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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields 4 Animal and Tissue Effects SUMMARY AND CONCLUSIONS The published literature regarding the exposure of animals and tissues to power-frequency electric and magnetic fields is discussed in this chapter. The committee focused on three areas of principal interest: carcinogenesis, reproduction and development, and neurobehavioral and neuroendocrine responses. On the basis of an evaluation of peer-reviewed literature, the committee has made the following conclusions: There is no convincing evidence that exposure to power-frequency electric or magnetic fields causes cancer in animals. A limited number of laboratory studies have been conducted to determine if any relationship between exposure to electric and magnetic fields and cancer exists. To date, no reports have been published showing demonstrable effects of electric-or magnetic-field exposures on the incidence of various types of cancer. However, some recent, as yet unreplicated laboratory evidence suggests a positive relationship between magnetic-field exposures at field strengths of approximately 100 µT (1 G) and the incidence of breast cancer in animals treated with carcinogens. There is no convincing evidence of adverse effects from exposure to power-frequency electric and magnetic fields on reproduction or development in animals. Reproduction and development in animals, particularly mammals, have not been shown to be affected by exposure to very-low-frequency electric or magnetic fields.
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields There is convincing evidence in animals of neurobehavioral responses to strong 60-Hz electric fields; however, adverse neurobehavioral effects of such fields have not been shown. Laboratory evidence clearly shows that animals can detect and respond behaviorally to electric fields. Evidence of behavioral responses in animals to ac magnetic fields is much more tenuous. In either case, general adverse behavioral effects have not been shown. There is evidence of neuroendocrine changes associated with 60-Hz magnetic-field exposure in animals; however, alterations in neuroendocrine functions have not been shown to cause adverse health effects. The majority of studies that investigated magnetic-field effects on pineal-gland function suggest that these fields might inhibit night-time pineal and blood melatonin concentrations; in those studies, the effective field strengths varied from 10 µT (0.1 G) to 5.2 mT (52 G). The data supporting an effect of sinusoidal electric fields on melatonin production are not compelling. Other than the observed changes in pineal function, an effect from magnetic-field exposure on other neuroendocrine or endocrine functions has not been clearly shown in the few studies reported. Despite the observed reduction in pineal and blood melatonin concentrations in animals as a consequence of magnetic-field exposure, no evidence to date shows that melatonin concentrations in humans are affected similarly. In animals in which melatonin changes were seen, no adverse health effects have been found to be associated with electric-or magnetic-field-related depression in melatonin. There is evidence that pulsed magnetic-field exposures greater than about 0.5 mT (5 G) are associated with bone-healing responses in animals. Replicable effects have been clearly shown in the bone-healing response of animals exposed to electric and magnetic fields at sufficiently high field strengths. CRITERIA FOR CONSIDERATION OF LITERATURE Consistent with the review guidelines established by the committee, only peer-reviewed literature is considered in this report unless otherwise noted. Results are reported only if they are exposure related and are statistically significant according to the authors' criteria unless otherwise noted. Greatest weight is given to studies that were confirmed in some manner in the peer-reviewed literature and that were blinded studies. USE OF ANIMAL STUDIES IN EVALUATING RISK Data from animal studies are an important component of estimating risk from nearly all agents. A gradient in the degree of an association between exposure to a toxic agent and the effects that agent can produce is called the dose-response relationship. The dose-response relationship forms the basis for the science of
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields toxicology and health physics and allows scientists to predict toxic or adverse health effects. The dose-response relationship is expected because interactions between organisms and chemicals and energy deposition occur according to the basic laws of physics and chemistry and therefore are predictable. Dose-response relationships are of two types: one describes the response of an individual to different doses of an agent, and one describes the distribution of responses of a population of individuals to different doses. When toxic or adverse effects are considered, individual dose-response relationships are characterized by a dose-related increase in the magnitude of the response. Interpretation of individual dose-response relationships can be confused by the multiple sites of action of most toxic agents. Each site has its own dose-response relationship. Population dose-response relationships consist of a specific end point and the dose required to produce that end point for each individual in the population. Three assumptions are made when considering dose-response relationships: The response is due to the agent administered. Although this assumption seems trivial in laboratory studies, it is not so apparent in epidemiologic studies. For example, epidemiologic studies might find an association between a response (disease) and one or more variables. Use of the term "dose-response" relationship in this context is always suspect until the variable is shown to be a representative factor of the putative causative agent. The response is related to the measurement of the dose. The most accurate way to determine dose-response curves is to measure the dose actually reaching the site at which an effect is detected within a cell. However, measuring the dose at the site of action generally is prohibitively expensive and has been done in only a few cases. Some measurement of exposure is nearly always substituted for a true measurement of dose. A quantifiable method of measuring and a precise means of expressing toxicity are available. Early in an investigation of the toxicity of an agent, the best end point for effects might not be apparent, but as more is known about the manifestations of toxicity, the dose-response relationship should become more quantifiable. These assumptions hold true for all types of toxic agents, presumably including extremely-low-frequency electric and magnetic fields, if such fields are found to exhibit toxicity. Types of Animal Studies Used in Descriptive Toxicology Two main principles underlie all descriptive animal studies of toxicity (as reviewed by Klaassen and Eaton 1991). The first is that the effects produced by an agent in laboratory animals are applicable to humans. The second is that exposure of laboratory animals to toxic agents in high doses is a valid method of discovering possible hazards in humans. Toxicity tests are not designed to
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields demonstrate that a chemical is safe but rather to characterize the toxic effects that can be produced. The toxicologic studies that are generally used to predict adverse effects in humans are Acute lethality Skin and eye irritations Sensitization Repeated dose (sometimes referred to as "subacute" toxicity) Subchronic toxicity Chronic toxicity Mutagenicity Developmental and reproductive toxicity Other tests, including those for immunotoxicity and toxicokinetics (absorption, distribution, biotransformation, and excretion). The most pressing issues with regard to residential electric-and magnetic-field exposure focus on carcinogenicity and possible adverse developmental and reproductive effects. Therefore, this discussion focuses on acute lethality, repeated dose, subchronic and chronic toxicity, mutagenicity, and developmental and reproductive toxicity tests, because these tests are used most often to address carcinogenicity and adverse developmental and reproductive effects. Acute Lethality The initial starting point for nearly all toxicologic studies is a determination of acute toxicity. The LD50 (the median lethal dose) and other acute toxic effects are determined for one or more routes of administration in one or more species and, in most currently used test regimes, are conducted over a 14-day period. Acute toxicity tests (1) provide a quantitative estimate of acute toxicity for comparison among substances; (2) identify target organs and other clinical signs of acute toxicity; (3) establish the reversibility of toxic responses; and (4) give guidance on dosages for other studies. The information obtained in acute toxicity studies forms the basis of the dosing regimes used in repeated-dose studies. In animal studies on the effects of exposure to electric and magnetic fields, acute toxicity studies involve effects from high-strength current flows. The physical effects and behavioral changes present in animals receiving perceptible electric shocks do not seem appropriate for the exposure conditions under which most people are exposed to electric and magnetic fields. Moreover, human data on electrocutions are sufficient to make animal testing unnecessary. Repeated-Dose Studies Repeated-dose studies are performed to obtain information on adverse effects after repeated administration and as an aid to establish the dosages for subchronic
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields toxicity studies. In most currently used test regimes, repeated-dose studies are performed after 14 days of exposure. Biologic effects reported in short-term studies using electric and magnetic fields are reviewed in this report. However, results from short-term studies often are not reproducible and are of questionable value in evaluating possible adverse health effects. Subchronic Toxicity Studies The principal goals of the subchronic toxicity study are to establish a no-observable-effect level (NOEL) and to further identify and characterize the organs affected by the test agent after repeated administration. Subchronic toxicity studies more precisely define the dose-response relationship of a test agent and provide the data needed to predict the appropriate dosages for chronic toxicity studies. Subchronic exposures can last for different periods of time, but in currently used test regimes, 90 days is the most common exposure duration. No subchronic toxicity studies using electric and magnetic fields have been conducted that meet the criteria necessary for defining subchronic toxicity. This deficiency is primarily due to the lack of repeatable toxic effects and the lack of a definition of dose-response relationships required from repeated-dose studies to establish dosages for a successful subchronic toxicity study. Chronic Toxicity Studies Dosage selection is critical to the successful completion of chronic toxicity studies. If dosages are too high, not enough animals will be alive at the end of a study to allow sufficient definition of the dose-response relationship to be useful for predicting adverse effects. If dosages are too low, not enough effects will be present to allow sufficient definition of the dose-response relationship to be useful for predicting adverse effects. Chronic exposure studies last longer than 90 days. Because humans are exposed to various types of electric and magnetic fields over their entire lifetime, exposures in chronic studies using rodents are most appropriately of 2 years duration. As is the case for subchronic toxicity studies, no chronic toxicity studies using power-frequency electric or magnetic fields have been conducted that meet the criteria necessary for defining subchronic adverse effects. The acute through subchronic dose-response relationships necessary for successful completion of chronic toxicity studies are not available. Developmental and Reproductive Studies Four types of animal tests are used to examine the potential of an agent to adversely affect reproduction and development—short-term, segment I, segment II, and segment III tests. Short-term tests use whole embryos in culture, organ cultures, and cell lines.
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields They are not used for assessing risk directly, but they can contribute greatly to the design of developmental and reproductive studies by providing an understanding of the mechanisms by which an agent adversely affects development and reproduction. Segment I tests are designed to address general fertility and reproductive performance. Segment I studies typically begin at an appropriate time before mating and last throughout gestation, lactation, and the first 3 weeks of life. The potential for an agent to cause birth defects (teratogenicity) is tested in segment II studies. Segment III tests address the potential for agents to cause toxicity after birth and often include multigenerational studies. To conduct reproductive and developmental studies properly, concentrations must be known that do not result in overt adverse effects in males and females; overt toxicity is widely known to have severe effects on reproduction and development in males and females. Thus, in the absence of good dose-response information from acute toxicity, repeated-dose, and subchronic toxicity studies, informative reproductive and developmental toxicity studies are nearly impossible to conduct. In studies involving electric and magnetic fields, the lack of repeatable reproductive and developmental effects and the lack of a definition of reproductive and developmental dose-response relationships are not surprising given similar negative results in studies of toxicity as discussed above. Cocarcinogenicity and Copromotion Studies of Electric and Magnetic Fields Carcinogenesis is a multistep, multipathway process, and carcinogens probably have different potencies for each of the different steps. Experimentally, it has been difficult to identify specific steps and determine which are necessary and sufficient to cause frank malignancy. Certain systems have been developed that provide evidence of malignant transformation in vitro or malignant tumors in vivo when subjected to combinations of agents. A possible observation in these systems is the determination of whether the potency of two agents can be enhanced when they are delivered together or in a specific sequence. The term ''initiator" is used for agents that are most potent when delivered first, and the term "promoter" is used for agents that are effective when delivered after initiators. Magnetic fields have been evaluated in those systems in vitro and in vivo; the data show negative and positive results. Each system is sensitive to the effect of different initiators and promoters; thus, negative data in one system do not necessarily contradict positive data in other systems. Positive results have not been replicated, but some of the data show a dose-response relationship for exposure to magnetic fields and to the interacting carcinogen. Thus, although the pattern of interaction of electric and magnetic fields with known carcinogens is not consistent, the possibility that magnetic fields in combination with some carcinogens produce transformation in these systems cannot be excluded at this
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields time. However, these few systems cannot predict hazard to human populations living in realistic environments. The doses of carcinogens and promoters used in combination with test agents, such as electric and magnetic fields, are invariably large and represent nonphysiologic exposure. The extent to which the highly treated cells in these test systems are representative of actual potential target cells in the soma of exposed individuals is tenuous. In experimental systems in which combinations of agents are used to produce an end point, extrapolation to lower concentrations that represent actual exposure concentrations in human populations is difficult. Thus, although data in these systems are useful for the study of mechanisms and identification of possible interactions, they offer little information on the potency of lower exposure concentrations of agents in the human environment. The data base that has been developed for initiation and promotion test systems is significant. These systems have shown positive results (i.e., enhanced carcinogenicity) for tests of copromotion and cocarcinogenicity with known and potent carcinogens, but positive results have also been observed when using other agents that are not considered potent carcinogens. For instance, acetic acid, beta-carotene, citrus oil, vitamin E, indomethacin, and putrescine have all yielded positive results in studies of copromotion or cocarcinogenicity using these in vivo test systems under certain conditions. Thus, the positive results in such tests are questionable until detailed studies have identified the underlying mechanism and the probable interaction of doses at environmental concentrations. Nevertheless, electric and magnetic fields, principally magnetic fields, have been shown to interact with carcinogens in some of these systems both in vitro and in vivo, and that fact raises some concern and deserves further attention. The committee provides suggestions for further study in this area in Chapter 7. CARCINOGENIC AND MUTAGENIC EFFECTS Because of epidemiologic reports of positive correlations between estimated exposures to power-frequency electromagnetic fields and cancer (see Chapter 5), considerable research interest has been generated concerning a possible connection between magnetic fields and cancer. To date, few laboratory animal studies have been published that bear directly on this question; however, an increasing number of investigations are being conducted. Studies that have been reported in the peer-reviewed literature examining the issue of magnetic-field exposure and cancer are discussed in the following pages and summarized in Appendix A, Table A4-1. Several approaches and animal models can be used in laboratory cancer studies. The selection of a specific model depends largely on the hypothesis chosen to evaluate a particular underlying mechanism. For example, if an agent, such as an electric or magnetic field, is tested for its potential to be a complete carcinogen (an agent that by its application alone causes cancer to develop), 1.5
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields to 2 years of exposure of mice or rats to the agent is necessary. During that time, exposure to other possibly confounding agents must be kept to a minimum. In this regimen, the animals are observed during the major portion of their lifetimes, and the number, type, and time of development of tumors are the critical end points. This type of study should include several dosage groups and requires a relatively large number of animals, particularly if the natural incidence of a tumor type is low. Studies evaluating complete carcinogenicity are quite expensive due to the length of time and the number of animals involved. Carcinogenesis is considered to be a multistep process; therefore, another approach is to assume the agent of interest acts either as an initiator or a promoter in which a two-phase protocol is required for testing. Initiation is defined as a genotoxic event in which the carcinogen interacts with the organism to affect the DNA directly. Promotion is operationally defined as an experimental protocol in which the promoting agent is applied subsequent to initiation and generally over a protracted time. Promotion is associated with a number of subcellular events that are generally nongenotoxic and is responsible for the conversion of initiated cells to cancerous cells. To evaluate electric and magnetic fields as an initiator, one high-dose exposure would be given followed by repeated exposures to a model promoter (e.g., 12-O-tetradecanoylphorbol-13-acetate, TPA) over a long-term period. If electric or magnetic fields were to be investigated for possible promotional effects, the animals would be exposed to a known initiator (e.g., 7,12-dimethylbenz[a]anthracene, DMBA) and subsequently exposed to electric or magnetic fields over a long-term period (e.g., months). The initiation and promotion approaches have the advantages of using fewer animals, less time, and less cost. However, a given model is usually limited to an evaluation of a specific type of cancer and might provide only general information on possible biologic mechanisms of the agent of interest and cancer development. Initiation and promotion studies use initiating or promoting agents, such as DMBA and TPA, respectively, at exposure concentrations that far exceed any possible comparable exposure concentrations in humans. Interpretation of such studies is for identification of possible toxic mechanisms, not for direct extrapolation to human risk. Complete Carcinogen Studies Few life-long animal studies examining power-frequency electric or magnetic fields as a complete carcinogen have been completed, although several are under way in the United States, Italy, Japan, and Canada. Several studies designed to evaluate magnetic fields as a promoter of cancer contained control groups that were exposed to magnetic fields without being exposed to a chemical initiator. These studies include a mammary tumor-promotion study in rats (Beniashvili et al. 1991), a lymphoma study in mice (Svedenstal and Holmberg 1993), and a mouse skin-tumor-promotion study (Rannug et al. 1993a). A major deficiency
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields of using such studies to evaluate complete carcinogenicity is the small size of groups involved. The Beniashvili et al. (1991) study found an increase in mammary gland tumors in rats exposed to magnetic fields at 20 µT for 3 hr per day as compared with unexposed animals. The other two studies (Rannug et al. 1993a; Svedenstal and Holmberg 1993) reported no increase in tumors with long-term exposure to magnetic fields at strengths of 500, 50, and 15 µT. Tumor-Initiation Studies No tumor-initiation studies of exposures to power-frequency electric or magnetic fields have been reported in the literature. Very little motivation exists for such studies because the energies involved are too weak to break chemical bonds. Furthermore, in vitro studies have not provided evidence that DNA molecules can be damaged directly by exposure to 50- or 60-Hz electric or magnetic fields. Tumor-Promotion Studies Despite the obvious need for promotion studies because of the suggested association between indirect measurements of exposure to electric and magnetic fields and cancer observed in epidemiologic investigations, few animal experiments have been completed. Skin-tumor promotion, after initiation with DMBA, was examined in mice exposed continuously to a 60-Hz magnetic field at 2 mT, 6 hr per day, 5 days per week, for up to 21-23 weeks (McLean et al. 1991). None of the exposed or sham-exposed mice developed papillomas. When magnetic-field exposure was combined with application of TPA, a slightly earlier development of tumors was observed in the field-exposed animals (Stuchly et al. 1992). Rannug and co-workers (1993a,b,c) conducted skin-tumor and liver-foci studies in Sweden. In the 2-year skin-tumor-promotion study, mice were initiated with DMBA, then exposed to 50-Hz magnetic fields at either 0.5 mT or 50 µT for 19-21 hr per day. No evidence of a field-exposure effect was observed either in the development of systemic or skin tumors or in skin hyperplasia. In the liver-foci study, rats were exposed to similar magnetic-field strengths over a 12-week period. The exposed animals showed no differences in foci development from the sham-exposed rats. In animals exposed to chemical promoter (phenobarbital) and the magnetic field, foci formation was slightly inhibited when compared with initiated-only animals. In a series of four experiments, rats were exposed for 91 days to 50-Hz magnetic fields at 30 mT (Mevissen et al. 1993). Initiation was accomplished with repeated oral doses of DMBA, and mammary tumors developed subsequently. In one experiment, the number of tumors per tumor-bearing animal was increased in animals exposed to the magnetic field. In a repeat of that experiment, however, no difference between exposed and sham-exposed animals was observed. This study is handicapped by the small number of animals in each group.
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields Before the Mevissen et al. (1993) study, a group in Georgia examined mammary carcinogenesis in magnetic-field exposed animals that were initiated with N-nitroso-N-methylurea (NMU) (Beniashvili et al. 1991). In the groups of animals exposed to a 60-Hz magnetic field at 20 µT for 3 hr per day for the lifetime of the animals, the incidence of NMU-induced mammary tumors increased over that in sham-exposed animals or in animals exposed for only 0.5 hr per day. An additional mammary carcinogenesis study was performed in which DMBA was used to initiate mammary tumors in rats. Löscher and co-workers (1993) reported a significant increase in mammary-tumor induction in the rats exposed to a magnetic field. All rats received four weekly doses of 5-mg DMBA beginning at 52 days of age. After DMBA administration, 99 rats were exposed to 50-Hz magnetic fields at a flux density of 0.1 mT for 24 hr per day for 3 months. Another 99 rats were sham exposed. After 3 months of exposure, mammary-tumor incidence was about 50% higher in the exposed group (51 tumors) than in the sham-exposed group (34 tumors). The difference was statistically significant ( p < 0.05). The tumors were also larger in the exposed group (p = 0.0134), but a difference was not found in the number of tumors per tumor-bearing rat. Note that this exposure is about 1,000 times that of the usual residential field strengths. REPRODUCTIVE AND DEVELOPMENTAL EFFECTS This section deals with in vitro and in vivo reproductive and developmental biologic effects of electric and magnetic fields at frequencies of 50 or 60 Hz in exposures that are relevant to those associated with power transmission and use. It is divided into considerations of effects of electric fields and magnetic fields. This division is somewhat artificial because all time-varying electric fields have an associated magnetic field; however, at these low frequencies, the fields can be considered independently to a high degree of accuracy. Nonmammalian and mammalian studies are also considered separately. The studies are summarized in Appendix A, Table A4-2. Nonmammalian Studies of 50- or 60-Hz Electric Fields Fish Embryonic effects of concurrent exposure to power-frequency electric and magnetic fields have been studied in Medaka fish by Cameron et al. (1985). Two-to four-cell-stage embryos were exposed for 48 hr either to 60-Hz electric fields that produced a current density of 300 mA/m2, to a magnetic field of 100 µT (1.0 G) root mean square (rms), or to combined fields. No significant developmental delays were reported immediately after exposure. Delays averaging 18 hr were detected 36-73 hr after removal from the magnetic field and
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields the combined field exposure. Developmental delays did not result in abnormal development or decreases in survival through hatching. Chicken The chicken embryo has been used to study potential effects of electric fields. Blackman et al. (1988a,b) studied brain tissue from embryos in chicken eggs exposed to 50- or 60-Hz fields at 10 V/m rms. The associated magnetic field was less than 70 nT (1 nT = 10-9 T) rms. Brain tissue was removed 1.5 days after hatching. The tissue was placed in a physiologic salt solution containing radioactive calcium and then placed in the same solution with no radioactive calcium and exposed to 50- or 60-Hz fields at 15.9 V/m rms and 73 nT rms for 20 min. The calcium efflux from the brain tissue of chicks exposed as embryos to 60-Hz fields was affected (see the description and analysis of these experiments in Chapter 3). The same phenomenon was not observed with embryos exposed to 50-Hz fields. Three replicates of the Blackman study by other laboratories have not produced consistent results. Mammalian Studies of 50- or 60-Hz Electric Fields Mice Male and female mice were exposed to either horizontal or vertical electric fields in two studies by Marino et al. (1976, 1980). In the first study, mice were exposed to electric fields at 10 and 15 kV/m that led to effects attributed by the authors to microshocks. The second study involved three generations of mice. Although the postnatal-weight gains were similar in exposed and unexposed mice, a higher mortality was observed in the exposed mice. This is the only report of that phenomenon, and the results have not been supported by data from studies conducted at other laboratories. Unlike the work of Marino and co-workers, Fam (1980) was unable to identify an exposure-related change in mortality of the progeny of mice exposed to 60-Hz electric fields at 240 kV/m. In this study, mice were exposed throughout gestation, the offspring were bred, and their litters were monitored for growth, blood histologic and biochemical changes, and histologic changes of major organs. In agreement with the results of Marino et al. (1980) except those on mortality, no changes were observed in growth or in any of the other measurements as a result of exposure. Kowalczuk and Saunders (1990) were unable to detect any exposure-related dominant lethal mutations in male mice exposed to 50-Hz electric fields at 20 kV/m. Males were exposed for 2 weeks before breeding, and no exposure-related effects in offspring were detected in in utero death, litter size, or viability of offspring. Females were not exposed.
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields magnetic fields has been reported in three mammals, the rat (two strains), the Djungarian hamster, and the baboon. Another reason for the interest in the reported melatonin changes is their potential relationship to the higher incidence of cancer reported in some epidemiologic studies. Two biologically plausible, although unproved, mechanisms theoretically describe a link between reduced melatonin concentrations and cancer initiation, promotion, and progression (Figure 4-2). According to Stevens (1987a,b), the increased secretion of prolactin and gonadal steroids, which are natural consequences of melatonin suppression (Reiter 1980), could lead to excessive proliferation of stem cells in the endocrine-system organs, thereby increasing the likelihood of tumor growth in these organs (e.g., breast and prostate tissue). Another theory relies on the observations related to the intracellular action of melatonin. In recent studies, melatonin was shown to be a potent hydroxyl radical scavenger (Tan et al. 1993a) and to prevent carcinogen-induced damage to nuclear DNA (Tan et al. 1993b, 1994). Thus, reduction in melatonin due to any cause might increase the likelihood of DNA damage and cancer initiation. Considering the observations that magnetic-field exposure might induce or prolong the half-life of free radicals (Grundeler et al. 1992; Nossol et al. 1993; Harkins and Grissom 1994), which are known to be scavenged by melatonin (Tan et al. 1993a), additional justification for an association between reduced melatonin production and cancer initiation is suggested. Furthermore, melatonin has been shown in a variety of test systems to reduce the growth of already initiated cancer cells (Blask 1993), so its reduction might also promote tumor growth. Despite the suggested associations between exposure to electric and magnetic fields, reduction in melatonin, and development of cancer, no direct experimental evidence links the field-induced reductions in melatonin to increased cancer risk. Thus, even though the explanations are biologically plausible and some experimental evidence supports the connection (Löscher et al. 1993), studies investigating the potential link need to be performed. Other than the melatonin-production effects, other neuroendocrine and hormonal effects of electric-or magnetic-field exposures seem to be minimal, although only a few studies have examined these interactions. The field exposures used to date seem not to constitute a significant stress to the animals. BONE HEALING AND STIMULATED CELL GROWTH Evidence showing that exposure to electric and magnetic fields influences both the normal functions and the healing processes in bone is considerable. Bone turnover and fracture healing have been reported to respond to electric and magnetic fields under a variety of circumstances. Bone-fracture healing, in particular, represents the most thoroughly documented example of effects of low-frequency, relatively low-strength electromagnetic energy on human tissues. The effects of exposure to electric and magnetic fields on bone tissue have been studied
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields FIGURE 4-2 The two theories that have been proposed to explain the potential association of reduced melatonin production with the alleged increase in cancer after exposure to electric and magnetic fields. On the left, reduced melatonin concentrations lead to an increased secretion of prolactin and gonadal steroids. That increase causes proliferation of cell division in breast or prostate tissue and stimulates growth of initiated cancer cells. On the right, melatonin suppression reduced the total antioxidative potential of the organism, thereby increasing the likelihood of damage by a carcinogen to the DNA of any cell. DNA damage can increase the risk of cancer particularly if electric- and magnetic-field exposure also increases the half-life of production of free radicals.
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields in vivo in experimental animals and in humans, and the molecular mechanisms of the effects have been studied in in vitro systems. The evidence shows that electric and magnetic fields affect signal-transduction processes in bone cells, principally osteoblasts. The effects of magnetic-field exposure on bone have been observed almost entirely at field strengths of 0.1-15 mT (1-150 G) for magnetic fields and 1-100 mA/cm2 for current density (which is proportional to the electric field); those strengths are orders of magnitude higher than the baseline values associated with household exposures. However, the field strengths reported to produce significant effects on bone overlap field strengths that can occur during intermittent exposures to household appliances or occupational electric equipment (Wilson et al. 1994). Little evidence can be found for effects of magnetic or electric fields on bone at magnetic-field strengths below 100 µT (1 G) or at current densities below 1 mA/cm2. Regulation and Cell Biology of Bone Bone turnover is controlled by a number of hormones, principally parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3. Those hormones act in bone largely by regulating activities of osteoblasts (cells that synthesize and calcify bone matrix) and osteoclasts (cells that resorb bone mineral and matrix); both hormones also maintain the balance of calcium and phosphate ions in the kidney and intenstine. PTH and 1,25-dihydroxyvitamin D3 cause increased resorption and decreased formation of bone when their concentrations are acutely raised (Auerbach et al. 1985), but both agents also promote bone formation at lower concentrations or over longer periods (Tam et al. 1982). Both agents probably exert their long-term actions directly on the cellular differentiation of osteoblasts and osteoclasts (Raisz 1977). Other hormones and cytokines also carry out specialized functions or play pathologic roles in bone metabolism (e.g., calcitonin, transforming growth factor ß (TGF-ß), interleukin 1, and PTH-like peptide) (Manolagas and Jilka 1995). The central role of the osteoblast in regulation of bone metabolism is emphasized by findings that the osteoblast is probably the primary target cell for PTH (Rodan and Martin 1981), which passes the hormonal regulatory message to other cell types by paracrine mechanisms. Bone fracture is invariably accompanied by trauma and hemorrhage. Subsequent to a fracture, a specialized remodeling structure called callus forms around the fracture site. Extensive proliferation, differentiation, and tissue turnover involving both osteoblasts and osteoclasts take place over the ensuing healing period, leading eventually to resorption of the callus tissue and strengthening of the new bone bridging the fracture (Bassett 1989). In some cases, callus formation and subsequent remodeling fail for various reasons, such as necrosis, failure to vascularize, or infection. These failures to heal might be persistent or even permanent in some cases. Resistance to healing (nonunion fractures) is the primary condition for which therapeutic electric and magnetic fields have been applied most often.
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields Other uses of electric and magnetic fields have been to promote bridging of congenital gaps (pseudoarthroses) in bone and to enhance the density of bone in cases of osteoporosis (Polk 1993). Endogenous electromagnetic Properties of Bone It is important to recognize that significant electric fields are a normal property of bone in living organisms. The modern era of research on this topic was initiated by a report showing that bone exhibited piezoelectric properties (Fukuda and Yasuda 1957). That finding was confirmed and extended to hydrated bone tissue by numerous investigators (Bassett and Becker 1962; Friedenberg and Brighton 1966; Cochran et al. 1968). Repetitive pulses of current density in the range of 10-100 mA/cm2, with electric fields of 20-200 mV/cm, are generated in bone during normal movement because of mechanical stresses on the bone (Bassett and Becker 1962; Pienkowski and Pollack 1983). Electric fields in normal bone are from two primary sources: (1) piezoelectric responses of the calcified bone matrix to mechanical loading (Anderson and Eriksson 1970), and (2) streaming potentials due to dynamic charge separation between the essentially static charges in the collagen fibers and the ionic charges in the surrounding mobile fluids, which stream during loading and relaxation of bone (Borgens 1984). The mineral component of bone (hydroxyapatite) apparently contributes to the piezoelectric process mainly as an insulator that limits dispersion of charges produced by compaction of collagen fibers (Pollack 1984). Another postulated source of endogenous electric fields in bone is the electric processes of living bone cells, which contribute significantly to the higher current densities detected in living bone as opposed to dead bone (Friedenberg et al. 1973; Bassett 1989). It is noteworthy in the context of the overall mission of this report that no report has been made of the magnetic component of the endogenous fields produced by bone. Moreover, in studies of the effects of various electric-and magnetic-field exposures on osteogenesis, Rubin et al. (1989) concluded that regardless of the magnetic characteristics of the applied field, the only factors relevant to biologic function in bone are those associated with the induced electric field. That conclusion has been supported by many studies and is generally accepted by most investigators in the area of research on electric-and magnetic-field effects on bone tissue (Brighton and McCluskey 1986; Bassett 1989; Polk 1993). For over a century, bone growth, remodeling, and turnover in normal organisms have been hypothesized to be subject to the influence of endogenously generated electric fields, and application of externally generated electric fields has been hypothesized to be therapeutically useful in treatment of fractures or defects in osteogenesis (reviewed in Brighton and McCluskey 1986). Fracture of bone dramatically enhances the generation of charges and the flow of current in the area around the fracture site, especially during the first few minutes or
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields hours after injury, and the magnitude of the currents surrounding the fracture is directly related to the healing of the fracture in subsequent processes (Friedenberg and Brighton 1966; Borgens 1984). Both piezoelectric and cellular electric processes are believed to contribute to fracture currents. Locally generated electric phenomena in normal bone remodeling and fracture healing are believed by many researchers to be involved in a process in which areas of bone that accumulate negative charge are subject to increased deposition of bone matrix, and areas of positive charge are subject to increased resorption of existing bone matrix (Dealler 1981). That hypothesis is based on observations that, during chronic flexure of living bone, the areas of bone undergoing compression are the sites of increased bone formation (''Wolff's law"; Wolff 1892) and increased negative charge (Fukuda and Yasuda 1957; Bassett and Becker 1962), and the areas undergoing tension are the sites of increased bone resorption and increased positive charge. Moreover, numerous experimental and clinical studies (e.g., Brighton et al. 1979) have confirmed that placing dc electrodes in bone produces increased bone formation in the immediate area of the negative electrode and increased bone resorption in the area of the positive electrode. A range of current densities, roughly 10-100 mA/cm2, has been reported to be optimal for observation of these effects; no effect has been observed at lower current densities, and cell death occurs at higher current densities (Friedenberg et al. 1970, Brighton and McCluskey 1986). Clinical Stimulation of Bone Healing with Electric and Magnetic Fields In 1964, Bassett and colleagues reported stimulation of bone growth in vivo with the use of implanted electrodes in unfractured dog bone (Bassett et al. 1964). That report led to a number of studies using various apparatus and having widely varying results (summarized in Hassler et al. 1977; Brighton and McCluskey 1986; Polk 1993). The first clearly documented successful studies of fracture healing using implanted electrodes were those reported by Friedenberg et al. (1971a,b), in which fibular fractures in rabbits were observed to heal much faster than those in sham-treated controls. Friedenberg et al. (1971a) applied 10 mA of dc field with the negative electrode implanted directly in the fracture site. In a single human case report, a nonunion fracture was healed by the application of a similar apparatus (Friedenberg et al. 1971b). Subsequent case reports and large clinical studies have convincingly documented that nonunion fractures and congenital bone defects (pseudoarthroses and failed arthrodeses) can be healed by means of implanted dc electrodes (Brighton et al. 1979). Pulsed fields have been used more widely than dc fields for clinical bone-healing devices, at least partly because devices producing pulsed fields can be made noninvasive. During early studies of the electromagnetic properties of bone, it was found that specific time-varying current pulses could be detected in bone undergoing stresses similar to those involved in locomotion (Bassett and Becker
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields 1962). Evidence also suggested that pulsed current delivered by implanted electrodes would decrease the amount of tissue damage due to electrolysis at the electrode surface (Levy and Rubin 1972). Bassett et al. (1974a) set out to influence osteogenesis by reproducing those pulses of current with noninvasive means as a way of avoiding the complications encountered with invasively implanted electrodes. Early attempts were made to produce pulsing currents in bone by placing the subject between electrostatically charged plates whose charge was altered rapidly (Bassett et al. 1974a). Subsequently, the Bassett group developed the strategy of using Helmholz induction to produce intratissue current flows by means of copper-wire induction coils placed noninvasively adjacent to the tissue (Bassett et al. 1974b). Electric pulses of 10-30 V applied to the induction coils were found to produce coupled pulses of about 1 mV in adjacent tissue at current densities estimated to be about 10 mA/cm2 in tissue. Although the amplitude and general waveform of the pulses produced by this device resembled those found in living bone, the time scale was abbreviated considerably (microseconds as opposed to fractional seconds in normal locomotion) for electronic design reasons (Bassett et al. 1977). In an initial series of clinical studies with this type of device, a pulsed waveform with a single 300-µsec positive voltage pulse was used and repeated 72 times per second. At least 70% of resistant nonunion fractures and pseudoarthroses were healed by treatment with that device (Bassett et al. 1977). Subsequently, larger clinical studies reported success rates for pulsed electric-field treatment of over 80% (Bassett 1989). Further developments in the induced pulsed electric signal involved use of a burst of about 20 200-µsec pulses, repeated 15 times per second, with a slightly improved success rate in fracture treatment (Bassett et al. 1982). The older single-pulse signal is apparently more effective in the treatment of osteonecrosis and disuse osteoporosis (Martin and Gutman 1978; Bassett 1983). A variety of other externally induced electric-and magnetic-field exposure have been used in animal and human studies (McClanahan and Phillips 1983). Success has varied. The device designed by Bassett's group and manufactured by Electro-Biology (Fair-field, N.J.) is approved by the U.S. Food and Drug Administration for clinical treatment of resistant fractures and pseudoarthroses. Side effects have been reported to be minimal. No evidence of increases in cancer or other diseases has been found despite the high field strengths used in comparison with environmental field strengths (Compere 1982; Bassett 1989). A small number of other clinical devices are also approved for use in stimulating bone healing. Most of these are based on either pulsed inductive fields or implanted dc electrodes. Some devices also use sine-wave extremely-low-frequency fields at a variety of frequencies (Polk 1993). Despite the strong evidence that healing of nonunion fractures and pseudoarthroses is accelerated by electric and magnetic fields, there is no convincing evidence that the treatments have any influence on the healing of uncomplicated fractures. Uncomplicated fractures have not been widely treated with electric or
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields magnetic-field procedures, however, for the simple reason that healing begins almost immediately in normal patients. Bassett (1982, 1983) suggests that once the final repair phases of the healing process have been triggered, whether by normal events or by exposure to electric and magnetic fields, treatment with the fields might only marginally accelerate the remaining events of fracture healing. On the other hand, such fields have been used to improve incorporation of bone grafts, to facilitate spinal fusions, and to improve certain types of osteoporosis (Friedenberg and Brighton 1981; Bassett 1983). Potential Mechanisms of Electric-and Magnetic-Field Effects on Bone The mechanistic bases have not been clearly established for the effects of either dc or pulsed electric fields on bone healing. Most evidence suggests that changes in osteoblast activities are the major functions responsible for bone responses to electric-and magnetic-field exposure (Watson and Downes 1979; Dealler 1981; Friedenberg and Brighton 1981; Bassett 1983). Although agreement is not explicit, different mechanisms might exist for the effects on osteoblasts by dc fields and by pulsed electric and magnetic fields (Polk 1993). Direct-current fields morphologically appear to stimulate osteogenesis mainly by stimulating the proliferation and differentiation of preosteogenic cells in the fibrocartilage matrix that fills the fracture gap in nonunion fractures (Friedenberg et al. 1974). Those cells then form new bone as if they had gone through an uninterrupted differentiation induced by the fracture process itself. Brighton and Friedenberg (1974) suggested that lowered oxygen tension in the area of the cathode might play an important role in triggering differentiation. Other possibilities are local changes in ionic concentrations or pH (Jahn 1968), stimulation of local nerves or blood vessels (Becker 1974), or direct membrane effects on cells by dc (Cone 1971). Bassett (1983), on the other hand, stressed the effects of pulsed electric and magnetic fields on functions of already differentiated bone cells rather than on precursors, suggesting that pulsed fields are less effective on osteogenesis as a proliferative process per se than it is on stimulating the function of existing bone cells at or near the fracture site. Bassett (1982, 1983) classified the demonstrated tissue effects of pulsed electric-and magnetic-field exposure as (1) a major and primary effect of reducing bone destruction, possibly by decreasing the sensitivity of bone cells to parathyroid hormone, (2) increased vascularization of the fracture site, (3) increased rates of bone formation by osteoblasts, and (4) for some pulsed EMF signals, decreased intracellular calcium concentrations in chondrocytes, a decrease that promotes replacement of chondrocytes by osteoblasts. Effects of Electric and Magnetic Fields on Signal Transduction in Bone Although the effects of exposure to electric and magnetic fields at the tissue level have been clarified somewhat by research over the past three decades, the
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields primary biochemical and biophysical effects at the molecular or ionic level remain obscure. One clear likelihood for the effects of such fields on bone is that the plasma membrane of target cells is likely to be the major site of action, regardless of subsequent cellular mechanisms. The current and voltage involved in these effects are much lower than those that might be required to overcome the resistance of the plasma membrane and induce intracellular effects directly (Adey 1983). Several laboratories showed that exposure to electric and magnetic fields produces modifications in the activities of the plasma membrane of skeletal tissue cells. For example, Luben and colleagues (Luben et al. 1982; Cain et al. 1987; Cain and Luben 1987) demonstrated that exposure of bone and bone cells in vitro to pulsed electric and magnetic fields causes a membrane-mediated desensitization of the osteoblast to parathyroid hormone. Colacicco and Pilla (1983) examined calcium-transport and sodium-transport processes, factors that are likely to be related to osteoblast function, in chick tibia exposed to pulsed electric and magnetic fields. Fitton-Jackson and Bassett (1980) demonstrated positive effects of pulsed magnetic fields on chondrogenesis and osteogenesis. Rodan and colleagues examined the effects of mechanical and electric stimulation on the activity of adenylate cyclase in skeletal tissues (Norton et al. 1977; Rodan et al. 1978). A number of other membrane effects of pulsed electric and magnetic fields were reported in a variety of systems (Schmukler and Pilla 1982; Adey 1983; Borgens 1984). McLeod and colleagues used a number of in vivo and in vitro systems to study the biophysical and cellular biologic properties of bone exposed to electric and magnetic fields. They showed that electric fields induced by devices promoting bone healing are the most likely operative influence on bone-cell function (Rubin et al. 1989) and that those induced fields can prevent bone loss associated with immobility (disuse osteoporosis). Studies with different frequencies of electric fields showed that bone cells are dependent on frequency in responding to electric fields (McLeod and Rubin 1990); the most effective frequencies are in the range of 10 to 30 Hz, closely matching the frequencies most often observed in living animal bones. Field strengths were calculated to be approximately 300 mV/cm at the most effective frequencies. Further studies with isolated osteoblast-like cells (McLeod et al. 1991) suggested that 20-Hz and 60-Hz electric fields at 1-10 mV/cm could cause transient increases in cytosolic calcium-ion concentrations, a finding that corresponds with that of Ozawa et al. (1989), who used a different osteoblast-like cell line to show that calcium ions were involved in activation of DNA synthesis by pulsed electric-field exposure. McLeod and colleagues investigated bone-cell proliferation as a function of exposure to 30-Hz electric fields at varying plating densities of cells. The cells treated with electric fields responded at medium densities by exhibiting a lowered rate of proliferation coupled with an increased alkaline phosphatase content (McLeod et al. 1993), suggesting that the field promoted differentiation toward a more active matrix-forming osteoblastic phenotype rather than a proliferative
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields stem-cell phenotype. Cell densities above and below the responsive densities showed no effects of the field, suggesting that some cooperative effect might be operating between cells. Such cooperative effects could include cell communication through gap junctions or more complex electric phenomena, such as the "cell-array" model of dielectric impedance proposed by Pilla (1993). A related approach was taken by Fitzsimmons et al. (1989, 1992), who suggested that the effects of exposure to low-frequency, low-strength electric fields on proliferation and differentiation of bone cells in vitro are related to the generation of growth factors or their receptors, especially insulin-like growth factor II. Field-induced changes in the differentiation state of cartilage cells in vitro were shown by Hiraki et al. (1987), whose findings indicated an increased expression of osteoblastic phenotypes in cultured rabbit chondrocytes exposed to a clinically effective bone-healing device. Changes in cell-proliferation rates were also studied by Ozawa et al. (1989), who showed that pulsed electric fields increased DNA synthesis in rapidly growing bone cells but not in bone cells that had already reached a contact-inhibited more-differentiated status. The uptake of calcium ions was correlated with those changes in DNA synthesis, suggesting a membrane-mediated mechanism. These studies indicate that exposure to electromagnetic fields induce changes in the differentiation state of treated osteogenic cultures such that increased matrix synthesis, increased calcification activities, and altered sensitivity to growth factors and systemic regulatory hormones combine to substantially increase formation and decrease resorption of bone. These findings are consistent with the in vivo observations of events during bone healing (Bassett et al. 1982). The basic mechanisms by which such changes in differentiation are brought about have not been thoroughly elucidated, although most researchers suggest that the primary locus of the effects might be at the cell membrane, where responses to most of the hormones and growth factors that regulate bone metabolism are localized (Luben 1991; Pilla 1993). A number of in vitro studies showed that pulsed electric and magnetic fields used in the most widespread clinical fracture-treatment devices (Bassett et al. 1977) produce activation of mouse osteoblasts by means of a strong inhibition of parathyroid hormone (PTH) responsiveness in the cells (Luben et al. 1982), leading to increases in synthesis of collagen (Rosen and Luben 1983), decreases in bone resorption, and accelerated differentiation of osteoblasts from stem cells (Cain and Luben 1987). The effects of electric-and magnetic-field exposure on PTH responses were found to be consistent with decreased coupling of receptors to adenylate cyclase via the stimulatory G protein (Cain et al. 1987). Release of interleukin growth factor II or other growth factors, as suggested by Fitzsimmons and colleagues (1992), could be important in the proliferative responses of less differentiated cells, and the release of transforming growth factor b might be a factor in inducing differentiation (Manolagas and Jilka 1995). However, the above chain of events, although plausible, has not been investigated in detail in any single laboratory or experimental system.
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields A Hypothetical Scenario for Electric-and Magnetic-Field Effects on Bone Based on observations of the biochemical effects of exposure to electric and magnetic fields on bone in vitro, a hypothetical model was developed to find ways to induce healing of bone in vivo. One key observation is that osteoblasts exposed to pulsed electric and magnetic fields for as little as 10 min exhibit a persistent desensitization to the effects of PTH on adenylate cyclase (Luben et al. 1982; Cain et al. 1987). Studies using biochemical probes of G-protein coupling (Cain et al. 1987) indicate that the ability of bound hormone-receptor complex to activate G-protein alpha subunits is impaired by treatment of the osteoblast with pulsed fields. The desensitization of the PTH receptor results in an increased rate of synthesis of collagen by the osteoblast (Luben et al. 1982; Rosen and Luben 1983) and a decreased rate of bone resorption by ostecolasts (Cain and Luben 1987). Both effects would tend to increase the amount of bone in a localized area exposed to pulsed fields in vivo, and those effects are in fact observed in healing bone under clinical circumstances (Bassett et al. 1982). There are some potential clues to the possible molecular mechanism of PTH receptor desensitization by electric and magnetic fields. Desensitization of other G-protein linked receptors is known to be associated with changes in the configuration of the transmembrane domains adjacent to intracellular phosphorylation sites, leading to phosphorylation of the receptor by intracellular enzymes (Sibley et al. 1988). These findings suggest that electric-and magnetic-field treatment might change the conditions at the cell-membrane surface in some as yet unknown way that changes the configuration of key residues of the PTH receptor, leading to desensitization of the receptor and a shift in the balance of osteoblast activities toward increased bone formation. In this regard, PKC is known to be involved in regulation of PTH-receptor desensitization (Ikeda et al. 1991), and the PTH receptor is known to contain phosphorylation sites for PKC but not other known protein kinases (Abou-Samra et al. 1992). Recent studies suggest that a key site of action of electric and magnetic fields might be the PKC enzyme (Uckun et al. 1995), but that finding has not been replicated independently. It should also be noted that studies of magnetic-field effects on ornithine decarboxylase (ODC) (which are well replicated) have all used protocols in which ODC is stimulated by the PKC-dependent phorbol ester signal pathway. Possible increases in cytosolic calcium (Ozawa et al. 1989; McLeod et al. 1991) might also participate in the desensitization of the PTH receptor by PKC. DISCUSSION Numerous studies in the laboratory have been initiated to determine the nature of the physical mechanisms involved in electric-and magnetic-field-induced effects and the extent of possible health hazards to living organisms in
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Possible Health Effects of Exposure to Residential Electric and Magnetic Fields an environment containing such fields. Biologic responses to exposure to electric and magnetic fields have been shown in many laboratories, and often they appear to be associated with the nervous system. In addition, unconfirmed or controversial data have been reported on observed effects that might be due to field exposure (e.g., changes in brain chemistry and morphology and alterations in reproduction and development). It is not yet known whether confirmed or putative effects are due to a direct interaction of the field with tissue or to an indirect interaction (e.g., a physiologic response due to detection or sensory stimulation by the field). Whether a biologic effect from exposure to electric or magnetic fields constitutes a health hazard has yet to be answered. Experiments have not confirmed pathologic effects, even after prolonged exposures to high-strength magnetic (10 mT) and high-strength electric (100 kV/m) fields. In the very few tumor-promotion studies that have been reported, results seem to be mixed; most studies show no association between exposure to electric and magnetic fields and increased tumor development. Although the data are not strong or entirely consistent, some experimental results using animal cancer models suggest a possible association of exposure to electric and magnetic fields and adverse health outcomes. The strongest laboratory evidence for an association between magnetic-field exposure and cancer development is in promotion of mammary carcinogenesis initiated by chemical carcinogens; however, the results have not been consistent. In these experiments, tumors must be initiated with a chemical carcinogen for the magnetic-field exposure to have its apparent effect. Some data also support the possibility that magnetic fields can act as a copromoter; magnetic fields alone, however, have not been shown to be effective in promoting cancer development.
Representative terms from entire chapter: