Multiple Chemical Sensitivity Etiology

Airway Genetics and Ambient Combustion Aerosol

MCS 3 Definition and Consensus Criteria

MCS 3a Criteria Amendment Research (CAR)

MCS 3aa Etiology: Consensus Author CAR Test (SPC)

MCS 3b CAR References

Multiple Chemical Sensitivity: 2015 Consensus Criteria

Abstract:

This review presents evidence that the Ambient Combustion Aerosol (ACA), while not claimed as exclusive cause, supports the underlying disease process of Multiple Chemical Sensitivity (MCS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Presented in an outline of Criteria Amendment Research (CAR) - beginning is with recognition that inflammatory cytokine release from damaged airway epithelium - including TRPA1 peptidergic terminals on c-fiber sensory nerves of the upper pulmonary and nasal airway are critical to the MCS inflammatory response - and numerous components of the ACA activate TRPA1. Pathways connect activation of TRPA1 to central sensitization, CNS dysfunction, oxidative stress, and increased cardiovascular disease risk. Direct penetration of ACA UFPM to the CNS also supports the disease process.

Respiratory cell tight junction defects, focal desquamation of epithelial cells, hypertrophy of glandular structures, lymphocytic infiltrates, proliferation of nerve fibers, high levels of nerve growth factor (NGF), substance P (SP), and vasoactive intestinal peptide (VIP), altered cytokine profile, elevated nitric oxide (NO), severe glutathione depletion, catalase deficiency, proatherogenic lipid changes, SPECT hypoactivity and electroencephalographic alterations have all been found in MCS subjects at baseline - before or without study provocation - indicating there is ongoing neurogenic inflammation driven by continuous exposure to the ACA.

Therefore while leaving five of the six 1999 Consensus Criteria essentially intact - the 2015 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: 2015 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

Outline

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

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 2008Bang 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 2011 concluded 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).

CAR 2 Sustained Inputs

Central sensitization is a form of functional plasticity resulting in pain hypersensitivity triggered by the activity evoked in dorsal horn neurons by input from chemically activated c-nociceptors (airway c fiber sensory receptors) including TRPA1 expressing peptidergic terminals. Latremoliere 2009 described central sensitization as a constantly changing mosaic of alterations in membrane excitability, reductions in inhibitory transmission, and increases in synaptic efficacy, mediated by many converging and diverging molecular players in a background of phenotypic switches and structural alterations.

Intense, repeated, and sustained inputs from exposed airway sensory nerves involve TRPA1, TRPV1, substance P, CGRP, NKA, cytokines, NO, BDNF, bradykinin, glutamate, NMDAR, AMPAR, and mGluR (Latremoliere 2009).

Central nervous system involvement in MCS has been evidenced by hyperalgesia (Tran 2013, Holst 2011), SPECT hypoactivity (Orriols 2009), and electroencephalographic alterations (Bell 1998, 1996).

CAR 3 Continuous Inflammation

Multiple Chemical Sensitivity (MCS) is an ongoing neurogenic inflammation evidenced by respiratory cell tight junction defects, focal desquamation of epithelial cells, hypertrophy of glandular structures, lymphocytic infiltrates, and proliferation of nerve fibers (Meggs 1997) - high levels of nerve growth factor (NGF), substance P (SP), and vasoactive intestinal peptide VIP (Kimata 2004), altered cytokine profile (Dantoft 2014), elevated nitric oxide (NO), severe glutathione depletion, catalase deficiency, and proatherogenic lipid changes (Deluca 2010, Baldwin 1998), SPECT hypoactivity (Orriols 2009), and electroencephalographic alterations (Bell 1998, 1996) - all at baseline - before or without study provocation.

Bascom 1992 reported MCS as altered function of the airway c-fiber nerves, epithelium or both - prior to biopsies confirming functional and structural alterations. The alteration depicted in biopsy results of MCS patients (Meggs 1997) is beyond the kind of damage seen in those not genetically sensitive (Calderon-Garciduenas 2008, 2003, 2001, 2000). The MCS alteration - without study provocation - but with ongoing exposure to the ambient combustion aerosol (ACA) and apparently there to stay - with its focal desquamation, multiplied nerves, and thickened basement membrane - appears attempting to maximize stimulus and exposure as if the tissue is independently addicted and craving for more - unfortunately this eventually translates via central sensitization to a monster in the CNS - as many an MCS person would perhaps secretly admit. Bascom 1997 concluded people reporting chemical sensitivity have altered structure and function of the neuroinflammatory system - since proven correct - and to a higher level of precision.

TRPA1 sensory receptors on c fiber sensory nerves activate through covalent modification of the channel protein - altered protein conformation and stability concerning specific amino acid residues on the receptor - especially cysteine - with resulting ion influx and disruptions in structural gating (Bessac 2008, Macpherson 2007, Hinman 2006, Veronesi 2006).

Most TRPA1 agonists react with cysteine thiols making glutathione important in limiting reactivity. MCS patients have severe glutathione depletion (Deluca 2010) - with each breath more reactive agonist is delivered increasing covalent modifications - what is normally considered a low exposure level can irreversibly modify the TRPA1 channel so it remains active after the irritant stimulus is removed (Bessac 2008a) - more precisely describing the initiating point for enhanced and prolonged inflammatory response of exposed c fiber nerves in damaged airway epithelium (Veronesi 2001).

Particulate matter including diesel exhaust particles - and numerous acidic, electrophilic, and oxidizing components of the ambient combustion aerosol (ACA) - to which all are continuously exposed - activate airway sensory c fiber nerves that express TRPA1, TRPV1, and substance P (Deering-Rice 2011, Hazari 2011, Costa 2010Taylor-Clark 2010, Caceres 2009, Anand 2008Bessac 2008), Nassenstein 2008Bautista 2006Inoue 2005, Kobayashi 2005, Veronesi 2001).

Therefore, the ACA supports the underlying disease process - including central sensitization from excessive noci-ceptor inputs (Latremoliere 2009).

CAR 4 Relentless Aerosol Provocation

Particulate matter air pollutants - particle agglomerates with adsorbed hydrocarbons, singlet non agglomerated nano particles, and acid sulfate - result of catalytic converter transformation of sulfur dioxide (Lucchini 2012) - carbonaceous cores coated with thousands of chemicals and heavy metals - many hazardous (Li 2011) - principle components of the ambient combustion aerosol (ACA) - diesel, gasoline, and other exhaust, woodsmoke, and tobacco smoke (MCS aa, OSHA 2012, Schauer 2002, 2001, 1999, Society of Automotive Engineers SAE 940233 1994) - induce upper respiratory, lung epithelial, and endothelial injury, persistent chronic inflammation in the respiratory tract, and systemic inflammation accompanied by the production of proinflammatory cytokines such as TNF alpha, IL-6, and IL-1 beta (Calderon-Garciduenas 2008, 2003, 2001 2000) - found elevated in MCS patients (Dantoft 2014).

These cytokines activate endothelial cells of the blood brain barrier (BBB), trigger cascades with increased nitric oxide (NO) production that opens the BBB (Calderon-Garciduenas 2008, Mohankumar 2008) - NO found elevated in MCS patients (Deluca 2010) and increase the output of acute phase proteins and circulating inflammatory cells from the liver and bone marrow ((Hiraiwa 2014, 2013, Hogg 2009, Goto 2004, Mukae 2001).

In addition to c fiber sensory nerve TRPA1 peptidergic mediated neurogenic inflammation and central sensitization from exposure to the numerous TRPA1 agonists in the ACA (Bessac 2008) - the ACA may also support the underlying disease process by direct penetration of ultra fine particles (UFPM) through damaged airway epithelium via trigeminal and olfactory nerve pathways to the CNS (MCS 11, Calderon-Garciduenas 2010Genter 2009, Matsui 2009, Elder 2006Lewis 2005).

CAR 5 Intense Airway Metabolism

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).

There are two principal fractions of adsorbed PAHs: one is quickly desorbed - and the other retained on particles for a long time (Gerde 1991Burtscher 1986, Adamson 1982, Natusch 1978).

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 1989Harmsen 1985, Lundborg 1984).

Approx 80% of rapidly desorbed PAHS are deposited on the thin alveolar type 1 epithelium deep in the lung (Yeh 1996) and become systemic quickly with blood concentration peaking in several minutes.
3/4 of blood activity from the rapidly absorbed B[a]P (benzo[a]pyrene) used in Gerde 2001 ceased in 10 minutes - nearly all within 30 - and by one hour completely leveled - mostly into conjugated phase ll metabolites (Fung 1999, Thompson 1989, Molliere 1987).

There is no conclusive or strongly suggestive evidence that genetic deficiency in detox enzymes accounts for the majority of Multiple Chemical Sensitivity (MCS A-1, 2, 14, Caccamo 2013, Berg 2010, Deluca 2010, Schnakenberg 2007, Mckeown-Eyssen 2004). For example, over 50% of the population have one or both of the GSTM1 or GSTT1 deletions (Block 2011, Piacentini 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.

However, approximately 20% of initially desorbed chemical from PM (particulate matter) of the ACA is deposited, slowly absorbed, and extensively metabolized in the thick upper respiratory and nasal epithelium at prolonged elevation of the local tissue concentration (Gerde 2001, 1997) - activating sensory receptors releasing inflammatory mediators - with  endogenous products of excessive inflammation - including cytokines and NO - eventually resulting in dysfunction of detox enzymes (Deluca 2010, Liptrott 2009, Oslund 2008, Chun 2002, Sterner-Kock 1999, Tinel 1999, Tanabe 1996, Tapner 1996, Nadin 1995, Stadler 1994, Khatsenko 1993).

In airway epithelial cells, DEP (diesel exhaust particles) via chemicals desorbed from the carbonaceous core involve a complexity of transduction and transcription factors (NFkB, MAPK, XRE, ARE, NrF2) and modification of cellular redox - with the secretion of inflammatory cytokines and induction of Phase I and II gene expression including CYP1A1 and NQO-1 (Baulig 2003a) - from a point of view excluding the sensory innervation.

This activity is with cost - the carbonaceous core of ACA PM considered a vector leading to sustained stimulation of the cells (Bonvallot 2001, 2000, Boland 2000, 1999, Baeza-Squiban 1999, Bayram 1998, Kumagai 1997, Thomas 1997)  - inhalation of combustion byproducts living on the edge - with the generation of reactive oxygen species, depletion of antioxidant defenses (Ziedinski 1999), DNA strand scission of plasmidic DNA (Stone 1998), and apoptosis of epithelial cells (Apogyan 2003a, Chin 1998).

It is impressive - the complex metabolism taking place in both the nasal and tracheal bronchial epithelium (Block 2012)  in close proximity to the critical c fiber sensory nerve receptors with their TRPA1 peptidergic terminals.

Instead of a more localized expression of metabolizing and antioxidant enzymes in solid airway epithelium protecting the nervous system - exposed nerves of damaged and inflamed epithelia result in activation of the TRP channels - elevated inflammatory mediators including substance P and cytokines - involvement of the immune system and increase of NO - endogenous products of inflammation to burden and suppress chemical defense systems (Deluca 2010, Liptrott 2009, Oslund 2008, Chun 2002, Sterner-Kock 1999, Tinel 1999, Tanabe 1996, Tapner 1996, Nadin 1995, Stadler 1994, Khatsenko 1993). Symptoms of MCS are often of a flu like pattern (Dantoft 2014, Bascom 1992) with increased congestion (Doty 1994) and hyperalgesia (Tran 2013, Holst 2011, Latremoliere 2009).

It can be concluded that once airway alteration is established - the nervous system more vulnerable - subsequent exposure to substances such as solvents and pesticides may greatly exascerbate the disease - especially concerning the CNS.

Many hundreds of studies depict the harm of ACA components - annual cost estimate in the US for premature death and illness due to air pollutants associated with motor vehicle use range in the hundreds of billion dollars with 95% attributed to ambient PM - principle component of the ACA (Pervin 2008, USDOTFHA 2000).

Evidence indicates the ACA may often be primary in causing MCS and ME/CFS by damaging the airway epithelium exposing the nerves - but the 2015 Consensus Criteria is conservative in stating the ACA supports the disease process.

CAR 6 Severe Oxidative Stress

It has been made clear there is a genetic sensitivity - a greater susceptibility among a subset of the population - often accompanying a psychological portrait Jung termed introverted intuition (MCS 15, Elberling 2009, Veronesi 2001, 2000, Roy 2000, Jung 1921) - and that exposure is to a continuous ambient combustion aerosol (ACA) of adsorbed chemicals on carbonaceous cores due to relentless inputs of exhaust and smoke. Vehicles have replaced nearly all human locomotion and there is not so much as a curfew of relief (Pervin 2008).

Those familiar with MCS and CFS might find it nearly inconceivable that all could originate as a chain reaction due to airway defects - but coherent pathways have been elucidated (Latremolier 2009, Calderon-Garciduenas 2008, 2000).

Substance P - elevated in MCS patients (Kimata 2004) primes and activates human neutrophils for superoxide, H2O2, and nitric oxide production (Oslund 2008, Sterner-Kock 1999, Tanabe 1996).

Dysfunction of chemical defense systems in MCS patients are mediated by redox active agents such as NO and inflammatory cytokines (Deluca 2010, Liptrott 2009, Oslund 2008, Chun 2002, Sterner-Kock 1999, Tinel 1999, Tanabe 1996, Tapner 1996, Nadin 1995, Stadler 1994, Khatsenko 1993). Depletion of phase II glutathione leads to severe oxidative stress and impaired elimination of phase I CYP metabolites. Catalase deficiency results in accumulated hydrogen peroxide leading to lipid peroxidation (Deluca 2010, Terlecky 2006).

Deluca 2010 found MCS patients have 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, N6, N3, arachidonic acid, and omega 3.

MCS and ME/CFS patients have a lipid profile and oxidant biology that is consistent with cardiovascular disease risk because atherosclerosis is mediated in large part by inflammatory and oxidative mechanisms including lipid peroxidation (Yang 2008, Kennedy 2005).

Lipid peroxidation includes decomposition of PUFA to form aldehydes such as 4-HNE, and losses of arachidonic acid may translate to increased lipid mediators of inflammation such as prostaglandins and leukotrienes (Deluca 2010).

Glutathione-s-transferases (GSTs) protect against oxidative damage to vascular endothelium from aldehydes such as 4-HNE, yet MCS patients have glutathione depletion and and a trend to high 4-HNE (Deluca 2010).

Peroxidized lipids such as prostaglandins may strongly contribute to platelet activation or vasoconstriction of the peripheral vasculature (Kennedy 2005, Fontana 2001, Sametz 1999).

Lipid peroxidation may also result in higher levels of oxLDL and lower HDL associated with the development of atherosclerosis (Kennedy 2005Nordin Fredrickson 2003).

Baldwin 1998 found increased cardiopulmonary disease risk in a community based sample having odor intolerance.

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 2014Maes 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).

Parenthetically, there may be several nutrient considerations in this regard within the bounds of normal physiologic intake:

Multiple units of glucose make up the starch of rice - metabolized with insulin release and a temporary rise in blood glucose and triglycerides. On contrast, fructose - recognized by its sweetness - does not involve insulin release or blood glucose rise - but triglycerides go up and remain high - increasing heart disease risk - especially in men (Chong 2007, Bantle 2000). Hepatic fructose metabolism results in partitioning of fatty acids towards esterification and impaired triglycerol clearance (Chong 2007).

Glucose as a simple sugar and fructose - or in combination as sucrose - such as in sweetened beverages and fruit juice - and even at low to moderate consumption - is shown to impair glucose and lipid metabolism, increase inflammation - and fructose intake is an independent predictor of a proatherogenic increase of smaller LDL particles (Aeberli 2011, 2007).

It is widely known that saturated fat, total fat, cholesterol, and refined grains - absent fiber, antioxidants, and other nutrients - are cardiovascular risk factors (Fisher-Wellman 2010, Jakobsen 2010, Siri-Tarino 2010 Delgado-Lista 2008, Klein-Platat 2005, Shi 2005Andersson 2002Robertson 2002Liu 2000, Friedman 1965).

A reduced antioxidant capacity and increased susceptibility to oxidative stress may occur if protein intake is low (Humayan 2007, Jackson 2004) - though increasing protein will not cure MCS.

Glutathione (y-glutamyl-cysteinyl-glycine; GSH) is synthesized from amino acids glutamate, cysteine, and glycine by the sequential action of y-glutamylcysteine synthetase (y-GCS) and GSH synthetase ( Wu 2004, Griffith 1999).

GSTM1 and GSTT1 - objects of the Deluca and Schnakenberg studies - concern the activation of Phase II enzymes known as GSH-S-transferases (GST) which catalyze the reaction of Glutathione (GSH) with electrophiles - a broad class of xenobiotic and endogenous compounds - including environmental toxins and reactive oxygen species (Block 2011, Manfredi 2009, Hayes 2005, Wu 2004, Griffith 1999).

In a condition such as MCS GSH depletion may be inevitable (Deluca 2010) either by excess utilization in spontaneous or GST catalyzed reactions or by suppression of synthesis such as with high levels of NO production (Lu 2009, Oslund 2008, Darmaun 2005, Wu 2004, Canals 2003, Griffith 1999, Sterner-Kock 1999, Tanabe 1996).

Adequate provision of the precurser amino acids glutamate, glycine, and especially the sulfur containing amino acids cysteine and methionine are critical for the maximization of GSH synthesis (Sekhar 2011, Lu 2009, Jackson 2004Lyons 2000, Bella 1999, Jahoor 1995, Grimble 1992). Cysteine is considered a semi-essential amino acid because it can also be derived from methionine - an essential amino acid (Griffith 1999a).

Mercury amalgam has a strong association with exascerbation of MCS (Pigatto 2013). However, it is not clear whether exposure from fish containing relatively low amounts of mercury has a net adverse effect on MCS - especially considering nutritional disadvantages of not including fish. Mercury is considered the most toxic nonradioactive element - partly because it bonds irreversibly with cysteine thiol groups (Mutter 2007) -  suggesting mercury is a powerful TRPA1 agonist - reversibility of bonds formed considered a major determinant of TRPA1 agonist potency (Bessac 2008).

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 2010Taylor-Clark 2010, Caceres 2009, Anand 2008Bessac 2008, Nassenstein 2008Bautista 2006Inoue 2005, Kobayashi 2005, Veronesi 2001)  - setting forth the MCS chain reaction including elevated plasma levels of neuropeptides, chemokines, cytokines, growth factors, and NO 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 (Dantoft 2014, Deluca 2010, Kimata 2004)

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).

Therefore, while leaving five of the six 1999 Consensus Criteria essentially intact - the 2015 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: 2015 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 mcsrr.org / Bartha P. et al. Multiple Chemical Sensitivity: a 1999 Concensus. Arch Env H 54:147-49 1999

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