SCIENTIFIC REPORT ON THE EFFECTS OF ELECTROMAGNETIC FIELDS ON THE HUMAN ENDOCRINE SYSTEM AND ASSOCIATED PATHOLOGIES

Transcription

1 BIOTECHNOLOGY INSTITUTE UNIVERSITY OF GRANADA "Intercellular Communication" Research Team DEPARTMENT OF PHYSIOLOGY FACULTY OF MEDICINE AVDA. MADRID, 11 E GRANADA (SPAIN) Dr. Darío Acuña Castroviejo Phone: Professor of Medical Physiology Fax: Granada, July 31, 2006 SCIENTIFIC REPORT ON THE EFFECTS OF ELECTROMAGNETIC FIELDS ON THE HUMAN ENDOCRINE SYSTEM AND ASSOCIATED PATHOLOGIES This report has been prepared and issued by Professor Dario Acuña Castroviejo, Professor of Physiology at the University of Granada, Secretary of the Institute of Biotechnology of the University, and co-editor of Journal of Pineal Research, the leading international journal in the field of melatonin, based on his knowledge and research experience in the field of endocrinology and specially of melatonin. Dr. Darío Acuña Castroviejo Professor of Physiology

2 SCIENTIFIC REPORT ON THE EFFECTS OF ELECTROMAGNETIC FIELDS ON THE HUMAN ENDOCRINE SYSTEM AND ASSOCIATED PATHOLOGIES 1. Background Human body health is maintained thanks to the perfect functioning of several regulatory systems, being the endocrine the one with a perfect control to maintain communication between the nervous and immune systems. Thus we speak of neuro-inmuno-endocrine system, responsible for the functional balance, that is, the body homeostasis, working in close communication. This intercommunication is possible because the cells of the three systems share specific receptors and other mediators. In turn, this relationship between the systems explains a series of events which explain that situations such as depression, emotional stress or anxiety, are accompanied by increased susceptibility to infections, cancer or autoimmune disease, which means poorer health and shorter longevity. By contrast, pleasant situations and optimistic vital status helps to overcome illness, and in general to have better health. Moreover, it has been confirmed that alterations of the immune system, as may happen in an infectious process, modify negatively the functionality of nervous and endocrine systems, and vice versa. In all these cases, health disorders are accompanied by a significant increase in oxidative stress and imbalance in redox state of the cell. Therefore, any impact on one of the system regulators affects the rest, which is of great importance in medicine, when seeking the causes of certain diseases.

3 2. Electromagnetic Fields Living beings are bioelectrical structures. Every living cell behaves as a dipole due to the potential difference across the cell membrane (between -10 and -100 mv). On the other hand, the Earth is surrounded by a static magnetic field of an average value of 500 mg and receives sporadic natural manifestations of solar magnetic ejections. Therefore, living beings have been subjected over millions of years to natural magnetic influences, which probably had and still have an influence on different biological functions. When magnetic and electric fields vary over time, electromagnetic fields are then created. The use of electrical power and telecommunications systems introduces in working and domestic environments electromagnetic radiation (non-ionizing radiation) with wave frequencies ranging between 100 KHz to 300 GHz. The proliferation of the number of sources emitting electromagnetic radiation has raised high concern and deep interest in knowing the influence of this physical factor on humans Biological interaction of electromagnetic fields The nature of the interaction between an electromagnetic radiation and biological matter depends on the frequency of emission. Frequency and wavelength are related, when frequency increases, wavelength decreases. Although electromagnetic spectrum is currently referred to as the main source of energy waves, sometimes electromagnetic energy acts itself as particulate matter rather than as waves, being this particularly true for high frequencies. The nature of these electromagnetic particles is important because it is the energy amount per particle (or photon, as these particles are called) which determines the biological effects electromagnetic energy will cause. Magnetic fields are difficult to shield

4 and they easily penetrate buildings and people. On the contrary, electric fields have little ability to penetrate skin or buildings. As static electric fields do not penetrate the body, it is assumed that any biological effect from routine exposure to static fields must be due to the magnetic component of the electric field. Because of their electrolyte composition, living beings are good electricity conductors. Ionic currents flow through cell membranes and intra and extracellular body fluids and especially through nerve and muscle cells exposed to a specific magnetic field. Furthermore, within biological systems there are magnetically influenciable structures, such as free radicals, that have paramagnetic properties. The response of a biological system to an external magnetic field depends as much on the intrinsic magnetic properties of the system as on the characteristics of the external field and the properties of the medium in which the phenomenon occurs. On the other hand, extremely low frequency non-ionizing radiations such as those from 50 Hz magnetic fields affect a large number of biochemical processes, among which: a) synthesis of nucleic acids (DNA and RNA), responsible for our genetic, heritage and proteins endowment; b) change the hormone production; c) modify the immune response, and d) change the degree of cell growth and differentiation, determining the appearance of cancer. From a physical standpoint, it is assumed that the main interaction between electromagnetic fields and the body occurs in the cell membrane and more specifically in the ion channels, being the calcium dependent the most actively involved in biological alterations Electromagnetic fields and free radicals Due to their conformation, free radicals are atoms and molecules that have the potential to damage body cells entering in contact with them. In the human body, free radicals are normally produced during aerobic cellular metabolism, primarily at mitochondrial respiratory

5 chain, by phagocytosis, synthesis of prostaglandins, and by the cytochrome P450 system in the liver. Free radicals can also be generated from non-enzymatic reactions such as oxygen reactions with organic compounds and those produced by ionizing and non-ionizing radiations. Damage to tissue may be serious enough to lead to cell death. Our body defends itself against free radicals attacks by the Endogenous Antioxidant System. This is why in our body there is a delicate balance between the production of free radicals, required by our immune system, and their neutralization when produced in excess. The loss of this balance in our body causes the most times the presence of excessive quantities of free radicals, inducing damage to macromolecules of the cell such as nucleic acidosis (DNA and RNA), proteins and lipids, which can lead to mutagenesis and cancer or cell death. In any case, this unbalance accelerates the aging process and enables the onset of various diseases. In living beings, free radicals formed physiologically are regulated by the antioxidant defense systems. When the production of free radicals increases over the defensive capacity of the cell, it is created a state of oxidative stress that lies behind many diseases. Environmental pollution, smoking, high processed foods meals and situations of physical and emotional stress trigger the production of free radicals in amount greater than the body can normally neutralize. So, these free radicals damage several different structures such as vascular endothelium (vascular lesions, atherosclerotic disease), neurons (neurodegenerative diseases like Parkinson's, Alzheimer's, etc.). The antioxidant defense biological systems consist of two groups molecules. A group consisting of enzymatic character systems, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GRD), glutathione-s-transferase (GST) and glucose-6-phosphate dehydrogenase (G6PD). And other group consisting of free radical scavenger molecules such as C and E vitamins, glutathione, and melatonin. Most of these systems act both upon the cytosol and the

6 mitochondria, being this second organelle the most important one in the prevention of oxidative damage and subsequent cell death. The adverse effects of electromagnetic fields include production increase of free radicals, both oxygen derived (ROS) and nitrogen derived (RNS) and decrease of antioxidant defenses. People exposed to these fields show a significant increase in SOD plasma levels and hydrogen peroxide, which fits with a SOD increase. Also, the total plasma antioxidant capacity decreases significantly in the exposed people, the serum concentration of malondialdehyde significantly increases after exposure, indicating an oxidation increase of cell membrane. At a subliminal level, the damage is present in heart diseases or in cataract induction after damage to eye lens proteins. As for cancer induction, electromagnetic fields are not ionizing and therefore may affect the processes of cell proliferation through the generation of free radicals, which in turn can act on the processes of neoplastic transformation of cells. Finally, a recent study indicates that electromagnetic fields stabilize free radicals in such a way that they increase their average life allowing for their greater dispersion. This increases the likelihood of damage to cell macromolecules, including nucleic acids, proteins and lipids. The suppression of cell proliferation induced by an electromagnetic field in the presence of antioxidants supports this way of damage Electromagnetic fields and associated pathologies Organic and cell functions are based, regulated and coordinated by differences between ionic and biochemical molecular gradients first and low-frequency and intensity electromagnetic differences afterwards. This initially biochemical and later electromagnetic activity is graphically expressed with electroencephalograms, electrocardiograms, electromyograms, and, more recently, with electromagnetograms. Electromagnetic waves generated by

7 electrical currents and microwaves (wire phone networks, mobile phone networks, radio frequencies, tv frequencies, civil and military radar systems and so on) interfere with and distort the normal functions of human organism. Despite certain controversy in scientific literature, several publications with sufficient methodological rigor have been issued on the harmful effects on exposed persons. The major adverse effects of exposure to electromagnetic fields include: a) Neurological disorders such as irritability, headaches, fatigue, hypotonia, hyperexcitability syndrome, somnolence, sensory alterations, tremors, dizziness. b) Mental disorders: mood and character disorders, depression, suicidal tendencies. c) Cardiopulmonary disorders: heart rate alterations, changes in blood pressure and peripheral vascular disorders. d) Reproductive disorders: menstrual cycle disorders, abortions, infertility and decreased sexual libido. e) Increased risk of some cancers such as childhood acute leukemia and central nervous system tumors. f) Dermatologic disorders: nonspecific dermatitis and skin allergies. g) Hormonal disorders: alterations in rate and levels of melatonin and other neurosecretory substances and sex hormones. h) Immune disorders: disorders of the anti-infective and anti-tumor immunosurveillance system. The potential risk of these complications is greater in the following population groups: pediatric age, the elderly, pregnant women and infants, and especially among metal prostheses and pacemakers users. Nowadays, the above is corroborated by the EPA

8 (Environmental Protection Agency) and the IARC (International Agency for Research on Cancer). Continued technological developments result in increasing incidence of this type of pollution. In the late seventies the first data appeared showing an association between electromagnetic fields and cancer, particularly childhood leukemia. Since then, there have been great number of epidemiological and laboratory studies to establish a relationship between exposure to electromagnetic fields and human disease. The IARC, global reference on cancer research indicates that exposure to 0.4 μt on doubles the risk of childhood leukemia in the affected population. An increased mortality rate of leukemia has been observed in workers whose labor is in environments with electromagnetic fields and in children living in homes near high voltage power lines. Countries like Sweden have recognized in their legislation the impact of electromagnetic fields generated by power lines on childhood leukemia. Other studies showed that most cases of sudden infant death occur in the proximity of electrified wiring networks, radio stations, high voltage lines and radar stations, that is, in areas exposed to strong electromagnetic fields. They also found an increased frequency in congenital malformations in children whose parents worked in high voltage generating sources, indicating a genotoxic effect of electromagnetic fields. 220 volts and 50 Hz electrical wiring installed in homes generate fields that raise the partial pressure of oxygen in the blood and hematocrit. Given that brain electrical activity of human being shows a periodicity ranging from 14Hz to 50 Hz in the state of wakefulness, and between 8Hz and 14Hz if in the state of relaxation, it is deduced that an external field of 50 Hz as the common electrical grid can induce states of nervousness (electrostress). Moreover, these fields can alter the fat and cholesterol balance in the blood, increase the production of cortisol and heighten blood pressure, which can lead to heart, kidney, gastrointestinal, nervous and other diseases. Other biological alterations due to action of intense artificial

9 electromagnetic fields include changes in body temperature, alterations in blood electrolyte balance, joint muscular pain, difficulty in colors perception, fatigue, loss of appetite, impaired central nervous system, stress, decreased platelet counts, and so on. In short, low intensity electromagnetic radiations may have an adverse impact and be the cause of the onset and development of cancer, affect the reproductive functions, cause allergies and depression, which indicates their clear involvement in the affections of the neuroinmunoendocrine system Electromagnetic fields and gene expression Experimental studies indicate that after exposure to electromagnetic fields EMF, immune system cells are activated and ROS and RNS production is increased. We studied the expression of genes in monocytes (immune system cells) derived from human umbilical cord blood after exposure to 1 mt. The results indicate altered expression in 986 genes. Expression of IL2, IL10, FOS genes is activated while HIOMT (melatonin synthesis enzyme) expression decreases, among many others. These results indicate the start up of a cellular pathway activation of monocytes, with an inhibition of melatonin production. These effects occur in the same way that the activation of immune system cells produced by bacterial lipopolysaccharides, responsible for the induction of sepsis and septic human shock, that is, a very severe systemic inflammatory reaction. In addition, ROS production after exposure to electromagnetic fields was of equal magnitude to that produced after administration of lipopolysaccharides. Therefore, electromagnetic fields directly influence the human genome, decrease melatonin levels and produce an inflammatory reaction whose effects can manifest in the medium and the long term.

10 2.5. Cognitive effects of electromagnetic fields One of the important considerations of little significance so far however is the effect of electromagnetic fields on the brain and the consequences in cognitive and behavioral levels. Evidence suggests that even brief exposures can induce changes in brain electrical activity, especially within the alpha frequency band (8-13 Hz). Also, another effect now being studied is the appearance of alterations after exposure to electromagnetic fields, and not only during the exposure itself. Several studies show significant effects on brain physiology and cognitive abilities after exposure to these fields. Among them decrease in recognition memory levels after exposure to100 μt for 1 second, and decrease of alpha activity levels in the occipital cortex, after 15 min exposure to 80 μt. 3. Endocrine mechanisms of the adverse effects of electromagnetic fields 3.1. The immune system From birth on, as humans, we are continually exposed to suffer infections and cancer malignancies, against which we would succumb if it was not because we have a complex physiological system that defends us from such menaces; the immune system. This system is responsible for the recognition of our own integrity and this way is able to defend each of us from strange menaces. The immune system consists of a variety of cells and molecules capable of recognizing and eliminating unlimited different agents foreign to the organism, among which not only invading microorganisms are included but also cells of our body continually maligned by the attacks, among other, from free radicals. The set of mechanisms in place to carry out this function is known as immune response, which consists of that very system cells activation. This activation is a set of processes that are well regulated, since an uncontrolled immune activation would mean, and indeed it does, the individual's death.

11 The immune system has specific innate or nonspecific functions and acquired or specific functions. The nonspecific response is developed and acts indiscriminate and immediately against any foreign agent that has managed to cross the body's natural barriers, or against any cell that has become cancerous. This response is carried out by a series of cells such as phagocytes (neutrophils, monocytes and macrophages) and "Natural Killer" cells (NK) (or naturally killer), which hold a first line of defense against strange agents. The action of phagocytic cells involves increased oxygen consumption and the consequent production of Reactive Oxygen Species (ROS), being the superoxide anion the first. The specific response is the responsibility of lymphocytes, which once have recognized the strange agent; one of their most representative actions is the ability to proliferate in an adequate number of cells able to face strange agents. With these properties the immune system has proven to be fundamental in the maintenance of body homeostasis, being a clear regulatory system, on equal terms with the classical regulatory systems, as the nervous and endocrine systems Electromagnetic fields and melatonin Functions of melatonin Melatonin is a stress hormone and, as such, its production is directed to counteract it. The pineal gland is an organ located in the center of the brain, which converts serotonin into melatonin at night. This circadian rhythm of melatonin is an essential signal for internal synchronization of a large number of endocrine and non endocrine rhythms as the sleep/wakefulness itself. Moreover, melatonin is a vital part of the endogenous antioxidant system of the human organism. The main melatonin effects could be classified into: a) antioxidant, to debug ROS/RNS and increase the expression of genes coding for antioxidant enzymes, b) anti-inflammatory, to repress the expression of genes that code for inducible

12 nitric oxide synthase (inos) and the inducible mitochondrial nitric oxide synthase (imtnos), and reduce the production of NO. Furthermore, melatonin stimulates the production of antibodies by the immune system, c) stimulating immune defenses by increasing the synthesis of antibodies, among other functions. Moreover, melatonin has important oncostatic effects; it reduces cancer cells proliferation and has neuroprotective effects, perhaps in part due to previous actions. The decline in melatonin production from the age of 35 on, has been interpreted as favoring the aging process and processes associated with it, such as cancer and neurodegeneration. Numerous studies endorse the preventive effect of melatonin administration against many changes associated with oxidative stress and its consequences Effects of electromagnetic fields on melatonin Recent studies have demonstrated the ability of electromagnetic radiations to decrease circulating melatonin levels, both in animals and humans. High voltage lines have a decisive influence in the decline of melatonin. After a month of exposure, melatonin levels are reduced by 40%, although after removal of the radiation source, these levels become stabilized. The decrease in melatonin production has as immediate consequence the alteration of the melatonin circadian rhythm, which causes depression and fatigue, symptoms well known to be expressed in individuals exposed to electromagnetic fields. Artificial electromagnetic fields have the same effect on the pineal gland as light, another melatonin production inhibitor. But whereas during the night, the absence of light stimulates melatonin production, exposure to electromagnetic fields is continuously for 24 hours, thereby preventing the nocturnal synthesis process of melatonin. In this regard, a very interesting study has been carried out in humans exposed to 1 μt around the head and 10 μt around the

13 rest of the body in their regular work environment. The reduced production of melatonin was found in women, and the decline was greater in women working during the night, indicating that there is a summation of effects between the exposure to light and electromagnetic fields. This would explain the decreased ability of the immune system and the cause of many insomnia or changes in behavior and mood disorders common to people exposed to electromagnetic fields. In the Battelle Pacific Northwest Laboratory (USA), 60 Hz electric fields and about 2 kv / m electric fields were proven to reduce the amount of melatonin produced at night, just when these levels should be maximized. There is evidence that a dose of 400 microwatts/cm2, inhibits melatonin secretion in humans. There is a very important fact to consider. Studies with volunteers subjected to electromagnetic fields of 20 μt for 8 hours per day, did not show a significant decrease in melatonin levels. Other evaluations, with exposure to 300 μt found no evidence of melatonin disruption. The problem in these studies was that 0.2 μt exposures were used as control, which may be the level at which chronic exposures inhibit melatonin. In fact, and this is of great importance, the ability of electromagnetic fields to inhibit melatonin seems to be at about relatively low levels, below 0.2 μt. This paradoxical effect is very similar to what happens with light, as the pineal gland melatonin production inhibition occurs within the range of 10 to 200 lux, while exposure to 50,000 lux have little influence of melatonin. The decrease in melotonin levels eliminates this important antioxidant and anti-inflammatory hormone. Because of oncostatic and stimulating actions of the immune system, the decrease in melatonin causes the body to lose these defense capabilities. On the other hand, it must be considered that melatonin also regulates the function of certain endocrine organs: the gonads, pituitary, thymus and hypothalamus.

14 Electromagnetic fields, melatonin and immune system Macrophages and neutrophils are immune cells responsible for the defense of the organism. Electromagnetic fields increase ROS production by these cells. An exposure to 0.5 mt for 45 min is able to activate macrophages and human monocytes, raising the ROS production. Macrophages play an essential role in the immune system. Activated macrophages have a high phagocytosis capacity and increased production of ROS and RNS. These free radicals are helpful in fighting against the invader (bacteria) but, when they occur after activation of these cells without the presence of infection, as in the case of exposure to electromagnetic fields, will cause serious damage to the body. Due to the high amount of melatonin in bone marrow, its decrease due to electromagnetic fields will lead to increased oxidative stress in marrow affecting at the same time the mother cells. These changes increase the risk of cancer such as lymphoma and leukemia, and other types of cancer such as breast cancer Electromagnetic fields, melatonin and breast cancer Estrogens are produced in the ovaries and they are steroid hormones. Their functions are the development and maintenance of women sexual characteristics, especially in the uterus, mammary gland and the distribution of fat, but other functions have also been described: they relieve symptoms of discomfort during menopause, they are hormones protecting against heart attacks and strokes, and against osteoporosis and diseases of the NBS. The changes in the endocrine system secondary to ovarian dysfunction are therefore very important and affect many functions of woman's body, including mood, memory, cognitive abilities, immune system functions, the musculoskeletal system and cardiovascular function. Estrogens bind to specific receptors in the cell nucleus, regulating gene expression in the respective

15 target organs, mainly the female reproductive tract, breast, pituitary, hypothalamus, bone, liver, cardiovascular system, central nervous system, skin, etc.. Given the importance of melatonin in the regulation of endocrine functions, we can deduce that the reduced levels of this hormone could be one of the keys to understanding the increased risk of contracting cancer in humans exposed to low frequency electromagnetic fields. It has been proposed that nocturnal melatonin suppression could explain the epidemiologically described association between occupational and residential electromagnetic exposure and increased cancer risk. People exposed to electromagnetic radiation may be at increased risk of breast cancer, either because the inhibition of melatonin can lead to increased production of prolactin and ovarian estrogens, or by a decrease of the inhibitor direct effect of melatonin on cell proliferation in breast cancer. In this regard, several studies suggest that if melatonin production is inhibited estrogen production rises (since melatonin slows down its production), thus increasing the risk of breast cancer. Indeed, the action of estrogen to accelerate cell growth in mammary gland is suppressed by melatonin at concentrations as low as 1 nm. However, the antitumor action of melatonin decreases drastically by the action of an electromagnetic field between 0.2 to 1.2 μt with a maximum activity at 1.2 μt. The same intensity of electromagnetic field inhibits the antiproliferative action of Tamoxifen, an antiestrogen drug used to treat breast cancer. In addition, the decrease of melatonin by electromagnetic fields can produce the release of cancer cells that were quiescent. In this sense it has been proved that electromagnetic fields block the inhibitory effect of melatonin in cancer cells growth Electromagnetic fields, melatonin and leukemia

16 In 1970 the first link between cancer and exposure to electromagnetic fields apperaed. There is a positive relationship between leukemia, lymphoma and NBS tumors and exposure to electromagnetic fields. In a case-control study, a direct relationship of childhood leukemia was found associated with electromagnetic fields of 0.2 μt. In adults, several studies have indicated risk of leukemia 6 times higher among workers at power plants. Other studies slightly lower that risk to a 3 times factor. This latest study, conducted in 4,000 cases of cancer among power plants workers in Canada and France, is very indicative. Currently, it has been documented the existence of at least twice the risk associated with exposure to electromagnetic fields higher than μt, having those exposures been classified as carcinogenic by the IARC. In addition, there is lots of epidemiological information that suggest a risk increase of certain types of cancer and noncancerous diseases associated with exposure to electromagnetic fields. Among them, amyotrophic lateral sclerosis, brain cancer and leukemia. Other studies have supported the large scale occurrence of leukemia in the U.S., Canada and the United Kingdom associated with exposure to magnetic fields. A study of 45 deaths in children, including 18 sudden deaths, showed that melatonin levels were much lower in babies who die suddenly in relation to other deaths. Hormone levels in the brain were 15 pg / ml, compared with 51 in the control group, and hormone levels in blood were 11 pg / ml on average in the 18 sudden deaths case and 35 pg / ml in the other group. The evaluation of electromagnetic fields in children is of great importance. The fetus, which does not produce melatonin, receives it through mother`s placenta, who produces more melatonin during pregnancy. The newly born does not produce significant amounts of melatonin until 6 months of age. Therefore, the fetus and children under 6 months are especially sensitive to electromagnetic fields. Undoubtedly, in these cases the lack of melatonin increases the risk of complications associated with it: mutations due to DNA damage and cancer, rapid growth

17 tumors, etc. In fact, the incidence of childhood leukemia has increased rapidly in recent decades in most industrialized countries. Although the causes of this disease are largely unknown, increasing exposure to electromagnetic fields in these countries and the disruption of melatonin may play a decisive role. 4. Conclusions 4.1. The data published by the Council of the American Physical Society and the National Research Council indicate that there is currently no final evidence that exposure to electromagnetic fields caused by power plants have a risk effect on human health. However, these organizations also indicate that, in relation to cancer breast and childhood leukemia, the possible factor of risk of the electromagnetic fields has not been clarified The main current problem of the situation of the partial ignorance of the effects of electromagnetic fields on human health is that studies on humans have involved a very small number of cases. Therefore, the lack of significant effects of exposure to electromagnetic fields may be due more to the lack of data and not to the absence of their effects. On the other hand, in many of the tests conducted to assess the effects of such exposure it was not used an appropriate methodology. Therefore it becomes necessary to extend the studies with modern neuroimaging technical means, as well as magneto-encephalography, which allows studying the brain electromagnetic activity with much greater accuracy The IARC evidences that, among other things, children are more sensitive to leukemia from exposure to EMF. This logically questions whether children living in advanced civilizations are more sensitive to these fields. To better assess the sensitivity of the children

18 to electromagnetic fields, it has been recently conducted an international workshop named "Sensitivity of Children to EMF Exposure" organized and sponsored by several international organizations, including the World Health Organization, the European Commission for Coordination on Electromagnetic Fields, the Swedish Radiation Protection Authority, the European Commission for Cooperation in the Field of Science and Technology Research, the International Commission for Non-Ionizing Radiation Protection and the School of Medicine of the University of Turkey, where it was organized in 2004 with the following considered proposals: -Examine the state of development at which children may be more sensitive to electromagnetic fields. -Possible effects of electromagnetic fields in children. -Identify points for further investigation. -Recommendations for national authorities of all countries until there is adequate scientific information In this workshop it has been consensuated that, with current knowledge, and given the uncertainty about the effects of electromagnetic fields on children, serious steps should be taken to reduce their exposure to electromagnetic fields, as well as the adoption of international standards. Such measures should be aimed at minimizing exposure to electromagnetic fields in schools and kindergartens, as well as on any other location where children remain a part of the day The hypothesis of melatonin endocrine disruption after exposure to electromagnetic fields becomes every time more consistent and can participate in the increased risk of many diseases associated to exposure to electromagnetic fields.

19 4.6. Final Conclusion: Given the risk factors, the relationship between exposure to electromagnetic fields, the melatonin production inhibition and the onset of different diseases, especially breast cancer and childhood leukemia, it is recommended that, while absence of more studies stating otherwise, power plants generating electromagnetic radiations should be located as far as possible from the population at risk. 5. Bibliography * Acuña-Castroviejo D, Scales G, Lopez LC, Milestones AB, Leon J. Melatonin and nitric oxide: Two required antagonists for mitochondrial homeostasis. Endocrine 2005; 27: * Acuña-Castroviejo D, Scales G, Tapias V, Rivas I. Melatonin, mitochondria, and neuroprotection. In: Melatonin: Present and Future, edited by Montilla P and Tunis I, New York, USA, Nova Science Publisher, Inc., 2006.

20 * Acuña-Castroviejo D, Scales G, León J, Khady H. Melatonin, biological rhythms and oxidative stress, in Salvador-Carulla L, Cano Sanchez A, and Cabo-Soler JR (eds), Longevity. Comprehensive health treaty in the second half of life: Madrid, Editorial Medica Panamericana, p , * Acuña-Castroviejo D, Martin M, Macias M, Scales G, León J, Khaldy H, Reiter RJ. Melatonin, mitochondria and cellular bioenergetics. J Pineal Res 2001, 30: * Blackman CF, Benan SG, House DE. The Influence of 1.2 microt, 60 Hz magnetic fields on melatonin and tamoxifen-induced inhibition of MCF-7 cell growth. Bioelectromagnetics 2001, 22: * Blalock JE. The immune system as the sixth sense. J Intern Med 2005; 257: * Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine / circadian melatonin signal. Endocrine 2005; 27: * Brocklehurst B, McLauchlan KA. Free radical mechanism for the effects of environmental electromagnetic fields on biological systems. Int J Radiat Biol 1996; 69:3-24. * Caplan LS, Schoenfeld ER, O'Leary ES, Leske MC. Breast cancer and electromagnetic fields - A review. Ann Epidemiol 2000; 10: * Cook CM, Saucier DM, Thomas AW, Prato FS. Exposure to ELF magnetic and ELFmodulated radiofrequency fields: The time course of physiological and cognitive effects observed in recent studies ( ). Bioelectromagnetics 2006; DOI /bem * De la Fuente M Effects of antioxidants on immune system aging. Eur J Clin Nutr 2002, 56: S5-S8. * De la Fuente M. The immune system as a marker of health and longevity. Antiaging Med 2004; 1: * De la Fuente M, Hernanz A, Vallejo MC. The immune system in the oxidation stress conditions of aging and hypertension. Favorable effects of antioxidants and physical exercise. Antioxidants Redox Sig 2005, 7: * Escames G, León J, Macías M, Khaldy H, Acuña-Castroviejo D. Melatonin counteracts lipopolysaccharide-induced expression and activity of mitochondrial nitric oxide synthase in rats. FASEB J 2003, 17: * Goodman R, Bassett CAL, Henderson AS. Pulsing electromagnetic Fields induce cellular transcription. Science 1983, 220: * Green PS, Simpkins JW. Neuroprotective effects of estrogens: potential mechanisms of action. Int J Dev Neurosci 2000, 18:

21 * Gruber CJ, Tschugguel W, Schneeberger C, Huber JH. Production and actions of estrogens, N Engl J Med 2002, 346: * Halliwell B, Gutteridge, MC. Free radicals in biology and medicine. Oxford Univ Press, * Harland JD, Liburdy RP. Environmental magnetic fields inhibit the antiproliferative action of tamoxifen and melatonin in a human breast cancer cell line. Bioelectromagnetics.1997, 18: * Harman, D. A theory based on free radical and radiation chemistry. J Gerontol 1956, 11: * Henshaw DL, Reiter RJ. Do magnetic fields cause increased risk of childhood leukemia via melatonin disruption? Bioelectromagnetics 2005, Suppl 7: S * IARC Monographs of the Evaluation of Carcinogenic Risks to Humans Nonionizing radiation, part 1: Static and extremely low-frequency (ELF) electric and magnetic fields. Volume 80, France: IARC Press, 150 Cours Albert Thomas, Lyon Cedex F-08. * Juutilainen J, Kumlin T. Occupational magnetic field exposure and melatonin. Interaction with light-at night. Bioelectromagnetics 2006, 27: * Juutilainen J, Lang S. Genotoxic, carcinogenic and teratogenic effects of electromagnetic fields. Introduction and overview. Mutat Res 1997, 387: * Liboff AR, Williams T, Strong DM, Wistar R. Time-varing magnetic fields: effects on DNA synthesis. Science 1984, 223: * Liburdy RP Biological Interactions of Cellular Systems with Time-Varying Magnetic Fields. Ann NY Acad Sci 1993, III : * Lin JC. Advances in electromagnetic fields in living systems. Volume 1. First Edition. Plenum Press. N.Y. pp , * Lopez LC, Scales G, Tapias V, Utrilla MP, Leon J, Acuña-Castroviejo D. Identification of an inducible nitric oxide synthase in diaphragm mitochondria from septic mice. Its relation with mitochondrial dysfunction and revention by melatonin. Int J Biochem Cell Biol 2006, 38: * Lupker M, Frahm J, Lantow M, Maercker C, Remondini D, Bersani F, Simko M. Gene expression analysis of ELF-MF exposed human monocytes indicating the involvement of the alternative activation pathway. Biochim Biophys Acta 2006; 1763:

22 * Miquel J, Economos AC, Fleming J, Johnson JE Jr. Mitochondrial role in cell aging. Exp Gerontol 1980; 15: * Nordstrom S, Birke E, Gustavsson L. Reproductive Hazards Among Workers at High Voltage Substations. Bioelectromagnetics 1983, 4: * Reiter RJ, Tan DS, Manchester LC, Qi W. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species. Cell Biochem Biophys 2001; 34: Proceedings of WHO-sponsored symposium on "Sensitivity to Children to EMF Exposure". Bioelectromagnetics Suppl. 2005, 7: S1. * Reiter RJ, Tan DX, Poeggeler B, Kavet R. Inconsistent suppression of nocturnal pineal melatonin synthesis and serum melatonin in rats exposed to pulsed DC magnetic fields. Bioelectromagnetics 1998; 19: * Reiter RJ. Melatonin suppression by static and extremely low frequency electromagnetic fields: relationship to the reported increased incidence of cancer. Rev Environ Health 1994, 10: * Reiter RJ. Static and extremely low frequency electromagnetic field exposure: reported effects on the circadian production of melatonin. J Cell Biochem 1993, 51: * Reiter RJ, Pineal melatonin: Cell biology of its synthesis and of its physiological interactions. Endocr Rev 1991, 12: * Sharma M, Palacios-Bois J, Schwartz G et al. Circadian rhythms of melatonin and cortisol in aging. Biol Psychiatry 1989, 25: * Simko M, Mattsson MO. Extremely low frequency electromagnetic fields as effectors of cellular responses in vitrpo: Possible immune cell activation. J Cell Biochem 2004; 93: * Stevens RG, Davis S, Thomas DB, Anderson LE, Wilson BW. Electric power, pineal function, and the risk of breast cancer. FASEB J 1992, 6: * Sturner WQ, Lynch HJ, Deng MH, Gleason RE, Wurtman RJ. Melatonin concentrations in the sudden infant death syndrome. Forensic Sci Int 1990, 45: * Takahashi K, Kaneko I, Date M, Fukada E. Influence of pulsing electromagnetic field on the frequency of sister-chromatid exchanges in cultured mammalian cells. Experientia 1987, 43: * Tenforde TS. ELF field Interactions at the animal, tissue, and cellular Levels. Electromagnetics Biol Med 1991, 39: * Tresguerres JAF, AF Tresguerres Centeno, Salam F. Reproduction II: Hypothalamicpituitary-ovarian axis, in Tresguerres JAF, Aguilar Benitez de Lugo E, Devesa Mugica J,

23 Esteban Moreno and B (eds), Treaty of Basic and Clinical Endocrinology: Madrid, Editorial Summary, p , * Wayne SJ, Rhyne RL, Garry PJ, Goodwin JS. Cell-mediated immunity as a predictor of morbility and Mortality in subjects over 60. J Gerontol 1990, 45: M45-M48. * Wertheimer CL, Leeper E. Electrical wiring configurations and childhood cancers. Am J.Epidemiol 1979, 109: * Wilson BW, CW Wright, Morris JE, Buschbom RL, Brown DP, Miller DL, Sommers- Flannigan R, Anderson LE. Evidence for an effect of ELF electromagnetic fields on human pineal gland function. J Pineal Res 1990; 9: * Yen-Patton GPA, Patton WF, Beer DH, Jacobson BS. Endothelial response to electromagnetic fields: stimulation of growth rate and angiogenesis in vitro. J Cell Physiol 1988, 134:37-46.