Airway Genetics and Ambient Combustion Aerosol

MCS 1a Etiology: 2019 Consensus Criteria

MCS 1a Etiology: 2019 MCS Consensus Criteria

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Outline

I. Please be an MCS Consensus Author

II. The 1999 and 2019 Consensus

III. Bessac 2008: TRPA1 Precision

IV. Outline of Consensus Article 3a

V. Part 1 of Consensus Article 3a

VI. Part 7 The Conclusion of Consensus Article 3a

VII. Links to Consensus Article 3a and the CAR Test

I. Please be an MCS Consensus Author

The 1999 MCS Consensus Criteria refer to MCS as manifestations of a syndrome - implying psychological - and in response to unrelated chemicals with no explanation.

The 2019 MCS Consensus Criteria - announced in 2015 - with Consensus Amendment Research (CAR) and TRPA1 Precision - correctly refers to MCS as a disease having a symptomatology supported by ongoing exposure to the Ambient Combustion Aerosol (ACA) and chemicals having greater acidic, electrophilic, oxidizing, or solvent properties [toxicity] increased further if instilled by particulate vector as in the ACA.

Please take the study course CAR Test and be an MCS Consensus Author placing the 2019 Consensus Article 3a in a professional journal and on medline.

II.The 2019 and 1999 Consensus

Multiple Chemical Sensitivity: 2019 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. Bessac 2008: TRPA1 Precision

Department of Pharmacology,
Yale University School of Medicine,
New Haven, Connecticut

BESSAC 2008:

...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

DEERING-RICE 2011:

"...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

NASSINI 2011:

...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)..."

Central sensitization begins with exposed sensory nerves - including TRPA1 expressing neurons - in damaged airway epithelium

Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts

LATREMOLIERE 2009:

"...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..."

Paris V University Hospital, France; and European Cancer and Environment Research Institute (ECERI), Brussels, Belgium

BELPOMME 2015:

"...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%...

...considering the self-reported symptoms of EHS and MCS, we serially measured the brain blood flow (BBF) in the temporal lobes of each case with pulsed cerebral ultrasound computed tomosphygmography. Both disorders were associated with hypoperfusion in the capsulothalamic area, suggesting that the inflammatory process involve the limbic system and the thalamus...

...cerebral hypoperfusion in one or two of the hemisphere in 50.5% of the cases...

...More precisely, by using pulsed ultrasound computed tomosphygmography, we found that in comparison to normal subjects, cerebral pulsatility in EHS and /or MCS patients was decreased or even completely abolished in one or the two temporal lobes (Figure 2), suggesting that BBF might be specifically decreased or abolished in this brain area. We found that this abnormality, although being not specific, was so frequently observed in these patients that it may represent a typical brain alteration similar to that found in Alzheimer’s disease and other neurodegenerative diseases (see Section "EHS/MCS as a possible sentinel pathological disorder”). This finding therefore, strongly suggests that brain could be the main target of environmental EMFs and/or chemicals in EHS and/or MCS patients, and that both cerebral hypoperfusion and subsequent histamine release whatever its neuronal or mast cell origin could be main contributing factors to BBB disruption. Furthermore, we found that cerebral blood pulsatility was quasi-constantly decreased in the capsulothalamic area of the temporal lobes, which includes the limbic system and the thalamus, and so correspond to particularly vulnerable areas to environmental stressors in the brain..."

The MCS chain reaction: stimulation of exposed sensory nerves including peptidergic TRPAI expressing terminals - in damaged airway epithelium - affects all systems - oxidative stress, detox enzyme dysfunction (Deluca 2010), cardiovascular atherogenesis (Bai 2013, Baldwin 1998), central sensitization (Latremoliere 2009), cerebral hypoperfusion (Belpomme 2015 ), and autonomic imbalance (Hazari 2011).

IV. Outline of Consensus Article 3a

Criteria Amendment Research (CAR)

1) Neurogenically Mediated

2) Sustained Inputs

3) Continuous Inflammation

4) Relentless Aerosol Provocation

5) Intense Airway Metabolism

6) Severe Oxidative Stress

7) Conclusion

V. Part 1 of Consensus Article 3a

CAR 1 Neurogenically Mediated

Susceptibility to Multiple Chemical Sensitivity (MCS) is neurogenically mediated - airway c fiber nerves and their TRPA1 peptidergic terminals - in damaged airway epithelium - are critical to the MCS inflammatory response (Nassini 2011, Taylor-Clark 2010, Caceres 2009, Bessac 2008,Veronesi 2001, 2000, Roy 2000, Meggs 1997).

Veronesi 2001, 2000, and Roy 2000 reported variable inflammatory sensitivity to PM - as reflected by inflammatory cytokine and neuropeptide release - relates to genetic quantitative differences in TRP peptidergic receptors and acid sensitive pathways found on c fiber sensory neurons that innervate the nasal and upper pulmonary airway. Deenervation of sensory c fibers resulted in failure to release inflammatory cytokine IL-6 demonstrating the sensory c fiber nerves as critical to cytokine release in response to PM and other irritants (Veronesi 2001).

Conditions associated with pollutants are characterized by damage to the epithelial barrier that lines the airway - including loss of neuropeptide deactivating enzymes and allowing the sensory fiber to physically extend closer to the airway lumen in proximity to inhaled particles resulting in enhanced and prolonged inflammatory response (Veronesi 2001).

TRPV1 is activated by chemical irritants, inflammatory mediators, and tissue damaging stimuli - most famously capsaicinoids and has been referred to as the capsaicin receptor (Veronesi 2006). Observing a lower cough threshold among MCS patients compared to controls when exposed to capsaicin - Nogami 2004 suggested such provocation as a diagnostic test for MCS. However, TRPA1 may be the major reactive irritant receptor (Bessac 2008).

TRPV1 deficient mice still showed sensitivity to electrophilic agents (acrolein) and solvents (styrene) Symanowicz 2004. TRPV1 lacked response to acrolein (Dinis 2004) - electrophilic irritants activated only a subset of capsaicin-sensitive neurons (Inoue 2005) - apparently those having TRPA1 - known to be expressed in a subset of TRPV1 expressing c fiber neurons.

Acrolein (aldehyde in smog and smoke) is a potent agonist of TRPA1 channels - cultured sensory neurons from TRPA1 deficient mice did not respond to this irritant suggesting TRPA1 is the only receptor for acrolein (Bautista 2006) - and ozone activates airway nerves via selective stimulation of the TRPA1 channel (Taylor-Clark 2010).

TRPA1 is activated by smoke constituents - methacrolein, methyl vinyl ketone, and croton aldehyde (Andre 2008, Escalera 2008), oxidizing agents including hypochlorite (Bessac 2008a), formaldehyde, acetaldehyde, tear gas agents, and industrial isocyanates (Bessac 2009, Brone 2008, Bang 2007, McNamara 2007).

Almost all oxidizing and electrophilic agents effect TRPA1 function (Bessac 2008).

Endogenous agonists include reactive oxygen species (ROS), hypochlorite, lipid peroxidation products, cyclopentenone prostaglandins, and isoprostanes (Bessac 2008).

The volatile organic chemical monoterpene ketone umbellone - outgas agent from the California Bay Laurel "headache tree" - stimulates the TRPA1 channel activating the trigeminovascular system. TRPA1 deficient mice failed to have the trigeminal response to umbellone. Nassini 2011concluded that TRPA1 agonism may be responsible for headache crisis in sensitive people after exposure to environmental pollutants and perfume.

TRPAI activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma and TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways (Caceres 2009).

Genetic deletion or pharmacological inhibition of TRPA1 impairs acute and inflammatory neuropeptide release and diminishes inflammatory leukocyte infiltration, mucus production, cytokine and chemokine levels, and airway hyperreactivity (Caceres 2009).

Taken together it is clear that the sensory c fiber nerves - including TRPA1 expressing peptidergic terminals - in damaged airway epithelium - mediate Multiple Chemical Sensitivity (MCS) - tissue injury having exposed and established prolonged activation of TRPA1 - with inflammatory sensitivity to multiple reactive chemicals (Bessac 2008).

VI. Part 7 The Conclusion of Consensus Article 3a

CAR 7 Conclusion

As explored in previous research points - the ambient combustion aerosol (ACA) supports the disease process because many ACA components activate airway c fiber sensory nerves that express TRPA1, TRPV1, and substance P (Deering-Rice 2011, Hazari 2011, Costa 2010, Taylor-Clark 2010, Caceres 2009, Anand 2008, Bessac 2008, Nassenstein 2008, Bautista 2006, Inoue 2005, Kobayashi 2005, Veronesi 2001) - setting forth the MCS chain reaction including elevated plasma levels of neuropeptides, chemokines, cytokines, growth factors, and NO (Dantoft 2014, Deluca 2010, Kimata 2004) that mediate serious and multiple dysfunction of metabolizing and antioxidant enzymes - 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 (Deluca 2010, Liptrott 2009, Oslund 2008, Chun 2002, Sterner-Kock 1999, Tinel 1999, Tanabe 1996, Tapner 1996, Nadin 1995, Stadler 1994, Khatsenko 1993)

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), and central sensitization - a functional synaptic plasticity resulting in pain hypersensitivity (Tran 2013, Holst 2011, Latremoliere 2009). 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.

Therefore, while leaving five of the six 1999 Consensus Criteria essentially intact - the 2019 Consensus corrects impression MCS is a syndrome in response to unrelated chemicals in a low level, commonly tolerated, non inciting background atmosphere.

Amendment includes language more consistent with intent (2,3,4) and information - especially concerning the ACA (3,4).

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: 2019 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

5) Symptoms involve multiple organ systems

VII. Links

MCS 1a 2019 MCS Consensus Criteria

MCS 2 The Etiology of MCS

MCS 2a Etiology: TRPA1 Precision

MCS 2a Etiology: Notes on References

MCS 2ab Etiology: Nasal Cytokines in Context

MCS 2 The Etiology of MCS

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)