Ferrum Phos
Banned
Full text: http://www.pathophysiologyjournal.com/article/S0928-4680(13)00038-2/fulltext
Abstract
Autism spectrum conditions (ASCs) are defined behaviorally, but they also involve multileveled disturbances of underlying biology that find striking parallels in the physiological impacts of electromagnetic frequency and radiofrequency radiation exposures (EMF/RFR). Part I (Vol 776) of this paper reviewed the critical contributions pathophysiology may make to the etiology, pathogenesis and ongoing generation of behaviors currently defined as being core features of ASCs. We reviewed pathophysiological damage to core cellular processes that are associated both with ASCs and with biological effects of EMF/RFR exposures that contribute to chronically disrupted homeostasis. Many studies of people with ASCs have identified oxidative stress and evidence of free radical damage, cellular stress proteins, and deficiencies of antioxidants such as glutathione. Elevated intracellular calcium in ASCs may be due to genetics or may be downstream of inflammation or environmental exposures. Cell membrane lipids may be peroxidized, mitochondria may be dysfunctional, and various kinds of immune system disturbances are common. Brain oxidative stress and inflammation as well as measures consistent with blood–brain barrier and brain perfusion compromise have been documented. Part II of this paper documents how behaviors in ASCs may emerge from alterations of electrophysiological oscillatory synchronization, how EMF/RFR could contribute to these by de-tuning the organism, and policy implications of these vulnerabilities. It details evidence for mitochondrial dysfunction, immune system dysregulation, neuroinflammation and brain blood flow alterations, altered electrophysiology, disruption of electromagnetic signaling, synchrony, and sensory processing, de-tuning of the brain and organism, with autistic behaviors as emergent properties emanating from this pathophysiology. Changes in brain and autonomic nervous system electrophysiological function and sensory processing predominate, seizures are common, and sleep disruption is close to universal. All of these phenomena also occur with EMF/RFR exposure that can add to system overload (‘allostatic load’) in ASCs by increasing risk, and can worsen challenging biological problems and symptoms; conversely, reducing exposure might ameliorate symptoms of ASCs by reducing obstruction of physiological repair. Various vital but vulnerable mechanisms such as calcium channels may be disrupted by environmental agents, various genes associated with autism or the interaction of both. With dramatic increases in reported ASCs that are coincident in time with the deployment of wireless technologies, we need aggressive investigation of potential ASC—EMF/RFR links. The evidence is sufficient to warrant new public exposure standards benchmarked to low-intensity (non-thermal) exposure levels now known to be biologically disruptive, and strong, interim precautionary practices are advocated.
2. Parallels in pathophysiology
2.1. Degradation of the integrity of functional systems
EMF/RFR exposures can yield both psychological and physiological stress leading to chronically interrupted homeostasis. In the setting of molecular, cellular and tissue damage, one would predict that the organization and efficiency of a variety of organelles, organs and functional systems would also be degraded. In this section we will review disturbances from EMF/RFR in systems (including include oxidative and bioenergetics metabolism, immune function and electrophysiological oscillations) that include molecular and cellular components subject to the kinds of damage discussed in the previous section. We will review disturbances that have been associated with EMF/RFR, and consider the parallel disturbances that have been documented in ASCs.
2.1.1. Mitochondrial dysfunction
Mitochondria are broadly vulnerable, in part because the integrity of their membranes is vital to their optimal functioning—including channels and electrical gradients, and their membranes can be damaged by free radicals which can be generated in myriad ways. Moreover, just about every step in their metabolic pathways can be targeted by environmental agents, including toxicants and drugs, as well as mutations [1]. This supports a cumulative ‘allostatic load’ model for conditions in which mitochondrial dysfunction is an issue, which includes ASCs as well as myriad other chronic conditions.
These electromagnetic aspects of mitochondrial physiology and pathophysiology could very well be impacted by EMF/RFR.
Other types of mitochondrial damage have been documented in at least some of the studies that have examined the impacts of EMF/RFR upon mitochondria. These include reduced or absent mitochondrial cristae [[4], [5], [6]], mitochondrial DNA damage [7], swelling and crystallization [5], alterations and decreases in various lipids suggesting an increase in their use in cellular energetics [8], damage to mitochondrial DNA [7], and altered mobility and lipid peroxidation after exposures [9]. Also noted has been enhancement of brain mitochondrial function in Alzheimer's transgenic mice and normal mice [10]. The existent of positive as well as negative effects gives an indication of the high context dependence of exposure impacts, including physical factors such as frequency, duration, and tissue characteristics [11].
Secondary mitochondrial dysfunction (i.e. environmentally triggered rather than rooted directly in genetic mutations) [[15], [16], [17], [18]] could result among other things from the already discussed potential for EMF/RFR to damage channels, membranes and mitochondria themselves as well as from toxicant exposures and immune challenges. In a meta-analysis of studies of children with ASC and mitochondrial disorder, the spectrum of severity varied, and 79% of the cases were identified by laboratory findings without associated genetic abnormalities [16].
2.1.2. Melatonin dysregulation
2.1.2.1. Melatonin, mitochondria, glutathione, oxidative stress
Melatonin is well-known for its role in regulation of circadian rhythms, but it also plays important metabolic and regulatory roles in relation to cellular protection, mitochondrial malfunction and glutathione synthesis [[19], [20], [21]]. It also helps prevent the breakdown of the mitochondrial membrane potential, decrease electron leakage, and thereby reduce the formation of superoxide anions [22]. Pharmacological doses of melatonin not only scavenge reactive oxygen and nitrogen species, but enhance levels of glutathione and the expression and activities of some glutathione-related enzymes [[21], [23]].
2.1.2.3. Melatonin and autism
Regarding melatonin status in people with ASCs, a recent meta-analysis summarized the current findings as indicating that “(1) Physiological levels of melatonin and/or melatonin derivatives are commonly below average in ASC and correlate with autistic behavior, (2) Abnormalities in melatonin-related genes may be a cause of low melatonin levels in ASD, and (3) … treatment with melatonin significantly improves sleep duration and sleep onset latency in ASD.” [44].
The meta-analysis also showed that polymorphisms in melatonin-related genes in ASC could contribute to lower melatonin concentrations or an altered response to melatonin, but only in a small percentage of individuals, since pertinent genes were found in only a small minority of those screened.
Based on the common presence of both sleep disorders and low melatonin levels, Bourgeron [45] proposed that synaptic and clock genes are important in ASCs, and that future studies should investigate the circadian modulation of synaptic function [45]. A number of melatonin-related genetic variants have been identified as associated with ASCs. Polymorphisms and deletions in the ASMT gene, which encodes the last enzyme of melatonin synthesis, have been found [[46], [47], [48]], and variations have been found as well for melatonin receptor genes [[46], [47], [49]]. CYP1A2 polymorphisms have been found in slow melatonin metabolisers, in whom melatonin levels are aberrant and initial response to melatonin for sleep disappeared in a few weeks [50].
2.1.3.1. Low-intensity exposures
The body's immune defense system is now known to respond to very low-intensity exposures [70]. Chronic exposure to factors that increase allergic and inflammatory responses on a continuing basis is likely to be harmful to health, since the resultant chronic inflammatory responses can lead to cellular, tissue and organ damage over time. Many chronic diseases are related to chronic immune system dysfunction. Disturbance of the immune system by very low-intensity electromagnetic field exposure is discussed as a potential underlying cause for cellular damage and impaired healing (tissue repair), which could lead to disease and physiological impairment [[71], [72]]. Both human and animal studies report that exposures to EMF and RFR at environmental levels associated with new technologies can be associated with large immunohistological changes in mast cells as well as other measures of immune dysfunction and dysregulation. Mast cells not only can degranulate and release irritating chemicals leading to allergic symptoms; they are also widely distributed in the body, including in the brain and the heart, which might relate to some of the symptoms commonly reported in relation to EMF/RFR exposure (such as headache, painful light sensitivity, and cardiac rhythm and palpitation problems).
2.1.4.1. Brain cells
Impact of EMF/RFR on cells in the brain has been documented by some of the studies that have examined brain tissue after exposure, although the interpretation of inconsistencies across studies is complicated by sometimes major differences in impact attributable to differences in frequencies and duration of exposure, as well as to differences in resonance properties of tissues and other poorly understood constraints on cellular response. These studies and methodological considerations have been reviewed in depth in several sections of the 2012 BioInitiative Report [[11], [99]]. A few examples of observations after exposure have included dark neurons (an indicator of neuronal damage), as well as alteration of neuronal firing rate [100], and upregulation of genes related to cell death pathways in both neurons and astrocytes [101]. Astrocytic changes included increased GFAP and increased glial reactivity [[102], [103], [104], [105]], as well as astrocyte-pertinent protein expression changes detected by Fragopoulou et al. [322] as mentioned above. Also observed has been a marked protein downregulation of the nerve growth factor glial maturation factor beta (GMF) which is considered as an intracellular signal transduction regulator in astrocytes, which could have significant impact on neuronal-glial interactions as well as brain cell differentiation and tumor development. Diminution of Purkinje cell number and density has also been observed, [106] including in two studies of the impacts of perinatal exposure [[107], [108]]. Promotion of pro-inflammatory responses in EMF-stimulated microglial cells has also been documented [109].
2.1.4.4. Brain blood flow and metabolism
While a large number of animal studies have documented blood–brain barrier (BBB) abnormalities from EMF/RFR exposures, only a few PET studies have been performed evaluating EMF exposure effects upon brain glucose metabolism. Volkow et al. performed PET scans both with and without EMF exposure (50 min of GSM-900 with maximum SAR of 0.901 W/kg), and the participants were blinded to the exposure situation [192]. A 7% increase in metabolism in the exposure situation compared to controls was identified regionally on the same side of the head as where the mobile phone was placed. The strength of the E-field from the phones correlated positively with the brain activation, which the authors hypothesized was from an increase in brain neuron excitability. A subsequent smaller study by Kwon et al. demonstrated not increased but decreased brain 18FDG uptake after GSM-900 exposure [193].
2.1.5.5. Autonomic dysregulation
Although there are a fair number of negative studies regarding the impact of EMF/RFR exposure on the autonomic nervous system, increased HRV and autonomic disturbances have been documented [[252], [253], [254], [255], [256]]. Buchner and Eger [257], in a study in rural Germany of the health impacts of exposures from a new base station yielding novel exposure to EMF/RFR, saw a significant elevation of the stress hormones adrenaline and noradrenaline during the first six months with a concomitant drop in dopamine, with a failure to restore the prior levels after a year and a half. These impacts were felt by the young, the old and the chronically ill, but not by healthy adults [257].
Neonate vulnerability was documented by Bellieni et al. [258] who found that heart rate variability is adversely affected in infants hospitalized in isolettes or incubators where ELF-EMF levels are in the 0.8 to 0.9 μT range (8 to 9 mG). Infants suffer adverse changes in heart rate variability, similar to adults [258]. This electromagnetic stress may have lifelong developmental impacts, based on a study showing that in-utero beta 2 agonist exposure can potentially induce a permanent shift in the balance of sympathetic-to-parasympathetic tone [259].
3. Implications
3.1. Exposures and their implications
Several thousand scientific studies over four decades point to serious biological effects and health harm from EMF and RFR [[298], [299]]. These studies report genotoxicity, single-and double-strand DNA damage, chromatin condensation, loss of DNA repair capacity in human stem cells, reduction in free-radical scavengers (particularly melatonin), abnormal gene transcription, neurotoxicity, carcinogenicity, damage to sperm morphology and function, effects on behavior, and effects on brain development in the fetus of human mothers that use cell phones during pregnancy. Cell phone exposure has been linked to altered fetal brain development and ADHD-like behavior in the offspring of pregnant mice [83].
Abstract
Autism spectrum conditions (ASCs) are defined behaviorally, but they also involve multileveled disturbances of underlying biology that find striking parallels in the physiological impacts of electromagnetic frequency and radiofrequency radiation exposures (EMF/RFR). Part I (Vol 776) of this paper reviewed the critical contributions pathophysiology may make to the etiology, pathogenesis and ongoing generation of behaviors currently defined as being core features of ASCs. We reviewed pathophysiological damage to core cellular processes that are associated both with ASCs and with biological effects of EMF/RFR exposures that contribute to chronically disrupted homeostasis. Many studies of people with ASCs have identified oxidative stress and evidence of free radical damage, cellular stress proteins, and deficiencies of antioxidants such as glutathione. Elevated intracellular calcium in ASCs may be due to genetics or may be downstream of inflammation or environmental exposures. Cell membrane lipids may be peroxidized, mitochondria may be dysfunctional, and various kinds of immune system disturbances are common. Brain oxidative stress and inflammation as well as measures consistent with blood–brain barrier and brain perfusion compromise have been documented. Part II of this paper documents how behaviors in ASCs may emerge from alterations of electrophysiological oscillatory synchronization, how EMF/RFR could contribute to these by de-tuning the organism, and policy implications of these vulnerabilities. It details evidence for mitochondrial dysfunction, immune system dysregulation, neuroinflammation and brain blood flow alterations, altered electrophysiology, disruption of electromagnetic signaling, synchrony, and sensory processing, de-tuning of the brain and organism, with autistic behaviors as emergent properties emanating from this pathophysiology. Changes in brain and autonomic nervous system electrophysiological function and sensory processing predominate, seizures are common, and sleep disruption is close to universal. All of these phenomena also occur with EMF/RFR exposure that can add to system overload (‘allostatic load’) in ASCs by increasing risk, and can worsen challenging biological problems and symptoms; conversely, reducing exposure might ameliorate symptoms of ASCs by reducing obstruction of physiological repair. Various vital but vulnerable mechanisms such as calcium channels may be disrupted by environmental agents, various genes associated with autism or the interaction of both. With dramatic increases in reported ASCs that are coincident in time with the deployment of wireless technologies, we need aggressive investigation of potential ASC—EMF/RFR links. The evidence is sufficient to warrant new public exposure standards benchmarked to low-intensity (non-thermal) exposure levels now known to be biologically disruptive, and strong, interim precautionary practices are advocated.
2. Parallels in pathophysiology
2.1. Degradation of the integrity of functional systems
EMF/RFR exposures can yield both psychological and physiological stress leading to chronically interrupted homeostasis. In the setting of molecular, cellular and tissue damage, one would predict that the organization and efficiency of a variety of organelles, organs and functional systems would also be degraded. In this section we will review disturbances from EMF/RFR in systems (including include oxidative and bioenergetics metabolism, immune function and electrophysiological oscillations) that include molecular and cellular components subject to the kinds of damage discussed in the previous section. We will review disturbances that have been associated with EMF/RFR, and consider the parallel disturbances that have been documented in ASCs.
2.1.1. Mitochondrial dysfunction
Mitochondria are broadly vulnerable, in part because the integrity of their membranes is vital to their optimal functioning—including channels and electrical gradients, and their membranes can be damaged by free radicals which can be generated in myriad ways. Moreover, just about every step in their metabolic pathways can be targeted by environmental agents, including toxicants and drugs, as well as mutations [1]. This supports a cumulative ‘allostatic load’ model for conditions in which mitochondrial dysfunction is an issue, which includes ASCs as well as myriad other chronic conditions.
These electromagnetic aspects of mitochondrial physiology and pathophysiology could very well be impacted by EMF/RFR.
Other types of mitochondrial damage have been documented in at least some of the studies that have examined the impacts of EMF/RFR upon mitochondria. These include reduced or absent mitochondrial cristae [[4], [5], [6]], mitochondrial DNA damage [7], swelling and crystallization [5], alterations and decreases in various lipids suggesting an increase in their use in cellular energetics [8], damage to mitochondrial DNA [7], and altered mobility and lipid peroxidation after exposures [9]. Also noted has been enhancement of brain mitochondrial function in Alzheimer's transgenic mice and normal mice [10]. The existent of positive as well as negative effects gives an indication of the high context dependence of exposure impacts, including physical factors such as frequency, duration, and tissue characteristics [11].
Secondary mitochondrial dysfunction (i.e. environmentally triggered rather than rooted directly in genetic mutations) [[15], [16], [17], [18]] could result among other things from the already discussed potential for EMF/RFR to damage channels, membranes and mitochondria themselves as well as from toxicant exposures and immune challenges. In a meta-analysis of studies of children with ASC and mitochondrial disorder, the spectrum of severity varied, and 79% of the cases were identified by laboratory findings without associated genetic abnormalities [16].
2.1.2. Melatonin dysregulation
2.1.2.1. Melatonin, mitochondria, glutathione, oxidative stress
Melatonin is well-known for its role in regulation of circadian rhythms, but it also plays important metabolic and regulatory roles in relation to cellular protection, mitochondrial malfunction and glutathione synthesis [[19], [20], [21]]. It also helps prevent the breakdown of the mitochondrial membrane potential, decrease electron leakage, and thereby reduce the formation of superoxide anions [22]. Pharmacological doses of melatonin not only scavenge reactive oxygen and nitrogen species, but enhance levels of glutathione and the expression and activities of some glutathione-related enzymes [[21], [23]].
2.1.2.3. Melatonin and autism
Regarding melatonin status in people with ASCs, a recent meta-analysis summarized the current findings as indicating that “(1) Physiological levels of melatonin and/or melatonin derivatives are commonly below average in ASC and correlate with autistic behavior, (2) Abnormalities in melatonin-related genes may be a cause of low melatonin levels in ASD, and (3) … treatment with melatonin significantly improves sleep duration and sleep onset latency in ASD.” [44].
The meta-analysis also showed that polymorphisms in melatonin-related genes in ASC could contribute to lower melatonin concentrations or an altered response to melatonin, but only in a small percentage of individuals, since pertinent genes were found in only a small minority of those screened.
Based on the common presence of both sleep disorders and low melatonin levels, Bourgeron [45] proposed that synaptic and clock genes are important in ASCs, and that future studies should investigate the circadian modulation of synaptic function [45]. A number of melatonin-related genetic variants have been identified as associated with ASCs. Polymorphisms and deletions in the ASMT gene, which encodes the last enzyme of melatonin synthesis, have been found [[46], [47], [48]], and variations have been found as well for melatonin receptor genes [[46], [47], [49]]. CYP1A2 polymorphisms have been found in slow melatonin metabolisers, in whom melatonin levels are aberrant and initial response to melatonin for sleep disappeared in a few weeks [50].
2.1.3.1. Low-intensity exposures
The body's immune defense system is now known to respond to very low-intensity exposures [70]. Chronic exposure to factors that increase allergic and inflammatory responses on a continuing basis is likely to be harmful to health, since the resultant chronic inflammatory responses can lead to cellular, tissue and organ damage over time. Many chronic diseases are related to chronic immune system dysfunction. Disturbance of the immune system by very low-intensity electromagnetic field exposure is discussed as a potential underlying cause for cellular damage and impaired healing (tissue repair), which could lead to disease and physiological impairment [[71], [72]]. Both human and animal studies report that exposures to EMF and RFR at environmental levels associated with new technologies can be associated with large immunohistological changes in mast cells as well as other measures of immune dysfunction and dysregulation. Mast cells not only can degranulate and release irritating chemicals leading to allergic symptoms; they are also widely distributed in the body, including in the brain and the heart, which might relate to some of the symptoms commonly reported in relation to EMF/RFR exposure (such as headache, painful light sensitivity, and cardiac rhythm and palpitation problems).
2.1.4.1. Brain cells
Impact of EMF/RFR on cells in the brain has been documented by some of the studies that have examined brain tissue after exposure, although the interpretation of inconsistencies across studies is complicated by sometimes major differences in impact attributable to differences in frequencies and duration of exposure, as well as to differences in resonance properties of tissues and other poorly understood constraints on cellular response. These studies and methodological considerations have been reviewed in depth in several sections of the 2012 BioInitiative Report [[11], [99]]. A few examples of observations after exposure have included dark neurons (an indicator of neuronal damage), as well as alteration of neuronal firing rate [100], and upregulation of genes related to cell death pathways in both neurons and astrocytes [101]. Astrocytic changes included increased GFAP and increased glial reactivity [[102], [103], [104], [105]], as well as astrocyte-pertinent protein expression changes detected by Fragopoulou et al. [322] as mentioned above. Also observed has been a marked protein downregulation of the nerve growth factor glial maturation factor beta (GMF) which is considered as an intracellular signal transduction regulator in astrocytes, which could have significant impact on neuronal-glial interactions as well as brain cell differentiation and tumor development. Diminution of Purkinje cell number and density has also been observed, [106] including in two studies of the impacts of perinatal exposure [[107], [108]]. Promotion of pro-inflammatory responses in EMF-stimulated microglial cells has also been documented [109].
2.1.4.4. Brain blood flow and metabolism
While a large number of animal studies have documented blood–brain barrier (BBB) abnormalities from EMF/RFR exposures, only a few PET studies have been performed evaluating EMF exposure effects upon brain glucose metabolism. Volkow et al. performed PET scans both with and without EMF exposure (50 min of GSM-900 with maximum SAR of 0.901 W/kg), and the participants were blinded to the exposure situation [192]. A 7% increase in metabolism in the exposure situation compared to controls was identified regionally on the same side of the head as where the mobile phone was placed. The strength of the E-field from the phones correlated positively with the brain activation, which the authors hypothesized was from an increase in brain neuron excitability. A subsequent smaller study by Kwon et al. demonstrated not increased but decreased brain 18FDG uptake after GSM-900 exposure [193].
2.1.5.5. Autonomic dysregulation
Although there are a fair number of negative studies regarding the impact of EMF/RFR exposure on the autonomic nervous system, increased HRV and autonomic disturbances have been documented [[252], [253], [254], [255], [256]]. Buchner and Eger [257], in a study in rural Germany of the health impacts of exposures from a new base station yielding novel exposure to EMF/RFR, saw a significant elevation of the stress hormones adrenaline and noradrenaline during the first six months with a concomitant drop in dopamine, with a failure to restore the prior levels after a year and a half. These impacts were felt by the young, the old and the chronically ill, but not by healthy adults [257].
Neonate vulnerability was documented by Bellieni et al. [258] who found that heart rate variability is adversely affected in infants hospitalized in isolettes or incubators where ELF-EMF levels are in the 0.8 to 0.9 μT range (8 to 9 mG). Infants suffer adverse changes in heart rate variability, similar to adults [258]. This electromagnetic stress may have lifelong developmental impacts, based on a study showing that in-utero beta 2 agonist exposure can potentially induce a permanent shift in the balance of sympathetic-to-parasympathetic tone [259].
3. Implications
3.1. Exposures and their implications
Several thousand scientific studies over four decades point to serious biological effects and health harm from EMF and RFR [[298], [299]]. These studies report genotoxicity, single-and double-strand DNA damage, chromatin condensation, loss of DNA repair capacity in human stem cells, reduction in free-radical scavengers (particularly melatonin), abnormal gene transcription, neurotoxicity, carcinogenicity, damage to sperm morphology and function, effects on behavior, and effects on brain development in the fetus of human mothers that use cell phones during pregnancy. Cell phone exposure has been linked to altered fetal brain development and ADHD-like behavior in the offspring of pregnant mice [83].
