but not aged rats
Wilson et al, 199952Siberian hamsters50 Hz- 100 or 500 T, continuous and/or intermittent30 min or 2 h before onset of darkness and for up to 3 h up to 42 daysPineal MelNighttimeDecrease of pineal Mel and NAT activity in short photoperiod
Fernie et al, 199981Kestrel60 Hz- current created a magnetic field of 30 μT and an electric field of 10 kV/m.For one or two breeding seasonPl Mel08 h-11 h (Males) and 13-15 h (females)Effect in adult males but not females. Long-term, but not short-term, MF exposure of adults suppressed in their fledglings. Seasonal shift
Huuskonen et al, 200154Female adult rats50 Hz- 13 or 130 μT24 h/day from day 0 of pregnancy; and killed during light and dark periods between 70 h and 176 h after ovulationSer MelNighttimeDecrease of Ser Mel concentration by 34 and 38% at 13 and 130 μT
Burchard et al, 200484Holstein heifers60 Hz- 10kV/m22h/day for 4 weeksSer Mel9 h, 10 h, 11 h, and 12 hInconsistent results between 2 replicates
Kumlin et al, 200555Female mice50 Hz- at 100 μT52 daysUrinary aMT6sNocturnal urine was collected 1, 3, 7, 14, 16 and 23 days after beginning of exposureSignificant day-night difference in the aMT6s levels. No effect on the total 24 h
Dyche et al, 201261Adult rats60 Hz- 1000 mG1 monthUrinary aMT6sUrine collected for the last 3 days of the exposure periodMild increase of nighttime aMT6s

Reports on the lack of effect of magnetic field on melatonin secretion in different animal species. Mel, melatonin; Pl, plasma; Ser, serum; aMT6s, 6 sulfatoxymelatonin; MF, magnetic field; NAT, serotonin N-acetyl transferase; NG, not given

Reference of the studySpeciesExposure characteristicsTiming of exposureFluid or pinealSampling timeEffect on melatonin secretion
Kato et al, 199449Adult rats50 Hz- 1 μT, horizontally or vertically oriented MF6 weeksPineal and Pl Mel12 h and 24 hNo effect
Lee et al, 1993, 199574,75Suffolk sheep60 Hz- 6 kV/m and 4 μTOverhead power lines (10 months)Ser Mel8 x 48 h periodsNo effect
Rogers et al, 199556Baboons60 Hz- 6 kV/m and 50 μT6 weeks 30 kV/m and 100 μT, 3 weeksSer MelNighttimeNo effect
Kroeker et al, 199668Rats0 Hz- 800 gaussbetween 12 hours and 8 daysPineal and Ser MelNighttimeNo effect
Yellon, 199658Adult Djungarian hamsters60 Hz- 100 μT15 min, 2 h before darkPineal and Ser MelNighttimeNo effect
Mevissen et al, 199672Adult rats50 Hz- 50 μT24 h/day, 7 days/week, for 91 daysSer MelNighttimeNo effect on DMBA-treated rats
Bakos et al, 1995; 199764,65Adult rats50 Hz- 1, 5, 100 or 500 μT24 hUrinary aMT6sDay/nightNo effect
Löscher et al, 199869Adult rats50 Hz- 100 μT18 h per day for one weekSer MelNighttime (3 samples)No effect
Yellon and Truong, 199877Adult Siberian hamster60 Hz- 100 μT 15 min per dayUp to 21 daysPinel and Ser MelNighttimeNo effect
Burchard et al, 199878Holstein cows60 Hz- 10 kV/m and a uniform horizontal magnetic field of 30 μTUp to 56 days of exposurePl Melevery 0.5 h for 14 starting at 17 hNo effect
John et al, 199870Adult rats60 Hz, 1 mT20 h/day for 6 weeksUrinary aMT6sCircadian patternNo effect in 3 experiments out of 4
de Bruyn et al, 200173Mice50 Hz- between 0.5 and 77 μT with an average of 2.75 μT24 h/day from conception until adult agePl Mel23 h-01 h30No effect
Fedrowitz et al, 200267Adult rats50 Hz- 100 μT24 h/day for 2 weeksPineal Melat 9 h30, 10h30, 12h30, 1h30No effect
Bakos et al, 200266Adult rats50 Hz- 100 or 50 microT8 h/day for 1 weekUrinary aMT6sNighttimeNo effect
Rodriguez et al, 200480Holstein cows60 Hz- vertical electric field of 10 kV/m and a horizontal magnetic field of 30 μTfor 16 h/day for 4 weeksPl MelOver 24 hNo effect during dark period. Daytime mel low
Burchard et al, 200779Holstein heifers60 Hz- 30 μT20 h/day for 4 weeksSer Mel09 h, 10 h, 11 hNo effect
Dell'omo et al, 200982Eurasian kestrels50 Hz-power lines high voltage: 4-8 μTBreeding seasonSer MelNGNo effect

The very first data on the topic deal with electric fields (not magnetic fields), and date back to 1981, with the report on the reduction of pineal melatonin and N-acetyltransferase (NAT), the key enzyme for melatonin synthesis, in rats exposed to electric fields 20 h/day for 30 days.39,40 Other reports, however, failed to find any effect, or were inconclusive or contradictory.41,42 Then the interest shifted from electric to magnetic fields, with a large number of studies devoted to the effects of ELF-EMF on melatonin levels in different animal species.43,44

Yellon45,46 and Wilson et al,47 documenting the effects of magnetic fields, were the first to report a reduction of both in pineal and plasma melatonin in Djungarian hamsters with a short exposure to a sinusoidal 100-μT magnetic field. In addition, Wilson et al47 also reported an increase in the concentration of norepinephrine in the suprachiasmatic nuclei, the central rhythm-generating system.

The majority of laboratory studies were then carried out on rats. Kato et al,48 in exposing male Wistar-King rats for 6 weeks to a 50-Hz circularly polarized sinusoidal magnetic field using increasing intensities, showed a decrease in pineal and plasma melatonin concentrations without any dose-response relationship. With the same protocol of exposure and species, but with a horizontal or vertical magnetic field, the same authors failed to find any effect on melatonin levels:49 Suspecting a possible interference of pigmentation, Kato et al50,51 then documented in Long-Evans rats the same intensities of a circularly polarized magnetic field and did indeed show a reduction of pineal and plasma melatonin concentrations. Other studies on rats or mice,52-55 baboons,56 and hamsters57,58 also showed a reduction in the nighttime peak of melatonin. The same team reported a phase delay in the nocturnal peak time of melatonin in hamsters,46,57,58 though they acknowledged in one paper that they were unable to replicate these findings, which make them inconclusive.58 Some authors have reported an increase in nighttime melatonin levels.59-61

With the aim of comparing short-term and long-term exposure effects, Selmaoui and Touitou62 used male Wistar rats housed in a 12:12 light:dark schedule and submitted to a 50-Hz sinusoidal magnetic field of 1, 10, or 100 μT intensity, either once for 12 h or repeatedly 18 h per day for 30 days. While a single 12-h exposure to a 1- or 10-μT magnetic field had no effect on plasma melatonin levels or NAT and hydroxyindole-O-methyltransferase (HIOMT) pineal activities, a 100-μT exposure significantly decreased 30% plasma concentrations of melatonin and depressed 23% pineal NAT activity (HIOMT activity unchanged) when compared with sham-exposed rats. In turn, the 30 days' repeated exposure showed that while the 1-μT intensity showed no effects on pineal function, both the 10- and 100-μT intensities resulted in an approximately 42% decrease of plasma melatonin levels. NAT activity was also decreased, and HIOMT activity remained unchanged. This study showed that a sinusoidal magnetic field alters plasma melatonin levels and pineal NAT activity, and that the sensitivity threshold varies with the duration of exposure, thus suggesting that magnetic fields may have a cumulative effect upon pineal function. This melatonin and NAT activity decrease was able to be replicated in adult rats in another study by Selmaoui and Touitou,63 while they also reported that aged rats were not affected by ELF-EMF. Löscher et al53 studied the effects of a 24 h/day, 7 days/week, and 3-month exposure to magnetic fields on female rats bearing DMBA-induced mammary tumors; the field intensities were similar to the domestic exposures recorded close to electric power facilities. Whereas a significant decrease of blood melatonin concentrations was observed with 1 μT, no influence on the development of the mammary tumors could be put in evidence.

Table lb presents data on different animal species reporting the lack of effect of ELF-EMF on the concentrations of pineal or blood melatonin and on the urinary concentration of 6-sulphatoxymelatonin, the main metabolite of the hormone. These reports were either inconsistent or failed to show any effect of ELF-EMF in species as different as rats or mice,64-73 sheep,74,75 baboons,76 Djungarian hamsters,58,77 cows or heifers,78-80 and kestrels.81,82

The comparison of Table la (effects on melatonin) and Table lb (lack of effects on melatonin) clearly shows that a number of these studies resulted in inconsistent data, even when the data were replicated by the same team with the same protocol and characteristics of exposure.48,49,57,58,83,84

Last, some authors studying the effects of exposure to ELF-EMF of various biological systems such as isolated pineal glands85-90 or MCF-7 cells91-96 were unable to arrive at definite conclusions (Table II).

Effects of magnetic fields on various biological systems in vitro. NE, norepinephrine; Mel: melatonin

Reference of the studyExposure characteristicsEnd pointEffect of MF on melatonin
Studies on rat and hamster isolated pineal glands
Lerchl et al, 19918533.7 Hz - 44 μT for 2.5 hNE stimulation of Mel production in ratDecreased production and release
Richardson et al, 1992860 Hz- 1 h to a pulsed 0.4-G static MFNAT activity and Mel in ratDecrease of NAT activity and Mel content
Rosen et al, 19988760 Hz- 50 μTNE stimulation of Mel release in ratDecreased release
Brendel et al, 20008850 Hz or 16.7 Hz- 86 μT for 8 hIsoproterenol stimulation of Mel production in Djungarian hamsterDecrease in Mel concentration
Lewy et al, 20038950 Hz- 1 mT for 4 hNE stimulation of Mel production in ratIncreased release
Tripp et al 20039050 Hz- 500 microT for 4 hMel release in rat pineal glandsNo effect
Studies on MCF-7 cell growth
Liburdy et al, 19939160 Hz- 1.2 μT for 7 daysMel inhibition of MCF-7 cell growthDecrease in growth inhibition
Harland and liburdy, 19979260 Hz- 1.2 μT for 7 daysTamoxifen and Mel inhibition of MCF-7 cell growthDecrease of Mel and Tamoxifen's inhibitory action
Blackman et al, 20019360 Hz- 1.2 μT for 7 daysTamoxifen and Mel inhibition of MCF-7 cell growthDecrease of Mel and Tamoxifen's inhibitory action
Ishido, 20019450 Hz- 1.2 or 100 μT for up to 7 daysMel inhibition of cAMP and DNA synthesis in MCF-7 cellsDecrease of inhibition induced by Mel
Leman et al, 2001952 Hz- 0.3 mT, 1h/day for 3 daysMel inhibition of breast cancer cellsNo effect
Girgert et al 20109650 Hz- 1.2 mT for 48 hSignal transduction of the Mel receptor MT1 in MCF-7Signal transduction involving MT1 was disrupted in MCF-7

Human studies

Much of the evidence for the melatonin hypothesis is based on data obtained in rodents with a 25% to 40% reduction in the hormonal concentration, though, as shown above, results on the effects of ELF-EMF in rodents and higher mammals provided controversial results. Since the 1990s several research papers have documented the effects of ELF-EMF on the secretion of melatonin in humans. Most research published has involved an acute exposure (from 30 min to 4 days on average) of healthy volunteers to ELF-EMF with different exposure characteristics (Tables IIIa and IIIb). The data on humans are controversial, since of the papers published about one third reported a decrease in melatonin secretion97-107 with, however, some comments to be mentioned such as the lack of evidence for a dose-response,97 or a decrease not exclusively related to ELF-EMF and found in some particular subgroups98-107 (Table IIIa). In contrast to the previous ones, two thirds of the reports failed to find any effect of ELF-EMF on melatonin secretion in humans ( Table IIIb). 108-130Most work published on humans dealt with short-term exposure for evident ethical reasons. Taking into account the data we have shown on rats of potentially cumulative effects of ELF-EMF,62 we performed a study in workers chronically exposed daily for 1 to 20 years, both in the workplace and at home, since the workers were housed near the substations. We showed no alteration in their melatonin secretion (plasma level or circadian profiles) which strongly suggests that ELF-EMF do not have cumulative effects on melatonin secretion in humans, and thus clearly rebuts the melatonin hypothesis that a decrease in blood melatonin concentration (or a disruption in its secretory pattern) explains the occurrence of clinical disorders or cancers possibly related to ELF-EMF.125

Magnetic field reports on a melatonin secretion decrease in humans. Mel, melatonin; aMT6s, 6 sulfatoxymelatonin; M, male; F: female; MF, magnetic field; NG, not given

Reference of the studySubjects (N)SexAge (years)Exposure characteristicsTiming of exposureFluid or pinealSampling timeEffect on melatonin secretion
Pfluger and Minder, 199697108MNG16 Hz- ~ 20 μT mean value in engine drivers30 min - 4 hUrinary aMT6sMorning and evening samplesDecrease of aMT6s in evening; No evidence for a dose-response
Arnetz and Berg, 19969847NGNG1 day exposure to video display unit (VDU)1 daySer MelMorning and afternoon samplesDecrease but exposure not exclusively related to 50/60 Hz
Wood et al, 19989944M18-4950 Hz- 20 μT, sinusoidal or square wave field, intermittent19 h-21 hPl Mel20 min, 30 min, or hourly at nightDelay and decrease of Mel in subgroup
Burch et al, 1998100142M22-6060 Hz- 0.1-0.2 μTOccupational exposureUrinary aMT6sMorning urine samplesNo effect at work, urinary aMT6s decreased at home
Burch et al, 1999101142M22-6060 Hz- occupational exposureOccupational exposure over a weekUrinary aMT6sOvernight urine samplesDecrease in aMT6s excreation in workers exposed to more stable fields during work.
Burch et al, 2000102MNG60 Hz- occupational exposure (electric utility worker), from 950 nT to 1.05 μT (exposure for < 2 h/day or > 2 h day)3 consecutive days monitoredUrinary aMT6sOvernight aMT6sDecrease in aMT6s excretion in workers exposed for > 2 h
Juutilainen et al, 200010360Fmean age ~ 4450 Hz- 0.3-1 μT and > 1 μT and 0.15 μTOccupational exposureUrinary aMT6sNighttime and morning urine collectionaMT6s excretion lower in exposed workers compared with office workers
Davis et al, 2001104203F20-7460 Hz- domestic exposure. Half of the subjects had mean levels of < 0.04 μTresidential 72 hUrinary aMT6sNighttime samplesDecrease, primarily in subgroup using medication
Burch et al, 2002105226 electric utility workersM18-6060 Hz- occupational exposureoccupational exposure: measures on 3 consecutive work daysUrinary aMT6sOvernight aMT6sDecrease in aMT6s associated with mobile phone use
Davis et al, 2006106115F20-4060 Hz- 5 to 10 mGAt night for 5 consecutive nightsUrinary aMT6sOvernight samplesDecrease
Burch et al, 2008107153MMean age = 440 Hz- 15nT to 30 nT + 60 Hz3 h, 24 h, 36 hUrinary aMT6sOvernight aMT6sDecrease in aMT6s associated with elevated geomagnetic activity

Magnetic field reports on the lack of effect on melatonin secretion in humans. Mel, melatonin; Pl, plasma; Ser, serum; Sal, saliva; aMT6s, 6 sulfatoxymelatonin; M, male; F, female; BMI, body mass index; MF, magnetic field; RF, radio frequency; NG, not given

Reference of the studySubjects (N)SexAge (years)Exposure characteristicsTiming of exposureFluidSampling timeEffect of MF on melatonin secretion
Wilson et al, 199010842F, MNGCPW electric blanket. 0.2-0.6 μT8 weeksUrinary aMT6sUrine voidingsNo effect
Schiffman et al, 19941099M22-340 Hz- Magnetic resonance imaging. 1.5 T01 hPl MelNighttime (2 samples)No effect
Selmaoui et al, 199611032M20-3050 Hz- 10 μT, to continuous or intermittent MF23 h-08 hSer Mel and urinary aMT6sEvery 2 h during the daytime, hourly during the nighttimeNo effect
Graham et al, 199611133M19-3460 Hz- 1 or 20 μT, intermittent23 h-07 hPl MelHourly at nightNo effect
Graham et al, 199711240M18-3560 Hz- 20 μT, continuous23 h-07 hPl MelHourly at nightNo effect
Akerstedt et al, 199911318F, M18-5050 Hz- 1 μT23 h-08 hPl MelAt 23 h 02h30 h, 05 h, and 08 hNo effect
Graham et al, 200011430M18-3560 Hz- 28.3 μT4 consecutive nights from 23 h - 07 hUrinary aMT6sOvernight urine samplesNo effect
Crasson et al, 200111521M20-2750 Hz- 100 μT, continuous or intermittent30 min at 13 h30 and 16 h30Ser Mel and Urinary aMT6sHourly from 20 h to 07 hNo effect
Graham et al, 200111624M19-3460 Hz- 127 μT, continuous or intermittent23 h - 07 hSer Mel and Urinary aMT6sHourly from 24 to 07 hNo effect
Graham et al, 200111746F, M40-6060 Hz-28.3 μT23 h - 07 hUrinary aMT6sMorning urine samplesNo effect
Griefahn et al, 20011187M16-2216.7 Hz- 200 μT18h - 02 hSal MelHourly for 24 hNo effect
Haugsdal et al, 200111911M23-430 Hz- 2-7 mT, 9 h22 h - 07 hUrinary aMT6s4 samples / 24 hNo effect
Hong et al, 20011209M23-3750 Hz-1-8 μT, electric 'sheet' over the body11 weeks at nightUrinary aMT6s5 times a dayNo effect
Levallois et al, 2001121416F20-7450 Hz- between 0.1 and 0.3 μTResidential exposureUrinary aMT6sOvernight urine samplesNo effect except in subgroup of women with high BMI
Griefahn et al, 20021227M16-2216.7 Hz, 0.2 mT17 h-01 hSal MelHourly for 24 hNo effect
Youngstedt et al, 2002123242F, M50-8160 Hz- Mean of one week exposure = 0.1 μTResidential exposure within bedUrinary aMT6sFractional urineNo effect
Kurokawa et al, 200312410M20-3750 Hz- 20 μT20 h-08 hSer MelHourly from 20 h to 08 hNo effect
Touitou et al, 200312530M31.5-4650 Hz- mean fields of 0.1-2.6 μTOccupational and residential exposure (1 to 20 years)Ser Mel and urinary aMT6sHourly from 20 h to 08 hNo effect
Warman et al, 200312619M18-3550 Hz- 200 or 300 μT2- H exposure between 17 h and 23 hSel Mel17 h and 10 hNo effect
Cocco et al, 200512751F, MMean age 56.650 Hz- from 0.0045 μT to 0.148 μTResidentialUrinary aMT6sAt 22 h and 08 hNo effect
Gobba et al, 200612859F, MMean age 42 and 4660 Hz- low exposed (≤0.2 μT) or higher exposed (>0.2 μT)3 consecutive days recorded for workersUrinary aMT6sMorning urineNo effect
Juutilainen and kumlin, 200612960FMean age 40 to 5350 Hz- from 0.1 to 2.5 μT3 consecutive weeksUrinary aMT6sMorning urineNo effect Inconclusive results with light exposure
Clark et al, 2007130127F12 to 8160 Hz- 20 nT to 130 nT and RF 0.04 μW/cm2 to 1.4 μW/cm2Residential for 2.5 daysUrinary aMT6sOvernightNo effect

ELF-EMF effects on cortisol and corticosterone

In contrast to the number of studies on the effects of ELF-EMF on melatonin secretion, few data are available in the literature on the pituitary adrenal axis. The hormones under study (corticosterone for rats, cortisol for other mammals), exposure characteristics (short- and long-term), and timing and duration of exposure (1 to 6 months) in different animal species are detailed in Table IV.

Effects of EMF on cortisol or corticosterone secretion in different animal species. Pl, plasma; Se, serum; NG, not given

Reference of the studySpeciesExposure characteristicsTiming of exposureFluid or pinealSampling timeEffect of MF on melatonin secretion
Papers reporting no effect
Free et al, 1981131Rats60 Hz- 100 kV/m20 h/day for 30 or 120 days (adults) or from 20 to 56 days of age (young)Ser corticosterone08 h30-12 h30No effect
Quinlan et al, 1985132Rats60 Hz- 100 kV/m; continuous or intermittent1 or 3 hSer corticosterone11 h or 13 hNo effect
Portet and Cabanes, 1988133Rabbits and rats50 Hz- 50 kV/mRabbit: 16 h/day from last 2 weeks of gestation to 6 weeks after birth. Rat: 8h/day for 4 weeksSer cortisol (rabbits) and corticosterone (rats)NighttimeNo effect
Thompson et al, 1995134Ewe lambs60 Hz- 500-kV transmission line (mean electric field 6 kV/m, mean magnetic field 40 mG)Up to 43 weeksSer cortisol48 h sampling (3-h intervals at daylight and hourly at nightNo effect
Burchard et al, 1996135Dairy cows (Holstein)60 Hz- 10 kV/m and 30 μTUp to 56 days of exposurePl cortisolTwice weeklyNo effect
Szemerszky et al, 2010136Rats50 Hz-0.5 mTfor 5 days, 8 h daily (short) or for 4-6 weeks, 24 h daily (long)Ser corticosteroneNGNo effect
Martinez-Samano et al, 2012137Rats60 Hz - 2.4 mT2 hours (12 h-14 h)Pl corticosteroneNGNo effect
Papers reporting an effect
Hackman and Graves, 1981138Rats60 Hz- 25 or 50 kV/m15 min per day up to 42 daysSer corticosteroneBefore and after exposureIncrease in serum levels at onset of exposure
Gorczynska and Wegrzynowicz, 1991139,140Rats1 and 10 mT1 h daily for 10 daysSer cortisolNighttimeIncrease
de Bruyn and de Jager, 1994141Mice60 Hz- 10 kV m-122 h per day for 6 generationsSer corticosteroneDay/nightElevated daytime but no effect on night-time levels
Picazo et al, 1996142Mice50 Hz- 15 μT14 weeks prior to gestation and 10 weeks post-gestationSer cortisolCircadianCircadian rhythm Altered
Bonhomme-Faivre et al, 1998145Mice50 Hz- 5 μTAfter 90 and 190 daysSer cortisolMorningOn day 190, exposed animals showed a decrease in the cortisol
Marino et al, 2001143Mice60 Hz- 500 μTFor 1-175 daysSer corticosteroneNighttimeChanges in Ser corticosterone
Mostafa et al, 2002144Rats50 HZ-200 μTUp to 2 weeksPl corticosteroneNGIncrease of plasma corticosterone

While the majority of papers failed to find any effect,131-137 others have reported either an increase in the hormonal concentrations138-144 or a decreased concentration.145 The results of these studies are thus inconsistent and contradictory. Comparison between studies revealed that the discrepancy in the results might be due in part to the difference in the animal species used (rabbit, ewe lambs, cows, rats, or mice), class of age, and duration and intensity of exposure. Another factor that should be taken into account is that glucorticoids (ie, cortisol or corticosterone) levels are sensitive to many stressors that might affect hormone levels. It is well known that handling or bleeding animals increase corticosterone, a stress marker, and it is thus important to ensure that any external confounding stressor has to be controlled.

Overall, these data suggest that no consistent effects have been seen in the stress-related hormones of the pituitary-adrenal axis in a variety of mammalian species. Data on ELF-EMF effects on cortisol in humans are scarce. We have found 7 papers on the matter (Table V).109,124,146-149 All of these papers report only on short exposure of adult volunteers to ELF-EMF, and all failed to find any effect.

Magnetic field reports on cortisol secretion in humans. Ser, serum; Pl, plasma; M, male; F, female; MF, magnetic field

Reference of the studySubjects (N)SexAge (years)Exposure characteristicsTiming of exposureFluidSampling timeEffect of MF on melatonin secretion
Maresh et al, 198814611M21-2960 Hz-9 kV/m and 20 μT2 hours of exposurePl cortisol10, 30, 60, 90 and 120No effect
Gamberale et al, 198914726M25-5250 Hz- 2.8 kV/m and 23.3 μT 4.5 h during working day10 h-12 h, 12h30-14 h30Ser cortisol06 h45-07 h, 12 h-12 h10, 16 h30-17 h10No effect
Selmaoui et al, 199714832M20-3050 Hz- 10 μT, continuous or intermittent23 h -08 hSer cortisolEvery 2 h during the daytime, hourly during the nighttimeNo effect
Akerstedt et al, 199911318F, M18-5050 Hz- 1 μT23 h -08 hPl cortisolAt 23 h 02 h30, 05 h, and 08 hNo effect
Kurokawa et al, 200312410M20-3750 Hz- 20 μT20 h-08 hSer cortisolHourly from 20 h to 08 hNo effect
Ghione et al, 200414910MMean age: 413 7 Hz- 80 μT1 hour of exposure between 9 h and 12hPl cortisol2 samples: one 15 min befor the start of the study and one after the end of exposure periodNo effect

Conclusion

We are all exposed to electric and magnetic fields of weak intensity. The levels of exposure of the general population range from 5 to 50 V/m for electric fields and from 0.01 to 0.2 μT for magnetic fields. The possible risk on health with exposure to electromagnetic fields became a concern to the public, which led to numerous studies by scientists on the topic. We have shown in this review that the reported studies are largely contradictory with regard to epidemiologic studies (about half of the studies found a relationship and the other half failed to find any), to the potential biological effects of ELF-EMF, and to the potentially mechanisms put forward; no clear explanations exist for these contradictory results. The relative risk (RR) which establishes the relation between exposure to ELF-EMF and cancer, is approximately 2 to 3. In the absence of clear explanation(s) a number of hypotheses have been raised. The characteristics of the magnetic field (linear or circular polarization, duration, timing), the animal species and, within a species, the strain appears to have a role in determining the biologic response obtained. Therefore, great care must be given when comparing data obtained in different animal species, even within a group as rodents, since differences have been described between rodent species and even between pigmented and albino breeds.

A possible change in the spatial structure of the photoreceptor pigment rhodopsin due to the electric field induced by the magnetic field has been proposed. Magnetic fields might also change either the electrical activity of the pinealocytes or their ability to produce melatonin, or both. With regard to the numerous studies performed on the effects of ELF-EMF on melatonin, the differences observed in animals and humans in these effects may be due to the differences in anatomical location and configuration of the pineal gland, and also the difference in the rest-activity cycle between rodents and humans. A different sensitivity to ELF-EMF could also be part of the explanation. Some human subjects may have greater sensitivity to ELF-EMF, but this is difficult to demonstrate because of the important interindividual variability in plasma concentration of melatonin. As far as melatonin is concerned, we have shown a lack of effect of ELF-EMF on melatonin (concentration and circadian rhythm) in workers exposed daily for up to 20 years in their workplace and at home, which strongly suggests that chronic ELF-EMF exposure appears to have no cumulative effects in human adults; this rebuts the “melatonin hypothesis” raised as an explanation for the deleterious sanitary effects of ELF-EMF.125

In the same way, the application of high-throughput omics technologies to investigate the influences of ELF-EMF is confronted with the heterogeneity among the biological materials investigated, which are as different as blood cells/vessels, tissue cells, nerves, and bacteria, and this makes it difficult to compare data and to arrive at firm conclusions on the potential effects of ELF-EMF on biological systems.150 As an example, most breast tumors become, resistant to tamoxifen, and it has been shown that ELF-EMF reduce the efficacy of tamoxifen in a manner similar to tamoxifen resistance. By exposing cells of the breast cancer line MCF-7 to ELF-EMF, it has been found that ELF-EMF alter the expression of estrogen receptor cofactors, which in the authors' view may contribute to the induction of tamoxifen resistance in vivo.151

Currently, the debate concerns the effects of ELF-EMF on children, with some data published in the literature pointing out the risk of childhood leukemia in relation to residential exposure, and underlining that this risk (the RR is around 2) can exist when children are chronically exposed to more than 0.4 μT.10 Large-scale collaborative studies are still needed to fill the gaps in our knowledge and provide answers to these numerous questions not yet resolved. Last, the deleterious risk of ELF-EMF on frail populations such as children and aged people may be greater and should be documented, at least for their residential exposure.

Figure 2.
Figure 2. Effects of chronic exposure of male rats to a sinusoidal 50-Hz magnetic field ( from 1 to 100 uT) on nocturnal pineal activity. The rats were exposed every day from 14:00 to 08:00 for 30 days at three different intensities. Only 10 and 1 00 uT were able to depress serum melatonin and pineal activity. No effect was observed on HIOMT activity. The asterisks indicate a significant difference (P<0.05) with the control group (Ctrl). Reproduced from ref 62: Selmaoui B, Touitou Y. Sinusoidal 50-Hz magnetic fields depress rat pineal NAT activity and serum melatonin. Role of duration and intensity of exposure. Life Sci. 1995;57:1351-1358. Copyright© Pergamon Press 1995
Figure 3.
Figure 3. Nocturnal plasma melatonin patterns (A) and 6-sulfatoxymelatonin concentration (6SM; B) in the first-void morning urine (20:00 to 08:00). This study was carried out in 15 healthy chronically (in the workplace and at home) exposed men (daily and for 1 to 20 years) to a 50-Hz magnetic field in search of any cumulative effect from those chronic conditions of exposure. Fifteen healthy unexposed men served as controls. As shown here, the exposed subjects experienced no change in the hormone levels or circadian patterns of melatonin. Reproduced from ref 125: Touitou Y, Lambrozo J, Camus F, Charbuy H. Magnetic fields and the melatonin hypothesis: a study of workers chronically exposed to 50-Hz magnetic fields. Am J Physiol Regul Integr Comp Physiol. 2003;284:R1 529-535. Copyright © American Physiological Society 2003