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 (found systemically elevated in ME/CFS [Maes 2012]),

neuron damage or loss, microglial activation (innate immune system macrophages of the brain - their job to engulf and digest but with cumulative collateral damage) indicated by increase of HLA-DR surface antigen positive cells and CD-14 lipopolysaccharide (LPS) receptors - LPS a potent inflammatory cell wall component of gram negative bacteria (endotoxin) commonly adsorbed on DEP (diesel exhaust particles) (Block 2004) - with resulting ROS (reactive oxygen species) and cytokine production, blood-brain barrier (BBB) dysfunction - changes in inflammatory , tight junction, and transport proteins of the cerebral vascular microvessels (3 to 8 micron diameter) that comprise the BBB - endothelial cell damage with increase in leukocyte adhesion molecules - and confirmed using Positive Emission Tomography - activated microglia and astrocytes evidencing brain neuroinflammation in ME/CFS patients - found to correlate with degree of cognitive impairment (Nakatomi 2014) - and two markers of BBB opening - nitrotyrosin and protein S100B - elevated in a subset of MCS and EHS (electrohypersensitivity) subjects (Belpomme 2015).

accumulation of Abeta-42 (42 amino acid form of amyloid beta) as neuronal, vascular and diffuse plaques, Abeta and alpha synuclein aggregation (associated with Alzheimers and Parkinsons Disease respectively) - CALDERON-GARCIDUENAS 2008:"...Both Abeta42 (42 amino acid-isoform of beta amyloid associated with Alzheimer's) and alpha synuclein ( an abundant brain 140-residue-protein linked to Parkinson's disease) are proteins capable of aggregation and misfolding (shown to occur more rapidly in conditions of PM exposure), leading to progressive neurodegeneration that develops insidiously over the lifetime of the individual (McGeer 2006, Jellinger 2003, Nguyen 2002, Selkoe 2002, 2001)...",

lipid peroxidation (systemically confirmed in MCS people [Deluca 2010]), astrogliosis evidenced by enhanced glial fibrilliary acid protein (GFAP) expression, and DNA damage (Block 2009, Calderon-Garciduenas 2008).

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).

Although more is worse - there is no safe level of chronic and repeated exposure to combustion byproducts including vehicle exhaust.

2015 Consensus Criteria for MCS

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 effected 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.

2015 Consensus Criteria for MCS

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

KIMATA 2004:

"...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..."

ORRIOLS 2009:

"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)..."

It may seem incomprehensible - present in every breath since birth - exhaust saturated in the olfactory region - and along the entire nasal and upper respiratory tract of sensory receptors - fine particles with adsorbed chemicals - particulate vector and a prolonged residence time (Li 2011, Bonvallot 2001) stored in lung tissue and lymph nodes for months and years - desorption in 2 phases - initial rapid burst and extended gradual release (Gerde 2001, 1997) a physiological hijacking in a continual particulate shower - the ambient combustion aerosol - nearly all are rum dumb on this issue.

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.

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.

GERDE 2001:

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)..."

LI 2011:

"...DEP injures respiratory epithelia via a luminal-apical unloading mechanism of DEP organics delivered by carbonaceous nanoparticles..."

BONVALLOT 2001:

"...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)..."

MATSUI 2009:

"...The results obtained support that nano-sized DEPs do in fact translocate to the central nervous system through the olfactory nerve..."

LEWIS 2005:

"...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..."

GENTER 2009:

"...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..."

MEGGS 1997:

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 ..."

CALDERON-GARCIDUENAS 2008:

"...Induction of upper respiratory , lung epithelial, and endothelial injury leading to persistent chronic inflammation in the respiratory tract and systemic inflammation. The systemic inflammation is accompanied by the production of pro-inflammatory cytokines such as TNF alpha, IL-6, and IL-1 beta...can...disrupt the BBB..."

...Breakdown of the nasal barrier in pollution exposed subjects may also contribute to brain inflammation by increasing the access of PM to the brain through the olfactory and trigeminal pathways..."

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..."

PERVIN 2008:

"...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..."

Therefore, as mentioned above the 2015 Consensus corrects impression MCS is a syndrome in response to unrelated chemicals in a low level, commonly tolerated, non inciting background atmosphere (Block 2009, Calderon-Garciduenas 2008, Veronesi 2001).

Because MCS - and environmentally caused disease in general - usually involves permanent proinflammatory alteration in the structure and function of the airway epithelium and its sensory innervation - there is no cure (Calderon-Garciduenas 2008, Veronesi 2001, Meggs 1997).

Though chemokines, growth factors, cytokines, and NO are elevated, glutathione depleted, catalase deficient, fatty acid profile altered indicating lipid peroxidation, and CNS changes measurable (Dantoft 2014, Tran 2013, Holst 2011, Deluca 2010, Orriols 2009, Millqvist 2005, Kimata 2004, Bell 1999, 1998) laboratory tests may have no utility for the patient - therefore mandatory testing is unethical and immoral.

However, it is important to acknowledge the physiological definition - not necessarily for the purpose of medical diagnosis - but to recognize this is an environmental crisis - not only to a subset of the population effected most acutely - but threatening life on earth (Rogers 2011) - a continuous combustion aerosol - and move the lifestyle to a higher level of morality making possible change to a non combustion basis.

We should be together in addressing the crisis of unrestrained growth and consumption. Consequences are catastrophic - geopolitical turmoil, overpopulation: 4.4 billion 1960/2015 - 3 to 7.4 billion in just 55 years (Worldometers 2015), resource loss, climate change, ocean acidification, mass extinction, speed, violence, pollution, injury, illness, and premature death.

It is to evaluate one's own attitude, character, behavior, and motives - and admit that all are of a grand scheme to destruction so long as the lifestyle of unrestrained growth, consumption, fast pace, preoccupation with competition and violence, and engagement of wasteful products, activities, and traditions persist - including billions of people taking a 4000 lb machine everywhere they go - rather than the healthful effort of walking - drawing upon thousands of years physical development and thoughtful reflection - a moral exertion - strength and integrity - choosing honesty, goodness, kindness, and love - to slow down and live environmentally consistent with those values.

With 1 billion people added to population in 15 years taught that unrestrained growth, consumption, and combustion fueled activity is okay - this world will not support all movement at 25-300 MPH - recognized is a need for Impossibly Good City Design - to slow down, walk more, change to non combustion vehicles, turn down thermostats, reduce population and consumption - using good moral judgement to protect a supporting environment.

MCS 3b Etiology 1, 2, & 3 References

MCS aj Impossibly Good

Mgt 101 Consume Less or Extinction

Mgt 101a Impossibly Good City Design

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