It is hoped the following will make clear that MCS Etiology and environmental implications have reached high understanding - in apparent sudden onset of MCS from an incidential or short term exposure - usually the disease pre-existed as a genetic disposition in a continuous combustion aerosol.

Caccamo 2013 - research group of the Deluca 2010 study - reversed earlier findings concerning gene variants in cytochrome P450 detox enzymes - instead now reporting agreement with Mckeown-Eyssen 2004 - finding certain CYP variants have different frequency of occurrence - though most occur in both MCS and control groups.

If these results hold true - they are not established cause - it is not known whether these variants confer protection or increase harm - if the latter they may be significant among a subset of MCS patients - keeping in mind gene variants in detox enzymes are not major etiology of MCS (Berg 2010 , Deluca 2010) and for example: over 50% of the population have one or both of the GSTM1 and GSTT1 deletions (Piacentini 2011, Block 2011, Ginsberg 2009, Hayes 1995) - Schnakenberg 2007 defined 52% of a general population sample as the chemically sensitive group - percentages not corresponding with the incidence of MCS.

The reported CYP variants of Caccamo 2013 are few relative to the many forms of cytochrome P450 expressed - making a major causative role in most cases less plausible and competing with the observation that sensitivity of the sense organs occurs along with an introverted intuitive cast of mind - both genetically determined (Jung 1921) - further supported by the relationship between genetic quantitative differences in neuropeptides, TRP receptors, and acid sensitive pathways on airway sensory nerves and contrasting inflammatory sensitivity of mouse strains (MCS 15, Veronesi 2001, 2000, Roy 2000). Also Elberling 2009 showed heritability concerning respiratory symptoms from perfume.

Therefore, the genetic basis of MCS - rather than proposed candidate genes - is a broader difference - a neural portrait of genetic factors determining the structure and function of the airway neuro-inflammatory system and subsequent central nervous system processing - not so much genetic defect - but greater sensitivity - a characteristic vulnerability to a polluted environment.

BLOCK M.L. ET AL. THE OUTDOOR AIR POLLUTION AND BRAIN HEALTH WORKSHOP. NEUROTOX 33: 972-84 2012:

"...There is no methodology that can comprehensively create a complete list of candidate genes. The potential list of candidate genes is likely impossible to comprehensively select a priori, as genes may play roles in chemical metabolism, cellular toxicity, neurotransmitter metabolism, or could even work indirectly (i.e., disrupt the metabolism of a nutrient involved in brain function). The selection of candidate genes is therefore subjective and will vary from investigator to investigator. This is the major limitation of this approach. In addition, it is unlikely that all the relevant genes and regulatory regions that modify the toxicity of ambient pollution are even known. Thus, a candidate gene approach can never comprehensively interrogate all the potential genetic modifiers of environmental toxicants..."

Putting MCS Etiology together - a coherent research base of facts and causal relationships:

DANTOFT T.M. ET AL. AN ELEVATED PRO-INFLAMMATORY CYTOKINE PROFILE IN MULTIPLE CHEMICAL SENSITIVITY. PSYCHONEUROENDOCRINOLOGY 40: 140-50 2014

The cytokine results of Deluca 2010 differed from expectations based on MCS Etiology research. However, those of Dantoft 2014 closely match - and were credited to a more sensitive 10 plex and 4 plex assay and addition of protease inhibitors.

Consistency since 1992:

Rebecca Bascom. Environmental and Airway Diseases Research Facility, University of Maryland School of Medicine, Baltimore MD.

BASCOM R. MULTIPLE CHEMICAL SENSITIVITY: A RESPIRATORY DISORDER. TOX IND H 8(4);221-28 1992:

"...the airway epithelium and the airway surface fluid it produces and regulates are the first line of defence against the multiple, "non-self" constituents in the 10-20,000 liters of air inhaled each day. The airway epithelium is not an inert barrier, as was once thought, but contains a great capacity for xenobiotic metabolism...the observation that the airway can release cytokines...flu-like symptoms, low grade fever, and fatigue that...usually begin several hours after the exposure and last up to 48 hours...a type of acute phase response. Cytokines are now recognized as responsible...

The Danish Research Centre for Chemical Sensitivities, Copenhagen University Hospital, Gentofte, Denmark

DANTOFT 2014:

"...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..."

Damaged airway epithelial barrier results in exposed sensory nerves and elevated cytokines

William Meggs. Division of Toxicology, Department of Emergency Medicine, East Carolina University School of Medicine, Greenville NC.

MEGGS 1993 :

"...Neurogenic inflammation is now a well defined physiological mechanism by which mediators are directly released from sensory neurons to produce vasodilitation, edema, and other manifestations of inflammation. The nerve fibers have been identified as slow velocity C-fibers and the regulation of neurogenic inflammation has been studied...important regulators of inflammation, interleukin 1 and interleukin 2, suppress central nervous system activity...Found elevated in MCS patients (Dantoft 2014)

MEGGS 1997:

....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..."

EMCH 2000:

"...it is likely TNF alpha inhibits gastric motility by directly affecting the sensitivity of gastric vagal control circuitry in the medulla. This vago-vagal reflex circuit is outside the blood brain barrier and therefore is readily accessible to large circulating peptides. Additionally TNF alpha increases vascular-brain permeability and TNF alpha may gain access to the brain through a specific transport system..." Found borderline enhanced in MCS patients (Dantoft 2014)

This inhibition of gastric motility or stasis is perceived as queasiness or nausea.

DANTOFT 2014:

...The variations in cytokine levels identified in the MCS group could be indicative of elevated immune activation or a chronic inflammatory stage mediated by increased levels of the pro-inflammatory cytokines IL-1 beta. Il-6, and TNF alpha...

... this is further supported by the increased IL-2 levels. IL-2 is involved in the proliferation and differentiation of lymphocytes, playing a key role in expansion of T-cell, NK cell, and B cell populations, including regulatory cells, during various phases of an immune response (Boyman and Sprent 2012)...

...IL-12p70 and IL-8/CXCL8 are often increased together with IL-1 beta, IL-6, and TNF alpha as mediators of the acute phase response to an infection. However, in contrast to IL-1 beta, IL-6, and TNF alpha which mediate both local and systemic effects, the effector functions of IL-8/CXCL8 and IL-12p70 are more isolated to specific tissue areas affected by inflammation (Parham 2009). Increased levels of IL-8/CXCL8 are therefore less likely to be measured in blood...

...It is...possible that the increased plasma IL-4 levels in MCS individuals could be derived from tissue-located IL-4 producing cells, such as eosinophils or mast cells, which may infiltrate exposed tissue types, e.g. lungs or nasal lamina propria, during a chemical exposure...

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.

VERONESI 2001:

...In normal physiological settings, the respiratory epithelial population and its sensory innervation act reciprocally to influence the growth, differentiation, and homeostasis of each other...These relationships are especially critical to the organism's inflammatory response...

...In all instances, sensory neurons release 10-200 fold higher levels of IL-6 (pro-inflammatory cytokine) relative to epithelial cells... Found elevated in MCS patients (Dantoft 2014)...conditions associated with chemical pollutants are characterized by damage to the epithelial barrier that lines the airways. Such damage not only results in the loss of critical neuropeptide deactivating enzymes (e.g. NEP) but allows the sensory fiber to physically extend closer to the airway lumen and in closer proximity to the inhaled PM particles...enhanced and prolonged inflammatory events...increased inflammatory response...

...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)..."

DANTOFT 2014:

"...It has been reported that IL-13 changes the mucosal epithelium from being an absorptive barrier to a mucus secreting one (Danahay 2002), thus tipping the balance toward increased absorption at low IL-13 levels. IL-13 is also involved in suppression of pro-inflammatory cytokine production from macrophages within inflamed tissue (Minty 1993) as well as in inhibition of Th1 propagation in lymph nodes and promotion of B-cell activation (Punnonen 1993). The decreased systemic levels of IL-13 may therefore be an indicator of diminished barrier protection, if the reduced IL-13 levels implicate reduced mucus production at mucosal surfaces, and also of reduced inhibition of pro-inflammatory cytokine production within tissues..."

CALDERON-GARCIDUENAS 2000:

"...a persistent ongoing airway inflammatory process the result of exposure to air pollutants in a sequential and chronic manner...the imbalance and dysregulation of cytokines and their ample systemic effects..." Found elevated in MCS patients (Dantoft 2014)

More than "sickness behavior", mood, anxiety, or depression

CALDERON-GARCIDUENAS 2008:

"...Breakdown of the nasal respiratory and olfactory epithelium and the BBB (Blood Brain Barrier) facilitates the access of systemic inflammatory mediators and components of air pollution to the central nervous system (CNS) (Calderon-Garciduenas 2004)...

...sustained exposures to significant levels of air pollutants including UFPM (ultrafine particulate matter) , PM2.5 (less than 2.5 microns), and PM-LPS produce brain neuroinflammation and neurodegeneration through at least four pathways:

1 Induction of upper respiratory, lung epithelial, and endothelial injury leading to persistent chronic inflammation in the respiratory tract and systemic inflammation. The systemic inflammation is accompanied by the production of pro-inflammatory cytokines such as TNF alpha, IL 6 and IL-1beta... Found elevated in MCS patients (Dantoft 2014)...these cytokines can activate endothelial cells in the BBB, disrupt the BBB...and trigger cascades...results in increased expression of nitric oxide synthase...and nitric oxide production that opens the BBB..."

2 We strongly support the importance of the olfactory pathway...since olfactory neurons are loaded with PM...will potentially translate into an abnormality in the limbic system...(Bedard 2004)...

3 The vagus/trigeminal (Lewis 2005) pathways are also crucial, given that PM enters the respiratory and digestive systems...

4 Direct access of UFPM to the brain, further accentuating an inflammatory response in the brain parenchyma...

ORRIOLS 2009:

"...Neurocognitive deficits were found, particularly after chemical challenge, in MCS patients. The parietotemporal cortex, which has been related to MCS owing to electroencephalographic alterations found in this area (Bell 1998), is involved in the processing of complex aspects of attention and, in conjunction with the hippocampus, in the formation of memory (Bell 1996). Our finding of brain SPECT hypoactivity in these areas and also in frontal-subcortical circuits (Salmon 2001) could, in part, explain neurocognitive defects in MCS patients. 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)..."

The ambient combustion aerosol - diesel 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 particle agglomerates with adsorbed hydrocarbons and singlet nonagglomerated nanoparticles

Lucchini 2012, Mohankumar 2008, Inoue 2005, Kittelson 1998, Cadle 1999, Kleeman 1999

damages airway epithelium and activates sensory nerves including TRPAI expressing terminals releasing neuropeptide substance P

Deering-Rice 2011, Hazari 2011, Li 2011, Taylor-Clark 2010, Baulig 2009, 2003a, Calderon-Garciduenas 2008, 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

Fine particles expected to reach the CNS via trigeminal and olfactory nerve pathways

Calderon-Garciduenas 2010, Genter 2009, Matsui 2009, Elder 2006, Lewis 2005

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).

DAVIES 2014:

A quantitative assessment of pedestrian PM exposure.

KIMATA 2004:

Results show ongoing stimulation by the Ambient Combustion Aerosol - elevated substance P (SP) and nerve growth factor (NGF) before study provocation:

SP before exposure to paint controls 38 MCS 105 after controls 39 MCS 153

NGF before exposure to paint controls 148 MCS 1129 after controls 156 MCS 1696

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.

MOHANKUMAR S.M.J. ET AL. PARTICULATE MATTER, OXIDATIVE STRESS, AND NEUROTOXICITY 29;479-88 2008:

"...acute CAPs (concentrated air particles from an urban community) exposure stimulate increases in cytokine levels in the nasal passages (Reichelman 2004)...after multiple exposure, the inflammatory cytokines may have enough time to enter systemic circulation and become detectable Found elevated in MCS patients (Dantoft 2014)...it is known that sub-chronic PM exposure produces pulmonary inflammation which results in systemic cytokine levels (Ruckerl 2007)...PM exposure is associated with pulmonary inflammation and the release of inflammatory cytokines and mediators from respiratory epithelia into the systemic circulation...

...Recent studies indicate that microglia can activate in response to circulating cytokines from the periphery and endogenous transmitters. Microglia located in proximity to fenestrated or "leaky" blood brain barriers can be signalled by circulating PM particles themselves or by inflammatory cytokines/chemokines being released systemically from the chronically inflamed airways...IL-1 is produced by respiratory epithelia in response to PM exposure... Found elevated in MCS patients (Dantoft 2014) can cross the blood brain barrier...prolonged increases in IL-1 levels causes the blood brain barrier to become leaky providing access to IL-1 and other circulating cytokines..."

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)...

...Over 5 months later particles in the lung and lymph nodes had only 37 and 59% of B[a]P desorbed - mostly during the initial rapid release - with the exception of more desorption from particles translocated to the lymph nodes - possibly due to environment within macrophages (Nyberg 1989, Harmsen 1985 , Lundborg 1984)..."

Bonvallot 2001:

"...CB (carbonaceous core) exhibit oxidative properties as they deplete the antioxidant defenses in the epithelial lining fluid (Ziedinski 1999) and induce DNA strand scission in plasmidic DNA (Stone 1998)...

...the carbonaceous core could be considered mostly as a vector allowing the entry of organic compounds into the cells and their slow diffusion leading to sustained stimulation of the cells as native diesel exhaust particles-induced NFkB DNA binding started later but was more persistent than that induced by organic extracts of diesel exhaust particles...(Boland 2000, 1999, Bonvallot 2000, Baeza-Squiban 1999, Bayram 1998, Kumagai 1997, Thomas 1997)..."

Li 2011:

"...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. Because large numbers of hazardous chemicals are present on DEP, its pathological effects on human airways are pleiotropic. We and others have found that DEP evokes the secretion of matrix metallo-proteinase-1 (MMP-1) from human bronchial epithelia (Li 2009, Amara 2007). Matrix metalloproteinase-1 (MMP-1) plays a role in tissue remodeling during development, inflammation, migration of inflammatory and malignant cells, and COPD and emphysemia pathogenesis (Segura-Valdez 2000). It also has neurotropic effects, possibly enhancing sensitization of airway-innervating sensory neurons, contributing to airway hypersensitization and chronic cough (Conant 2004)..."

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)...

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

BESSAC 2008:

...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)...

...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)..."

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)..."

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...

The MCS chain reaction: stimulation of exposed sensory nerves including peptidergic TRPAI expressing terminals - in damaged airway epithelium - effects all systems - central sensitization, detox enzyme dysfunction, oxidative stress, cardiovascular atherogenesis (Bai 2013), and autonomic imbalance (Hazari 2011).

DELUCA 2010:

"...Notwithstanding the absence of genetic defects in CYPs, recent studies have increasingly implicated various inflammatory stimuli, first of all, pro-inflammatory cytokines (Chun 2002, Nadin 1995, Tapner 1996, Tinel 1999) to cause changes in the activities and expression levels of CYPs through nitric oxide signalling (Chun 2002, Stadler 1994). For example, drug metabolizing CYPs such as CYP3A4 and CYP2B6, which are constitutively expressed in human mono nuclear cells, have been significantly repressed by IFN Gamma or IL-2 (Liptrott 2009)...

...Our results suggest that serious and multiple dysfunctions of chemical defense systems found in MCS patients may mainly not depend on genetic defects, but instead may rely on non-genetic modifications of metabolizing/antioxidant enzyme expression and/or activity, mediated by redox active agents such as NO and inflammatory cytokines..."Found elevated in MCS patients (Dantoft 2014, Deluca 2010)

...Dysfunction of two major antioxidant enzymes and depletion of glutathione inevitably leads to severe oxidative stress and impaired elimination of phase 1 oxidation metabolites. Excessive amounts of hydrogen peroxide due to catalase deficiency will initiate a non enzymatic free radical driven chain reaction of lipid peroxidation implicated in a number of human pathologies..."

OSLUND 2008:

"...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)..."

HAZARI 2011:

"...the airways are innervated by sensory nerves bearing transient receptor potential (TRP) channels; namely, member A1 (TRPA1), and member V1 (TRPV1), which detect different types of noxious chemicals, including many of those found in the complex mixtures of common air pollutants such as DE (diesel exhaust). Activation of these nerves by airborne irritants such as ozone or acrolein causes centrally mediated autonomic "imbalance", which produces ventilatory, pulmonary, and cardiovascular function changes (Bessac 2008, Ghelfi 2008, Bautista 2006)..."

Why are MCS people naturally sensitive - genetically predisposed?

JUNG 1921:

Baynes Translation

"...the introverted intuitive...extraordinary dependence upon the sense impression...compensation to the thin upper air of the conscious attitude...hypersensibility of the sense organs..."

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..."

VERONESI 2001:

"...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)...

...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..."

Conclusion: Definition and Etiology of MCS

MCS is usually genetic vulnerability in the nasal and tracheo 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, 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 combustion byproduct aerosol - diesel 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 particle agglomerates with adsorbed hydrocarbons and singlet nonagglomerated nanoparticles 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

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)

resulting 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 - 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 1999, 1998), and central sensitization - a functional synaptic plasticity resulting in pain hypersensitivity (Tran 2013, Holst 2011, Latremoliere 2009)