Frey Ch2 on the Nature of Electromagnetic Field Interactions With Biological 2010
Transcript of Frey Ch2 on the Nature of Electromagnetic Field Interactions With Biological 2010
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On the nature of electromagnetic field 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 fields 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 thatevolved over millions of years in a world with a relatively weak
magnetic field and with few electromagnetic (em) energy emitters. As is
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characteristic of living organisms, they interacted with and adapted to
this environment of electric and magnetic fields. One example of thisadaptation
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 toregulate various critical cellular systems; we see this in the complex of
circadian rhythms. Fish, birds, and even the duckbill platypus developedsystems to use electromagnetic fields to sense prey and to navigate.Electromagnetic fields are involved in neural membrane function; even
protein conformation involves the interactions of electrical fields.
But as has often been the case in the history of science, thoughthese were interesting observations, they were disconnected bits and
pieces that made no real impact; they didn't fit the frame of reference of
the time. Further, the technology and techniques needed to do muchwith the information did not exist. Thus, the very broad importance ofthe interactions of electromagnetic fields with biological systems was
not really recognized. But that was yesterday. Now, as James Burke1might put it, is (figuratively) the day the Universe changed. This chapter is intended to give the reader a sense of how muchof the data fits together and to indicate some of the implications for
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biology. To do this, I will not talk about the trees so much; instead, Iwill describe part of the forest. I will integrate a number of lines ofresearch on the interaction of exogenous electromagnetic fields 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 laboratoryevidence indicating that em fields can promote cancer. Second, I willdetail the effects electromagnetic fields have on neural and
neuroendocrine systems. Then I will summarize the relevantinformation on how the neural and immune systems interact. With theforegoing as a foundation, I will then integrate it all and spell out one
means by which exogenous electromagnetic fields may promote cancer.
Some of the data that suggests electromagnetic field exposure
promotes cancer
Both epidemiological and laboratory studies suggest thatelectromagnetic fields promote cancer. The evidence to date indicate aninfluence on a number of different cancers, among these are thelymphomas and leukemias as well as nervous system and breast cancers.
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Savitz et al 2noted, for example, that surveys suggest anincreased risk of leukemia among men with occupational exposure to
electromagnetic fields.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. Theirresults 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 cancerassociated with high-current electrical wiring configurations (HCCs)
near the patient's residence. They note that such wiring can exposeoccupants of the residence to alternating magnetic fields at a level which
may produce physiological effects. Several patterns in the data they feltsuggested that HCCs and cancer may be causally linked; a dose-response relationship was found. The association did not appear to bean 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 first exposure to the HCCs and cancer diagnosis was
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seen. This, they concluded, is consistent with a hypothesis of cancerpromotion produced by magnetic field exposure.
In an occupational mortality analysis of adult male death records
filed in Washington State in the years 1950-1982, Milham 4found thatleukemia and the non-Hodgkin's lymphomas show increased
proportionate mortality ratios (PMRs) in workers employed in
occupations with apparent exposure to electromagnetic fields.Specifically, nine occupations were considered to have electric or
magnetic field exposures. Eight of the nine occupations had PMRincreases for leukemia and seven of the nine occupations had PMRincreases for the lymphoma category. He concludes that his findingssupport the hypothesis that electric and magnetic fields may becarcinogenic.
In another study, Milham5conducted a population-based study ofmortality in US amateur radio operators.Washington State andCalifornia amateur radio operators were found through the 1984 US
Federal Communications Commission Amateur Radio Station and/or
Operator License file. A statistically significant increased mortality wasseen for cancers of the lymphatic tissues, a category that includes
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multiple myeloma and non-Hodgkin's lymphomas. Mortality due toacute myeloid leukemia was significantly elevated.
Wertheimer et al 6
determined that certain subtypes of cancer
(notably nervous system cancer) showed an association with two indices
of exposure to 60 Hz alternating magnetic fields. Similarities were seenin people putatively exposed to such fields 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 andnonexposed groups suggest that prolonged field exposure may act as a
cancer promoter.
Savitz 7designed a case-control study to assess the relationbetween residential exposure to magnetic fields and the development of
childhood cancer. Exposure was assessed by in-home electric andmagnetic field measurements under low and high power use conditions
and wire configuration codes, a surrogate measure of long-term
magnetic field levels. Measured magnetic fields under low power useconditions had a modest association with cancer incidence; a cutoff
score of 2.0 milligauss resulted in an odds ratio of 1.4 for total cancersand somewhat larger odds ratios for leukemias, lymphomas and softtissue sarcomas.
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Demers et al. 8examined occupational exposure in a case-controlstudy of breast cancer in men. Each subject in the study reported thetwo longest-held occupations during his life. These occupations were
grouped into five categories, each with at least some putative em field
exposure. Those men with no expected exposure formed the unexposedreferent category. After assigning each subject to an exposure categorybased upon occupation, the number of cases in each category was
compared to the number of controls. There was an estimated 1.8-foldincreased risk of breast cancer in the combined five exposed categories
compared to the unexposed category. One of the expected frequent fieldexposure categories had a six-fold increased risk of breast cancer. Tynes and Andersen 9of the Cancer Registry of Norway reportedon 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
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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 first three age categories were combined and theanalysis repeated, the M-H statistic was 4.38 and the Chi-square statistic
was 7.9 (p = .005) When the first 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 wasignored 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 ofthe 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-typeanalysis 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 occurredearlier 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."
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Beniashvile et al 11found that low-frequency electromagneticfields 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 fields. Variablemagnetic fields induced mammary gland cancer much more frequently
than static ones. They also found that electromagnetic fields reduced themean latent period of tumor development.
Loscher 12 determined if an alternating low flux densitymagnetic field has tumor promoting or co-promoting effects in female
rats. Mammary tumors were induced by the chemical carcinogen 7,12-dimethylbenz(a)anthracene DMBA. In controls, DMBA inducedtumors in about 40% of the animals within thirteen weeks of the first
application. Eight weeks after DMBA application the exposed ratsexhibited significantly more tumors than sham-exposed animals. Thisdifference in the rate of tumor development was observed throughout the
period of exposure. At the end of a three-month period of magnetic fieldexposure the tumor incidence in exposed rats was 50% higher than in
sham exposed rats, a statistically significant difference. Further the sizeof the tumors was significantly larger in the exposed compared to sham
exposed rats.
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There are additional studies, both epidemiological andexperimental, that indicate exposure to electromagnetic fields 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 thisquestion in the remainder of the chapter. In the process, I will integratea wide diversity of data and will show how the wide range of effects of
electromagnetic fields can be understood within one framework.Electromagnetic fields affect neural and neuroendocrine systems
There is a substantial data base indicating that the dopamine,opiate and pineal systems are influenced by electromagnetic fields.There are also data indicating that calcium channels in the cell
membranes are involved.
Dopamine and opiate systems. In 1976, I hypothesized that thedopamine systems of the brain, in part, mediate the effects of exposure
to electromagnetic fields 13. A series of experiments carried out to testthe hypothesis indicated that the dopamine systems of the brain are
involved. Specifically, Frey and Wesler found that exposure of ananimal to electromagnetic energy modified stereotypic behaviors; these
involve the nigrostriatal dopamine system 14,15. In another test, Freyand Gendlemen found that exposure of animals to em energy degraded
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motor coordination and balance which also involves the dopamine
system16. Wesler and Frey reported that em energy exposure interactsdifferentially with high and low doses of apomorphine17,18.
This latter
suggests a differential influence of em energy on D1 and D2 receptors.Related to the above findings, is the finding of Stith and Erwin that
exposure of rats to low intensity em energy significantly decreased
tyrosine hydroxylase activity in the hypothalamus and brain stem 19.They report a significantly greater effect with pulsed energy than with
continuous wave energy of the same power level. Dopamine issynthesized from tyrosine and tyrosine hydroxylase acts on tyrosine in a
rate limiting step. They also report a reversible decrease in dopamine inthe hypothalamus and brain stem.
Then Frey and Wesler extended the dopamine hypothesis toinclude the opiate systems of the brain 14. Freydeveloped the dopamine-opiate hypothesis further and provided a comprehensive integration of
the evidence indicating an effect of electromagnetic fields on the brain's
dopamine-opiate systems 20. I also reported at that time on experimentsusing psychoactive drugs to test the hypothesis. In additionalexperiments, Frey and Wesler used the conditioned emotional response
(CER) to further test the dopamine-opiate hypothesis 21,22. They found
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that once CER testing began, significant differences in suppression ratios
appeared between em energy exposed and sham exposed groups. Theexposed animals exhibited enhanced suppression of response during the
warning signal. This is classically interpreted as heightenedemotionality.Frey and Wesler later reported finding that exposure to lowintensity em energy potentiates the effects of low doses of morphine;
this effect is comparable to that found with dopamine inhibitors 23. Inanother test of the dopamine-opiate system hypothesis, Frey and Spector
predicted that aggression induced by light tail pressure would be
modified 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 onpolysynaptic neuronal pathways throughout the CNS. They are thoughtto modify the action of gamma-aminobutyric acid (GABA). Haloperidolappears to act by post-synaptic blockade ofCNS dopamine receptors.The interaction of em energy exposure and chlordiazepoxide (librium)
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treatment was explored using stereotypic behavior as a test. 25 A two-way Analysis of Variance showed a significant difference (p
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apomorphine, d-amphetamine, and morphine in animals exposed to em
energy 26. They found exposure enhanced apomorphine effects andattenuated amphetamine effects.
They reported that morphine effects
were also enhanced. Miller et al, using 60 Hz magnetic fields, foundthat exposure to an em field attenuated the behavioral response of mice
to morphine 27.
Kavaliers and Ossenkopp in a series of studies examined theeffects of exposure to a 0.5 Hz rotating magnetic field on morphine-
induced analgesia. Mice were chronically exposed for 5-10 days andthis eliminated the day-night rhythm in analgesia by reducing the night
levels to those found during the day. This effect dissipated several daysafter 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
significantly reduced 29,30. The nocturnal reduction was greater than theday-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
significantly reduced compared to non exposed controls 30.
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In another study 31mice were pre-exposed to a rotating magneticfield for 60 minutes and then treated with mu, kappa, delta and sigma
opiate agonists.
Magnetic field 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 a0.5 Hz RMF has significant and differential influences 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 field prior to the daily injectionsresulted in significantly reduced levels of tolerance. The role of centralcalcium ion levels in magnetic field modifications of morphine-induced
analgesia and hyperactivity in mice were also explored. Animals weregiven an intracerebroventricular injection of a calcium ionophore and achelator. The calcium ionophore potentiated the inhibitory action of thefield on the analgesic and locomotor effects of morphine. The calcium
chelator blocked these effects. The authors later concluded that theseresults, together with the finding that calcium ions antagonize morphine-
induced analgesia indicate that exposure to magnetic fields alters
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morphine-induced analgesia via changes in calcium mechanisms. Theyalso note that disturbances in the geomagnetic field ("magnetic storms")
have been shown to influence nocturnal morphine-induced analgesia in
mice 33in a manner consistent with the laboratory findings. Approaching from a different standpoint, there is evidence thatGABA 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 andin vivo studies that there is a reciprocal dopamine-acetylcholine balance
in the caudate. Kalin and Sheltonhave shown in a series of experimentsthat the opiate and benzodiazepine systems regulate certain primate
defensive behaviors 35. They conclude that these systems work togetherto mediate responses important to survival. Gruen et al report thatperinatal exposure to benzodiazepines leads to behavioral changes that
are present in adults 36. The authors state that their data indicate thesechanges may be associated with modification of mesolimbic dopamine
function. Antelman et al have shown that a single injection of abenzodiazepine significantly sensitizes rats to the later administration of
haloperidol 37. This indicates a time dependent sensitization bybenzodiazepines and, by implication, GABA neurons. They suggest that
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such acute stimulation of GABA neurons triggers the progressive
development of a long term antidopaminergic effect. Giorgi et al reportthat 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 emfield exposure and anticholinesterase drugs 39. They found complexinteractions and suggested that use of such drugs could provide
significant information on the effects of em energy exposure. Theirfindings 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 thereis a reciprocal dopamine-acetylcholine balance in the caudate.
Nakas et al and Jamakosmanovic considered the effect ofrepeated daily exposure to em energy on levels of acetylcholinesterase in
the brain 40,41. They found that chronic exposure to the energy inducedsignificant depression of acetylcholinesterase activity in the brain. Theyalso found other effects which led them to suggest that the central
nervous system is very sensitive to exposure to low intensity em energy.
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In another study, it was reported that em energy exposureattenuated the effect of ethanol and also amphetamine 42. The authorsalso 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 aswould 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 betweendrugs and em field exposure and suggested that the field parameters are
an important variable in the nature of the effect obtained. Thomas alsofound an increase in response rate with chlordiazepoxide and em energy
exposure44.
There is now a substantial body of data that indicates brainsystems, in particular the opiate-dopamine systems, are influenced by
exposure to brief, very low intensity electromagnetic fields. Thedopamine-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
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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 authorsstate that the results indicate that melatonin, in vivo, inhibits dopamine
synthesis selectively in the retina. They also suggest that the increase inretinalNAT 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 invivo support for their in vitro findings 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 foundthat 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 preventedby simultaneous injection with the opioid antagonist naloxone.Naloxone also blocked the effects of beta-endorphin and melatonia +
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beta-endorphin injections. Further, naloxone blocked ahypophysectomy-dependent increase in [3H]FNZ binding. These resultsindicate that modulation of melatonin dependent changes on brain
benzodiazepine receptors involve opioid peptides.
In another study 47, a single population of opioid receptors wasidentified in the pineal gland using [3H] diprenorphine and otherligands. Specifically, the effects of both opioid receptor agonists andantagonists on the basal activity of N-acetyltransferase were examined in
bovine pineal explants in culture. Morphine, an opioid receptor agonist,significantly increased the activity of N-acetyltransferase in a dose-
dependent fashion. In addition, the stimulatory effect of morphine wasinhibited by naloxone, an opioid receptor antagonist. The resultsindicate 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 Maestroniand Conti 48to stimulate the release of opioid peptides from activatedCD4+T lymphocytes. These immuno-derived opioids orlymphomorphins cross reacted with anti-beta-endorphin and anti-met-
enkephalin antisera and bound to opioid receptors in the thymus. The
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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 thatmelatonin induced activated T lymphocytes to release opioid peptides
with immuno-enhancing and anti-stress properties. Then they presentevidence that these peptides cross react with anti-beta-endorphin and
anti-met-enkephalin antisera, and bind specifically to thymic opioid
receptors. Furthermore, the same antisera injected in prednisolonetreated 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 melatoninand absence of antigen activation, negated the effect of such antisera
which demonstrates the physiological relevance of this melatonin-
immuno-opioids network.Aloyo et al 50found that pineal membranes possess a single class
of high-affinity binding sites for the opioid peptide beta-E. Theysuggest that beta-E binds to delta opioid sites and exclude the possibility
of significant binding to mu, kappa and epsilon sites. They conclude that
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methionine-enkephalin. The author concludes his results suggest thatpineal 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, thepineal is involved in the effects of electromagnetic fields on biosystems.Some of the evidence is summarized in the next section.
Electromagnetic fields affect pineal gland function andmelatonin.Rudolph et al 53noted that electrophysiologicalinvestigations show magnetic fields (MFs) influence spontaneous
activity of pineal cells in the pigeon, guinea pig and rat. They point outthat it also has been shown that static magnetic fields interfere with the
melatonin synthesizing system. They note that the magnetic field effectsare 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. Melatoninas well as enzymes involved in its synthesis such as hydroxyindole-O-
methyltransferase (HIOMT) and serotonin-N-acetyltransferase (NAT)
are depressed by MFs. They investigated in some detail themagnetosensitivity of the rat's pineal cAMP system. Rats were exposedfor one hour during the dark phase to a static magnetic field inverting
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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 field did not seem to influence pineal
function. They concluded that MFs act upon the pineal melatoninsynthesizing system via interaction with the cell membrane.
Stehle et al 54 exposed male and female naturally pigmented andalbino Mongolian gerbils, as well as Sprague-Dawley (SD) rats, to a 60o
rotation of the horizontal component of the ambient MF. Alteration ofnocturnal pineal melatonin content and NAT activity were the dependent
variables.. In pigmented gerbils, MF exposure resulted in no significantchange in pineal melatonin synthesis. In contrast, albino gerbils and SDrats showed significant decreases in pineal NAT activity and melatonin
content following MF exposure. The pigmentation of the retina, theyconclude, plays a crucial role.
Another author 55concludes that chronic exposure to electric ormagnetic fields can disrupt normal circadian rhythms in rat pineal
serotonin-N-acetyltransferase activity as well as serotonin andmelatonin concentrations. At least in the rat, he states, these fields mayinterfere with tonic aspects of neuronal input to the pineal gland, giving
rise to what may be termed "functional pinealectomy." He notes that
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such disruptions in circadian rhythmicity of pineal melatonin secretion
have been associated with depressive disorders in humans.There has also been a determination 56
that a 6 week exposure to
a 50 Hz magnetic field influences melatonin synthesis in 11-18 week old
male rats. The animals were exposed continuously to a rotatingmagnetic field of 1, 5, 50, or 250 T. The levels of plasma and pinealgland melatonin were determined by radioimmunoassay. A significantdecrease in melatonin was observed between the control group and
groups exposed to a magnetic field at a flux density in excess of 1 T
during the night.
The effect of pulsed static magnetic fields on rat pineal melatoninsynthesis has been studied at different times of the day. Exposure tomagnetic fields during mid- or late dark phase significantly suppressed
pineal N-acetyltransferase activity, as well as the melatonin content inthe pineal gland. These variables were not influenced by magnetic fieldswhen the exposure occurred early in the dark phase or during the light
period. The authors conclude that responsiveness of the pineal gland tomagnetic field perturbations varies as a function of the time of day.
There was significant inhibition of serotonin-N-acetyltransferaseactivity and melatonin content in rat pineal glands stimulated with the
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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 field 58.
A 2 hour
exposure to a pulsed magnetic field
also resulted in a significant reduction in isoproterenol induced
serotonin-N-acetyltransferase activity.
Another author 59reports that the circadian rhythm of melatoninproduction (high melatonin levels at night and low during the day) in the
mammalian pineal gland is modified not only by visible portions of the
electromagnetic spectrum, i.e., light, but also by exposure to extremelylow frequency electromagnetic fields as well as static magnetic fields.He notes that both light and electromagnetic field exposure at night
depress the conversion of serotonin to melatonin. He points out thatsinusoidal magnetic field exposure has been shown to interfere with the
nocturnal melatonin forming ability of the pineal gland. Static magneticfields, he notes have been repeatedly shown to perturb circadianmelatonin rhythm. The field strengths in these studies that he cites werealmost always in the geomagnetic range, 0.2 to 0.7 Gauss. He concludesthat these experiments show that several parameters in the indole
cascade in the pineal gland are modified by field exposure, i.e. pineal cAMP levels, N-acetyltransferase activity (the rate limiting enzyme in
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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 withdepressed melatonin synthesis. He believes that the same kinds of
disturbances in pineal melatonin production can be induced by either
light exposure or by electromagnetic field exposure at night.In sum, there is a clear body of evidence that establishes that
electromagnetic fields influence pineal gland function and melatonin.Thus we have the interrelated systems, the dopamine, opiate and pineal
all showing an electromagnetic field influence. The question then iswhat is the proximate cause. One of these is discussed in the followingsection. 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 field 60. Subsequently, they investigatedthe effect of the Ca2+antagonist, methoxyverapamil, on this response.
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Methoxyverapamil was administered to the regenerating segment of
nerve via implanted osmotic minipumps. Magnetic field exposureincreased regeneration distances in the control group's vehicle perfused
nerves. This increase was blocked by perfusion with methoxyverapamilat a concentration which alone failed to affect the outgrowth of nerve
fibers. They concluded that this indicated that Ca2+fluxes are involvedin mediating the biological actions of magnetic fields.
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 coordinationbetween the ionic processes at inner and outer surfaces. They state thatthey found these processes are affected by both electric and magnetic
fields, but in different ways. The opposite effects on Na,K-ATPaseactivity they found likely are related to different charge motions in the
enzyme. Electric fields, they believe, to lead to increases in ion bindingat the enzyme surface. Magnetic fields, they say, could be affectingcharge movements within the protein (e.g., electron shifts due to ATP-
splitting) that coordinate the two surfaces of the enzyme. They feel that
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such charge movements within the enzyme are likely related to electron
transport processes in mitochondria or gating currents in ion channels.
Blackman et al 62
point out that numerous studies have
demonstrated that extremely low frequency electromagnetic fields, or
radio frequency fields amplitude modulated at low frequency, can alterthe efflux of calcium ions from CNS derived samples such as chick
brain. They point out that three research groups have shown that arange of frequencies between 6 and 20 Hz are effective. They extendedthis line of experimentation with further data collection. Then theyanalysed 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 indicatedthe existence of three frequency-dependent patterns in the data.
Blackman et al note in another paper 63that they previouslyreported that in vitro exposure of chick forebrain tissue to a 50 MHz
radio frequency electromagnetic field, amplitude modulated at 16 Hz,
enhanced the efflux of calcium ions within only two power density
ranges. They confirmed and extended those results in this study bytesting at another set of power densities which included the range of the
previous study. An enhanced efflux of calcium ions was found at 1.75,
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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. Theforegoing studies and others clearly indicate that there are frequency and
intensity windows in the effects.
In a study of calcium influx 64, it was found that such increasedduring mitogen-activated signal transduction in thymic lymphocytes
exposed to a 22 mT 60 Hz magnetic field. The plateau phase rather thanthe early phase of calcium signaling was influenced. This wasdetermined by separating in time the early release of calcium from
intracellular stores from the influx of extracellular calcium. Alterationof the plateau phase of calcium signaling indicates, according to the
author, that the calcium channel is the site of field interaction. Inaddition, 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 Liboff65,
Blackman 66and Lednev 67. Space constraints do not allow a discussionof 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
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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 thatlight 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 jun-B messenger RNA in the SCN of golden hamsters and slightly elevate c-
jun messenger RNA levels. Light also increases the amount of a proteincomplex in the SCN that specifically binds to sites on DNA known to
mediate regulation by the AP-1 transcription factor. The investigatorsfound 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. Theyconclude that light and the circadian pacemaker interact to regulate a
specific set of immediate-early genes in the SCN that may participate in
entrainment of the circadian clock.
But light is not the only em field that has such effects. Phillips etal 71note that they found that exposure of the human T-lymphoblastoid
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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 influenced
by magnetic field 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 briefly touched on here.I found that micron wavelength emission was associated with
stimulation of live unmylinated blue crab nerves (p = .008) 72. Theemission detected was considerably greater than that which could be
expected from a black-body nerve model; it was more than two ordersof magnitude greater, i.e. 6w/cm2. Heating artifact from stimulationwas shown to not account for the emission detected. It was found thatthe 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 differencespectra between resting and excited nerves in the micron wavelength
region. Difference peaks appeared when the nerve was active with a
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propagated action potential. They concluded from the evidence that itappears 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 havewavelengths in the domain 2-7 . He notes that this lies exactly in theregion 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 significance of this is particularly high sincethe above mentioned spectral domain corresponds to vibro-rotational
transitions of proteins. The implications of these findings forunderstanding the response of ion complexes to electromagnetic fields
are of some significance. There are also other implications forinformation transfer in the nervous system, but that is another story.
Neural and immune systems interact
Stefano 75considers the evidence for bidirectionalinterrelationships among the neuroendocrine, nervous and immune
systems to be quite overwhelming. He states that the evidence comes
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from neurochemistry, molecular neurobiology, neurophysiology,
neuroanatomy, immunology and the behavioral sciences. His point iswell 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 influence immunologically competent cells.Specific immune cells are not only capable of responding to
neuropeptides, but also of synthesizing them. The author points out thatthere 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 opioidpeptides on polymorphonuclear leukocytes, monocytes, and
lymphocytes have been demonstrated. There are also indications of aninfluence on cellular adherence. This latter will be touched on in the lastsection since it is critical for cancer metastases.
Farrar 76states that the regulation of immune system functioninvolves a variety of polypeptidic substances called interleukins. Hepoints out that these are growth and differentiation factors that regulate
the mature immune response and hematopoiesis. He then goes on topresent data from molecular and biochemical that demonstrate
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reciprocity in the production of neuroendocrine hormones and
interleukins, and their receptors in brain and immune cells. Heconcludes 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 notethat it has been demonstrated that an innocuous stimulus paired with anunconditioned aversive stimulus can acquire immunomodulatory
properties. They point out that the data indicate that endogenous opioidactivity is responsible for the alterations in immune function by
unconditioned aversive stimulation. They conclude that endogenousopioid activity is involved in CS-induced alterations of immune
function. Moreover, they believe that their finding of a lack ofeffectiveness 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 ofinteractions at molecular and cellular levels between the nervous system
and the immune system. They points out that it has been demonstrated
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that the opioid neuropentapeptide methionine-enkephalin (Met-Enk) is
involved in humoral and cell-mediated immune reactions. Further, Met-Enk injected peripherally produces a dual and dose-dependent
immunomodulatory effect: high doses suppress, low doses potentiate
immune reactivity.
Tsung-Ping et al 79note that specific s binding sites have beenidentified in the mammalian brain and lymphoid tissue. They found thatcertain gonadal and adrenal steroids, particularly progesterone, were
found to inhibit sreceptor binding in homogenates of brain and spleen.Their findings 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 inthe central nervous, endocrine and immune systems and also in certainperipheral tissues. Further, the s receptor is a neuronal substrate thatbinds several psychoactive compounds; these include cocaine, some
steroids and benzomorphan. They note that many newer atypicalantipsychotic drugs also bind to the s receptor and progesterone and
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that certain steroids have been shown to be endogenous ligands for the s
receptor.
Ovadia et al 81
state 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 notethat IL-1 and IL-2 receptors are present not only on lymphocytes but in
brain tissue as well. Further, they state, many past studies demonstratethat neuropeptides and neurotransmitters can modulate the activity of
immune cells. They point out that several neurotransmitter receptors inlymphocytes have been described, including dopaminergic, cholinergic,B-adrenergic, peptidergic and others for opiates. They, in their ownwork, characterized dopamine and opiate receptors on isolatedmembranes of rat lymphoctyes.
Weber 82et al state that the periaqueductal gray matter of themesencephalon (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 morphineinto 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
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peripheral administration of the opiate antagonist naltrexone. They
conclude that their findings 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 wasinvolved in blood-brain-barrier permeability change in response to
exposure to electromagnetic fields.*
The possibility of subcortical immunomodulation wasinvestigated by Neveu et al 83. The substantia nigra, which is criticallyinvolved with dopamine, was lesioned with the neurotoxin 6-hydroxydopamine. Four and six weeks after left or right lesions of thesubstantia 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 mayoccur at the subcortical level. They conclude that central dopamine isinvolved in neuroimmunomodulation.
Devoino et al 84found that activation of GABA-receptors withmuscimol or activation of BD receptors with diazepam or tazepam had
stimulatory effects upon immunogenesis. A decrease in GABA BD-
receptor-ionophore complex activity led to suppression of immune
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response. They state that the immunomodulatory action of the GABA-ergic system is of central origin and can occur only when the
hypothalamo-pituitary system is intact.They conclude that their results
indicate that the influence of the GABA-ergic system onimmunogenesis requires the participation of both the dopaminergic and
serotoninergic systems.
The authors of another study85state that there is substantialevidence that magnetic fields can reduce opiate-induced analgesia, with
alterations in calcium channel function and/or calcium ion flux being
implicated in the mediation of these inhibitory effects. They carried outexperiments 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 fields. Their results suggest that PKC
has antagonistic effects on opiate-mediated analgesia in the snail, and
the inhibitory effects of magnetic fields on opiate-induced analgesia
involve alterations in PKC.
In sum, there is clear evidence that the neural and immunesystems interact. Further, many of the interactions involve the samesubsystems that are involved in electromagnetic field effects.
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A means by which electromagnetic fields may influence cancer
As we have seen above, one of the bioeffects of electromagneticfields is on the nervous system through an influence at the cell
membrane. This perturbs neurochemistry, with changes in thedopamine, opiate and melatonin systems. Because of the interactionsthese latter have with the immune system, it would be expected that em
fields would have an influence on cancer promotion and possibly
genesis. And there is evidence that this means is effective. Some of theevidence is summarized below.
Zagon & McLaughlin 86found that naltrexone had bothstimulatory and inhibitory effects, depending on the dosage, on the
growth of S20Y neuroblastoma in A/Jax mice. Inoculation ofneuroblastoma cells in control mice resulted in 100 percent tumor
incidence within 29 days. Daily injections of 0.1 milligram ofnaltrexone 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 milligramsof naltrexone per kilogram, which blocked morphine-induced analgesia
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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 thatnaltrexone inhibited the induction of rat mammary tumors by 7,12-
dimethylbenz(a)anthracene (DMBA). They extended the studies toevaluate the effectiveness of naltrexone as an antitumor agent. Theytested the effect of it, given daily in the diet, on the growth of
established DMBA-induced mammary tumors. Tumors continued togrow actively in the control group. In contrast, the naltrexone-supplemented diet significantly decreased the size of the established
mammary tumors. This growth suppression was rapidly reversed upontransfer of the rats from naltrexone treatment to the control diet. Theyobserved that the inhibitory effect of naltrexone is restricted to the
hormonally responsive mammary tumors.
Mayford et al 88found in aplysia that long-term sensitization ofthe gill- and siphon-withdrawal reflex results in the formation of new
synaptic connections between the presynaptic siphon sensory neurons
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and their target cells. These structural changes can be mimicked, whenthe 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 down-
regulated in the sensory neurons in response to serotonin. The loss ofcell 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 findings indicate that the variantmight be involved in the early steps leading to an immune response.Further experiments confirmed 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 peripheralblood mononuclear cells to extremely low frequency pulsed
electromagnetic fields (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
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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 fields 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 offootshock (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 tointermittent, but not continuous, footshock decreased mitogen-
stimulated proliferation of T lymphocytes. They found that the cytotoxicactivity of rat splenic natural killer (NK) cells is reduced by only the
intermittent foot-shock. In both cases, naltrexone given before thestressor prevented the immunosuppression, and high doses of morphine
mimicked the opioid effect of stress on NK cells. They also concludedthat 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.
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Cotzias & Tang 92found that a high propensity for breast cancerin 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 field can act at thecellular level to influence the growth of human estrogen-dependent
breast cancer cells. They believe the magnetic fields act at cellularlevels to enhance breast cancer cell proliferation by blocking melatonin's
natural oncostatic action. They report what appears to be a dosethreshold between 2 and 12 mG. The authors suggest that themechanisms of action may involve modulation of signal transductionevents associated with melatonin's regulation of cell growth.
One other aspect of this picture is that melatonin is an effectiveendogenous free radical scavenger. Polggeler et al94note that the pinealindolamine 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 ofage-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-deficient
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and more sensitive to oxidative stress. And this is one of the categoriesthat is reported to be particularly sensitive to electromagnetic fields.
In sum, there is evidence that the means described here may be
one way by which electromagnetic fields may influence the occurrence
and course of cancer.
Discussion
In this chapter, I've integrated a number of lines of research onthe interaction of exogenous electromagnetic fields with biological
systems from the cell level, to system, to whole organism level. Ishowed how the data are different facets of a common theme. And I'veindicated some of the implications of importance to biology by
developing the analyses within the context of cancer. Specifically, I
detailed some of the epidemiological and laboratory evidence indicating
that em fields may promote cancer. Second, I spelled out the effects thatelectromagnetic fields 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 discussedone means by which exogenous electromagnetic fields may promote
cancer.
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There are other sections of the forest beside those that I'vedescribed, i.e. other interactions of em fields 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 finding that electric fields can
disturb lipid monolayers, a finding that has implications for the structure
and composition of biological membranes. Structure and composition iscritical to the function of the membrane proteins that I discussed above.I could also discuss the implications of Harkins and Grissom's report
96of a magnetic field effect on an enzyme reaction involving radical pairrecombination rates. Many enzymes appear to use radical chemistry inthe conversion of substrates to products. There are also relevant findings,
by others, on the redistribution of cell surface receptors. And as seen inan earlier section, there are clear relationships with melatonin and the
dopamine-opiate systems. There is much more that I could spell outand discuss, but much that is important is well defined by others in the
chapters that I've included in this book.
In sum, this chapter is not intended to be comprehensive. It isintended to provide the reader with an integrative framework or context
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with which to view the abundance of information from diverse lines of
research that are detailed in the other chapters in this book. AsBurke1
might 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 field
interactions with biological systems. These results will ultimately helpchange the face of biology.
The foregoing also provides the reader with a sense of the changein the Universe that is taking place in one portion of the current
revolution in biology, i.e. in research on the interactions of
electromagnetic fields with biological systems. And it also indicates how
pervasive are the interactions and their broad implications for biology.Endogenous and exogenous electromagnetic fields are fundamental
factors regulating life. Fully understanding their interactions withbiological systems will be a quantum leap in biology.
Footnote
* Frey, et al 97determined that low intensity em fields modify theblood-brain-barrier (BBB). Immediately after exposure, rats wereinjected intravenously with sodium fluorescein, a fluorescent dye
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classically used for such studies that normally does not pass the BBB.Compared to sham-exposed controls, fluorescence 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 exposingrats to em fields to assess the uptake of several radioactive neutral polar
substances in the brain. Barrier permeability increases were observed.It was also found that em fields of the same average power but different
pulse characteristics produced different uptake levels. Albert 99exposedChinese hamsters to em fields and injected them with various electron
dense tracers. Specimens were then prepared for light and electronmicroscopic examination. The exposed and sham-exposed groupsdiffered 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 isdependent on normal iron metabolism; it plays a crucial role in
neuroleptic-induced dopamine supersensitivity. The dopaminergicantagonist 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 permeabilityof the blood-brain-barrier to [14C]alpha-aminoisobutyric acid in 10-12
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week and 28-30 week old rats. Following intraperitoneal injection ofhaloperidol an increase in the permeability of the BBB was observed in
older rats.References
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