Multiple Chemical Sensitivity Etiology
Airway Genetics and Ambient Combustion Aerosol
MCS Etiology 2018 Update: Activated Microglia
MCS 3 Definition and Consensus Criteria
MCS 3a Criteria Amendment Research Points (CAR)
MCS 3aa Etiology: Consensus Author CAR Test (SPC)
MCS Etiology 2018 Update: Activated Microglia
MCS Etiology is the most advanced and credible research work and comprehensive bibliography of data relevant to Multiple Chemical Sensitivity.
If not acknowledged and corrected - environmental illness and rapidly warming climate will continue due to PM aerosol and greenhouse gases.
Nakatomi 2014 - overlooked earlier and recently added to MCS Etiology bibliography - confirmed using Positive Emission Tomography - increase of activated microglia and astrocytes evidencing brain neuroinflammation in ME/CFS patients and found to correlate with degree of cognitive impairment.
SPC 7 and part of SPC 9 of the CAR Test are presented below - addressing the expectation of increased activated microglia not only in Alzheimers (AD) and Parkinsons (PD) - but also in MCS and ME/CFS. The CAR Test instructs: for each SPC choose the INCORRECT statement. SPC 7k and SPC 9h are the easy to identify incorrect statements for SPC 7 and 9 - two of the 35 SPC comprising the online (or book form) CAR Test.
SPC 7 ACA UFPM: Olfactory, BBB, AD, PD, MCS, and ME/CFS
SPC 7a)
BLOCK 2009:
"...Major sources of PM2.5 include oil refineries, metal processing facilities, tailpipe and brake emissions from mobile sources, residential fuel combustion, power plants and wildfires (Muhlfeld 2008, Rothen-Rutishauser 2008, Valavanidis 2008).
However, UFPM is widely implicated in PM-associated pathology, as their nanometer size makes these particles the most effective size for lung deposition, penetration, and effects extending beyond the respiratory tract (Craig 2008). The primary contributors to UFPM are tailpipe emissions from mobile sources (motor vehicles, aircraft, and marine vessels) (Muhlfeld 2008)...
...Alarmingly, UFPM levels are unmonitored and unregulated in the USA, but exposure is estimated to be high..."
SPC 7b)
GILLESPIE 2013:
"...Numerous clinical and experimental studies have...identified the brain to be neurochemically and neuropathologically affected by various types and sizes of PM air pollution (Gerlofs-Nijland 2010, Campbell 2009, 2005, Calderon-Garciduenas 2008, 2007, Sunyer 2008, Zanchi 2008, Sirivelu 2006, Block 2004)...
...In the central nervous system (CNS), oxidative stress is largely mediated by microglia, which are macrophage-like, phagocytic cells that are activated by a broad range of stimuli, including PM (Sama 2007, Block 2004) and nanoparticles (Long 2006). Once activated, the microglia produce multiple reactive oxygen species (ROS) such as hydrogen peroxide, hydroxyl radicals and peroxynitrites (Block 2007, Fariss 2005) that can diffuse from their plasma membrane and damage nearby neurons..."
SPC 7c)
"...Ultrafine (nano-size particles) and fine particles are the most notorious of air pollution components, penetrating lung tissue compartments to reach the capillaries and circulating cells, or constituents (e.g. erythrocytes) (Valavanidis 2008)...
...ultrafine particles have a large surface to volume ratio (Rothen-Rutishauser 2008) and easily penetrate cellular membranes (Geiser 2005). This provides insight into why UFPM is able to traverse traditional barriers in the lung and the BBB, including why PM is found in neurons and carried in erythrocytes...
SPC 7d)
...The nasal olfactory pathway is believed to be a key portal of entry, where inhaled nanoparticles have been shown to reach trigeminal nerves, brainstem, and hippocampus (Wang 2008, 2007)...particulate matter has been observed in human olfactory bulb periglomerular neurons and particles smaller than 100nm were observed in intraluminal erythrocytes from frontal lobe and trigeminal ganglia capillaries (Calderon-Garciduenas 2008)...air pollution components reach the brain (Peters 2006), even penetrating deep into the parenchyma...
...Alzheimer's (AD) and Parkinsons Disease (PD) share early pathology in the olfactory bulb, nuclei, and pathways, with olfactory deficits being one of the earliest findings in both diseases (Doty 2008)...
SPC 7e)
...As the most prevalent neurodegenerative disease (Hirtz 2007), Alzheimer's Disease (AD) affects more than 4 million people in the United States and an estimated 27 million are affected worldwide (Wimo 2006). Parkinsons Disease (PD) is a devastating movement disorder and is the second most prevalent neurodegenerative disease (Hirtz 2007), affecting 1-2% of the population over the age of 50 (Thomas 2007)..."
"...Parkinson's disease (PD) is a progressive neurodegenerative disease affecting about 1.6% of the general population aged over 65 (deRijk 1997)...
...The clinical symptoms of PD, manifest as the loss of initiation and control of movement and appear only after a substantial loss of dopaminergic neurons (50-60%) in the substantia nigra pars compacta (SNpc) in the midbrain (Pakkenberg 1991)..."
SPC 7f)
BLOCK 2004:
"...DEP (diesel exhaust particles) are selectively toxic to DA (dopaminergic) neurons through microglia-mediated ROS production...
...A predominant pathology of PD is the specific degeneration of DA neurons, while other neuronal subtypes remain generally unaffected. The neuron-glia culture model used in this study demonstrates that DEP neurotoxicity is selective to DA neurons...
...DA neurons possess reduced antioxidant capacity, as evidenced by low intracellular glutathione that render DA neurons more vulnerable to oxidative stress and microglial activation, relative to other cell types (Loeffler 1994). Additionally, the mesencephalon houses the SN and contains 4.5 times as many microglia when compared with the cortex (Kim 2000)...
...our data show that DEP activate microglia, that microglia are crucial to DEP-induced DA neurotoxity, that DEP stimulated microglia to produce free radicals (superoxide), and that NADPH oxidase is the source of DEP-induced microglial ROS responsible for DA neurotoxicity..."
SPC 7g)
...The toxicity and immune-stimulating characteristics of DEP in the lung have been linked to both the adsorbed chemicals on the outside of the carbon particle and the physical characteristics of the particle itself (Ma 2002)...
...several compounds known to be toxic to DA neurons (polyaromatic hydrocarbons, quinones, and transition metals) are also found on DEP (Ma 2002). However, most of the potentially neurotoxic compounds adsorbed to DEP induce oxidative stress through redox-cycling with cytochrome P450 activity (Ma 2002, Kumagai 1995) and not through NADPH oxidase activation...
...carbon black particles, which lack all chemical and biological adsorbed compounds, have been shown to produce oxidative stress in cells through the NADPH oxidase pathway (Ma 2002). Together this supports that physiochemical factors of DEP are culpable in microglia activation..."
"...In airway epithelial cells, DEP (diesel exhaust particles) via their organic components (polycyclic aromatic hydrocarbons PAHs including benzo[a]pyrene desorbed from the carbonaceous core), modify the cellular redox state...induce phase I (CYP1A1) and phase II (NQO-1) gene expression and can be metabolized,,,numerous genes implicated in detoxification...activated via xenobiotic responsive element and ARE (antioxidant responsive element) as well as in the secretion of proinflammatory cytokines via NFkB responsive element (Bonvallot 2001)..."
"...catalytic activities of cytochrome P450 are known to produce ROS directly and also generate biologic reactive intermediates, including quinones, which produce ROS by redox cycling (Bolton 2000)...
...CB (carbonaceous core) exhibit oxidative properties as they deplete the antioxidant defenses in the epithelial lining fluid (Ziedinski 1999) and induce DNA strand scission in plasmidic DNA (Stone 1998)...
...the carbonaceous core could be considered mostly as a vector allowing the entry of organic compounds into the cells and their slow diffusion leading to sustained stimulation of the cells as native diesel exhaust particles-induced NFkB DNA binding started later but was more persistent than that induced by organic extracts of diesel exhaust particles...(Boland 2000,1999, Bonvallot 2000, Baeza-Squiban 1999, Bayram 1998, Kumagai 1997, Thomas 1997)..."
SPC 7h)
"...Breakdown of the nasal respiratory and olfactory epithelium and the BBB (Blood Brain Barrier) facilitates the access of systemic inflammatory mediators and components of air pollution to the central nervous system (CNS) (Calderon-Garciduenas 2004)...
...sustained exposures to significant levels of air pollutants including UFPM (ultrafine particulate matter) , PM2.5 (less than 2.5 microns), and PM-LPS produce brain neuroinflammation and neurodegeneration through at least four pathways...
...1 Induction of upper respiratory, lung epithelial, and endothelial injury leading to persistent chronic inflammation in the respiratory tract and systemic inflammation. The systemic inflammation is accompanied by the production of pro-inflammatory cytokines such as TNF alpha, IL 6 and IL-1beta...these cytokines can activate endothelial cells in the BBB, disrupt the BBB...and trigger cascades...results in increased expression of nitric oxide synthase...and nitric oxide production that opens the BBB...
...2 We strongly support the importance of the olfactory pathway...since olfactory neurons are loaded with PM...will potentially translate into an abnormality in the limbic system...(Bedard 2004)...
..3 The vagus/trigeminal (Lewis 2005) pathways are also crucial, given that PM enters the respiratory and digestive systems...
...4 Direct access of UFPM to the brain, further accentuating an inflammatory response in the brain parenchyma...
...Long term exposure to air pollution should be considered a risk factor for both Alzheimer's and Parkinsons diseases and APOE 4 allele carriers could have a higher risk of developing AD..."
SPC 7i)
SPECT studies of MCS patients
"Neurologic dysfunction observed prior to chemical exposure could point to persistent subclinical neurologic changes. In fact, basal SPECT brain cortical hypoactivity was found in our [MCS] patients. In animal models, inflammation and permanent damage of the olfactory neuronal pathways could result from translocation of inhaled ultrafine particles to the brain (Elder 2006)..."
SPC 7j)
Revisiting remarks from SPC 5: Those with MCS and ME/CFS have elevation of IL-1beta, IL-6, and other cytokines with increased COX-2 (cyclooxygenase-2), NFkB (nuclear factor kB), and iNOS (inducible nitric oxide synthase) confirmed in ME/CFS (Maes 2007a, 2007b) - and Orriols 2009 found MCS people have olfactory dysfunction - in that regard members of the AD, PD, MCS family - one might suspect ME/CFS may also join.
There may not be any data on whether AD and PD occur more frequently as a comorbidity with MCS or ME/CFS.
On a personal anecdotal note: some 24 years ago - for 7 months this CAR test author and MCS sufferer took care of a retired music professor with PD named Al Suvak - he preferred his window open while sleeping and when a smoker visited - not smoking in the house but bringing in residue - I was bothered by it and Al's nose would run.
SPC 7k)
We love our cars and trucks - Block 2004 findings that DEP (diesel exhaust particles) are formidable adversaries of the critical Parkinson's Disease (PD) dopaminergic neurons via microglial activation and subsequent oxidative burst - collateral damage of microglia DEP phagocytosis - is just an in vitro study - not to worry.
And just because AD and PD are accompanied with or preceded by olfactory dysfunction indicating airway defects and increased penetration of UFPM including DEP - with PM confirmed in the OB (olfactory bulb) of human subjects (Calderon-Garciduenas 2010, 2008) doesn't matter either.
PD symptoms are not apparent until nearly half the dopaminergic neurons are destroyed (Datla 2007, Merck 1999, Pakkenberg 1991) - do we have termites or what?
We will not admit the thief in the bank vault might have something to do with the robbery. Thousands of studies - we don't like science. Until DEP tells us in their own language they are bad - there is not enough proof - we cannot and will not be convinced - and besides we are proud of Rudolph Diesel's achievement - more miles per gallon of fuel makes a great battlefield advantage and sales incentive. And just to make sure you know where we are coming from: global air and water temperatures are up - therefore it is a mini ice age.
SPC 9 Veronesi: Sensory Nerve Insight
(9f-h presented here - click on link to the complete SPC)
SPC 9f)
An additional complication concerns more particles reaching the lower airway to be involved with alveolar macrophages because of the less than intact respiratory nasal mucosa that Meggs 1997, Calderon-Garciduenas 2001, and Veronesi 2001 have described - resulting in greater release of polymorphonuclear leukocytes (PMN) from the bone marrow and still more cytokine production.
Biopsy of MCS subjects
"...There are defects in the tight junctions between respiratory epithelial cells, focal desquamation of the epithelial cells in places, hypertrophy of glandular structures, lymphocytic infiltrates, and proliferation of sensory nerve fibers..."
CALDERON-GARCIDUENAS 2001:
"...PM clearance from the nose depends largely on intact mucociliary mechanisms, and whereas deposition of particles larger than 3 microns (um) takes place in the anterior part of the nose (devoid of ciliated epithelium), particles beween 0.5 and 3 um are filtered by an intact respiratory nasal mucosa and transported by ciliary propulsion to the nasopharynx (Fry 1973)...
...Chronic exposures to air pollutants pose significant public health concerns for healthy individuals as well as those at higher risk, such as asthmatics and patients with compromised cardiorespiratory function. A compromised nasal epithelium has a diminished ability to protect itself and the lower respiratory tract..."
"...We conclude that repeated exposure to PM-10 (particulate matter less than 10 microns in diameter) stimulates the bone marrow to increase the production of polymorphonuclear leukocytes (PMN) in the marrow and accelerate the release of more immature PMN into the circulation. The magnitude of these changes was related to the amount of particles phagocytosed by alveolar macrophages..."
"...alveolar macrophages, epithelial and other cells interact with the particles to produce a wide variety of cytokines and chemokines that generate a local inflammatory immune response. These mediators spill over into the blood to stimulate the bone marrow to increase the release of leukocytes from the marrow, and the liver to increase the production of a variety of acute phase proteins. This systemic response is associated with vascular activation and the progression of the atherosclerotic process..."
Baldwin 1998 found increased cardiopulmonary disease risk in a community based sample having odor intolerance.
It is cause, effect, and catastrophe - illness and premature death - perpetuated by the use of combustion based transportation and woodstoves.
"...elevation in the levels of circulating leukocytes is an important predictor of both an excessive decline in lung function (Chan-Yeung 1988) and increased all cause mortality (Weiss 1995)..."
"...The results in this study show that a low level of atmospheric PM is associated with a decrease in bone marrow stimulation, which results in decreased circulating segmented PMN, band formed PMN, and monocyte counts...IL-6 levels were parallel with band formed counts...
...It is considered that the atmospheric PM level is one of the important factors affecting circulating leukocyte counts and basal inflammatory status...
...Multiple regression test showed that PM levels had more significant effects on segmented PMN, band formed PMN, and monocyte counts than cigarette smoking and type of work..."
"...Of all the pollutants, inhalable particles (PM-10) showed the strongest association with adverse respiratory health effects (Schwartz 1995)...data from large population cohorts have indicated an association between exposure to PM and cardiovascular morbidity and mortality (Brook 2010, Eftim 2008, Miller 2007, Pope 2004)...due to the systemic inflammatory response induced by exposure to PM air pollution (Hogg 2009)..."
Sensory nerves - including TRPA1 expressing peptidergic terminals - exposed in a damaged airway epithelium of tight junction defects and focal desquamation (Meggs 1997) - in contact with ACA PM and other chemicals - are activated to excessive release of neurotransmitters (Kimata 2004, Veronesi 2001, Meggs 1997). MCS people suffer intense, repeated, and sustained input - changes in neural plasticity referred to as central sensitization ( Latremoliere 2009) - and evidence electroencephalographic alterations (Bell 1998, 1996) and SPECT hypoactivity strongly suggestive of UFPM to the CNS (Calderon-Garciduenas 2010, 2008, Orriols 2009, Elder 2006).
SPC 9g)
Because MCS people have airway defects there may be a sharing of at least some aspects of the following description (Block 2009, Calderon-Garciduenas 2008).
Airway breakdown occurs universally beginning in childhood among non-smoking residents of ACA PM 2.5, UFPM, and PM LPS - highly polluted Mexico City (MC) (Calderon-Garciduenas 2008,2001) - and is accompanied by a closely investigated CNS pathology of neuroinflammation - subclinical early - but associated with eventual neurodegeneration due to ACA PM, adsorbed compounds, byproducts of ozone exposure (photochemical smog resulting principally from vehicle exhaust), and cytokines reaching the brain.
The CNS condition includes increased inflammatory markers iNOS (inducible nitric oxide synthase), TNF alpha, Il-1beta, COX-2 (cyclooxygenase-2), and NFkB (nuclear factor kB) especially in frontal cortex, substantia nigrae, and vagus nerves (found systemically elevated in ME/CFS [Maes 2012]),
neuron damage or loss, microglial activation (innate immune system macrophages of the brain - their job to engulf and digest but with cumulative collateral damage) indicated by increase of HLA-DR surface antigen positive cells and CD-14 lipopolysaccharide (LPS) receptors - LPS a potent inflammatory cell wall component of gram negative bacteria (endotoxin) commonly adsorbed on DEP (diesel exhaust particles) (Block 2004) - with resulting ROS (reactive oxygen species) and cytokine production, blood-brain barrier (BBB) dysfunction - changes in inflammatory, tight junction, and transport proteins of the cerebral vascular microvessels (3 to 8 micron diameter) that comprise the BBB - endothelial cell damage with increase in leukocyte adhesion molecules - and confirmed using Positive Emission Tomography - activated microglia and astrocytes evidencing brain neuroinflammation in ME/CFS patients - found to correlate with degree of cognitive impairment (Nakatomi 2014) - and two markers of BBB opening - nitrotyrosin and protein S100B - elevated in a subset of MCS and EHS (electrohypersensitivity) subjects (Belpomme 2015).
accumulation of Abeta-42 (42 amino acid form of amyloid beta) as neuronal, vascular and diffuse plaques, Abeta and alpha synuclein aggregation (associated with Alzheimers and Parkinsons Disease respectively) - CALDERON-GARCIDUENAS 2008:"...Both Abeta42 (42 amino acid-isoform of beta amyloid associated with Alzheimer's) and alpha synuclein ( an abundant brain 140-residue-protein linked to Parkinson's disease) are proteins capable of aggregation and misfolding (shown to occur more rapidly in conditions of PM exposure), leading to progressive neurodegeneration that develops insidiously over the lifetime of the individual (McGeer 2006, Jellinger 2003, Nguyen 2002, Selkoe 2002, 2001)...",
lipid peroxidation (systemically confirmed in MCS people [Deluca 2010]), astrogliosis evidenced by enhanced glial fibrilliary acid protein (GFAP) expression, and DNA damage (Block 2009, Calderon-Garciduenas 2008).
In contrast, non-smoking residents of less polluted cities Veracruz and Tlaxcala - upon the same examination appeared in good shape during childhood - but four of the five oldest subjects age 27 and above - 27, 36, 40, and 45 demonstrated either dysruption of the BBB (blood-brain barrier) by confocal microscopy for tight junction abnormalities (Zonula Occlulens ZO-1) or Abeta42 (42 amino acid-isoform of beta amyloid) immunoreactivity by immunohistochemistry in olfactory bulb and cortical neurons of one subject - and in diffuse and mature senile plaques in another - a preAlzheimer's-like indicator of brain neuroinflammation (Calderon-Garciduenas 2008).
Although more is worse - there is no safe level of chronic and repeated exposure to combustion byproducts including vehicle exhaust.
SPC 9h)
Damage to the barrier that lines the airways and proliferation of exposed sensory nerve fibers found in MCS people (Meggs 1997) does not result in a neuroimmune inflammatory response to ACA PM and other chemicals with systemic multi-organ implications.
MCS 3 Definition and Concensus Criteria
MCS 3a Criteria Amendment Research Points (CAR)
MCS 3aa Etiology: Concensus Author CAR Test (SPC)
Lost from website - google MCS Etiology
Nakatomi Y. et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: A 11C-(R)-PK11195 PET Study. Journal of Nuclear Medicine 55(6): 945-50 Pubmed 24665088, 2014
Summary: increase in activated microglia and astrocytes using positive emission tomography (PET) - positive correlation between activated microglia and astrocytes in the amygdala, thalamus, and midbrain - and cognitive impairment of these subjects.
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