Neuroendocrine mediated effects of electromagnetic-field exposure: possible role of the pineal gland

Reports from recent epidemiological studies have suggested a possible association between extremely low frequency (ELF; including 50- or 60-Hz) electric- and magnetic-field exposure, and increased risk of certain cancers, depression, and miscarriage. ELF field-induced pineal gland dysfunction is a possible etiological factor in these effects. Work in our laboratory and elsewhere has shown that ELF electromagnetic-field exposure can alter the normal circadian rhythm of melatonin synthesis and release in the pineal gland. Consequences of reduced or inappropriately timed melatonin release on the endocrine, neuronal, and immune systems are discussed. Laboratory data linking ELF field exposure to changes in pineal circadian rhythms in both animals and humans are reviewed. The authors suggest that the pineal gland, in addition to being a convenient locus for measuring dyschronogenic effects of ELF field exposure, may play a central role in biological response to these fields via alterations in the melatonin signal.     

Static and extremely low frequency electromagnetic field exposure: Reported effects on the circadian production of melatonin

The circadian rhythm of melatonin production (high melatonin levels at night and low during the day) in the mammalian pineal gland is modified by visible portions of the electromagnetic spectrum, i.e., light, and reportedly by extremely low frequency (ELF) electromagnetic fields as well as by static magnetic field exposure. Both light and non-visible electromagnetic field exposure at night depress the conversion of serotonin (5HT) to melatonin within the pineal gland. Several reports over the last decade showed that the chronic exposure of rats to a 60 Hz electric field, over a range of field strengths, severely attenuated the nighttime rise in pineal melatonin production; however, more recent studies have not confirmed this initial observation. Sinusoidal magnetic field exposure also has been shown to interfere with the nocturnal melatonin forming ability of the pineal gland although the number of studies using these field exposures is small. On the other hand, static magnetic fields have been repeatedly shown to perturb the circadian melatonin rhythm. The field strengths in these studies were almost always in the geomagnetic range (0.2 to 0.7 Gauss or 20 to 70 μtesla) and most often the experimental animals were subjected either to a partial rotation or to a total inversion of the horizontal component of the geomagnetic field. These experiments showed that several parameters in the indole cascade in the pineal gland are modified by these field exposures; thus, pineal cyclic AMP levels, N-acetyltransferase (NAT) activity (the rate limiting enzyme in pineal melatonin production), hydroxyindole-O-methyltransferase (HIOMT) activity (the melatonin forming enzyme), and pineal and blood melatonin concentrations were depressed in various studies. Likewise, increases in pineal levels of 5HT and 5-hydroxyindole acetic acid (5HIAA) were also seen in these glands; these increases are consistent with a depressed melatonin synthesis. The mechanisms whereby non-visible electromagnetic fields influence the melatonin forming ability of the pineal gland remain unknown; however, the retinas in particular have been theorized to serve as magnetoreceptors with the altered melatonin cycle being a consequence of a disturbance in the neural biological clock, i.e., the suprachiasmatic nuclei (SCN) of the hypothalamus, which generates the circadian melatonin rhythm. The disturbances in pineal melatonin production induced by either light exposure or non-visible electromagnetic field exposure at night appear to be the same but whether the underlying mechanisms are similar remains unknown.     

Electric field exposure alters serum melatonin but not pineal melatonin synthesis in male rats

Sprague-Dawley male rats, maintained in a 14:10 h light:dark cycl were exposed for 30 days (starting at 56 days of age) to a 65 kV/m, 60 Hz electric field or to a sham field for 20 h/day beginning at dark onset. Pineal N-acetyltransferase (NAT), hydroxy-indole-o-methyl transferase (HIOMT), and melatonin as well as serum melatonin were assayed. Preliminary data on unexposed animals indicated that samples obtained 4 h into the dark period would reveal either a phase delay or depression in circadian melatonin synthesis and secretion. Exposure to electric fields for 30 days did not alter the expected nighttime increase in pineal NAT, HIOMT, or melatonin. Serum melatonin levels were also increased at night, but the electric field-exposed animals had lower levels than the sham-exposed animals. Concurrent exposure to red light and the electric field or exposure to the electric field at a different time of the day-night period did not reduce melatonin synthesis. These data do not support the hypothesis that chronic electric field exposure reduces pineal melatonin synthesis in young adult male rats. However, serum melatonin levels were reduced by electric field exposure, suggesting the possibility that degradation or tissue uptake of melatonin is stimulated by exposure to electric fields. © 1994 Wiley-Liss, Inc.     

60-Hz electric-field effects on pineal melatonin rhythms: time course for onset and recovery

Rats exposed for 3 weeks to uniform 60-Hz electric fields of 39 kV/m (effective field strength) failed to show normal pineal gland circadian rhythms in serotonin N-acetyl transferase activity and melatonin concentrations. The time required for recovery of the melatonin rhythm after cessation of field exposure was determined to be less than 3 days. The rapid recovery suggests that the overall metabolic competence of the pineal is not permanently compromised by electric-field exposure, and that the circadian rhythm effect may be neuronally mediated.     

Circularly polarised MF (500 micro T 50 Hz) does not acutely suppress melatonin secretion from cultured Wistar rat pineal glands

Magnetic fields (MF, 50 Hz) have been proposed to affect melatonin production in mammals; however, there is very little data about the mechanism by which this possible interaction may occur. Here we describe results from the first study in which circularly polarised 50 Hz MF have been administered to isolated pineals in highly controlled conditions. Melatonin release from isolated Wistar rat pineal glands, dissected 2 h after light onset ZT 2, was measured in a flow through culture system, during and after exposure to a 4 h MF similar in nature and magnitude to that produced in extremely close proximity to a high voltage power line (500 micro T 50 Hz circularly polarised). Melatonin release from isolated pineals was comparable to that observed in previous studies, plateauing to approximately 100 pg/ml/30 min. No significant alterations in pineal melatonin release were caused by exposure to the MF when compared to sham exposure (< 1 micro T). These results suggest that if the circadian system is acutely responsive to MF exposure of this nature, an intact circadian axis may be necessary in order to observe an effect on the production on melatonin from the pineal gland     

Magnetic field effects on pineal indoleamine metabolism and possible biological consequences.

In recent years, there has been a great deal of publicity concerning the possible health effects of electric and/or magnetic field exposure. One of the most frequently reported observations after the exposure of animals to either electric or magnetic fields relates to alterations in the metabolism of serotonin (5HT) to melatonin within the pineal gland. This review summarizes these results particularly in animals exposed to intermittently inverted, non-time varying magnetic fields, i.e., pulsed static magnetic fields. When exposure occurs at night, the conversation of 5HT to melatonin is typically depressed, not unlike that after light exposure at night. The mechanisms by which pulsed magnetic fields alter the ability of the pineal to convert 5HT to the chief pineal hormone melatonin remains unknown but may involve effects on any or all of the following: the retinas, the suprachiasmatic nuclei, the peripheral sympathetic nervous system, and the pinealocytes. Results to date suggest that induced electrical currents (eddy currents) produced by the pulsed magnetic fields are particularly detrimental to pineal indoleamine metabolism and may be an important causative factor in the metabolic changes measured. The physiological consequences of perturbations in the melatonin rhythm induced by magnetic field exposure remain unknown.     

No short-term effects of high-frequency electromagnetic fields on the mammalian pineal gland

There is ample experimental evidence that changes of earth-strength static magnetic fields, pulsed magnetic fields, or alternating electric fields (60 Hz) depress the nocturnally enhanced melatonin synthesis of the pineal gland of certain mammals. No data on the effects of high-frequency electromagnetic fields on melatonin synthesis is available. In the present study, exposure to 900 MHz electromagnetic fields [0.1 to 0.6 mW/cm², approximately 0.06 to 0.36 W/kg specific absorption rate (SAR) in rats and 0.04 W/kg in Djungarian hamsters; both continuous and/or pulsed at 217 Hz, for 15 min to 6 h] at day or night had no notable short-term effect on pineal melatonin synthesis in male and female Sprague-Dawley rats and Djungarian hamsters. Pineal synaptic ribbon profile numbers (studied in rats only) were likewise not affected. The 900 MHz electromagnetic fields, unpulsed or pulsed at 217 Hz, as applied in the present study, have no short-term effect on the mammalian pineal gland. Bioelectromagnetics 18:376–387, 1997. © 1997 Wiley-Liss, Inc.     

No association between occupational exposure to ELF magnetic field and urinary 6-sulfatoximelatonin in workers

A suppression in melatonin secretion is one of the mechanisms proposed to explain the possible adverse effects of extremely low frequency magnetic fields (ELF-MF), but the results of research are inconclusive. This study investigated the effect of occupational ELF-MF exposure on 6-sulfatoximelatonin (6-OHMS). Exposure was monitored for three complete work shifts in 59 workers using personal exposure meters. Environmental exposure was also evaluated. Urinary 6-OHMS in morning samples, an indicator of night-time melatonin production, was measured. Urine was collected twice on Friday and the following Monday. Workers were classified according to ELF exposure as low exposed (0.2 microT): 6-OHMS did not differ between groups (P > .05) in either Friday or Monday urine samples. In addition, 6-OHMS was not related to exposure under multivariate analysis. The ratio between 6-OHMS in Monday versus Friday samples was also calculated to test the hypothesis of a possible variation in pineal function after 2 days, interruption of occupational ELF-MF exposure: again no exposure-related difference was observed. Our results do not support the hypothesis that occupational exposure to ELF-MF significantly influences melatonin secretion.     

Comparing performances of logistic regression and neural networks for predicting melatonin excretion patterns in the rat exposed to ELF magnetic fields

Various studies have been reported on the bioeffects of magnetic field exposure; however, no consensus or guideline is available for experimental designs relating to exposure conditions as yet. In this study, logistic regression (LR) and artificial neural networks (ANNs) were used in order to analyze and predict the melatonin excretion patterns in the rat exposed to extremely low frequency magnetic fields (ELF‐MF). Subsequently, on a database containing 33 experiments, performances of LR and ANNs were compared through resubstitution and jackknife tests. Predictor variables were more effective parameters and included frequency, polarization, exposure duration, and strength of magnetic fields. Also, five performance measures including accuracy, sensitivity, specificity, Matthew's Correlation Coefficient (MCC) and normalized percentage, better than random (S) were used to evaluate the performance of models. The LR as a conventional model obtained poor prediction performance. Nonetheless, LR distinguished the duration of magnetic fields as a statistically significant parameter. Also, horizontal polarization of magnetic fields with the highest logit coefficient (or parameter estimate) with negative sign was found to be the strongest indicator for experimental designs relating to exposure conditions. This means that each experiment with horizontal polarization of magnetic fields has a higher probability to result in “not changed melatonin level” pattern. On the other hand, ANNs, a more powerful model which has not been introduced in predicting melatonin excretion patterns in the rat exposed to ELF‐MF, showed high performance measure values and higher reliability, especially obtaining 0.55 value of MCC through jackknife tests. Obtained results showed that such predictor models are promising and may play a useful role in defining guidelines for experimental designs relating to exposure conditions. In conclusion, analysis of the bioelectromagnetic data could result in finding a relationship between electromagnetic fields and different biological processes. Bioelectromagnetics 31:164–171, 2010. © 2009 Wiley‐Liss, Inc.     

50-Hz SINUSOIDAL MAGNETIC FIELD EFFECT ON IN VITRO PINEAL N-ACETYLTRANSFERASE ACTIVITY

Some studies have shown a decrease in pineal N-acetyltransferase (NAT) activity and/or blood melatonin concentration in rodents exposed to extremely low-frequency (ELF) and low magnetic flux density electromagnetic fields. The mechanism/s involved in such effects are not known. It has been hypothesized that the magnetic fields (MF) could act on the pineal gland directly and/or indirectly through the retina. The aim of this work was to study whether MFs could modify NAT activity through a direct effect on the gland. Pineal glands obtained from rats sacrificed in the middle of the dark period were exposed during a 1-h incubation to 10-, 100-, or 1,000-μT, 50-Hz, sinusoidal MFs. The results showed that the glands exposed to the highest magnetic flux density responded with a significant decrease in NAT activity. The data obtained from these experiments support the idea that the pineal gland can be directly affected by ELF electromagnetic fields.     

Reduction of the nocturnal rise in pineal melatonin levels in rats exposed to 60-Hz electric fields in utero and for 23 days after birth

Rats exposed to 60-Hz electric fields of either 10, 65, or 130 kV/m from conception to 23 days of age exhibited reduced peak nighttime pineal melatonin contents compared to unexposed controls. As a group, the exposed rats also exhibited a phase delay, estimated at approximately 1.4 hours, in the occurrence of the nocturnal melatonin peak. No clear dose-response relationship was noticed over the range of electric field strengths used as treatments in these experiments. These are the first studies concerned with the effects of electric field exposure on the pineal melatonin rhythm in immature rats. The findings are generally consistent with those obtained using adult rats, where electric field exposure has been shown to abolish the nighttime rhythm in pineal melatonin concentrations.     

Pulsed static magnetic field effects on in-vitro pineal indoleamine metabolism.

In-vitro rat pineal glands stimulated with the beta-adrenergic receptor agonist isoproterenol to induce melatonin synthesis and exposed for 1 h to a pulsed 0.4-G static magnetic field demonstrated significant inhibition of serotonin-N-acetyltransferase activity and melatonin content. 2-h exposure to pulsed magnetic field also resulted in a significant reduction in isoproterenol-induced serotonin-N-acetyltransferase activity. These results support the idea that the cultured pineal gland can be affected directly by artificially generated weak magnetic fields.     

Exposure of welders and other metal workers to ELF magnetic fields

This study assessed exposure to extremely low frequency (ELF) magnetic fields of welders and other metal workers and compared exposure from different welding processes. Exposure to ELF magnetic fields was measured for 50 workers selected from a nationwide cohort of metal workers and 15 nonrandomly selected full-time welders in a shipyard. The measurements were carried out with personal exposure meters during 3 days of work for the metal workers and 1 day of work for the shipyard welders. To record a large dynamic range of ELF magnetic field values, the measurements were carried out with “high/low” pairs of personal exposure meters. Additional measurements of static magnetic fields at fixed positions close to welding installations were done with a Hall-effect fluxmeter. The total time of measurement was 1273 hours. The metal workers reported welding activity for 5.8% of the time, and the median of the work-period mean exposure to ELF magnetic fields was 0.18 μT. DC metal inert or active gas welding (MIG/MAG) was used 80% of the time for welding, and AC manual metal arc welding (MMA) was used 10% of the time. The shipyard welders reported welding activity for 56% of the time, and the median and maximum of the workday mean exposure to ELF magnetic fields was 4.70 and 27.5 μT, respectively. For full-shift welders the average workday mean was 21.2 μT for MMA welders and 2.3 μT for MIG/MAG welders. The average exposure during the effective time of welding was estimated to be 65 μT for the MMA welding process and 7 μT for the MIG/MAG welding process. The time of exposure above 1 μT was found to be a useful measure of the effective time of welding. Large differences in exposure to ELF magnetic fields were found between different groups of welders, depending on the welding process and effective time of welding. MMA (AC) welding caused roughly 10 times higher exposure to ELF magnetic fields compared with MIG/MAG (DC) welding. The measurements of static fields suggest that the combined exposure to static and ELF fields of MIG/MAG (DC) welders and the exposure to ELF fields of MMA (AC) welders are roughly of the same level. Bioelectromagnetics 18:470–477, 1997. © 1997 Wiley-Liss, Inc.     

Inconsistent suppression of nocturnal pineal melatonin synthesis and serum melatonin levels in rats exposed to pulsed DC magnetic fields

The purpose of these experiments was to determine whether the exposure of rats at night to pulsed DC magnetic fields (MF) would influence the nocturnal production and secretion of melatonin, as indicated by pineal N-acetyltransferase (NAT) activity (the rate limiting enzyme in melatonin production) and pineal and serum melatonin levels. By using a computer-driven exposure system, 15 experiments were conducted. MF exposure onset was always during the night, with the duration of exposure varying from 15 to 120 min. A variety of field strengths, ranging from 50 to 500 μT (0.5 to 5.0 G) were used with the bulk of the studies being conducted using a 100 μT (1.0 G) field. During the interval of DC MF exposure, the field was turned on and off at 1-s intervals with a rise/fall time constant of 5 ms. Because the studies were performed during the night, all procedures were carried out under weak red light (intensity of <5 μW/cm²). At the conclusion of each study, a blood sample and the pineal gland were collected for analysis of serum melatonin titers and pineal NAT and melatonin levels. The outcome of individual studies varied. Of the 23 cases in which pineal NAT activity, pineal melatonin, and serum melatonin levels were measured, the following results were obtained; in 5 cases (21.7%) pineal NAT activity was depressed, in 2 cases (8.7%) studies pineal melatonin levels were lowered, and in 10 cases (43.5%) serum melatonin concentrations were reduced. Never was there a measured rise in any of the end points that were considered in this study. The magnitudes of the reductions were not correlated with field strength (i.e., no dose-response relationships were apparent), and likewise the reductions could not be correlated with the season of the year (experiments conducted at 12-month intervals under identical exposure conditions yielded different results). Duration of exposure also seemed not to be a factor in the degree of melatonin suppression. The inconsistency of the results does not permit the conclusion that pineal melatonin production or release are routinely influenced by pulsed DC MF exposure. In the current series of studies, a suppression of serum melatonin sometimes occurred in the absence of any apparent change in the synthesis of this indoleamine within the pineal gland (no alteration in either pineal NAT activity or pineal melatonin levels). Because melatonin is a direct free radical scavenger, the drop in serum melatonin could theoretically be explained by an increased uptake of melatonin by tissues that were experiencing augmented levels of free radicals as a consequence of MF exposure. This hypothetical possibly requires additional experimental documentation. Bioelectromagnetics 19:318–329, 1998. © 1998 Wiley-Liss, Inc.     

Do cocarcinogenic effects of ELF electromagnetic fields require repeated long‐term interaction with carcinogens? Characteristics of positive studies using the DMBA breast cancer model in rats

The carcinogenic or cocarcinogenic potential of extremely low frequency (ELF; 50 or 60 Hz) magnetic fields (MFs) has been evaluated worldwide in diverse animal model systems. Though most results have been negative, weakly positive or equivocal results have been reported in several cancer models, including the rat DMBA (7,12-dimethylbenz[a]anthracene) model of mammary cancer. Based on the experimental conditions used in studies in which cocarcinogenic effects of ELF MF were found, it was recently proposed that MF exposure may potentiate the effects of known carcinogens only when the animals are exposed to both MF and carcinogen during an extended period of tumor development, i.e., when the carcinogen is given repeatedly during MF exposure. This review summarizes a series of experiments from our group, showing cocarcinogenic MF effects in the DMBA breast cancer model in rats, to test whether the above proposal is confirmed by existing data. Flux densities of 50 or 100 microT significantly increased the growth of mammary tumors, independent of whether DMBA was given in a single administration or repeatedly over a prolonged period. Thus, these data do not substantiate the hypothesis requiring repeated doses of DMBA during MF exposure. Instead, several other aspects of study design and experimental factors are identified that seem to be critical for the detection of cocarcinogenic effects of MF exposure in the rat DMBA mammary cancer model. These include the rat subline used, the dose of DMBA, the duration of MF exposure, the flux density, the background (sham control) tumor incidence, and the location of mammary tumors in the mammary gland complex. These and other experimental aspects may explain why some laboratories did not detect cocarcinogenic MF effects in the DMBA model. We hope that direct comparison of MF bioeffects in different rat sublines and further evaluation of other experimental differences between studies on MF exposure in the DMBA model will eventually determine which genetic and environmental factors are critical for potential carcinogenic or cocarcinogenic effects of ELF MF exposure.     

Miniature-probe measurements of electric fields and currents induced by a 60-Hz magnetic field in rat and human models

A miniaturized probe was designed and built to provide detailed data on fields induced by a uniform 60-Hz magnetic field in homogeneous models of rat and human. The probe employed three silver wires twisted and potted in an 8-cm hypodermic needle. The exposed tips of the wires formed three sensing electrodes with a centered ground; highly sensitive voltage measurements were enabled by a lock-in amplifier. Tests were conducted in a 1-mT rms field that was uniform within +/- 5%. The models were made by casting 1.5% agar at 1-S/m conductivity into plastic-foam molds. The rat model was scaled 1:1 as an adult (22 cm length; mass about 640 g). The human model was scaled 1:4 as an adult (height = 46.5 cm; mass 1.4 kg). The probe was inserted into each model in several regions, and readings of induced fields were made under different exposure geometries. Maximal strengths of fields induced near the surface of the torso were as high as 120 microV/cm in the laterally exposed rat model. Data extrapolated from the quarter-scale human model revealed that an induced field as high as 700 microV/cm could occur at the torso of a frontally exposed human adult. An overall size-scale factor of about 5 appears to be appropriate for experimental exposures of rats that are intended to simulate currents induced in human beings by magnetic fields. The average strength of electric fields induced in the torso by a 1-mT magnetic field is comparable to that by a vertical electric-field at 60 kV/m and 28 kV/m, respectively, for the rat and human.     

Light-dependent and -independent behavioral effects of extremely low frequency magnetic fields in a land snail are consistent with a parametric resonance mechanism

Exposure to extremely low frequency (ELF) magnetic fields has been shown to attenuate endogenous opioid peptide mediated antinociception or “analgaesia” in the terrestrial pulmonate snail, Cepaea nemoralis. Here we examine the roles of light in determining this effect and address the mechanisms associated with mediating the effects of the ELF magnetic fields in both the presence and absence of light. Specifically, we consider whether the magnetic field effects involve an indirect induced electric current mechanism or a direct effect such as a parametric resonance mechanism (PRM). We exposed snails in both the presence and absence of light at three different frequencies (30, 60, and 120 Hz) with static field values (B_DC) and ELF magnetic field amplitude (peak) and direction (B_AC) set according to the predictions of the PRM for Ca²⁺. Analgaesia was induced in snails by injecting them with an enkephalinase inhibitor, which augments endogenous opioid (enkephalin) activity. We found that the magnetic field exposure reduced this opioid-induced analgaesia significantly more if the exposure occurred in the presence rather than the absence of light. However, the percentage reduction in analgaesia in both the presence and absence of light was not dependent on the ELF frequency. This finding suggests that in both the presence and the absence of light the effect of the ELF magnetic field was mediated by a direct magnetic field detection mechanism such as the PRM rather than an induced current mechanism. Bioelectromagnetics 18:284–291, 1997. © 1997 Wiley-Liss, Inc.     

Interaction of static and extremely low frequency electric and magnetic fields with living systems: health effects and research needs

An international seminar was held June 4-6, 1997, on the biological effects and related health hazards of ambient or environmental static and extremely low frequency (ELF) electric and magnetic fields (0-300 Hz). It was cosponsored by the World Health Organization (WHO), the International Commission on Non-Ionizing Radiation Protection (ICNIRP), the German, Japanese, and Swiss governments. Speakers provided overviews of the scientific literature that were discussed by participants of the meeting. Subsequently, expert working groups formulated this report, which evaluates possible health effects from exposure to static and ELF electric and magnetic fields and identifies gaps in knowledge requiring more research to improve health risk assessments. The working groups concluded that, although health hazards exist from exposure to ELF fields at high field strengths, the literature does not establish that health hazards are associated with exposure to low-level fields, including environmental levels. Similarly, exposure to static electric fields at levels currently found in the living and working environment or acute exposure to static magnetic fields at flux densities below 2 T, were not found to have demonstrated adverse health consequences. However, reports of biological effects from low-level ELF-field exposure and chronic exposure to static magnetic fields were identified that need replication and further study for WHO to assess any possible health consequences. Ambient static electric fields have not been reported to cause any direct adverse health effects, and so no further research in this area was deemed necessary.