Ferrum Phos
Banned
Full text: http://www.pathophysiologyjournal.com/article/S0928-4680(13)00037-0/fulltext
Abstract
Although autism spectrum conditions (ASCs) are defined behaviorally, they also involve multileveled disturbances of underlying biology that find striking parallels in the physiological impacts of electromagnetic frequency and radiofrequency exposures (EMF/RFR). Part I of this paper will review the critical contributions pathophysiology may make to the etiology, pathogenesis and ongoing generation of core features of ASCs. We will review 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 will review 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. 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 worsening 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. Physiological pathogenesis and mechanisms of autism spectrum conditions
2.1.2. More than brain
Although ‘autism’ has long been considered to be a psychiatric or neurological brain-based disorder [[12], [13]], people diagnosed with ASCs often have many biological features including systemic pathophysiological disturbances (such as oxidative stress, mitochondrial dysfunction and metabolic and immune abnormalities) [[14], [15], [16], [17]] as well as symptomatic medical comorbidities (such as gastrointestinal distress, recurrent infections, epilepsy, autonomic dysregulation and sleep disruption) [[18], [19], [20], [21], [22], [23], [24], [25], [26]] in addition to the core defining behaviors [27]. Because of variability among individuals, the relevance of many of these biological features has been dismissed as secondary and not intrinsically related to the ‘autism.’
2.2.2. Mechanisms that operate actively throughout the life-course
EMF/RFR effects can occur within minutes (Blank, 2009) and may, in part, explain clinical reports of ‘intermittent autism’ – for example, some children with mitochondrial disease who have ups and downs of their bioenergetics status ‘have autism’ on their bad days but don’t display autistic features on their good days [77]. These children with their vulnerable, barely compensated mitochondria could very well be teetering right at the brink of a minimally adequate interface of metabolic and electrophysiological dysfunction. Everyday exposures to allergens, infection, pesticide on the school playground, as well as EMF/RFR interference with electrophysiology might reasonably contribute to the bad days. Stabilizing more optimal nervous system performance [78] including through environmental control of excessive EMF/RFR exposure could perhaps achieve more ‘good days’.
EMF/RFR exposures have demonstrated biological effects at just about every level at which biology and physiology have been shown to be disrupted in ASCs. Further EMF/RFR has been shown to potentiate the impact of various toxicants when both exposures occur together [80]; this may be additive or more than additive. This suggests that EMF/RFR may synergize with other contributors and make things worse. A cascade of exposures interacting with vulnerabilities in an individual can potentially lead to a tipping point for that person, such as the phenomenon of autistic regression experienced by a substantial subset of people with ASCs.
3. Parallels in pathophysiology
3.1.1. Cellular stress
3.1.1.1. Oxidative stress
Autism (ASC) research indicates that oxidative stress may be a common attribute amongst many individuals with autism. In the past decade the literature on this has moved from a trickle to a flood. Studies document reduced antioxidant capacity, increased indicators of oxidative stress and free radical damage, alterations in nutritional status consistent with oxidative stress, altered lipid profiles, and pertinent changes not only in blood but also in brain tissue. Associations of ASCs with environmental exposures such as air pollution and pesticides are indirectly supportive as well, since such exposures are linked in other literature to oxidative stress [[43], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101]].
Less often mentioned in the ASC pathophysiology literature is that it is also well established that EMF/RFR exposures can be associated with oxidative damage. Published scientific papers that demonstrate the depth of EMF and RFR evidence reporting oxidative damage in human and animal models are profiled by Lai and colleagues [[102], [103], [104]]. These cellular effects can occur at low-intensity, legal levels of exposure that are now ‘common environmental levels’ for pregnant women, the fetus, the infant, the very young child, and the growing child as well as for adults. Electromagnetic fields (EMF) can enhance free radical activity in cells [[105], [106]] particularly via the Fenton reaction, and prolonging the exposure causes a larger increase, indicating a cumulative effect. The Fenton reaction is a catalytic process of iron to convert hydrogen peroxides, a product of oxidative respiration in the mitochondria, into hydroxyl free radical, which is a very potent and toxic free radical [[103], [104]]. Free radicals damage and kill organelles and cells by damaging macromolecules, such as DNA, protein and membrane components.
Further indications of a link to oxidative stress are findings that EMF and RFR at very low intensities can modulate glutamate, glutathione and GABA, and affect mitochondrial metabolism. Alterations in all these substances and processes have been documented in ASCs [[25], [86], [89], [90], [92], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127]]. On the EMF/RFR side, Campisi et al. (2010) report that increased glutamate levels from 900 MHz cell phone frequency radiation on primary rat neocortical astroglial cell cultures induced a significant increase in ROS levels and DNA fragmentation after only 20 min with pulsed RFR at non-thermal levels [128].
Aberrations in glutathione metabolism and deficiencies in reserves of reduced glutathione are increasingly associated with ASCs, both systemically and in the brain. The parallel with EMF/RFR impacts here is strong, since glutathione reduction associated with EMF/RFR is reported in at least twenty three relevant research studies in both human and animal studies since 1998, including the following citations [[130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144]]. It is increasingly appreciated that glutathione is a final common pathway, a critical piece of environmentally vulnerable physiology, as glutathione reserves are compromised by an enormous number of environmental stressors, so that the cumulative impact upon glutathione may be far greater than could be predicted by the magnitude of any specific exposure [145], which supports an ‘allostatic loading’ model.
3.1.2.2. Calcium channels
EMF/RFR exposures have been shown to alter or disturb calcium signaling [185] through a variety of mechanisms, including membrane leakage [186], alteration of calcium-binding proteins and GFAP reactivity [[187], [188]], and altered ultrastructural distribution of calcium and calcium-activated ATPases after exposure [189]. Adey (2002) provided an overview of key studies on calcium efflux and the importance of calcium in cell signaling. “Early studies described calcium efflux from brain tissue in response to ELF exposures [[190], [191]], and to ELF-modulated RF fields [[190], [191], [192], [193]]. Calcium efflux from isolated brain subcellular particles (synaptosomes) with dimensions under 1.0 μm also exhibit an ELF modulation frequency-dependence in calcium efflux, responding to 16 Hz sinusoidal modulation, but not to 50 Hz modulation, nor to an unmodulated RF carrier [194]. In the same and different cell culture lines, the growth regulating and stress responsive enzyme ornithine decarboxylase (ODC) responds to ELF fields [[170], [195]] and to ELF-modulated RF fields.” [[168], [170], [171], [196]].
3.1.3. Junctions and barriers
Such connections between cells can also be altered by electromagnetic fields and radiofrequency exposures, at least under certain circumstances. High frequency magnetic fields have been observed to be associated with a sharp decrease in intercellular gap junction-like structures, in spite of increased gene expression for pertinent proteins [209]. Changes in tight junctions have been observed upon exposure to microwave and x-ray irradiation [210].
3.1.4.1. Genotoxicity
Genotoxicity has been proposed as a mechanism for the generation of ‘de novo’ mutations (found in children but not their parents) being found in ASCs [260]. Reviews and published scientific papers on genotoxicity and EMF report that both ELF-EMF and RFR exposures are genotoxic – i.e., damaging to DNA – under certain conditions of exposure, including under conditions of intermittent and/or chronic ELF and RFR exposure that are of low-intensity and below current world safety standards [[104], [105], [261], [262], [263], [264], [265], [266]]. Types of genetic damage reported have included DNA fragmentation and single- and double-strand DNA breaks, micronucleation and chromosome aberrations, all of which indicate genetic instability [[102], [103]].
3.1.4.1.3. Implications of genotoxicity
The issue of genotoxicity puts the contribution of genetic variation into a different light – as something that needs to be accounted for, not necessarily assumed as the starting point. In this regard it has been speculated that the apparent higher rates of autism in Silicon Valley, discussed in the past as related to ‘geek genes’[296], might be conditioned by higher levels of exposure to EMF/RFR. The relationship between the greater vulnerability of male sperm than of female eggs to adverse effects of EMF/RFR exposure and the marked (4:1) predominance of paternal origin of de novo point mutations (4:1 bias), also deserves further careful attention [268].
Abstract
Although autism spectrum conditions (ASCs) are defined behaviorally, they also involve multileveled disturbances of underlying biology that find striking parallels in the physiological impacts of electromagnetic frequency and radiofrequency exposures (EMF/RFR). Part I of this paper will review the critical contributions pathophysiology may make to the etiology, pathogenesis and ongoing generation of core features of ASCs. We will review 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 will review 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. 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 worsening 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. Physiological pathogenesis and mechanisms of autism spectrum conditions
2.1.2. More than brain
Although ‘autism’ has long been considered to be a psychiatric or neurological brain-based disorder [[12], [13]], people diagnosed with ASCs often have many biological features including systemic pathophysiological disturbances (such as oxidative stress, mitochondrial dysfunction and metabolic and immune abnormalities) [[14], [15], [16], [17]] as well as symptomatic medical comorbidities (such as gastrointestinal distress, recurrent infections, epilepsy, autonomic dysregulation and sleep disruption) [[18], [19], [20], [21], [22], [23], [24], [25], [26]] in addition to the core defining behaviors [27]. Because of variability among individuals, the relevance of many of these biological features has been dismissed as secondary and not intrinsically related to the ‘autism.’
2.2.2. Mechanisms that operate actively throughout the life-course
EMF/RFR effects can occur within minutes (Blank, 2009) and may, in part, explain clinical reports of ‘intermittent autism’ – for example, some children with mitochondrial disease who have ups and downs of their bioenergetics status ‘have autism’ on their bad days but don’t display autistic features on their good days [77]. These children with their vulnerable, barely compensated mitochondria could very well be teetering right at the brink of a minimally adequate interface of metabolic and electrophysiological dysfunction. Everyday exposures to allergens, infection, pesticide on the school playground, as well as EMF/RFR interference with electrophysiology might reasonably contribute to the bad days. Stabilizing more optimal nervous system performance [78] including through environmental control of excessive EMF/RFR exposure could perhaps achieve more ‘good days’.
EMF/RFR exposures have demonstrated biological effects at just about every level at which biology and physiology have been shown to be disrupted in ASCs. Further EMF/RFR has been shown to potentiate the impact of various toxicants when both exposures occur together [80]; this may be additive or more than additive. This suggests that EMF/RFR may synergize with other contributors and make things worse. A cascade of exposures interacting with vulnerabilities in an individual can potentially lead to a tipping point for that person, such as the phenomenon of autistic regression experienced by a substantial subset of people with ASCs.
3. Parallels in pathophysiology
3.1.1. Cellular stress
3.1.1.1. Oxidative stress
Autism (ASC) research indicates that oxidative stress may be a common attribute amongst many individuals with autism. In the past decade the literature on this has moved from a trickle to a flood. Studies document reduced antioxidant capacity, increased indicators of oxidative stress and free radical damage, alterations in nutritional status consistent with oxidative stress, altered lipid profiles, and pertinent changes not only in blood but also in brain tissue. Associations of ASCs with environmental exposures such as air pollution and pesticides are indirectly supportive as well, since such exposures are linked in other literature to oxidative stress [[43], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101]].
Less often mentioned in the ASC pathophysiology literature is that it is also well established that EMF/RFR exposures can be associated with oxidative damage. Published scientific papers that demonstrate the depth of EMF and RFR evidence reporting oxidative damage in human and animal models are profiled by Lai and colleagues [[102], [103], [104]]. These cellular effects can occur at low-intensity, legal levels of exposure that are now ‘common environmental levels’ for pregnant women, the fetus, the infant, the very young child, and the growing child as well as for adults. Electromagnetic fields (EMF) can enhance free radical activity in cells [[105], [106]] particularly via the Fenton reaction, and prolonging the exposure causes a larger increase, indicating a cumulative effect. The Fenton reaction is a catalytic process of iron to convert hydrogen peroxides, a product of oxidative respiration in the mitochondria, into hydroxyl free radical, which is a very potent and toxic free radical [[103], [104]]. Free radicals damage and kill organelles and cells by damaging macromolecules, such as DNA, protein and membrane components.
Further indications of a link to oxidative stress are findings that EMF and RFR at very low intensities can modulate glutamate, glutathione and GABA, and affect mitochondrial metabolism. Alterations in all these substances and processes have been documented in ASCs [[25], [86], [89], [90], [92], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [118], [119], [120], [121], [122], [123], [124], [125], [126], [127]]. On the EMF/RFR side, Campisi et al. (2010) report that increased glutamate levels from 900 MHz cell phone frequency radiation on primary rat neocortical astroglial cell cultures induced a significant increase in ROS levels and DNA fragmentation after only 20 min with pulsed RFR at non-thermal levels [128].
Aberrations in glutathione metabolism and deficiencies in reserves of reduced glutathione are increasingly associated with ASCs, both systemically and in the brain. The parallel with EMF/RFR impacts here is strong, since glutathione reduction associated with EMF/RFR is reported in at least twenty three relevant research studies in both human and animal studies since 1998, including the following citations [[130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144]]. It is increasingly appreciated that glutathione is a final common pathway, a critical piece of environmentally vulnerable physiology, as glutathione reserves are compromised by an enormous number of environmental stressors, so that the cumulative impact upon glutathione may be far greater than could be predicted by the magnitude of any specific exposure [145], which supports an ‘allostatic loading’ model.
3.1.2.2. Calcium channels
EMF/RFR exposures have been shown to alter or disturb calcium signaling [185] through a variety of mechanisms, including membrane leakage [186], alteration of calcium-binding proteins and GFAP reactivity [[187], [188]], and altered ultrastructural distribution of calcium and calcium-activated ATPases after exposure [189]. Adey (2002) provided an overview of key studies on calcium efflux and the importance of calcium in cell signaling. “Early studies described calcium efflux from brain tissue in response to ELF exposures [[190], [191]], and to ELF-modulated RF fields [[190], [191], [192], [193]]. Calcium efflux from isolated brain subcellular particles (synaptosomes) with dimensions under 1.0 μm also exhibit an ELF modulation frequency-dependence in calcium efflux, responding to 16 Hz sinusoidal modulation, but not to 50 Hz modulation, nor to an unmodulated RF carrier [194]. In the same and different cell culture lines, the growth regulating and stress responsive enzyme ornithine decarboxylase (ODC) responds to ELF fields [[170], [195]] and to ELF-modulated RF fields.” [[168], [170], [171], [196]].
3.1.3. Junctions and barriers
Such connections between cells can also be altered by electromagnetic fields and radiofrequency exposures, at least under certain circumstances. High frequency magnetic fields have been observed to be associated with a sharp decrease in intercellular gap junction-like structures, in spite of increased gene expression for pertinent proteins [209]. Changes in tight junctions have been observed upon exposure to microwave and x-ray irradiation [210].
3.1.4.1. Genotoxicity
Genotoxicity has been proposed as a mechanism for the generation of ‘de novo’ mutations (found in children but not their parents) being found in ASCs [260]. Reviews and published scientific papers on genotoxicity and EMF report that both ELF-EMF and RFR exposures are genotoxic – i.e., damaging to DNA – under certain conditions of exposure, including under conditions of intermittent and/or chronic ELF and RFR exposure that are of low-intensity and below current world safety standards [[104], [105], [261], [262], [263], [264], [265], [266]]. Types of genetic damage reported have included DNA fragmentation and single- and double-strand DNA breaks, micronucleation and chromosome aberrations, all of which indicate genetic instability [[102], [103]].
3.1.4.1.3. Implications of genotoxicity
The issue of genotoxicity puts the contribution of genetic variation into a different light – as something that needs to be accounted for, not necessarily assumed as the starting point. In this regard it has been speculated that the apparent higher rates of autism in Silicon Valley, discussed in the past as related to ‘geek genes’[296], might be conditioned by higher levels of exposure to EMF/RFR. The relationship between the greater vulnerability of male sperm than of female eggs to adverse effects of EMF/RFR exposure and the marked (4:1) predominance of paternal origin of de novo point mutations (4:1 bias), also deserves further careful attention [268].