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On the nature of electromagnetic eld interactions with biological systems.

Allan H Frey Chapter 2 ELECTROMAGNETIC FIELD INTERACTIONS WITH BIOLOGICAL SYSTEMS: AN INTEGRATION OF THE DATA ON MECHANISMS WITH PARTICULAR REFERENCE TO CANCER Allan H. Frey Biology has been in a revolution this last decade, a fact that is hardly news to most of the readers of this book. It's an exciting time; a new world of knowledge and techniques. And as part of this revolution, in recent years a body of data on the interactions of exogenous and endogenous electromagnetic elds with biological systems has accumulated which is profoundly changing our understanding of biological function. It goes to the heart of biology. Living organisms are complex electrochemical systems that evolved over millions of years in a world with a relatively weak magnetic eld and with few electromagnetic (em) energy emitters. As is

characteristic of living organisms, they interacted with and adapted to this environment of electric and magnetic elds. One example of this adaptation is the visual system which is exquisitely sensitive to emissions in the very narrow portion of the em spectrum that we call light. Organisms, including humans, also adapted by using em energy to regulate various critical cellular systems; we see this in the complex of circadian rhythms. Fish, birds, and even the duckbill platypus developed systems to use electromagnetic elds to sense prey and to navigate. Electromagnetic elds are involved in neural membrane function; even protein conformation involves the interactions of electrical elds. But as has often been the case in the history of science, though these were interesting observations, they were disconnected bits and pieces that made no real impact; they didn't t the frame of reference of the time. Further, the technology and techniques needed to do much with the information did not exist. Thus, the very broad importance of the interactions of electromagnetic elds with biological systems was not really recognized. But that was yesterday. Now, as James Burke

put it, is (guratively) the day the Universe changed.

This chapter is intended to give the reader a sense of how much of the data ts together and to indicate some of the implications for

biology. To do this, I will not talk about the trees so much; instead, I will describe part of the forest. I will integrate a number of lines of research on the interaction of exogenous electromagnetic elds with biological systems at the cell level, system level and whole organism level. I will show how the data are different facets of a common theme. And to indicate some of the implications of importance to biology, I will develop the picture within the context of cancer. First, I will detail some of the epidemiological and laboratory evidence indicating that em elds can promote cancer. Second, I will detail the effects electromagnetic elds have on neural and neuroendocrine systems. Then I will summarize the relevant information on how the neural and immune systems interact. With the foregoing as a foundation, I will then integrate it all and spell out one means by which exogenous electromagnetic elds may promote cancer. Some of the data that suggests electromagnetic eld exposure promotes cancer Both epidemiological and laboratory studies suggest that electromagnetic elds promote cancer. The evidence to date indicate an inuence on a number of different cancers, among these are the lymphomas and leukemias as well as nervous system and breast cancers.

Savitz et al 2noted, for example, that surveys suggest an increased risk of leukemia among men with occupational exposure to electromagnetic elds. They assembled eleven relevant data sets in order to assess the consistency of this pattern and to identify occupations deserving closer examination. They then did a detailed analysis. Their results for total leukemia show an excess risk for men in exposed occupations with a more elevated risk for acute leukemia and particularly acute myelogenous leukemia. As with childhood cancer, Wertheimer et al 3found adult cancer associated with high-current electrical wiring congurations (HCCs) near the patient's residence. They note that such wiring can expose occupants of the residence to alternating magnetic elds at a level which may produce physiological effects. Several patterns in the data they felt suggested that HCCs and cancer may be causally linked; a doseresponse relationship was found. The association did not appear to be an artifact of age, urbanicity, neighborhood, or socioeconomic level. The association was clearest where cancer caused by urban/industrial factors was least apt to obscure the effect and a distinct pattern of latency between rst exposure to the HCCs and cancer diagnosis was

seen. This, they concluded, is consistent with a hypothesis of cancer promotion produced by magnetic eld exposure. In an occupational mortality analysis of adult male death records led in Washington State in the years 1950-1982, Milham 4found that leukemia and the non-Hodgkin's lymphomas show increased proportionate mortality ratios (PMRs) in workers employed in occupations with apparent exposure to electromagnetic elds. Specically, nine occupations were considered to have electric or magnetic eld exposures. Eight of the nine occupations had PMR increases for leukemia and seven of the nine occupations had PMR increases for the lymphoma category. He concludes that his ndings support the hypothesis that electric and magnetic elds may be carcinogenic. In another study, Milham5conducted a population-based study of mortality in US amateur radio operators.Washington State and California amateur radio operators were found through the 1984 US Federal Communications Commission Amateur Radio Station and/or Operator License le. A statistically signicant increased mortality was seen for cancers of the lymphatic tissues, a category that includes

multiple myeloma and non-Hodgkin's lymphomas. Mortality due to acute myeloid leukemia was signicantly elevated. Wertheimer et al 6determined that certain subtypes of cancer (notably nervous system cancer) showed an association with two indices of exposure to 60 Hz alternating magnetic elds. Similarities were seen in people putatively exposed to such elds by their occupations and in those putatively exposed to high current power lines near their homes. They concluded that incidence-age patterns observed in exposed and nonexposed groups suggest that prolonged eld exposure may act as a cancer promoter. Savitz 7designed a case-control study to assess the relation between residential exposure to magnetic elds and the development of childhood cancer. Exposure was assessed by in-home electric and magnetic eld measurements under low and high power use conditions and wire conguration codes, a surrogate measure of long-term magnetic eld levels. Measured magnetic elds under low power use conditions had a modest association with cancer incidence; a cutoff score of 2.0 milligauss resulted in an odds ratio of 1.4 for total cancers and somewhat larger odds ratios for leukemias, lymphomas and soft tissue sarcomas.

Demers et al. 8examined occupational exposure in a case-control study of breast cancer in men. Each subject in the study reported the two longest-held occupations during his life. These occupations were grouped into ve categories, each with at least some putative em eld exposure. Those men with no expected exposure formed the unexposed referent category. After assigning each subject to an exposure category based upon occupation, the number of cases in each category was compared to the number of controls. There was an estimated 1.8-fold increased risk of breast cancer in the combined ve exposed categories compared to the unexposed category. One of the expected frequent eld exposure categories had a six-fold increased risk of breast cancer. Tynes and Andersen 9of the Cancer Registry of Norway reported on an occupational study that encompassed the entire nation. Standardized Incidence Ratios for breast cancer based on all working men in the 1960 census were calculated over the years 1961 to 1985. Among men who held occupations that the authors considered to have potential exposure, there were twice as many cases observed as were expected. Laboratory studies have also found cancers. Kunz et al 10carried out a long term low intensity radio frequency energy exposure study on

rats. They found that when all age categories (1-6 mos, 7-12, 13-18, 19-24, 25-30) for primary malignant lesions were considered, the M-H estimate of the odds ratio was 4.27 and the Chi-square statistic was 7.66 (p = .006). When the rst three age categories were combined and the analysis repeated, the M-H statistic was 4.38 and the Chi-square statistic was 7.9 (p = .005) When the rst four age categories were combined (leaving two categories--1-24 and 25-30 months), the M-H statistic was 4.47 and the Chi-square was 6.97 (p = .008). When age at death was ignored completely, the M-H estimate of the relative risk was 4.46 and the Chi-square was 8.00 (p = .005). Thus they found that the estimate of the odds ratio and the Chi-square statistic were both insensitive to the way the data were grouped with respect to age at death. A survival-type analysis also was done using time of death as the endpoint if a primary malignant lesion were present. The log-rank statistic was 7.63 (p = . 006). This latter analysis suggested that the primary tumors occurred earlier in the exposed group than in the sham exposed. They concluded "To summarize the above results, primary malignancies are somewhat more likely to be present in exposed animals than in the sham exposed. This (the cancers) should not be considered as some artifact of the data, since different analyses led to similar results."

Beniashvile et al 11found that low-frequency electromagnetic elds enhance the induction of mammary gland tumors in rats using nitrosomethyl urea. The tumor incidence depended on the duration of exposure to static (dc) and variable (ac) magnetic elds. Variable magnetic elds induced mammary gland cancer much more frequently than static ones. They also found that electromagnetic elds reduced the mean latent period of tumor development. Loscher 12 determined if an alternating low ux density magnetic eld has tumor promoting or co-promoting effects in female rats. Mammary tumors were induced by the chemical carcinogen 7,12dimethylbenz(a)anthracene DMBA. In controls, DMBA induced tumors in about 40% of the animals within thirteen weeks of the rst application. Eight weeks after DMBA application the exposed rats exhibited signicantly more tumors than sham-exposed animals. This difference in the rate of tumor development was observed throughout the period of exposure. At the end of a three-month period of magnetic eld exposure the tumor incidence in exposed rats was 50% higher than in sham exposed rats, a statistically signicant difference. Further the size of the tumors was signicantly larger in the exposed compared to sham exposed rats.

There are additional studies, both epidemiological and experimental, that indicate exposure to electromagnetic elds promote cancer. Thus, the question arises as to what could be the mechanisms by which cancer would be promoted by such exposures. I will address this question in the remainder of the chapter. In the process, I will integrate a wide diversity of data and will show how the wide range of effects of electromagnetic elds can be understood within one framework. Electromagnetic elds affect neural and neuroendocrine systems There is a substantial data base indicating that the dopamine, opiate and pineal systems are inuenced by electromagnetic elds. There are also data indicating that calcium channels in the cell membranes are involved. Dopamine and opiate systems. In 1976, I hypothesized that the dopamine systems of the brain, in part, mediate the effects of exposure to electromagnetic elds 13. A series of experiments carried out to test the hypothesis indicated that the dopamine systems of the brain are involved. Specically, Frey and Wesler found that exposure of an animal to electromagnetic energy modied stereotypic behaviors; these involve the nigrostriatal dopamine system 14,15. In another test, Frey and Gendlemen found that exposure of animals to em energy degraded

motor coordination and balance which also involves the dopamine system16. Wesler and Frey reported that em energy exposure interacts differentially with high and low doses of apomorphine17,18. This latter suggests a differential inuence of em energy on D1 and D2 receptors. Related to the above ndings, is the nding of Stith and Erwin that exposure of rats to low intensity em energy signicantly decreased tyrosine hydroxylase activity in the hypothalamus and brain stem 19. They report a signicantly greater effect with pulsed energy than with continuous wave energy of the same power level. Dopamine is synthesized from tyrosine and tyrosine hydroxylase acts on tyrosine in a rate limiting step. They also report a reversible decrease in dopamine in the hypothalamus and brain stem. Then Frey and Wesler extended the dopamine hypothesis to include the opiate systems of the brain 14. Freydeveloped the dopamineopiate hypothesis further and provided a comprehensive integration of the evidence indicating an effect of electromagnetic elds on the brain's dopamine-opiate systems 20. I also reported at that time on experiments using psychoactive drugs to test the hypothesis. In additional experiments, Frey and Wesler used the conditioned emotional response (CER) to further test the dopamine-opiate hypothesis 21,22. They found

that once CER testing began, signicant differences in suppression ratios appeared between em energy exposed and sham exposed groups. The exposed animals exhibited enhanced suppression of response during the warning signal. This is classically interpreted as heightened emotionality.Frey and Wesler later reported nding that exposure to low intensity em energy potentiates the effects of low doses of morphine; this effect is comparable to that found with dopamine inhibitors 23. In another test of the dopamine-opiate system hypothesis, Frey and Spector predicted that aggression induced by light tail pressure would be modied by exposure to em energy 24. In a series of three experiments, it was found that there was a substantial decrease in aggressive behavior. The incident power densities were as low as 50 microwatts/cm2. Another prediction I made from the dopamine-opiate hypothesis is that there would be interactions of low intensity em energy exposure with naloxone treatment as well as with chlordiazepoxide and haloperidol treatment 21. The benzodiazepines act selectively on polysynaptic neuronal pathways throughout the CNS. They are thought to modify the action of gamma-aminobutyric acid (GABA). Haloperidol appears to act by post-synaptic blockade ofCNS dopamine receptors. The interaction of em energy exposure and chlordiazepoxide (librium)

treatment was explored using stereotypic behavior as a test. 25 A twoway Analysis of Variance showed a signicant difference (p <.05) for total stereotypic time. In sum, Chlordiazepoxide had the expected effect on stereotypic behavior and this was modied by a limited, very low intensity exposure to em elds. The interaction of em energy exposure and naloxone treatment was explored using the classic analgesia test tail ick. Naloxone is an opiate antagonist and would tend to reduce tail ick latency to an aversive stimulus. Naloxone increased sensitivity to the aversive stimulus as would be expected and exposure to the em eld blocked the naloxone effect. The interaction of em energy exposure and haloperidol treatment was also explored using the analgesia test tail ick. On treatment days the haloperidol-injected em-exposed group had a signicantly greater latency than on the pre-treatment day (p <.05). In contrast, the haloperidol-injected sham-exposed group did not differ in latency from its pre-treatment day. The difference in latency between the two groups on the treatment days was signicant (p <.05). Others have carried out experiments and reported additional data supporting an inuence of electromagnetic elds. on the dopamineopiate systems. For example, Lai et al explored the effects of

apomorphine, d-amphetamine, and morphine in animals exposed to em energy 26. They found exposure enhanced apomorphine effects and attenuated amphetamine effects. They reported that morphine effects were also enhanced. Miller et al, using 60 Hz magnetic elds, found that exposure to an em eld attenuated the behavioral response of mice to morphine 27. Kavaliers and Ossenkopp in a series of studies examined the effects of exposure to a 0.5 Hz rotating magnetic eld on morphineinduced analgesia. Mice were chronically exposed for 5-10 days and this eliminated the day-night rhythm in analgesia by reducing the night levels to those found during the day. This effect dissipated several days after exposure ended but could be re-established by re-exposure 28. When mice were exposed for only sixty minute periods, both day-time and night-time levels of morphine-induced analgesia were found to be signicantly reduced 29,30. The nocturnal reduction was greater than the day-time effect and the effects dissipated within 24 hours. When mice, of a strain which displays hyperactivity after morphine treatment, were exposed and then treated with morphine, their activity levels were signicantly reduced compared to non exposed controls 30.

In another study 31mice were pre-exposed to a rotating magnetic eld for 60 minutes and then treated with mu, kappa, delta and sigma opiate agonists. Magnetic eld pre exposure was found to inhibit the day-time analgesic effects of the mu agonist (morphine), the kappa agonist (U-50, 488 H) and the delta agonist (D-ala2-D-leu5-enkephalin) but not the sigma agonist (SKF-10,047). The authors conclude that exposure to a
0.5 Hz RMF has signicant and differential inuences on the various opioid systems.

In an additional study 32, mice were given daily injections of morphine. They developed tolerance to the effects of the morphine; after 5 to 7 days the morphine treated mice did not differ from control animals. Thirty minute exposures to the eld prior to the daily injections resulted in signicantly reduced levels of tolerance. The role of central calcium ion levels in magnetic eld modications of morphine-induced analgesia and hyperactivity in mice were also explored. Animals were given an intracerebroventricular injection of a calcium ionophore and a chelator. The calcium ionophore potentiated the inhibitory action of the eld on the analgesic and locomotor effects of morphine. The calcium chelator blocked these effects. The authors later concluded that these results, together with the nding that calcium ions antagonize morphineinduced analgesia indicate that exposure to magnetic elds alters

morphine-induced analgesia via changes in calcium mechanisms. They also note that disturbances in the geomagnetic eld ("magnetic storms") have been shown to inuence nocturnal morphine-induced analgesia in mice 33in a manner consistent with the laboratory ndings. Approaching from a different standpoint, there is evidence that GABA inhibits dopamine neurons originating in the substantia nigra and may act synergistically with dopamine in the striatum by depressing acetylcholine interneurons 34. This ties into evidence from in vitro and in vivo studies that there is a reciprocal dopamine-acetylcholine balance in the caudate. Kalin and Sheltonhave shown in a series of experiments that the opiate and benzodiazepine systems regulate certain primate defensive behaviors 35. They conclude that these systems work together to mediate responses important to survival. Gruen et al report that perinatal exposure to benzodiazepines leads to behavioral changes that are present in adults 36. The authors state that their data indicate these changes may be associated with modication of mesolimbic dopamine function. Antelman et al have shown that a single injection of a benzodiazepine signicantly sensitizes rats to the later administration of haloperidol 37. This indicates a time dependent sensitization by benzodiazepines and, by implication, GABA neurons. They suggest that

such acute stimulation of GABA neurons triggers the progressive development of a long term antidopaminergic effect. Giorgi et al report that several beta-carboline derivatives modify dopamine metabolism in the prefrontal cortex via benzodiazepine recognition sites 38. Ashani et al explored the combined effects of low intensity em eld exposure and anticholinesterase drugs 39. They found complex interactions and suggested that use of such drugs could provide signicant information on the effects of em energy exposure. Their ndings tie into the evidence noted above that GABA inhibits dopamine neurons originating in the substantia nigra and may act synergistically with dopamine in the striatum by depressing acetylcholine interneurons. This also relates to evidence from in vitro and in vivo studies that there is a reciprocal dopamine-acetylcholine balance in the caudate. Nakas et al and Jamakosmanovic considered the effect of repeated daily exposure to em energy on levels of acetylcholinesterase in the brain 40,41. They found that chronic exposure to the energy induced signicant depression of acetylcholinesterase activity in the brain. They also found other effects which led them to suggest that the central nervous system is very sensitive to exposure to low intensity em energy.

In another study, it was reported that em energy exposure attenuated the effect of ethanol and also amphetamine 42. The authors also reported that pulsed but not continuous em energy exposure decreased hippocampal choline uptake, a measure of cholinergic nerve activity. This effect was blocked by the opiate antagonist naloxone as would be expected in the context of the dopamine-opiate hypothesis. Schrot et al used chlordiazepoxide, chlorpromazine, and diazepam and found that the latter two decreased response rate in animals on an operant conditioning schedule, while chlordiazepoxide increased response rate 43. They found complex interactions between drugs and em eld exposure and suggested that the eld parameters are an important variable in the nature of the effect obtained. Thomas also found an increase in response rate with chlordiazepoxide and em energy exposure44. There is now a substantial body of data that indicates brain systems, in particular the opiate-dopamine systems, are inuenced by exposure to brief, very low intensity electromagnetic elds. The dopamine-opiate system hypothesis suggests that one way these effects could occur is through an alteration of dopamine receptor sites by changing protein conformation at the neuronal membrane; binding of

dopamine would be inhibited and calcium metabolism would be altered. This will be discussed in a later section. Dopamine-opiate systems interact with the pineal system. In one study 45, the administration of melatonin, either peripherally or intraocularly, to light-exposed chicks dose-dependently increased serotonin N-acetyltransferase (NAT) activity in the retina. The authors state that the results indicate that melatonin, in vivo, inhibits dopamine synthesis selectively in the retina. They also suggest that the increase in retinalNAT activity evoked by melatonin is an indirect effect, resulting from the disinhibition of the NAT induction process by a dopaminergic (inhibitory) signal. The authors conclude that their results provide in vivo support for their in vitro ndings that a mutually antagonistic interaction between melatonin and dopamine occurs. Gomar et al 46found that melatonin modulates brain benzodiazepine binding sites and their circadian rhythm. They found that melatonin beta-endorphin and melatonia + beta-endorphin all increased [3H]FNZ binding to a similar extent and in a dose-related manner. The effects of melatonin on [3H]FNZ binding were prevented by simultaneous injection with the opioid antagonist naloxone. Naloxone also blocked the effects of beta-endorphin and melatonia +

beta-endorphin injections. Further, naloxone blocked a hypophysectomy-dependent increase in [3H]FNZ binding. These results indicate that modulation of melatonin dependent changes on brain benzodiazepine receptors involve opioid peptides. In another study 47, a single population of opioid receptors was identied in the pineal gland using [3H] diprenorphine and other ligands. Specically, the effects of both opioid receptor agonists and antagonists on the basal activity of N-acetyltransferase were examined in bovine pineal explants in culture. Morphine, an opioid receptor agonist, signicantly increased the activity of N-acetyltransferase in a dosedependent fashion. In addition, the stimulatory effect of morphine was inhibited by naloxone, an opioid receptor antagonist. The results indicate the existence of pineal opioid receptors, which the authors believe play a pivotal role in the synthesis of melatonin and its action in synchronizing pineal events. The pineal neurohormone melatonin was shown by Maestroni and Conti 48to stimulate the release of opioid peptides from activated CD4+T lymphocytes. These immuno-derived opioids or lymphomorphins cross reacted with anti-beta-endorphin and anti-metenkephalin antisera and bound to opioid receptors in the thymus. The

investigators consider lymphomorphins to be the mediators of the immuno-enhancing and anti-stress action of endogenous and/or exogenous melatonin. Maestroni et al cite their previous work 49which showed that melatonin induced activated T lymphocytes to release opioid peptides with immuno-enhancing and anti-stress properties. Then they present evidence that these peptides cross react with anti-beta-endorphin and anti-met-enkephalin antisera, and bind specically to thymic opioid receptors. Furthermore, the same antisera injected in prednisolone treated mice prevented the normal recovery of thymus cellularity and the capacity to mount a primary antibody response against T-dependent antigens. Surgical pinealectomy, i.e. inhibition of endogenous melatonin and absence of antigen activation, negated the effect of such antisera which demonstrates the physiological relevance of this melatoninimmuno-opioids network. Aloyo et al 50found that pineal membranes possess a single class of high-afnity binding sites for the opioid peptide beta-E. They suggest that beta-E binds to delta opioid sites and exclude the possibility of signicant binding to mu, kappa and epsilon sites. They conclude that

endogenous or circulating opioid peptides modulate pineal function by interaction with delta opioid sites. Trentini 51notes that the female rat's age-related reproductive decline is accompanied by progressive impairment of the neuroendocrine mechanisms that regulate LH secretion. The biosynthetic activity of the pineal gland is markedly depressed and the nocturnal secretion of melatonin decreases signicantly. In their experimentation, they demonstrate that melatonin replacement delays the increase in LH serum levels and the decrease in LH response to GnRH that occurs in 18 month old control animals. Further, they showed that melatonin treatment prevents the loss of LH response to naloxone that appears in control rats at about that age. They conclude that the age related decrease in circulating melatonin during the night contributes to the reproductive decline of aging, and that this effect involves the central opioid system. It has been reported 52that preproenkephalin A (ppEnk) mRNA has been identied in extracts of rat pineal gland using oligonucleotides complementary to nonoverlapping regions of this mRNA. Using a highly specic radioimmunoassay, rat pineals were shown to contain

methionine-enkephalin. The author concludes his results suggest that pineal ppEnk gene products may contribute to pineal functioning. As indicated by the foregoing, the dopamine, opiate and pineal systems are interrelated. As with the dopamine and opiate systems, the pineal is involved in the effects of electromagnetic elds on biosystems. Some of the evidence is summarized in the next section. Electromagnetic elds affect pineal gland function and melatonin.Rudolph et al 53noted that electrophysiological investigations show magnetic elds (MFs) inuence spontaneous activity of pineal cells in the pigeon, guinea pig and rat. They point out that it also has been shown that static magnetic elds interfere with the melatonin synthesizing system. They note that the magnetic eld effects are only found during the dark phase when pineal melatonin and cyclic adenosine monophosphate (cAMP) levels are high, but not during the light phase, when pineal melatonin and cAMP levels are low. Melatonin as well as enzymes involved in its synthesis such as hydroxyindole-Omethyltransferase (HIOMT) and serotonin-N-acetyltransferase (NAT) are depressed by MFs. They investigated in some detail the magnetosensitivity of the rat's pineal cAMP system. Rats were exposed for one hour during the dark phase to a static magnetic eld inverting

the horizontal component of the natural MF; these animals showed a 38% decrease in pineal cAMP content compared to a non-exposed control group. A zero magnetic eld did not seem to inuence pineal function. They concluded that MFs act upon the pineal melatonin synthesizing system via interaction with the cell membrane. Stehle et al 54 exposed male and female naturally pigmented and albino Mongolian gerbils, as well as Sprague-Dawley (SD) rats, to a 60o rotation of the horizontal component of the ambient MF. Alteration of nocturnal pineal melatonin content and NAT activity were the dependent variables.. In pigmented gerbils, MF exposure resulted in no signicant change in pineal melatonin synthesis. In contrast, albino gerbils and SD rats showed signicant decreases in pineal NAT activity and melatonin content following MF exposure. The pigmentation of the retina, they conclude, plays a crucial role. Another author 55concludes that chronic exposure to electric or magnetic elds can disrupt normal circadian rhythms in rat pineal serotonin-N-acetyltransferase activity as well as serotonin and melatonin concentrations. At least in the rat, he states, these elds may interfere with tonic aspects of neuronal input to the pineal gland, giving rise to what may be termed "functional pinealectomy." He notes that

such disruptions in circadian rhythmicity of pineal melatonin secretion have been associated with depressive disorders in humans. There has also been a determination 56that a 6 week exposure to a 50 Hz magnetic eld inuences melatonin synthesis in 11-18 week old male rats. The animals were exposed continuously to a rotating magnetic eld of 1, 5, 50, or 250 T. The levels of plasma and pineal gland melatonin were determined by radioimmunoassay. A signicant decrease in melatonin was observed between the control group and groups exposed to a magnetic eld at a ux density in excess of 1 T during the night. The effect of pulsed static magnetic elds on rat pineal melatonin synthesis has been studied at different times of the day. Exposure to magnetic elds during mid- or late dark phase signicantly suppressed pineal N-acetyltransferase activity, as well as the melatonin content in the pineal gland. These variables were not inuenced by magnetic elds when the exposure occurred early in the dark phase or during the light period. The authors conclude that responsiveness of the pineal gland to magnetic eld perturbations varies as a function of the time of day. There was signicant inhibition of serotonin-N-acetyltransferase activity and melatonin content in rat pineal glands stimulated with the

beta-adrenergic receptor agonist isoproterenol which induces melatonin synthesis, when they were exposed, in vitro, for 1 hour to a pulsed 0.4 G static magnetic eld 58. A 2 hour exposure to a pulsed magnetic eld also resulted in a signicant reduction in isoproterenol induced serotonin-N-acetyltransferase activity. Another author 59reports that the circadian rhythm of melatonin production (high melatonin levels at night and low during the day) in the mammalian pineal gland is modied not only by visible portions of the electromagnetic spectrum, i.e., light, but also by exposure to extremely low frequency electromagnetic elds as well as static magnetic elds. He notes that both light and electromagnetic eld exposure at night depress the conversion of serotonin to melatonin. He points out that sinusoidal magnetic eld exposure has been shown to interfere with the nocturnal melatonin forming ability of the pineal gland. Static magnetic elds, he notes have been repeatedly shown to perturb circadian melatonin rhythm. The eld strengths in these studies that he cites were almost always in the geomagnetic range, 0.2 to 0.7 Gauss. He concludes that these experiments show that several parameters in the indole cascade in the pineal gland are modied by eld exposure, i.e. pineal cAMP levels, N-acetyltransferase activity (the rate limiting enzyme in

pineal melatonin production), hydroxyindole-O-methyltransferase (HIOMT) activity (the melatonin forming enzyme), and that pineal and blood melatonin levels are depressed. Increases in pineal levels of serotonin and 5-hydroxyindole acetic acid (5HIAA) have also been found in the pineal; he notes that these increases are consistent with depressed melatonin synthesis. He believes that the same kinds of disturbances in pineal melatonin production can be induced by either light exposure or by electromagnetic eld exposure at night. In sum, there is a clear body of evidence that establishes that electromagnetic elds inuence pineal gland function and melatonin. Thus we have the interrelated systems, the dopamine, opiate and pineal all showing an electromagnetic eld inuence. The question then is what is the proximate cause. One of these is discussed in the following section. It should be noted that other neural systems are also involved, as has been hinted at in some of the evidence discussed in these last three sections. Ion complexes and the signal cascade. Rusovan et al found that regeneration of the rat sciatic nerve is stimulated if rats are exposed to a 50 Hz sinusoidal magnetic eld 60. Subsequently, they investigated the effect of the Ca2+antagonist, methoxyverapamil, on this response.

Methoxyverapamil was administered to the regenerating segment of nerve via implanted osmotic minipumps. Magnetic eld exposure increased regeneration distances in the control group's vehicle perfused nerves. This increase was blocked by perfusion with methoxyverapamil at a concentration which alone failed to affect the outgrowth of nerve bers. They concluded that this indicated that Ca2+uxes are involved in mediating the biological actions of magnetic elds. Blank and Soo 61note that Na,K-ATPase, the "ion pump" enzyme in cell membranes, is activated by the binding of Na and K ions on opposite faces of the enzyme; ion pumping occurs when ATP is split on the inside surface. Operation of the enzyme involves coordination between the ionic processes at inner and outer surfaces. They state that they found these processes are affected by both electric and magnetic elds, but in different ways. The opposite effects on Na,K-ATPase activity they found likely are related to different charge motions in the enzyme. Electric elds, they believe, to lead to increases in ion binding at the enzyme surface. Magnetic elds, they say, could be affecting charge movements within the protein (e.g., electron shifts due to ATPsplitting) that coordinate the two surfaces of the enzyme. They feel that

such charge movements within the enzyme are likely related to electron transport processes in mitochondria or gating currents in ion channels. Blackman et al 62point out that numerous studies have demonstrated that extremely low frequency electromagnetic elds, or radio frequency elds amplitude modulated at low frequency, can alter the efux of calcium ions from CNS derived samples such as chick brain. They point out that three research groups have shown that a range of frequencies between 6 and 20 Hz are effective. They extended this line of experimentation with further data collection. Then they analysed their data using calculated P-values, a function that combines at each frequency the differences between the means of the exposed and sham groups with the variance of each group. The analyses indicated the existence of three frequency-dependent patterns in the data. Blackman et al note in another paper 63that they previously reported that in vitro exposure of chick forebrain tissue to a 50 MHz radio frequency electromagnetic eld, amplitude modulated at 16 Hz, enhanced the efux of calcium ions within only two power density ranges. They conrmed and extended those results in this study by testing at another set of power densities which included the range of the previous study. An enhanced efux of calcium ions was found at 1.75,

3.85, 5.57, 6.82, 7.65, 7.77, and 8.82 mW/cm2; no change was observed at 0.75, 2.30, 4.50, 5.85, 7.08, 8.19, 8.66, 10.6, and 14.7 mW/cm2. The foregoing studies and others clearly indicate that there are frequency and intensity windows in the effects. In a study of calcium inux 64, it was found that such increased during mitogen-activated signal transduction in thymic lymphocytes exposed to a 22 mT 60 Hz magnetic eld. The plateau phase rather than the early phase of calcium signaling was inuenced. This was determined by separating in time the early release of calcium from intracellular stores from the inux of extracellular calcium. Alteration of the plateau phase of calcium signaling indicates, according to the author, that the calcium channel is the site of eld interaction. In addition, he concludes that the interaction site is the cell surface which is relevant to the discussion on micron wavelength emission later in this section. Well worked out theoretical views on calcium ion involvement, with vibro-rotational transitions, have been developed by Liboff 65, Blackman 66and Lednev 67. Space constraints do not allow a discussion of the data in this chapter; but they can be read in other chapters of this book with additional theoretical views by Liboff. The subsequent signal

cascade within the cell, following from the calcium ion effects is also discussed in other chapters 68,69. But note should be taken of some other relevant work 70. The suprachiasmatic nuclei (SCN) of the hypothalamus are the primary pacemaker for circadian rhythms in mammals. It has been found that light stimuli that synchronize this circadian clock induce expression of the c-fos gene in the rodent SCN; this suggests a role for fos in circadian entrainment. Appropriate light stimuli also induce the expression of junB messenger RNA in the SCN of golden hamsters and slightly elevate cjun messenger RNA levels. Light also increases the amount of a protein complex in the SCN that specically binds to sites on DNA known to mediate regulation by the AP-1 transcription factor. The investigators found that light regulation of both jun-B messenger RNA expression and AP-1 binding activity depends on circadian phase for it is only light that shifts behavioral rhythms that induce jun-B and AP-1 expression. They conclude that light and the circadian pacemaker interact to regulate a specic set of immediate-early genes in the SCN that may participate in entrainment of the circadian clock. But light is not the only em eld that has such effects. Phillips et al 71note that they found that exposure of the human T-lymphoblastoid

cell line, CCRF-CEM, to a 1 gauss sinusoidal magnetic eld at 60 Hz alters transcription of 4 specic genes: c-fos, c-jun, c-myc, and protein kinase C (b form). In subsequent studies, they evaluated MF induced alterations in the binding activity of several transcription factors, including AP-1, CREB, SRF, SP-1, and TFIID. They found that MF exposure of CCRF-CEM cells for 30 min caused a 50-70% decrease in the level of AP-1 binding activity. Further studies indicated that the decreased AP-1 binding activity was probably the result of decreased functional c-jun protein. Since, they note, the state of phosphorylation of 3 ser/thr residues abutting the C-terminal DNA-binding domain can determine the DNA-binding activity of c-jun-containing AP-1 complexes, they tested the effect of MF exposure on "upstream" events that can affect c-jun phosphorylation. They report nding that in MF exposed CCRF-CEMcells: 1) both membrane-associated and total cellular protein kinase C activity were decreased; 2) IP3 levels were decreased in 50-60% of their experiments; 3) total cellular tyrosine kinase activity was decreased in 60% of their experiments; 4) in a single experiment, the activation state of ras p21 protein (i.e., the ratio GTP/ GDP) was increased. They point out that all of these observations are consistent with decreased c-jun DNA-binding activity as a result of

increased phosphorylation (or decreased dephosphorylation) of the ser/ thr residues abutting the DNA-binding domain of c-jun protein. They conclude that their experiments link related events which are inuenced by magnetic eld exposure; and which occur at the plasma membrane, in the cytoplasm and in the nucleus. Looking at the phenomena from a completely different viewpoint, there are other data and theory that are of relevance and that will be briey touched on here. I found that micron wavelength emission was associated with stimulation of live unmylinated blue crab nerves (p = .008) 72. The emission detected was considerably greater than that which could be expected from a black-body nerve model; it was more than two orders of magnitude greater, i.e. 6 w/cm2. Heating artifact from stimulation was shown to not account for the emission detected. It was found that the emission came from a location near the nerve surface and must have been in certain bands of wavelength, i.e. 10.5 to 6.5 , 5.5 to 3.5 , and a very narrow band at 2.5 . Following up on this, Sherebrin, et al 73examined difference spectra between resting and excited nerves in the micron wavelength region. Difference peaks appeared when the nerve was active with a

propagated action potential. They concluded from the evidence that it appears likely that the difference peaks were due to phospholipids in the nerve membrane and that they may be related to conformational changes. Margineanu 74, after a series of studies, concluded that the nerve membrane must be able to release and also to absorb electromagnetic energy corresponding to 4-15 kcal/mol. The quanta of such energy have wavelengths in the domain 2-7 . He notes that this lies exactly in the region where the electromagnetic emission as well as shifts in the absorption spectrum of active nerves were reported by the foregoing authors. He states that the signicance of this is particularly high since the above mentioned spectral domain corresponds to vibro-rotational transitions of proteins. The implications of these ndings for understanding the response of ion complexes to electromagnetic elds are of some signicance. There are also other implications for information transfer in the nervous system, but that is another story. Neural and immune systems interact Stefano 75considers the evidence for bidirectional interrelationships among the neuroendocrine, nervous and immune systems to be quite overwhelming. He states that the evidence comes

from neurochemistry, molecular neurobiology, neurophysiology, neuroanatomy, immunology and the behavioral sciences. His point is well taken. The National Library of Medicine even has a category "neuroimmunomodulation" in its MeSH data base. Neuropeptides, particularly opioids, whose multiple roles in the nervous system are well established, are known to inuence immunologically competent cells. Specic immune cells are not only capable of responding to neuropeptides, but also of synthesizing them. The author points out that there is clear evidence that these substances, in addition to their interaction with the neuroendocrine apparatus, play a role in immune processes. In particular, he notes that the effects of endogenous opioid peptides on polymorphonuclear leukocytes, monocytes, and lymphocytes have been demonstrated. There are also indications of an inuence on cellular adherence. This latter will be touched on in the last section since it is critical for cancer metastases. Farrar 76states that the regulation of immune system function involves a variety of polypeptidic substances called interleukins. He points out that these are growth and differentiation factors that regulate the mature immune response and hematopoiesis. He then goes on to present data from molecular and biochemical that demonstrate

reciprocity in the production of neuroendocrine hormones and interleukins, and their receptors in brain and immune cells. He concludes that he has shown by molecular and biochemical analyses that lymphocytes produce and bind neuroendocrine hormones. Lysle et al 77note that recent research has shown that presentations of an unconditioned aversive stimulus, such as electric shock, can induce alterations in immune function in rats. They also note that it has been demonstrated that an innocuous stimulus paired with an unconditioned aversive stimulus can acquire immunomodulatory properties. They point out that the data indicate that endogenous opioid activity is responsible for the alterations in immune function by unconditioned aversive stimulation. They conclude that endogenous opioid activity is involved in CS-induced alterations of immune function. Moreover, they believe that their nding of a lack of effectiveness of N-methylnaltrexone in attenuating the CS-induced immunomodulatory effect suggests that the opioid receptors involved in the effect are located in the central nervous system. Jankovic et al 78state that there are a large number of interactions at molecular and cellular levels between the nervous system and the immune system. They points out that it has been demonstrated

that the opioid neuropentapeptide methionine-enkephalin (Met-Enk) is involved in humoral and cell-mediated immune reactions. Further, MetEnk injected peripherally produces a dual and dose-dependent immunomodulatory effect: high doses suppress, low doses potentiate immune reactivity. Tsung-Ping et al 79note that specic s binding sites have been identied in the mammalian brain and lymphoid tissue. They found that certain gonadal and adrenal steroids, particularly progesterone, were found to inhibit sreceptor binding in homogenates of brain and spleen. Their ndings suggest to them that steroids are naturally occurring ligands for s receptors and state that this raises the possibility that these sites mediate some aspects of steroid-induced mental disturbances as well as alterations in immune function. In another report 80they point out that the s receptor exists in the central nervous, endocrine and immune systems and also in certain peripheral tissues. Further, the s receptor is a neuronal substrate that binds several psychoactive compounds; these include cocaine, some steroids and benzomorphan. They note that many newer atypical antipsychotic drugs also bind to the s receptor and progesterone and

that certain steroids have been shown to be endogenous ligands for the s receptor. Ovadia et al 81state that receptors that are shared by the CNS and the immune system may be part of an assembly of mechanisms whereby these systems can modulate each other's activity. They note that IL-1 and IL-2 receptors are present not only on lymphocytes but in brain tissue as well. Further, they state, many past studies demonstrate that neuropeptides and neurotransmitters can modulate the activity of immune cells. They point out that several neurotransmitter receptors in lymphocytes have been described, including dopaminergic, cholinergic, B-adrenergic, peptidergic and others for opiates. They, in their own work, characterized dopamine and opiate receptors on isolated membranes of rat lymphoctyes. Weber 82et al state that the periaqueductal gray matter of the mesencephalon (PAG) subserves a variety of diverse autonomic functions and also appears to be a site for opiate action in the induction of immunosuppression. They found that microinjections of morphine into the PAG, but not into the other opiate receptor-containing neuroanatomical sites, resulted in a rapid suppression of natural killer (NK) cell activity. The NK cell suppression could be blocked by prior

peripheral administration of the opiate antagonist naltrexone. They conclude that their ndings show that certain central actions of opiates that produce changes in NK cell function are mediated through opiate receptors in the PAG and identify a brain region involved in opiate regulation of immune function. It is interesting that this region was involved in blood-brain-barrier permeability change in response to exposure to electromagnetic elds.* The possibility of subcortical immunomodulation was investigated by Neveu et al 83. The substantia nigra, which is critically involved with dopamine, was lesioned with the neurotoxin 6hydroxydopamine. Four and six weeks after left or right lesions of the substantia nigra, spleen lymphocyte mitogenesis was found to be depressed or enhanced, respectively, as compared to sham operated controls. Their results indicate that asymmetrical brain modulation may occur at the subcortical level. They conclude that central dopamine is involved in neuroimmunomodulation. Devoino et al 84found that activation of GABA-receptors with muscimol or activation of BD receptors with diazepam or tazepam had stimulatory effects upon immunogenesis. A decrease in GABA BDreceptor-ionophore complex activity led to suppression of immune

response. They state that the immunomodulatory action of the GABAergic system is of central origin and can occur only when the hypothalamo-pituitary system is intact. They conclude that their results indicate that the inuence of the GABA-ergic system on immunogenesis requires the participation of both the dopaminergic and serotoninergic systems. The authors of another study85state that there is substantial evidence that magnetic elds can reduce opiate-induced analgesia, with alterations in calcium channel function and/or calcium ion ux being implicated in the mediation of these inhibitory effects. They carried out experiments designed to explore the effects of protein kinase C (PKC), a calcium/diacylgycerol/phospholipid-dependent protein kinase, on opiate-induced analgesia and its involvement in mediating the inhibitory effects of exposure to magnetic elds. Their results suggest that PKC has antagonistic effects on opiate-mediated analgesia in the snail, and the inhibitory effects of magnetic elds on opiate-induced analgesia involve alterations in PKC. In sum, there is clear evidence that the neural and immune systems interact. Further, many of the interactions involve the same subsystems that are involved in electromagnetic eld effects.

A means by which electromagnetic elds may inuence cancer As we have seen above, one of the bioeffects of electromagnetic elds is on the nervous system through an inuence at the cell membrane. This perturbs neurochemistry, with changes in the dopamine, opiate and melatonin systems. Because of the interactions these latter have with the immune system, it would be expected that em elds would have an inuence on cancer promotion and possibly genesis. And there is evidence that this means is effective. Some of the evidence is summarized below. Zagon & McLaughlin 86found that naltrexone had both stimulatory and inhibitory effects, depending on the dosage, on the growth of S20Y neuroblastoma in A/Jax mice. Inoculation of neuroblastoma cells in control mice resulted in 100 percent tumor incidence within 29 days. Daily injections of 0.1 milligram of naltrexone per kilogram of body weight in neuroblastoma inoculated experimental mice, which blocked morphine-induced analgesia for 4 to 6 hours per day, resulted in a 33 percent tumor incidence, a 98 percent delay in the time before tumor appearance, and a 36 percent increase in survival time. Neuroblastoma inoculated mice receiving 10 milligrams of naltrexone per kilogram, which blocked morphine-induced analgesia

for 24 hours per day, had a 100 percent tumor incidence, a 27 percent reduction in the time before tumor appearance, and a 19 percent decrease in survival time. They conclude that naltrexone modulates tumor response and suggest that the endorphin-opiate receptor system is involved in neuro-oncogenic events. Abou-Issa and Tejwani 87note that previous studies showed that naltrexone inhibited the induction of rat mammary tumors by 7,12dimethylbenz(a)anthracene (DMBA). They extended the studies to evaluate the effectiveness of naltrexone as an antitumor agent. They tested the effect of it, given daily in the diet, on the growth of established DMBA-induced mammary tumors. Tumors continued to grow actively in the control group. In contrast, the naltrexonesupplemented diet signicantly decreased the size of the established mammary tumors. This growth suppression was rapidly reversed upon transfer of the rats from naltrexone treatment to the control diet. They observed that the inhibitory effect of naltrexone is restricted to the hormonally responsive mammary tumors. Mayford et al 88found in aplysia that long-term sensitization of the gill- and siphon-withdrawal reex results in the formation of new synaptic connections between the presynaptic siphon sensory neurons

and their target cells. These structural changes can be mimicked, when the cells are maintained in culture, by application of serotonin, an endogenous facilitating neurotransmitter in Aplysia. A group of cell surface proteins, designated Aplysia cell adhesion molecules was downregulated in the sensory neurons in response to serotonin. The loss of cell adhesion control has been implicated in metastases. Arch et al 89found that a CD44 variant, critical in cell adhesion, is transiently expressed in certain macrophages and T- and B- cells in response to antigen stimulation. These ndings indicate that the variant might be involved in the early steps leading to an immune response. Further experiments conrmed that the CD44 variant is essential in the activation of immature lymphocytes into mature immune cells in the lymph nodes. Cossarizza et al 90found that exposure of human peripheral blood mononuclear cells to extremely low frequency pulsed electromagnetic elds (PEMFs) increased both the spontaneous and the PHA- and TPA-induced production of interleukin-1 (IL-1) and IL-6. Their results indicate that cells of the monocytic lineage, which are good producers of both IL-1 and IL-6, can be important cellular targets for PEMFs. They state that considering these cytokines are among the most

pleiotropic ones, these data can help us understand the previously reported effects of PEMFs on the proliferation of human lymphocytes and the effects exerted by such elds on cartilage and bone cells, whose physiological activity is highly dependent on IL-1 and IL-6. Terman et al 91compared intermittent and continuous patterns of footshock (yielding opioid and non-opioid analgesia, respectively). They found that only parameters causing opioid analgesia are immunosuppressive and tumor enhancing and that these effects are blocked by naltrexone. They showed that exposure of rats to intermittent, but not continuous, footshock decreased mitogenstimulated proliferation of T lymphocytes. They found that the cytotoxic activity of rat splenic natural killer (NK) cells is reduced by only the intermittent foot-shock. In both cases, naltrexone given before the stressor prevented the immunosuppression, and high doses of morphine mimicked the opioid effect of stress on NK cells. They also concluded that the experience of "helplessness" is important for the immunosuppressive and tumor-enhancing effects; and that opioid peptides causing analgesia associated with "helplessness" are also involved in mediating these immunologic and oncologic effects.

Cotzias & Tang 92found that a high propensity for breast cancer in mice was associated with low dopamine-stimulated adenylate cyclase activity in the brain, low spontaneous motorization, and low motor responses to injections of the precursor, L-dopa. Liburdy et al 93found that a 60 Hz magnetic eld can act at the cellular level to inuence the growth of human estrogen-dependent breast cancer cells. They believe the magnetic elds act at cellular levels to enhance breast cancer cell proliferation by blocking melatonin's natural oncostatic action. They report what appears to be a dose threshold between 2 and 12 mG. The authors suggest that the mechanisms of action may involve modulation of signal transduction events associated with melatonin's regulation of cell growth. One other aspect of this picture is that melatonin is an effective endogenous free radical scavenger. Polggeler et al94note that the pineal indolamine reacts with the highly toxic hydroxyl radical and protects against oxidative damage to biomolecules within every cellular compartment. They state that the rate of aging and the time of onset of age-related diseases in rodents can be retarded by the administration of melatonin or treatments that preserve the endogenous rhythm of melatonin formation. Aged animals and humans are melatonin-decient

and more sensitive to oxidative stress. And this is one of the categories that is reported to be particularly sensitive to electromagnetic elds. In sum, there is evidence that the means described here may be one way by which electromagnetic elds may inuence the occurrence and course of cancer. Discussion In this chapter, I've integrated a number of lines of research on the interaction of exogenous electromagnetic elds with biological systems from the cell level, to system, to whole organism level. I showed how the data are different facets of a common theme. And I've indicated some of the implications of importance to biology by developing the analyses within the context of cancer. Specically, I detailed some of the epidemiological and laboratory evidence indicating that em elds may promote cancer. Second, I spelled out the effects that electromagnetic elds have on neural and neuroendocrine systems. Then I summarized the relevant information on how the neural and immune systems interact. With that as a foundation, I then discussed one means by which exogenous electromagnetic elds may promote cancer.

There are other sections of the forest beside those that I've described, i.e. other interactions of em elds with biological systems and other mechanisms that could be discussed. Just out of my own research, I could discuss interactions with the placental barrier, as well as with the microwave hearing phenomenon, electrosensory systems and the heart. I could also talk about Lee et al's 95 nding that electric elds can disturb lipid monolayers, a nding that has implications for the structure and composition of biological membranes. Structure and composition is critical to the function of the membrane proteins that I discussed above. I could also discuss the implications of Harkins and Grissom's report

a magnetic eld effect on an enzyme reaction involving radical pair

recombination rates. Many enzymes appear to use radical chemistry in the conversion of substrates to products. There are also relevant ndings, by others, on the redistribution of cell surface receptors. And as seen in an earlier section, there are clear relationships with melatonin and the dopamine-opiate systems. There is much more that I could spell out and discuss, but much that is important is well dened by others in the chapters that I've included in this book. In sum, this chapter is not intended to be comprehensive. It is intended to provide the reader with an integrative framework or context

with which to view the abundance of information from diverse lines of research that are detailed in the other chapters in this book. As Burke1might put it, my intent in this chapter is to provide a new structure for the reader to view the results of the diverse, seemingly disconnected, bits and pieces of research on electromagnetic eld interactions with biological systems. These results will ultimately help change the face of biology. The foregoing also provides the reader with a sense of the change in the Universe that is taking place in one portion of the current revolution in biology, i.e. in research on the interactions of electromagnetic elds with biological systems. And it also indicates how pervasive are the interactions and their broad implications for biology. Endogenous and exogenous electromagnetic elds are fundamental factors regulating life. Fully understanding their interactions with biological systems will be a quantum leap in biology. Footnote * Frey, et al 97determined that low intensity em elds modify the blood-brain-barrier (BBB). Immediately after exposure, rats were injected intravenously with sodium uorescein, a uorescent dye

classically used for such studies that normally does not pass the BBB. Compared to sham-exposed controls, uorescence was seen at the diencephalon level of the brain, as well as at the level of the mes- and metencephalon. Oscar and Hawkins 98extended the work by exposing rats to em elds to assess the uptake of several radioactive neutral polar substances in the brain. Barrier permeability increases were observed. It was also found that em elds of the same average power but different pulse characteristics produced different uptake levels. Albert 99exposed Chinese hamsters to em elds and injected them with various electron dense tracers. Specimens were then prepared for light and electron microscopic examination. The exposed and sham-exposed groups differed in that exposed animals showed tracer penetration of the BBB. Other studies have been done which showed similar changes. Ben-Shachar et al 100state that dopaminergic function is dependent on normal iron metabolism; it plays a crucial role in neuroleptic-induced dopamine supersensitivity. The dopaminergic antagonist haloperidol and chlorpromazine alter the blood brain barrier of the rat and enhance the normally restricted iron transport into the brain. Saija et al101studied the effect of haloperidol on the permeability of the blood-brain-barrier to [14C]alpha-aminoisobutyric acid in 10-12

week and 28-30 week old rats. Following intraperitoneal injection of haloperidol an increase in the permeability of the BBB was observed in older rats. References 1. Burke J. The day the Universe Changed. Boston: Little, and Co, 1985. 2. Savitz DA, and Calle EE. Leukemia and occupational exposure to electromagnetic elds. J Occup Med 1987; 29(1):47-51. 3. Werthheimer N, and Leeper E. Adult cancer related to electrical wires near the home. Int J Epidemiol 1982; 11(4):345-355. 4. Milham Jr. S. Mortality in workers exposed to electromagnetic elds. Environ Health Perspect 1985; 62:297-300. 5. Milham Jr S. Increased mortality in amateur radio operators due to lymphatic and hematopoietic malignancies. Am J Epidemiol 1988; 127(1):50-4. 6. Wertheimer N, and Leeper E. Magnetic eld exposure related to cancer subtypes. Ann NY Acad Sci 1987; 502:43-54.

7. Savitz DA, Wachtel H, Barnes FA, et al . Case-control study of childhood cancer and exposure to 60 Hz magnetic elds. Am J Epidemiol 1988; 128(1):21-38. 8. Demers PA, Thomas DB, Rosenblatt KA, et al. Occupational exposure to electromagnetic radiation and breast cancer in males. Am J Epidemiol 1990; 132:775-6. 9. Tynes T, and Andersen A. Electromagnetic elds and male breast cancr. Lancet 1990; 336:1596. 10. Kunz LL, Johnson RB, and Thompson ,. et al . Effects of long-term low level radiofrequency radiation exposure on rats. V8, Univ. ofWashington, Seattle, WA. 1985. 11. Beniashvili DS, Bilanishvili VG, and Menabde MZ. Low-frequency electromagnetic radiation enhances the induction of rat mammary tumors by nitrosomethyl urea. Cancer Letters 1991; 61:75-79. 12. Loscher W, Mevissen M, and Lehmacher W, et al. Tumor promotion in a breast cancer model by exposure to a weak alternating magnetic eld. Cancer Letters 1993; 71:75-81. 13. Frey AH, and Spector J. Irritability and aggression in mammals as affected by exposure to electromagnetic energy. Abstracts of papers presented at the URSIAnnual Meeting, Amherst, MA, 1976.

14. Frey A, .and Wesler L. Modication of tail pinch consummatory behavior in microwave energy exposure. Abstracts of papers presented at the URSI Annual