Multiple Chemical Sensitivity Etiology
Airway Genetics and Ambient Combustion Aerosol
MCS 2a Etiology: TRPA1 Precision
MCS 2a Etiology: TRPA1 Precision
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Outline
I. Consistency Since 1992
II. TRPA1 Precision
III. To The CNS
IV. The Study of all Studies
V. Detox Enzyme Dysfunction
VI. Genetically Sensitive
VII. Conclusion: Definition and Etiology of MCS
VIII. Links
"...the airway epithelium and the airway surface fluid it produces and regulates are the first line of defence against the multiple, "non-self" constituents in the 10-20,000 liters of air inhaled each day. The airway epithelium is not an inert barrier, as was once thought, but contains a great capacity for xenobiotic metabolism...the observation that the airway can release cytokines...flu-like symptoms, low grade fever, and fatigue that...usually begin several hours after the exposure and last up to 48 hours...a type of acute phase response. Cytokines are now recognized as responsible...
The Danish Research Centre for Chemical Sensitivities, Copenhagen University Hospital, Gentofte, Denmark
"...plasma levels of IL-1 beta, IL-2, IL-4, and IL-6 were found to be statistically significantly increased in MCS, TNF alpha was borderline enhanced, whereas IL-13 was downregulated..."
Division of Toxicology, Department of Emergency Medicine, East Carolina University School of Medicine, Greenville NC.
"...Neurogenic inflammation is now a well defined physiological mechanism by which mediators are directly released from sensory neurons to produce vasodilitation, edema, and other manifestations of inflammation. The nerve fibers have been identified as slow velocity C-fibers and the regulation of neurogenic inflammation has been studied...important regulators of inflammation, interleukin 1 and interleukin 2, suppress central nervous system activity...Found elevated in MCS patients (Dantoft 2014)
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..."
... this is further supported by the increased IL-2 levels. IL-2 is involved in the proliferation and differentiation of lymphocytes, playing a key role in expansion of T-cell, NK cell, and B cell populations, including regulatory cells, during various phases of an immune response(Boyman and Sprent 2012)...
National Health Effects and Research Laboratory (NHEERL), Cellular and Molecular Branch, Neurotoxicology Division, US Environmental Protection Agency, Research Triangle Park, North Carolina. Cato Research LTD., Durham, North Carolina.
...In normal physiological settings, the respiratory epithelial population and its sensory innervation act reciprocally to influence the growth, differentiation, and homeostasis of each other...These relationships are especially critical to the organism's inflammatory response...
...In all instances, sensory neurons release 10-200 fold higher levels of IL-6 (pro-inflammatory cytokine) relative to epithelial cells... Found elevated in MCS patients (Dantoft 2014)...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...
Also at NHEERL US EPA
" A compromised nasal epithelium has a diminished ability to protect itself and the lower respiratory tract..."
"...a persistent ongoing airway inflammatory process the result of exposure to air pollutants in a sequential and chronic manner...the imbalance and dysregulation of cytokines and their ample systemic effects..." Found elevated in MCS patients (Dantoft 2014)
"...The decreased systemic levels of IL-13 may therefore be an indicator of diminished barrier protection, if the reduced IL-13 levels implicate reduced mucus production at mucosal surfaces, and also of reduced inhibition of pro-inflammatory cytokine production within tissues..."
"...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...".
Reactive and Measurable
Department of Allergy, Ujitakeda Hospital, Umonji, Uji, Uji-City, Kyoto Prefecture, Japan
"...plasma levels of SP (substance P), VIP (vasoactive intestinal peptide), and NGF (nerve growth factor), but not histamine are significantly (p<0.01 by ANOVA) elevated in sMCS patients...
exposure to VOC further increased levels of SP, VIP, and NGF...exposure to VOC also increased plasma histamine levels...
these results indicate that sMCS patients may suffer from ongoing neurogenic inflammation which is aggravated by VOC..."
"...after capsaicin provocation the patients showed a significant increase in NGF which was related to capsaicin cough sensitivity...SHR (sensory hypereactivity) is real and measurable, demonstrating a pathophysiology in the airways of these patients compared to healthy subjects...
The Center for Comparative Respiratory Biology and Medicine and Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California
"...substance P...Found elevated in MCS patients (Kimata 2004)... primes and activates human neutrophils for superoxide, H2O2, and nitric oxide production (Sterner-Kock 1999, Tanabe 1996)..."
II. TRPA1 Precision
Department of Pharmacology,
Yale University School of Medicine,
New Haven, Connecticut
"...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)...
...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)..."
Departments of Pharmacology & Toxicology, Anesthesiology, and Neurobiology & Anatomy, University of Utah, 30 South 2000 East, Salt Lake City, Utah 84112, United States
"...A number of studies have correlated responses to urban PM, including DEP (diesel exhaust particles) 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... Found elevated in MCS patients (Kimata 2004) (Hazari 2011, Teles 2009, Anand 2008, Nassenstein 2008, Kobayashi 2005)..."
Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy
...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)..."
The Department of Biochemistry and Molecular Biology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA
"...the site of action of air-borne environmental irritants is TRPA1 receptor on trigeminal nerve terminals in the epithelium of nasal mucosa...
...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..."
"...Both TRPA1 and TRPV1 may contribute to the development of hypersensitivity to noxious stimulations (i.e. hyperalgesia) (Lamotte 1992, Obata 2005, Bautista 2006, Kwan 2006, Dhaka 2006). In addition TRPA1 is activated by certain environmental irritants such as acrolein (Bautista 2006) that fail to activate TRPV1..."
III. To The CNS
Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts
"...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..."
Environmental Public Health Division, US EPA, Research Triangle Park, North Carolina, USA
"...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 (diesel exhaust). 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)..."
Servei de Pneumologia, Hospital Universitari Vall d' Hebron, Barcelona, Catalonia, Spain
SPECT of MCS Subjects
"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)..."
Department of Urban and Environmental Engineering, Kyoto University, Japan
Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA 02115, USA
Division of Environmental Health Sciences, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan
"...The results obtained support that nano-sized DEPs do in fact translocate to the central nervous system through the olfactory nerve..."
Community Environmental Health Program, College of Pharmacy, University of New Mexico Health Sciences Center, MSC 9 5360, Albuquerque, NM 87131-0001, USA
"...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..."
Department of Environmental Health, University of Cincinnati, Cincinnati, OH
"...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..."
IV. The Study of all Studies
Instituto Nacional de Pediatría, Mexico City, Mexico
The College of Health Professions and Biomedical Sciences, The University of Montana, Missoula, Montana, USA
South Shore Psychiatric Program, Harvard University, Brockton, Massachusetts, USA
Departamento de Estadística, Universidad de Valparaíso, Chile
Centro de Ciencias de la Atmósfera, Universidad Nacional Autónoma de México, Mexico City, Mexico
Davidson Honors College, The University of Montana, Missoula, Montana, USA
Pathology Department, Instituto Nacional de Cancerología, Mexico City, Mexico
Center for Environmental Medicine, Asthma and Lung Biology, and Department of Pediatrics,
University of North Carolina, Chapel Hill, North Carolina, USA
Previously at NHEERL US EPA
"...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..."
Institute of Environmental Medicine, Division of Inhalation Toxicology, Stockholm Sweden
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)..."
Laboratoire de Cytophysiologie et Toxicologie Cellulaire, Université Paris VII, Paris; and INSERM U490, Centre Universitaire des Saints-Pères, Paris, France
"...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)..."
ADDENDUM TO THE 1997 FEDERAL HIGHWAY COST ALLOCATION STUDY FINAL REPORT. U.S. DEPARTMENT OF TRANSPORTATION. FEDERAL HIGHWAY ADMINISTRATION MAY 2000:
"...Total social costs of air pollution associated with motor vehicle use are
estimated to range from $30 billion to $349 billion per year (Delucchi 1998). Most of those costs are associated with premature death and illness caused by particulate matter, including both direct particulate emissions and the secondary formation of particulates from other emissions. The wide range of air pollution cost estimates is indicative of the many uncertainties surrounding costs of motor-vehicle-related air pollution..."
Health Economics Program (HEP), Department of Clinical Sciences and Department of Economics, Lund University, SE-205 02 Malmö, Sweden,
"...Moreover, ambient PM, including sulfates, nitrates, and organic aerosols, accounts for about 95% of the total damage cost, and mortality related to ambient PM accounts for about 70% of the total damage cost..."
V. Detox Enzyme Dysfunction
Gene variants in detox enzymes are not major etiology of MCS (Berg 2010, Deluca 2010) and for example: over 50% of the population have one or both of the GSTM1 and GSTT1 deletions (Piacentini 2011, Block 2011, Ginsberg 2009, Hayes 1995) - Schnakenberg 2007 defined 52% of a general population sample as the chemically sensitive group - percentages not corresponding with the incidence of MCS.
DELUCA 2010 whose case group was diagnosed MCS by Cullen criteria (Cullen 1987), found no significant differences in allele and genotype frequencies of CYP's, UGT, GSTM, GSTT, and GSTP between MCS and control groups.
The Danish Research Centre for Chemical Sensitivities, Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Ledreborg Allé 40, 2.th., DK-2820 Gentofte, Denmark
"...In conclusion, based upon a considerable number of study participants, we were not able to confirm previous findings of substantial importance of gene variants in CYP2D6, NAT2, PON1, MTHFR, and CCK2R to MCS and self-reported chemical sensitivity..."
Laboratory of Tissue Engineering & Skin Pathophysiology, Dermatology Institute (IDI IRCCS), Rome, Italy.
"...Notwithstanding the absence of genetic defects in CYPs, recent studies have increasingly implicated various inflammatory stimuli, first of all, pro-inflammatory cytokines (Chun 2002,Nadin 1995, Tapner 1996, Tinel 1999) to cause changes in the activities and expression levels of CYPs through nitric oxide signalling (Chun 2002, Stadler 1994)...
...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..."
VI. Genetically Sensitive
Why are MCS people naturally sensitive - genetically predisposed?
Princeton University Press - Jung's Psychological Types - considered a monumental work in Psychology
R.F.C. Hull Translation
"...extraordinary dependence on sense impressions...this compensates the rarified air of the intuitive's conscious attitude...hypersensitivity of the sense organs..."
NHEERL US EPA
"...taken together, the above in vivo and in vitro studies suggested that the variable inflammatory sensitivity to PM observed in different mouse strains (ie Balb/C, B6) related to quantitative differences in the neuropeptide, VR1 (now TRP) receptors and acid sensitive pathways found on sensory neurons that innervate the nasal and upper pulmonary airway. Such data showed how genetically determined differences in sensory neural pathways could influence expressions of PM-induced airway inflammation...genetic differences are thought to underlie these variations and have been experimentally demonstrated for ozone (Kleeberger 1995, Zhang et al 1995), nitrogen dioxide (Holroyd et al 1997), and diesel exhaust (Ichinose et al 1997, Miyabara et al 1998)..."
Taken together, these data suggest that capsaicin and acid-sensitive irritant receptors, located on somatosensory cell bodies and their nerve fiber terminals, subserve PM-induced airway inflammation and are quantitatively different in responsive and nonresponsive mouse strains..."
In the present study, we use RT-PCR, cobalt histochemistry and immunocytochemical techniques to show that the expression of capsaicin (VR1) and Substance P (NK-1) receptors and the release of inflammatory cytokines and neuropeptides are higher in sensory neurons from BALB/c mice relative to the B6 strain.
These data suggest that the strain-specific inflammatory response to PM and other irritants (i.e. capsaicin, acid sensitive) seen in vivo and in vitro models of PM inflammation is subserved by sensory and neuropeptide receptors..."
Heritability of respiratory symptoms has been shown.
The Danish Research Centre for Chemical Sensitivities, Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Ledreborg Allé 40, 2.th., DK-2820 Gentofte, Denmark
"...In conclusion, we found an increased familial occurrence of perfume-related respiratory symptoms where 35% of phenotypic variation was due to additive genetic effects and 65% was due to individual specific environmental effects..."
VII. Conclusion: Definition and Etiology of MCS
2019 Physiological Definition of MCS
MCS is usually genetic vulnerability in the nasal and tracheal bronchial upper pulmonary airway epithelial cell population and its sensory innervation - including quantitative differences in neuropeptides, TRP receptors, and acid sensitive pathways critical to the homeostatic regulation of inflammatory neuroimmune response
MCS 15, Veronesi 2001, 2000, Roy 2000, Jung 1921
which becomes altered to a proinflammatory condition
Deering-Rice 2011, Hazari 2011, Li 2011, Taylor-Clark 2010, Baulig 2009, 2003a, Calderon-Garciduenas 2008, 2001, 2000, Veronesi 2003, 2002a, 2002b, 2001, 2000, 1999a, 1999b, Agopyan 2003, 2003a, Bonvallot 2001, 2000, Gerde 2001, 1997, Oortgiesen 2000, Roy 2000, Chin 1998,Miyabara 1998,1998a, Steerenberg 1998, Meggs 1997
in a continuous ambient combustion byproduct aerosol (ACA) - diesel, gasoline, propane and other exhaust, woodsmoke, and tobacco smoke
Gillespie 2013, Block 2012, 2009, OSHA 2012, Pakkanen 2003, Schauer 2002, 2001, 1999, US DOT FHA 2000, Society of Automotive Engineers SAE 940233 1994
including UFPM, PM2.5, and PM LPS - particle agglomerates with adsorbed hydrocarbons, singlet nonagglomerated nanoparticles, and acid sulfate resulting from catalytic converter transformation of sulfur dioxide
Lucchini 2012, Mohankumar 2008, Inoue 2005, Kittelson 1998, Cadle 1999, Kleeman 1999
Fine particles expected to reach the CNS via trigeminal and olfactory nerve pathways
MCS 11, Calderon-Garciduenas 2010, Genter 2009, Matsui 2009, Elder 2006, Lewis 2005
ACA PM induced release of inflammatory cytokines including IL-1 beta and IL-6 from alveolar macrophages, epithelial cells, and exposed sensory nerves in damaged airway epithelium - found elevated in MCS and ME/CFS (Dantoft 2014, Maes 2012) - stimulate the bone marrow to increase output of platelets and polymorphonuclear leukocytes (PMN), accelerate more immature PMN (band cells) into the circulation prone to sequestration in microvascular beds - and increase the liver output of acute phase proteins including fibrinogen, CRP, and C-reactive protein - all associated with vascular activation and the extent of atherosclerosis (Hiraiwa 2014, 2013, Hogg 2009, Goto 2004, Mukae 2001) - and indicated by elevated PMN-elastase, lysozyme, and neopterin confirmed in ME/CFS (Maes 2012).
Induction of upper respiratory, lung epithelial and endothelial injury leading to persistent chronic inflammation in the respiratory tract and systemic inflammation accompanied by the production of IL-6 and IL-1beta elevated in MCS and ME/CFS (Dantoft 2014, Maes 2012) may activate endothelial cells of brain capillaries opening the BBB (blood-brain barrier) involving upregulation of COX-2 (cyclooxygenase-2), activation of NFkB (nuclear factor kB), and increased expression of iNOS (inducible nitric oxide synthase) found in ME/CFS (Calderon-Garciduenas 2008, Maes 2007a, 2007b).
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 (systemically elevated in ME/CFS [Maes 2012]),
neuron damage or loss, increased microglial activation confirmed in ME/CFS and found to correlate with degree of cognitive impairment (Nakatomi 2014) 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 reactive oxygen species (ROS) 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,
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).
If cause and effect were isolated - one breath of exhaust would exceed in reactivity all personal exposures of a careful person over several days - and yet the exhaust is continuous. Failure to recognize the effect of combustion byproduct particulate with adsorbed incompletely combusted gasoline and diesel fuel hydrocarbon - inhaled at every breath - has been a grand illusion.
Perhaps impossible to express delicately - but the point needs to be made - worrying about a smell in the refrigerator or other perception is missing it - those exposures are relatively minor. They are riding on a continuous horizontal coning (Chapter 4) of tailpipe, chimney, and smokestack combustion particulate with its adsorbed hydrocarbon component - obviously the most significant cumulative and ongoing exposure (Block 2009). For that there is billions in health care costs (Pervin 2008, US DOT FHA 2000) and need for a non-combustion way of life.
VIII. Links
MCS 1a 2019 MCS Consensus Criteria
MCS 2a Etiology: TRPA1 Precision
MCS 2a Etiology: Notes on References
MCS 2ab Etiology: Nasal Cytokines in Context
MCS 3 Definition and Consensus Criteria
MCS 3a Etiology: Criteria Amendment Research (CAR)
MCS 3a AKA Multiple Chemical Sensitivity: 2019 Consensus Criteria
MCS 3aa Etiology: Consensus Author CAR Test (SPC)
MCS 3b Etiology: CAR References A-H including MCS 1, 2, &3
MCS 3b Etiology: CAR References I-Q including MCS 1, 2, &3
MCS 3b Etiology: CAR References R-Z including MCS 1, 2, &3
MCS 3b Etiology: References of MCS 3a only
MCS 3g CAR Nutritional Considerations
MCS ad Etiology: Naturally Sensitive
MCS ae Etiology: Airway Reactivity
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