Multiple Chemical Sensitivity Etiology
Airway Genetics and Ambient Combustion Aerosol
2016 MCS Consensus Key Point Summary
2016 MCS Consensus Key Point Summary
AKA What's Wrong with 1999 Consensus Language
AKA I Don't React to Exhaust; Only to Chemicals
AKA Kimata 2004: Aerosol PM plus Paint
Contents
2016 MCS Consensus Key Point Summary
Kimata 2004: Aerosol PM plus Paint
What's Wrong with 1999 Consensus Language
The 1999 Consensus
The 2016 Consensus
Key Point Summary Documentation in Brief
References
2016 MCS Consensus Key Point Summary
Central Sensitization: chronic, intense, sustained inputs of peripheral nociceptors including the TRPA1 and TRPV1 channels - changes in neural plasticity resulting from those excessive inputs.
Excessive Inputs: due to airway damage leaving subclinical gaps in the epithelium exposing the nerves - established by human autopsies, biopsies, and laboratory experiments.
TRPA1: activated by the ambient aerosol - if TRPA1 is shutdown disease process is muted - exposed TRPA1 and other receptors in damaged airway epithelium are in contact with components of the ambient aerosol - the CNS receives the inputs and neural plasticity is altered.
Aerosol PM: chemical laden vector with a long residence time - prolonged stimulation of receptors.
Hyper-inflammatory Immune Response: initiated by the exposed receptors with the release of substance P (SP) and other mediators of inflammation including high cytokines and NO - results in detox enzyme dysfunction and increased oxidative stress.
Detox Enzyme Dysfunction: genetics of detox unlikely cause - occurrence of genetic deletions the same in MCS and control groups. One or both of GSTM1 and GSTT1 deletions occur in over 50% of the population. MCS people are genetically sensitive - a susceptible airway epithelial sensory innervation.
Kimata 2004: Aerosol PM plus Paint
"Give away" nerve exposure markers
Before exposure to paint: lit by the ambient aerosol:
substance P (SP) MCS 105 Controls 38
nerve growth factor (NGF) MCS 1129 Controls 148
vasoactive intestinal peptide VIP) MCS 43 Controls 10
Histamine (H) MCS 271 Controls 260
But notice:
Histamine is flat same as controls - aerosol is subjectively masked due to the continuous aspect of the ambient aerosol.
After exposure to paint: all markers increase - histamine released by the sudden exposure spike.
SP MCS 153 Controls 39
NGF MCS 1696 Controls 156
VIP MCS 68 Controls 11
Histamine (H) MCS 534 Controls 260
The paint exposure rides on top of already elevated baseline inflammation. Regardless of initial cause of the MCS condition the disease process is supported by the ambient aerosol - the largest exposure of all - especially for those careful about personal exposures.
What's Wrong with 1999 Consensus Language
1) "reproducible with repeated exposure" - ambiguous and not necessary - an MCS person should be expected to react like a BIC pen? First time every time? Same way, Jose? Some kind of provocation demonstration?
2) okay - the condition is chronic - maintained as point 1) of the 2016 Consensus
3) who says exposures are "low level" or "commonly tolerated"? from a clinical point of view? or sub-clinical? short term? or long term? Who says "syndrome"? Is this a poorly understood syndrome physiological or psychological? MCS is a disease with a well understood symptomatology abundant with physiological evidence. Replace with point 2) of the 2016 Consensus.
4) "when the incitants are removed"? Who says all the incitants are removed? There is a continuous presence of ambient combustion aerosol fluctuating often unpredictably. This is not a disease of simply bouncing from one indoor or personal exposure to another. Replace with point 3) of the 2016 Consensus.
5) "multiple chemically unrelated substances"? Not a clue? Mum is the word? Do MCS people react to water? Is there any motive to the madness? Are they just goofballs with a psychiatric syndrome reacting to anything? Chemicals to which MCS people react have acidic, electrophilic, oxidizing, or solvent properties necessary to activate sensory receptor terminals - most notably TRPA1. Replaced with point 4) of the 2016 Consensus.
6) okay - symptoms involve multiple organ systems - maintained as point 5) of the 2016 Consensus
Multiple Chemical Sensitivity: 2016 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
Key point Summary Documentation in Brief
Central Sensitization begins with exposed sensory nerves - including TRPA1 expressing neurons - in damaged airway epithelium
"...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...
Excessive Inputs result from damaged airway epithelial barrier and exposed sensory nerves
Bellina Veronesi and Marga Oortgiesen. National Health Effects and Research Laboratory, Cellular and Molecular Branch, Neurotoxicology Division, US Environmental Protection Agency, Research Triangle Park, North Carolina. Cato Research LTD., Durham, North Carolina.
"...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..."
William Meggs. Division of Toxicology, Department of Emergency Medicine, East Carolina University School of Medicine, Greenville NC.
MEGGS 1997: Biopsies of MCS patients
"...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..."
TRPA1 expressing peptidergic terminals on exposed sensory nerves
"...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).
"...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 (Kimata 2004) (Hazari 2011, Teles 2009, Anand 2008, Nassenstein 2008, Kobayashi 2005)...
...three cysteine residues were crucial for channel activation (Macpherson 2007)...activation of TRPA1 by covalent modification through reactive irritants...
...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)..."
...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)..."
Aerosol PM
"...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..."
"...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)..."
Hyperinflammatory Immune 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)
...BALB/c mice were deenervated of polymodal sensory c fibers by neonatal capsaicin treatment. Sensory neurons , dissected from the DGR (dorsal root ganglia) of these deenervated animals and exposed to various PM (50mg/ml) or prototype irritants failed to release IL-6 in response - implicating the sensory c fibers as critical to cytokine release in response to PM..."
(Gavett 1998, Scheerens 1996, Satoh 1993, Yeadon 1992, Nielsen 1991, Prior 1990, Hayes 1981)..."
BASCOM R. MULTIPLE CHEMICAL SENSITIVITY: A RESPIRATORY DISORDER. TOX IND H 8(4);221-28 1992:
"...multiple chemical sensitivity represents an amplification of the non-specific immune response...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..."
More than "sickness behavior", mood, anxiety, or depression
"...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)..."
Calderon-Garciduenas 2010, Genter 2009, Matsui 2009, Elder 2006, Lewis 2005
"...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)..."
"...The systemic upregulation of MCP-1 is of particular interest in view of the influence of MCP-1 on permeability of the BBB (Yadav 2010). Specifically, MCP-1 is involved in the recruitment of both monocytes/macrophages and activated lymphocytes into the CNS and induces an increase in brain endothelial permeability..." Deluca 2010: MCP-1 results MCS 20 Controls 10
TRPAI agonism and oxidative stress
"...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)..."
"...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)..."
double the chemokine MCP-1, twice growth factor PDGF, and 8 times VEGF - a 3 fold reduction in catalase activity, severe glutathione depletion, double nitric oxide, and a fatty acid profile of lipid peroxidation - increased SFA with losses in PUFA, N-6, N-3, arachidonic acid, and omega 3.
"...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..."
Dysfunction of Detox Enzymes
"...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..."
"...we did not find any significant differences in GSTs allele or genotype distribution between patients as compared with data previously published in healthy volunteers (table 4) (Garte et al., 2001)......there exist serious and multiple dysfunctions of chemical defensive systems in MCS patients. These dysfunctions may mainly depend not on genetic defects but on non-genetic modifications of metabolizing/antioxidant enzyme expression and/or activity, mediated by redox active agents such as NO and inflammatory cytokines..."
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..."
"...the variable inflammatory sensitivity to PM observed in different mouse strains (ie Balb/C, B6) related to quantitative differences in the neuropeptide, VR1 receptors (now TRP) 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 1995), nitrogen dioxide (Holroyd 1997), and diesel exhaust (Ichinose 1997, Miyabara 1998)..."
MCS is usually genetic vulnerability in the 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 - which become altered to a proinflammatory condition - airway damage and exposed c-fiber nerves - TRPA1 expressing peptidergic terminals - in a continuous combustion byproduct aerosol 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 - resulting in elevated plasma levels of neuropeptides, chemokines, cytokines, growth factors, and NO that mediate serious and multiple dysfunction of chemical defense systems.There is no such thing as an "unstimulated" MCS subject group or a low level of exposure. The aerosol is everywhere - indoors and out - continuous horizontal coning (Chapter 4).2016 MCS Consensus Key Point Summary
AKA What's Wrong with 1999 Consensus Language
AKA I Don't React to Exhaust; Only to Chemicals
AKA Kimata 2004: Aerosol PM plus Paint
Contents
2016 MCS Consensus Key Point Summary
Kimata 2004: Aerosol PM plus Paint
What's Wrong with 1999 Consensus Language
The 1999 Consensus
The 2016 Consensus
Key Point Summary Documentation in Brief
References
2016 MCS Consensus Key Point Summary
Central Sensitization: chronic, intense, sustained inputs of peripheral nociceptors including the TRPA1 and TRPV1 channels - changes in neural plasticity resulting from those excessive inputs.
Excessive Inputs: due to airway damage leaving subclinical gaps in the epithelium exposing the nerves - established by human autopsies, biopsies, and laboratory experiments.
TRPA1: activated by the ambient aerosol - if TRPA1 is shutdown disease process is muted - exposed TRPA1 and other receptors in damaged airway epithelium are in contact with components of the ambient aerosol - the CNS receives the inputs and neural plasticity is altered.
Aerosol PM: chemical laden vector with a long residence time - prolonged stimulation of receptors.
Hyper-inflammatory Immune Response: initiated by the exposed receptors with the release of substance P (SP) and other mediators of inflammation including high cytokines and NO - results in detox enzyme dysfunction and increased oxidative stress.
Detox Enzyme Dysfunction: genetics of detox unlikely cause - occurrence of genetic deletions the same in MCS and control groups. One or both of GSTM1 and GSTT1 deletions occur in over 50% of the population. MCS people are genetically sensitive - a susceptible airway epithelial sensory innervation.
Kimata 2004: Aerosol PM plus Paint
"Give away" nerve exposure markers
Before exposure to paint: lit by the ambient aerosol:
substance P (SP) MCS 105 Controls 38
nerve growth factor (NGF) MCS 1129 Controls 148
vasoactive intestinal peptide VIP) MCS 43 Controls 10
Histamine (H) MCS 271 Controls 260
But notice:
Histamine is flat same as controls - aerosol is subjectively masked due to the continuous aspect of the ambient aerosol.
After exposure to paint: all markers increase - histamine released by the sudden exposure spike.
SP MCS 153 Controls 39
NGF MCS 1696 Controls 156
VIP MCS 68 Controls 11
Histamine (H) MCS 534 Controls 260
The paint exposure rides on top of already elevated baseline inflammation. Regardless of initial cause of the MCS condition the disease process is supported by the ambient aerosol - the largest exposure of all - especially for those careful about personal exposures.
What's Wrong with 1999 Consensus Language
1) "reproducible with repeated exposure" - ambiguous and not necessary - an MCS person should be expected to react like a BIC pen? First time every time? Same way, Jose? Some kind of provocation demonstration?
2) okay - the condition is chronic - maintained as point 1) of the 2016 Consensus
3) who says exposures are "low level" or "commonly tolerated"? from a clinical point of view? or sub-clinical? short term? or long term? Who says "syndrome"? Is this a poorly understood syndrome physiological or psychological? MCS is a disease with a well understood symptomatology abundant with physiological evidence. Replace with point 2) of the 2016 Consensus.
4) "when the incitants are removed"? Who says all the incitants are removed? There is a continuous presence of ambient combustion aerosol fluctuating often unpredictably. This is not a disease of simply bouncing from one indoor or personal exposure to another. Replace with point 3) of the 2016 Consensus.
5) "multiple chemically unrelated substances"? Not a clue? Mum is the word? Do MCS people react to water? Is there any motive to the madness? Are they just goofballs with a psychiatric syndrome reacting to anything? Chemicals to which MCS people react have acidic, electrophilic, oxidizing, or solvent properties necessary to activate sensory receptor terminals - most notably TRPA1. Replaced with point 4) of the 2016 Consensus.
6) okay - symptoms involve multiple organ systems - maintained as point 5) of the 2016 Consensus
Multiple Chemical Sensitivity: 2016 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
Key point Summary Documentation in Brief
Central Sensitization begins with exposed sensory nerves - including TRPA1 expressing neurons - in damaged airway epithelium
"...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...
Excessive Inputs result from damaged airway epithelial barrier and exposed sensory nerves
Bellina Veronesi and Marga Oortgiesen. National Health Effects and Research Laboratory, Cellular and Molecular Branch, Neurotoxicology Division, US Environmental Protection Agency, Research Triangle Park, North Carolina. Cato Research LTD., Durham, North Carolina.
"...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..."
William Meggs. Division of Toxicology, Department of Emergency Medicine, East Carolina University School of Medicine, Greenville NC.
MEGGS 1997: Biopsies of MCS patients
"...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..."
TRPA1 expressing peptidergic terminals on exposed sensory nerves
"...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).
"...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)...
...three cysteine residues were crucial for channel activation (Macpherson 2007)...activation of TRPA1 by covalent modification through reactive irritants...
...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)..."
...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)..."
Aerosol PM
"...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..."
"...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)..."
Hyperinflammatory Immune 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)
...BALB/c mice were deenervated of polymodal sensory c fibers by neonatal capsaicin treatment. Sensory neurons , dissected from the DGR (dorsal root ganglia) of these deenervated animals and exposed to various PM (50mg/ml) or prototype irritants failed to release IL-6 in response - implicating the sensory c fibers as critical to cytokine release in response to PM..."
(Gavett 1998, Scheerens 1996, Satoh 1993, Yeadon 1992, Nielsen 1991, Prior 1990, Hayes 1981)..."
BASCOM R. MULTIPLE CHEMICAL SENSITIVITY: A RESPIRATORY DISORDER. TOX IND H 8(4);221-28 1992:
"...multiple chemical sensitivity represents an amplification of the non-specific immune response...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..."
More than "sickness behavior", mood, anxiety, or depression
"...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)..."
Calderon-Garciduenas 2010, Genter 2009, Matsui 2009, Elder 2006, Lewis 2005
"...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)..."
"...The systemic upregulation of MCP-1 is of particular interest in view of the influence of MCP-1 on permeability of the BBB (Yadav 2010). Specifically, MCP-1 is involved in the recruitment of both monocytes/macrophages and activated lymphocytes into the CNS and induces an increase in brain endothelial permeability..." Deluca 2010: MCP-1 results MCS 20 Controls 10
TRPAI agonism and oxidative stress
"...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)..."
"...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)..."
double the chemokine MCP-1, twice growth factor PDGF, and 8 times VEGF - a 3 fold reduction in catalase activity, severe glutathione depletion, double nitric oxide, and a fatty acid profile of lipid peroxidation - increased SFA with losses in PUFA, N-6, N-3, arachidonic acid, and omega 3.
"...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..."
Dysfunction of Detox Enzymes
"...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..."
"...we did not find any significant differences in GSTs allele or genotype distribution between patients as compared with data previously published in healthy volunteers (table 4) (Garte et al., 2001)......there exist serious and multiple dysfunctions of chemical defensive systems in MCS patients. These dysfunctions may mainly depend not on genetic defects but on non-genetic modifications of metabolizing/antioxidant enzyme expression and/or activity, mediated by redox active agents such as NO and inflammatory cytokines..."
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..."
"...the variable inflammatory sensitivity to PM observed in different mouse strains (ie Balb/C, B6) related to quantitative differences in the neuropeptide, VR1 receptors (now TRP) 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 1995), nitrogen dioxide (Holroyd 1997), and diesel exhaust (Ichinose 1997, Miyabara 1998)..."
MCS is usually genetic vulnerability in the 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 - which become altered to a proinflammatory condition - airway damage and exposed c-fiber nerves - in a continuous combustion byproduct aerosol 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 - resulting in elevated plasma levels of neuropeptides, chemokines, cytokines, growth factors, and NO that mediate serious and multiple dysfunction of chemical defense systems.There is no such thing as an "unstimulated" MCS subject group or a low level of exposure. The aerosol is everywhere - indoors and out - continuous horizontal coning (Chapter 4).Views: 13
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