Multiple Chemical Sensitivity Etiology
Airway Genetics and Ambient Combustion Aerosol
MCS 3ab: MCS Community - Unprofessional Conflict of Interest
MCS 3ab: MCS Community - Unprofessional Conflict of Interest
Expertise from the Most Prestigious Academic, Medical, and Government Research Facilities
Outline
I. Conflict of Interest
A. Serious Disease - Not Low Level
B. Reality Dismissed
C. MCS Community Reputation
D. I Know Nothing I See Nothing
E. Ann's New World Dictionary
F. Informed Simplicity
1. Environmental Illness
2. MCS
II. MCS 2020 Consensus Criteria
III. Receptors and Agonists
A. Early Recognition
B. Increased Precision
IV. Ambient Environment
A. PM Defined
B. Airway Metabolism
V. Multiple Organ Systems
A. MCS Chain Reaction
B. Summary of Some Detail
I. Conflict of Interest
A. Serious Disease - Not Low Level
While authors may have intended generous inclusivity - the 1999 MCS Consensus language - in light of present scientific knowledge - lacks adequate disclosure. The toxic ambient environment is dismissed as low level, commonly tolerated - and a serious disease of genetics and exposure is called a syndrome in response to unrelated chemicals. With 1999 language - false physiological and psychological explanations prosper.
B. Reality Dismissed
Conflict of interest says climate change doesn't exist. MCS Community conflict of interest dictates the toxic ambient combustion aerosol PM 2.5 and UFPM with thousands of adsorbed chemicals and metals on carbonaceous cores doesn't exist. This is the same aerosol with CO2 causing global warming.
C. MCS Community Reputation
There has been refusal to acknowledge the highly qualified research professionals who have reported the serious harm of toxic ambient environment - many of whom don't say MCS out loud - avoiding association with the disreputable MCS Community.
D. I Know Nothing I See Nothing
Wikipedia renamed MCS idiopathic intolerance - we don't know what it is disease, and ME/CFS was renamed Systemic Exertion Intolerance Disease (SEID) by Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - the Institute of Medicine, National Academies Press 2015. The renaming is inappropriate. ME/CFS people are not intolerant of their exertion - they are intolerant of the toxic environment in which the exertion is taking place - immune activation - elevated systemic inflammatory markers (Maes 2012) and brain neuroinflammation including increase of activated microglia and astrocytes found to correlate with the degree of cognitive impairment (Nakatomi 2014).
The renaming serves conflict of interest by minimizing the relationship between toxic ambient environment and disease.
E. Ann's New World Dictionary
Under rating ambient combustion aerosol (ACA) toxicity - much like climate change - is failure to recognize the obvious. At predicted catastrophic global 4 degree F rise - 2 already - if urgent action is not taken - at 4 two July years at 88 - new average 92 - third year 31 July days at 100. We have already seen grouping temperature in 2020 - way above record heat, drought, and wildfires.
Concerning the ACA, obviously every breath exhaust and smoke is making people sick. My efforts have been met with: you don't like the message - alienate the messenger. Though we should be friends, I have received discourtesy. In loving concern for all of us: Cynthia Wilson, Pamela Gibson, Martin Pall, Maff (Matthew) Iain Hogg, and our more outspoken polluted air advocates - we should all be together - we should be friends.
Pamela, Albert Donnay, and Leonard Jason are 1999 Consensus authors. Albert says MCS has increased because the air is too clean - Northwest Washington D.C. is too clean? Leonard said: "Looks good, thorough" but then disappeared - except he may be principle in renaming ME/CFS - Systemic Exertion Intolerance Disease. In other words, according to Leonard - running in Chicago exhaust - sick and tired when you are done is because you are intolerant of your exertion! Don't you know it feels better to run in clean air than in vehicle exhaust?
Ann reports on her website that the air is dramatically cleaner. According to the Ann McCampbell New World Dictionary of the English Language: clean air is clean air - and polluted air is defined as dramatically clean. According to EPA - bad and worse air quality categories are good and moderate - when actually air quality is poor in every US Census district. In most areas, the best you get is a bad day. Don't you know that a continuous gook exists over two thirds of the United States 100% of the time - urban and rural?
Taken together, according to the MCS Community: we are intolerant of our physical, systemic, and cognitive exertion in the dramatically clean air. Therefore, the environment gets a whitewash - fault is with the defective susceptibles - MCS, ME/CFS, asthma, AD, PD, COPD, some cancer, exascerbation of heart disease and stroke - because the air is dramatically clean.
The 1999 Consensus reverses reality. The truth is MCS people are genetically sensitive to a polluted environment. Pollution not always visible and rum dumb - you forget every breath is polluted. Bad becomes good - and spiked to recognition it becomes moderate. Neurotic - maladapted to reality - you don't correct the problem. That's why we need 2020 Consensus language - 1999 language is rum dumb neurotic - 2020 language is reality.
The difference between 1999 and 2020 is receptors and agonists - activation by aerosol constituents. MCS people demonstrate continuous inflammation at baseline - before any personal or study provocation - elevated neuropeptide release from sensory nerve receptors, cerebral hypoperfusion and hypoactivity, altered immune markers, and severe multiple dysfunction of detox enzymes.
Most onset of MCS and increased presence of abnormal baseline measures occur at older age - consistent with the cumulative effects of ambient exposure.
It was not lost on Orriols 2009 that dramatically clean ambient UFPM is responsible for baseline cerebral hyporperfusion and hypoactivity in MCS people:
"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 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)..."
More than Elder 2006 have confirmed UFPM to be culprit:
"...Tight junctions are critical barrier features in tissues throughout the body. In the olfactory epithelium, tight junctions are found at the apical surface of cells, adjacent to the nasal airways..."
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 ..."
"...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-1 beta...can...disrupt the BBB...
...Breakdown of the nasal barrier in pollution exposed subjects may also contribute to brain inflammation by increasing the access of PM to the brain through the olfactory and trigeminal pathways..."
"...The results obtained support that nano-sized DEPs (diesel exhaust particles) do in fact translocate to the central nervous system through the olfactory nerve..."
"...Although the neuronal architecture of the olfactory and trigeminal systems differ , the fact that both have sensory receptors within the nasal epithelium and project directly to the CNS suggest that similar pathways for toxicant entry may exist ...
...These data support the conclusion that a similar pattern of uptake may occur within the trigeminal system as has been observed in the olfactory system...
...into the CNS in concentrations greater than those found with systemic distribution and without penetrating the blood-brain barrier...
...These data underscore the importance of considering routes of toxicant entry that allow for bypassing of the protection afforded by the blood brain barrier, and the importance of understanding the conditions under which these pathways are operative..."
F. Informed Simplicity
1. Environmental Illness
Although MCS is likely a neural portrait of genetic differences - more receptors on airway sensory neurons and greater neuropeptide release (Veronesi 2001, 2000, Roy 2000) - there is complexity concerning the interaction of toxic environment and genetic predisposition - usually impossible to interrogate all the genetic contributions to an individual case. However, summed up in a statement of informed simplicity and proper acknowledgement: sick from inhaling air pollution defines the umbrella term environmental illness - toxic ambient environment and personal exposure history combined with genetics determine the specific disease. Personal exposure history may include not only chemical - but also EMF, x-rays, infections, medications, drugs, exercise, and nutritional factors.
ME/CFS, AD, PD, and COPD are also environmental illness as in the following:
ME/CFS
Nakatomi 2014 found brain neuroinflammation using positive emission tomography (PET) including activated microglia and astrocytes in correlation with the degree of cognitive impairment.
MAES 2012:
"...Inflammatory and oxidative and nitrosative stress (IO & NS) pathways play a key role in the pathophysiology of ME/CFS (Maes 2010). The findings encompass a low grade inflammation, as indicated by an increased production of nuclear factor kB (NFkB), and cyclooxygenase (COX-2), and inducible nitric oxide synthase (iNOS) (Maes 2007a, 2007b); immune activation with increased expression of activation markers, e.g. CD8+ and CD38+ and HLA-DR+ markers (Lorusso 2009); increased levels of cytokines including interleukin(IL) 1 alpha, IL-1beta, IL-4, IL-5, IL-6 and lowered IL-8, IL-13, and IL-15 levels (Fletcher 2009, Lorusso 2009)..."
AD and PD
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...
...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 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)..."
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...
...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..."
"...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..."
COPD
"...DEP injures respiratory epithelia via a luminal -apical unloading mechanism of DEP organics delivered by carbonaceous nanoparticles...
...the particles' carbonaceous cores are coated with thousands of organics and heavy metals. Because large numbers of hazardous chemicals are present on DEP, its pathological effects on human airways are pleiotropic. We and others have found that DEP evokes the secretion of matrix metallo-proteinase-1 (MMP-1) from human bronchial epithelia (Li 2009, Amara 2007). Matrix metalloproteinase-1 (MMP-1) plays a role in tissue remodeling during development, inflammation, migration of inflammatory and malignant cells, and COPD and emphysemia pathogenesis (Segura-Valdez 2000). It also has neurotropic effects, possibly enhancing sensitization of airway-innervating sensory neurons, contributing to airway hypersensitization and chronic cough (Conant 2004)...
...TRPV4-p19s, a human genetic polymorphism previously identified as a COPD susceptibility locus (Zhu 2009), increases MMP-1 activation via increased Ca-2+ influx, providing a mechanistic link between human airway epithelia signaling, airway disease and air pollution...
...TRPV4-p19s as a gain-of-function Ca-2+ permeable channel in a human respiratory epithelia cell line, in response to DEP, links COPD pathogenesis to pathologically increased Ca2+ influx into human respiratory epithelia elicited by a globally relevant air pollutant (DEP)...
...our results imply that two human genetic polymorphisms are linked to respiratory health, TRPV4-p19s and MMP-1(-1607G/GG), thus highlighting the concept of disease susceptibility as a function of genetic "makeup" combined with environmental insults..."
2. MCS
MCS 2020 Consensus language - a statement of informed simplicity - makes proper acknowledgment and disclosure - facts firmly supported by the most qualified - while inclusivity of the 1999 MCS Consensus is maintained.
Please coauthor the MCS 2020 Consensus - professionalism, inclusivity, and proper acknowledgement.
Data relevant to MCS 2020 language is presented below (III, IV, V). Although genetics is not explicitly included in Consensus language - please see
MCS 3ad: MCS Genetics - Likely a Neural Portrait for a concise summary.
It is important to note MCS cannot be explained as simply due to genetic detox enzyme deletion - studies with diagnosed MCS subjects have shown that such deletions occur no more often among MCS people than in the general population (Berg 2010, Deluca 2010). Earlier studies - widely misreported - had smaller numbers (Mckeown-Eyssen 2004) or improper subject group (Schnakenberg 2007, Mckeown-Eyssen 2004, Haley 1999) - Schnakenberg subjects 52% of a general population sample filling out a questionnaire, Mckeown-Eyssen 100% women, and Haley - gulf war veterans. Detox enzyme dysfunction in MCS people usually occurs as a result of elevated systemic inflammation (Deluca 2010, Liptrott 2009, Oslund 2008, Terlecky 2006, Chun 2002, Sterner-Kock 1999, Tinel 1999, Tanabe 1996, Tapner 1996, Nadin 1995, Stadler 1994, Khatsenko 1993).
II. MCS 2020 Consensus Criteria
Please coauthor the MCS 2020 Consensus Criteria.
While leaving five of the six 1999 Consensus Criteria essentially intact - the 2020 Consensus corrects impression MCS is a syndrome in response to unrelated chemicals in a low level, commonly tolerated, non inciting background atmosphere.
Pt 1 of the 1999 Consensus is not included because reproducibility of symptoms upon repeated exposure is affected by masking and overlap of continuous exposure to the ACA and other chemicals - saturating trigeminal and olfactory receptor sites and eliciting both immediate and delayed precipitation of symptomatology.
Multiple Chemical Sensitivity: 2020 Consensus Criteria
1) The condition is chronic
2) Levels of exposure to which most do not attribute symptoms result in precipitation of symptomatology
3) Symptoms may improve when incitants are removed - however exposure to the Ambient Combustion Aerosol (ACA) supporting the disease process is continuous
4) Responses occur to multiple chemicals - usually those having greater acidic, electrophilic, oxidizing, or solvent properties [toxicity] increased further if instilled by particulate vector as in the ACA
5) Symptoms involve multiple organ systems
The 1999 Consensus: 1) symptoms are reproducible with repeated exposure 2) the condition is chronic 3) low levels of exposure [lower than previously or commonly tolerated] result in manifestations of the syndrome 4) symptoms improve or resolve when the incitants are removed 5) responses occur to multiple chemically unrelated substances 6) symptoms involve multiple organ systems
III. Receptors and Agonists
Airway defects increase exposure of receptors to chemicals - including PM which acting as vector - carry adsorbed chemicals and metals. MCS relevant chemicals are those having properties of TRP agonism. The ambient combustion aerosol includes many TRP receptor agonists.
A. Early Recognition
"...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...tumor necrosis factor is produced by lymphocytes..."
MEGGS 1999:
"...The mechanism by which inflammatory conditions are provoked by chemicals is via chemoreceptors on sensory nerve C-fibers with the release of substance P and other mediators of neurogenic inflammation...progression of inflammation to organ damage is possible to those who continue to be exposed..."
"...neurogenic inflammation. In this process, a cascade of cellular and sub-cellular events...the sensory nervous system and its peptidenergic transmitters (i.e. SP, CGRP, NKA) initiate and sustain this inflammation...
...Once released these pro-inflammatory peptides interact with a variety of immune (e.g. lymphocytes, neutrophils, macrophages, eosinophils) and non immune (e.g. smooth muscle, endothelial cells of the vasculature, epithelial cells that line the lumen of the airways and gut, keratinocytes of the skin) target cells...overt symptoms of inflammation (e.g. erythema, edema, vasodilitation, vasoconstriction, mucous secretion) through the phenomenon of the axon reflex... on involvement of the immune system, the initial symptoms of inflammation are exacerbated and perpetuated with resulting tissue damage...
...conditions associated with chemical pollutants are characterized by damage to the epithelial barrier that lines the airways...
... Such damage not only results in the loss of critical neuropeptide deactivating enzymes (e.g. NEP) but allows the sensory fiber to physically extend closer to the airway lumen and in closer proximity to the inhaled PM particles...enhanced and prolonged inflammatory events...increased inflammatory response..."
B. Increased Precision
"...A number of studies have correlated responses to urban PM, including DEP with activation of airway sensory neurons, particularly C and A beta fibers that express Transient Receptor Potential Ankyrin-1 (TRPA1), TRP Vanilloid-1 (TRPV1), and substance P (Hazari 2011, Costa 2010, Anand 2008, Nassenstein 2008, Kobayashi 2005)...
...TRPA1 and V1 are members of the superfamily of ion channels, and numerous TRP receptors including TRPA1, V1-4, and M8 are highly expressed in the respiratory tract where they can function as environmental sensors...
...TRPA1, M8, and V1-4 all respond to specific chemical irritants (Vriens 2009, Venkatachalam 2007, Voets 2005) and activation of either TRPA1 or V1 in pulmonary sensory nerves causes neurogenic inflammation via the release of substance P (SP) and neurokinin A (NKA) (Baraldi 2010)...
...TRPV1, V3, V4, and M8, but seemingly not TRPA1 or V2, are also expressed by airway epithelial cells, and activation of TRPV1 (Teles 2009, Agopyan 2004, 2003, Veronesi 2003, 2001, 2000, Oortgiesen 2000) and TRPM8 (Sabnis 2008) in these cells by prototype agonists and select forms of environmental PM is coupled with proinflammatory cytokine/chemokine production and apoptosis..."
"...TRPV1 is unlikely to represent the major reactive irritant receptor. TRPV1-deficient mice showed normal respiratory sensitivity to electrophilic agents (acrolein) and solvents (styrene)...(Symanowicz 2004)...TRPV1 lacked responsiveness to acrolein (Dinis 2004)...electrophilic irritants activated only a subset of capsaicin-sensitive neurons (Inoue 2005)...
...TRPA1 (transient receptor potential ankyrin 1) is expressed in a subpopulation of TRPV1-expressing c-fiber neurons...
...acrolein (aldehyde in smog and smoke)...is a potent agonist of...TRPA1 channels (Bautista 2006)...cultured sensory neurons from TRPA1-deficient mice lacked any responsiveness to this irritant suggesting that TRPA1 is the sole chemosensory receptor for acrolein (Bautista 2006)...
...TRPA1 is activated by (smoke constituents) methacrolein, methyl vinyl ketone, and croton aldehyde (Andre 2008, Escalera 2008)...oxidizing agents...hypochlorite (chlorine gas)...(Bessac 2008a)...formaldehyde, acetaldehyde, tear gas agents, and industrial isocyanates (Bang 2007, Bessac 2009, Brone 2008, McNamara 2007)...almost all oxidizing and electrophilic chemicals will affect TRPA1 function...endogenous agonists include reactive oxygen species (ROS), hypochlorite, lipid peroxidation products, cyclopentenone prostaglandins, and isoprostanes...
...a potential explanation for the diversity of TRPA1 agonists (Hinman 2006, Macpherson 2007)...TRPA1 is activated through covalent modification of the channel protein (agreement with Veronesi 2006)...
...aldehydes such as acrolein are strong electropliles and react with cysteine residues (amino acid component of protein)...Hypochlorite, hydrogen peroxide, and other reactive oxygen species directly oxidize cysteine thiols to sulfinic and sulfonic groups (Pereire 1973)...
...TRPA1 can be locked into a constitutively active state, indicating saturation of a reactive site (Hinman 2006)...
...three cysteine residues were crucial for channel activation (Macpherson 2007)...activation of TRPA1 by covalent modification through reactive irritants...dose response relationships and activation kinetics of TRPA1 do not conform to standard pharmacological paradigms and are highly dependent on the chemical status of the cellular and tissue environment...
...TRPA1 agonists show wide divergence, sometimes one or two orders of magnitude...TRPA1 agonist activity will depend on the reversible or irreversible nature of the chemical bonds formed and on agonist membrane permeability...
...since most TRPA1 agonist can react with thiols, cellular and extracellular reduced glutathione levels will affect the reach and potency of inhaled airway irritants. Once glutathione is depleted, either as a consequence of disease or during extended exposures, TRPA1 may respond more strongly (Deluca 2010 found MCS people have severe glutathione depletion). With each breath more reactive agonist is delivered, leading to an increase in covalent modifications and heightened TRPA1 activity...robust TRPA1 induced irritation even at low subacute exposure levels...once irreversibly modified channels may remain active for extended periods of time even when the irritant stimulus is removed...(Bessac 2008a)...
...The multiple chemical sensitivity of TRPA1...tissue injury may sensitize TRPA1 channels through inflammatory signaling pathways, thereby establishing prolonged hypersensitivity to multiple reactive chemicals (Bandell 2004, Bautista 2006, Dai 2007, Jordt 2004)..."
"...the site of action of air-borne environmental irritants is TRPA1 receptor on trigeminal nerve terminals in the epithelium of nasal mucosa. The expression of TRPV1 receptors in trigeminal neurons innervating the nasal mucosa has been demonstrated by receptor binding (Rinder 1996) and immunocytochemical studies (Damann 2006, Dinh 2003)...
...In summary, our results demonstrate that TRPA1 receptor activation by environmental irritants stimulates CGRP release from trigeminal neurons and increases cerebral blood flow and may contribute to headache associated with environmental irritants..."
"...The California bay laurel...the 'headache tree'...inhalation...can cause severe headache crises...
...monoterpene ketone umbellone, the major volatile constituent...
...umbellone stimulates the transient receptor potential ankryin 1 (TRPA1) channel in a subset of peptidergic nocioceptive neurons (recall Bessac 2008 above), activating the trigeminovascular system...
...present data also strengthen the hypothesis that a series of agents, including chlorine, cigarette smoke, formaldehyde, and others that are known to be headache triggers and recently identified as TRPA1 agonists, utilize the activation of this channel on trigeminal nerves to produce head pain...
...our observations identify umbellone, via its selective TRPA1-agonism, as a trigeminovascular stimulator...for the headache-inducing properties of California bay laurel...a similar pathway may represent the underlying mechanism responsible for headache crises triggered in sensitive people by a series of compounds present in environmental pollutants and botanical perfumes/odours (Blau and Solomon 1985, Kelman 2007, Friedman 2009)..."
IV. Ambient Environment
A. PM Defined
"...The major components of PM include transition metals, sulfate and nitrate ions, organics, minerals, adsorbed gases, and biocontaminants (e.g., endotoxins, mold, pollen), attached to a core of carbonaceous material. The size of the particulates found in PM has been inversely related to its inflammatory damage (Pedata 2010, Valavanidis 2008, deHaar 2006, Oberdorster 1996) with smaller, ultra fine size particles being more toxic to the target tissue..."
HIRAIWA 2013:
"...PM-2.5 and UFPM (ultra fine particulate matter less than 0.1 micron median aerodynamic diameter) are primarily derived from direct emissions from combustion processes such as vehicle use of fossil fuel products, wood burning, and coal burning (Bernstein 2004)...several studies have shown that PM 2.5 and UFPM have the strongest association with adverse cardiovascular effects (Franck 2011, Stolzel 2007 ), which is a direct consequence of the systemic response induced by these particles (Nemmar 2002, Nemmar 2001)..."
B. Airway Metabolism
From a point of view not emphasizing the sensory innervation - and also keeping in mind many MCS people develop detox enzyme dysfunction.
During combustion particles are generated and PAHs (polycyclic aromatic hydrocarbons) form in the gas phase. When the exhaust cools - PAHs adsorb or condense on the particles (Burtscher 1998).
rapidly desorbed PAHs "...are deposited, slowly absorbed, and extensively metabolized in airway epithelium at prolonged elevation of the local tissue concentration (Gerde 1997)...
...Over 5 months later particles in the lung and lymph nodes had only 37 and 59% of B[a]P desorbed - mostly during the initial rapid release - with the exception of more desorption from particles translocated to the lymph nodes - possibly due to environment within macrophages (Nyberg 1989, Harmsen 1985, Lundborg 1984)..."
"...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)..."
BLOCK 2012:
"...The epithelium of olfactory mucosa has high activity and expression of cytochrome P450 (CYP) isoforms including CYP1A2, 2A, 2B, 2E, and 2G (Longo 2000, Livertoux 1996, Voight 1993). These phase I enzymes catalyze the biotransformation of ambient air pollutants such as polycyclic aromatic hydrocarbons, semi-quinones and quinones into toxic metabolites, such as mutagenic epoxide or reactive oxygen species...
...phase II enzymes in the nasal cavity epithelium, such as UFP-glucuronosyltransferase, epoxide hydrolase, sulfotransferases, and glutathione-S-transferases (Bond 1988), function to detoxify the reactive metabolites formed by CYP dependent activities. Thus, the appropriate balance of phase I and II enzymes in the epithelium of olfactory mucosa may provide a first line of defence for the brain, limiting axonal transport of ambient air pollutants and toxic metabolites from the olfactory nerve cells to the olfactory bulb..."
"...Our results suggest that serious and multiple dysfunctions of chemical defense systems found in MCS patients may mainly not depend on genetic defects, but instead may rely on non-genetic modifications of metabolizing/antioxidant enzyme expression and/or activity, mediated by redox active agents such as NO and inflammatory cytokines..." Found elevated in MCS patients (Dantoft 2014, Deluca 2010)
...Dysfunction of two major antioxidant enzymes and depletion of glutathione inevitably leads to severe oxidative stress and impaired elimination of phase 1 oxidation metabolites. Excessive amounts of hydrogen peroxide due to catalase deficiency will initiate a non enzymatic free radical driven chain reaction of lipid peroxidation implicated in a number of human pathologies..."
V. Multiple Organ Systems
A. MCS Chain Reaction
"...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... Found elevated in MCS patients (Dantoft 2014)...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..."
The MCS chain reaction: stimulation of exposed sensory nerves including peptidergic TRPAI expressing terminals - in damaged airway epithelium - affects all systems - central sensitization (Latremoliere 2009), detox enzyme dysfunction (Deluca 2010, Liptrott 2009, Oslund 2008, Terlecky 2006, Chun 2002, Sterner-Kock 1999, Tinel 1999, Tanabe 1996, Tapner 1996, Nadin 1995, Stadler 1994, Khatsenko 1993), oxidative stress (Deluca 2010), cerebral hypoperfusion (Belpomme 2015, Orriols 2009), cardiovascular atherogenesis (Bai 2013, Baldwin 1998), and autonomic imbalance (Dantoft 2015, Hazari 2011).
"...central sensitization...activity or use dependent form of functional synaptic plasticity that resulted in pain hypersensitivity...triggered by the activity evoked in dorsal horn neurons by input from c-nociceptors...chemical activation of nociceptors by irritant compounds...the TRPA1 channel...TRPV1 channels...
...The key features of acute activity-dependent central sensitization are that it is induced with a short latency (seconds) by intense, repeated, or sustained nociceptor inputs and typically lasts for tens of minutes to several hours in the absence of further nociceptor input...
...It generally requires activation of NMDA receptors for its induction, and these receptors contribute to its maintenance. Nevertheless, as reviewed above, multiple different triggers can contribute to the establishment of this form of central sensitization: glutamate acting on NMDAR, but also on AMPAR and mGluR, the neuropeptides substance P and CGRP, the kinin bradykinin, as well as BDNF and NO..."
"...cerebral hypoperfusion in one or two of the hemisphere in 50.5% of the cases...
Near 40% had a increase in histaminemia (especially when both conditions were present), indicating a chronic inflammatory response can be detected in these patients.
Nitrotyrosin, a marker of both peroxynitrite (ONOO°-) production and opening of the blood-brain barrier (BBB), was increased in 28% the cases. Protein S100B, another marker of BBB opening was increased in 15%.
Circulating autoantibodies against O-myelin were detected in 23%, indicating EHS and MCS may be associated with autoimmune response.,
We found increased Hsp27 and/or Hsp70 in 33% of the patients.
We serially measured the brain blood flow (BBF) in the temporal lobes of each case with pulsed cerebral ultrasound computed tomosphygmography (UCTS). Both disorders were associated with hypoperfusion in the capsulothalamic area, suggesting that the inflammatory process involve the limbic system and the thalamus. Our data strongly suggest that EHS and MCS can be objectively characterized and routinely diagnosed by commercially available simple tests. Both disorders appear to involve inflammation-related hyper-histaminemia, oxidative stress, autoimmune response, capsulothalamic hypoperfusion and BBB opening, and a deficit in melatonin metabolic availability; suggesting a risk of chronic neurodegenerative disease..."
"...a single exposure to particulate matter (PM) or gaseous air pollutants has the potential to "sensitize" the heart to subsequent arrhythmogenic stimuli, which is further worsened by the presence of underlying cardiovascular disease (Hazari 2009)...
...the airways are innervated by sensory nerves bearing transient receptor potential (TRP) channels; namely, member A1 (TRPA1), and member V1 (TRPV1), which detect different types of noxious chemicals, including many of those found in the complex mixtures of common air pollutants such as DE. Activation of these nerves by airborne irritants such as ozone or acrolein causes centrally mediated autonomic "imbalance", which produces ventilatory, pulmonary, and cardiovascular function changes (Bessac 2008, Ghelfi 2008, Bautista 2006)..."
"...the MCS group perceived the n-butanol exposure as being more intense, more unpleasant and rated symptoms to be of greater magnitude compared to controls...additionally, individuals with MCS had higher than normal pulse rate and lower than normal pulse rate variability...indicating abnormal regulation of the sympathetic branch of the autonomic nervous system during the exposure..."
B. Summary of Some Detail
Airway damage and exposed C-fiber nerves - including TRPA1 expressing peptidergic neurons (Materazzi 2013, Battacharya 2008, Bessac 2008, Veronesi 2001, Meggs 1997, 1996, 1993)
reactive and measurable (Millqvist 2005, Nogami 2004)
result in the MCS chain reaction: elevated plasma levels of neuropeptides, chemokines, cytokines, growth factors, and NO that mediate serious and multiple dysfunction of metabolizing and antioxidant enzymes (Deluca 2010, Liptrott 2009, Oslund 2008, Chun 2002, Sterner-Kock 1999, Tinel 1999, Tanabe 1996, Tapner 1996, Nadin 1995, Stadler 1994, Khatsenko 1993) - endogenous production of electrophiles and oxidants in an environment of oxidative stress - glutathione depletion and catalase deficiency - suppression of cytochrome P450 and aryl hydrocarbon receptor activity - high levels of hydrogen peroxide and 4 HNE - an atherogenic fatty acid profile of lipid peroxidation (Dantoft 2014, Deluca 2010, Kimata 2004) and increased cardiopulmonary disease risk (Baldwin 1998)
ongoing flu-like symptoms (Dantoft 2014, Bascom 1992)
porphyrin abnormalities (Hahn 1997, Daniell 1997)
and central nervous system effects - xenobiotic penetration including UFPM (ultrafine particulate matter) and mediators of inflammation - intense, repeated, and sustained inputs from exposed airway sensory nerves - including TRPA1 expressing peptidergic terminals - involving TRPA1, TRPV1, substance P, CGRP, NKA, cytokines, NO, BDNF, bradykinin, glutamate, NMDAR, AMPAR, and mGluR (Materazzi 2013, Nassini 2011, Latremoliere 2009, Battacharya 2008) cause neurocognitive impairment, SPECT hypoactivity, permanent neuronal damage - reduced inhibitory activity in the olfactory pathways to the orbito-frontal cortex and the limbic system (Orriols 2009, Elder 2006), electroencephalographic alterations (Bell 1998, 1996), central sensitization - a functional synaptic plasticity resulting in pain hypersensitivity (Tran 2013, Holst 2011, Latremoliere 2009), and Belpomme 2015 - in measurement of reduced brain blood flow in the temporal lobes reported cerebral capsulothalamic hypoperfusion - a potentially lightheaded hypoxia in approx 50% of MCS cases further confirming involvement of the limbic system and thalamus in the inflammatory process.
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).
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