Multiple Chemical Sensitivity Etiology
Airway Genetics and Ambient Combustion Aerosol
Appendix: Added Splash IV, V
IV. MCS 2ac Etiology: Belpomme 2015 - Formula or Reality?
Outline
A. Real World Environmental Context
B. Formula Excludes Knowledge
C. Three Principle Errors
1. Improper MCS Subject Group
2. Miscalculation of S100B and NTT Data
3. Suggested Biomarkers are ot Diagnostic
D. Corrected Data in Context
E. MCS Intuition: The Noblest Gift
A. Real World Environmental Context
The task of secondary reviews and primary research articles is to present information that reflects adequate knowledge relevant to the topic - including the Real World environmental context.
The four point summary of Calderon-Garciduenas 2008 closely resembles the progression of MCS - every breath 24/7/365 involves the ambient combustion aerosol (ACA) - along with sulfate and nitrate - thousands of chemicals, metals, and endotoxins complexed to carbonaceous cores with lengthy tissue residence time (Baulig 2009, 2003a, Bonvallot 2001, 2000, Gerde 2001, Boland 2000, Baeza-Squiban 1999, Bayram 1998, Kumagai 1997, Thomas 1997) - supporting continued elevated basal inflammatory status in MCS people.
Calderon-Garciduenas 2008 and 2001 report on autopsies and biopsies of clinically healthy children and young adults of non smoking households in Mexico City, Mexico - autopsies performed after accidental sudden death. 100% of the subjects were found to have serious airway breakdown and brain damage attributable to ambient air pollution. Their research did not focus on the sensory nerves specific to MCS - for that turn to Bessac 2008, Veronesi 2001, 2000, Roy 2000, and many others included on the Etiology website.
B. Formula Excludes Knowledge
Belpomme 2015 is both valuable and misleading. As with many primary studies, Belpomme 2015 seeks to gather facts and create data that support the working hypothesis or formula. The mistake made is elevating all that conforms to the formula as reality - and all outside the formula is held out of consciousness - irrelevant or "poor knowledge".
"...In view of the poor knowledge of pathogenesis and etiology of EHS and MCS, most mainstream medical, sanitary and societal bodies maintain there is not sufficient scientific proof to support the concept that clinical symptoms experienced by EHS and/or MCS self-reporting patients are really caused by EMF and/or chemical exposure..."
The Extraverted Thinking Type
"...the formula gains such ascendancy that all other possible standpoints are thrust into the background..."
...current research failed to attribute a causal origin to EHS and/or MCS. Case-control epidemiologic studies and provocation studies, globally have failed to demonstrate a causal link between EMF and EHS , as it may also be the case for chemicals and MCS..."
Provocation and epidemiologic studies highlighted below point to a causal relationship between chemicals and MCS (Dantoft 2015, Orriols 2009, Milqvist 2005, Kimata 2004, Nogami 2004)
and air quality monitors reveal greater hospital admissions and morbidity on days with higher ambient PM levels (Pervin 2008, Pope III 2004, USDOTFHA 2000).
"...the MCS group perceived the n-butanol exposure as being more intense, more unpleasant and rated symptoms to be of greater magnitude compared to controls...additionally, individuals with MCS had higher than normal pulse rate and lower than normal pulse rate variability...indicating abnormal regulation of the sympathetic branch of the autonomic nervous system during the exposure..."
Orriols 2009 found major brain differences comparing MCS and control groups challenged with measured air concentrations: paint components methyl acetate, methyl ethyl ketone, toluene, butyl acetate, xylene, methanol; perfume components ethanol, limonene; petrol components hexanes, heptanes, octanes, benzene; and glutaraldehyde.
"...after capsaicin provocation the patients showed a significant increase in NGF which was related to capsaicin cough sensitivity...SHR (sensory hypereactivity) is real and measurable, demonstrating a pathophysiology in the airways of these patients compared to healthy subjects..."
"...The findings of the present study indicate that the mechanisms underlying MCS may originate in the sensory nervous system..." - MCS cough occurring in response to capsaicin at concentrations far less (.150) than both the control group (1.120) and the chronic cough group (.630).
"...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..."
An episode of perfume or paint (VOC) may result in pain and histamine release in temporary response - but tailpipe and chimney emissions persist - catalytic converter production of aerosol acid sulfate along with chemicals, metals, and endotoxins on carbonaceous particle cores with lengthy tissue residence time supporting continuous elevated inflammation.
USDOTFHA 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..."
"...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..."
Reference to periods of time without environmental stressors is not realistic:
"...we thus wonder whether the 60% of patients in our series who were not associated with detectable increased histamine levels may in fact be patients who were not exposed to environmental EMF and/ or chemical stressors just before histamine measurement..."
The Ambient Combustion Aerosol (ACA) is continuous in all US census districts - urban and rural. Histamine fluctuates above normal among MCS people in response to spikes riding on the ACA camel's back - symptoms become more acute leading many to believe that incidental chemical exposure responsible for those spikes constitute the causative bulk of the illness - yet by objective measure there is continued elevated inflammation aggravated by those spikes.
"...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)..."
Would it be preferred to inhale burning perfume - chemical bound to carbon cores for lengthy tissue residence time in every breath for the rest of a lifetime - as is the situation with ambient vehicle exhaust?
C. Three Principle Errors
Belpomme 2015 makes major contributions - but to avoid misleading the reader three principle errors must be emphasized.
1. Improper MCS Subject Group
The MCS subject inclusion criteria were altered from that of the 1999 Consensus. Those not exhibiting obvious acute upper airway symptoms were excluded.
"...we systematically added a seventh clinical criteria to the six ones already defined during the 1999 consensus meeting on MCS, in order to further characterize clinically MCS and distinguish it from EHS. Accordingly patients with MCS, unlike EHS patients, were characterized not only by the simple odor intolerance, but more specifically by symptoms of mucous inflammation in the nose, the oropharynx and/or the laryngotracheo-bronchus tract; manifesting clinically as rhinitis, oropharyngeal dysesthesia or laryngitis and/or bronchospasms, respectively..."
The exclusion requirement can be expected to tilt the MCS subject group to those experiencing chronic smoke inhalation or other spiking exposure that would elicit those acute symptoms - often accompanied with histamine release - thereby the percentage of subjects having elevated histamine is exaggerated compared to a truly average representation of MCS subjects. Belpomme 2015 reports 36% of MCS patients had elevated histamine while Kimata 2004 found histamine levels in MCS normal at baseline before the spiking exposure to paint.
2. Miscalculation of S100B and NTT Data
Miscalculation of S100B and NTT data in Table 4 apparently resulted in formula overreach - exaggerating the percentage of subjects having elevated S100B, NTT, or both - and eventually the assertion - without supporting data - that perhaps all subjects have markers of BBB disruption that are undetected.
"...as indicated in Table 4, it appears that increased levels of protein S100B and/or NTT can be detected in approximately 55%–60% of the cases...
...Using protein S100B and NTT as biomarkers our data tend to show that BBB opening could be detected in 55%–60% of patients; but this result does not mean the remaining cases could not have been associated with BBB opening we were unable to detect..."
Presence of elevated S100B, NTT, or both in EHS and MCS subjects is incorrectly stated to be 55-60% instead of 35-40%, and elevation of S100B, NTT, histamine, 2 of the 3, or all is overstated to occur in 70-80% of subjects - rather than approx 50%.
Table 4 consists of 3 columns with similar calculation error made in all columns. There is confusion because S100B and NTT were not tested in the same number of subjects. And the determination of overlap where both S100B and NTT were elevated in the same subjects was performed with a third group having a different number of subjects.
To illustrate the correction of data required in all 3 columns - here is analysis of EHS column 1 of Table 4. Its a little brain teaser - rounding numbers for convenience S100B is found elevated in 15% of the subjects and NTT elevated in 30% which totals 45%; however the total having one, the other, or both is lower due to overlap where an unknown number have both elevated at the same time. Expectation would be that at least half of the S100B incidence overlaps with NTT so that the total percentage of subjects having S100B, NTT, or both elevated is approx 35%.
At this point the overlap is not determined - instead a third group (250 subjects) were measured to determine the overlap - with the overstated result of one, the other, or both at 53%. If results in the third group are consistent with incidence in the first two groups, 15% S100B, 30% NTT - then 15% of the 250 subjects have elevated S100B = 37.5 subjects; round to 35. And 30% for NTT of the 250 = 75 subjects; equals 110 having one or the other elevated - but now concerns subtracting for the overlap. With a finding of 23 subjects having both elevated 110 + 23 equals the mistaken 53% (133 of 250 subjects); the 23 should have been subtracted, 110 - 23 = 87 of 250 subjects; 35%.
To be clear - there is little doubt - the approx 15 and 30% values for S100B and NTT were the total percentage of subjects having elevation of each respectively - including where coincident with elevation of the other in the same patient - the article abstract declares those values consistent with that interpretation.
3. Suggested Biomarkers are not Diagnostic
The proposed reliable diagnostic markers are not specific to MCS and are only elevated in the minority at any given time, 15% S100B, 30% NTT, 23% auto-antibodies against myelin, 33% Hsp27/Hsp70, and less than 40% histamine. Therefore, they cannot be recommended as diagnostic tools - nor should anyone be pressured into such blood tests. And recall the near 40% histamine result is likely tilted upward by the improper MCS subject group inclusion criteria requiring acute respiratory symptoms.
A defect in melatonin metabolic availability (decreased 6 OHMS/creatinin ratio) was reported in all cases - and is associated with chronic insomnia and fatigue.
Despite flaws concerning knowledge of context, MCS subject inclusion criteria, math calculations, suggested diagnostic application, and conclusions (formula overreach) - the data presented by Belpomme 2015 is a major contribution to the understanding of MCS and EHS. The similarity of findings comparing MCS and EHS is impressive.
As with proposed biomarkers; decrease in plasma D3 approx 25% of subjects and increase of high sensitivity C reactive protein (hs-CRP) in 14% - changes occurring under conditions of increased systemic inflammation - are not exclusively specific to MCS - and each found divergent from normal in a minority of patients.
"...Near 40% had a increase in histaminemia (especially when both conditions were present), indicating a chronic inflammatory response can be detected in these patients. Oxidative stress is part of inflammation and is a key contributor to damage and response. 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%. Circulating autoantibodies against O-myelin were detected in 23%, indicating EHS and MCS may be associated with autoimmune response., we found increased Hsp27 and/or Hsp70 in 33% of the patients. 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. Our data strongly suggest that EHS and MCS can be objectively characterized and routinely diagnosed by commercially available simple tests. Both disorders appear to involve inflammation-related hyper-histaminemia, oxidative stress, autoimmune response, capsulothalamic hypoperfusion and BBB opening, and a deficit in melatonin metabolic availability; suggesting a risk of chronic neurodegenerative disease..."
D. Corrected Data in Context
The corrected percentage of patients having elevated markers of BBB disruption: S100B, NTT, or both 35-40; instead of 55-60%, represents a large minority of subjects at any given time rather than a majority - strongly supporting that BBB disruption is secondary as MCS becomes more severe.
It has long been held by credible researchers: conditions associated with chemical pollutants involve damage to the barrier that lines the airways.
"...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..."
"...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..."
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 ..."
"...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..."
While Belpomme 2015 has focused on BBB disruption as associated with cerebral hypoperfusion - Orriols 2009 referred to the penetration of UFPM directly to the CNS via the olfactory nerves (Gillespie 2013, Pedata 2010, Araujo 2009, Phalen 2009, Schmid 2009, Valavanidis 2008, Calderon-Garciduenas 2008, deHaar 2006, Kreyling 2006, 2004, Donaldson 2003, Oberdorster 1996). Many researchers have confirmed that UFPM of the ACA have pathways to the CNS through both the olfactory and trigeminal sensory innervation - especially in damaged nasal and upper pulmonary airway epithelium.
"...cerebral hypoperfusion in one or two of the hemisphere in 50.5% of the cases...
...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..."
ORRIOLS 2009:
"...MCS patients present brain signal photon emission computed tomography (SPECT) and psychometric scale changes...
...In comparison to controls, cases presented basal brain SPECT hypoperfusion in small cortical areas of the right parietal and both temporal and fronto-orbital lobes. After chemical challenge, cases showed hypoperfusion in the olfactory, right and left hippocampus, right parahippocampus, right amygdala, right thalamus, right and left Rolandic and right temporal cortex regions (p<0.01)...
...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)..."
...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..."
"...The results obtained support that nano-sized DEPs (diesel exhaust particles) do in fact translocate to the central nervous system through the olfactory nerve..."
"...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..."
E. MCS Intuition: The Noblest Gift
MCS is not a mysterious pathology of inflammation and blood-brain barrier disruption - MCS usually originates as a genetic naturally sensitive disposition - with sensory innervation not designed to keep a low profile in an atmosphere of excessive noxious stimuli.
Primarily in the thick upper airway and nasal epithelium - contrasted with the thin type 1 alveolar region deep in the lung (Gerde 2001) - are TRPA1 receptors on peptidergic terminals expressing substance P (Deering-Rice 2011, Hazari 2011, Nassini 2011, Costa 2010, Taylor-Clark 2010, Caceres 2009, Anand 2008, Bessac 2008, Nassenstein 2008, Bautista 2006, Inoue 2005, Kobayashi 2005, Veronesi 2001); proinflammatory neurotransmission continues even when airway symptoms seem less acute (Kimata 2004).
In the manner of a chain reaction, consequences of chronically elevated basal inflammatory status proceed secondarily as disease severity increases over decades. The ambient combustion aerosol (ACA) supports 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 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, Calderon-Garciduenas 2008, 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), 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.
Sensitivity in vivo and in vitro:
"...taken together, the above in vivo and in vitro studies suggested that the variable inflammatory sensitivity to PM observed in different mouse strains (ie Balb/C, B6) related to quantitative differences in the neuropeptide, VR1 (now TRP) receptors 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 et al 1995), nitrogen dioxide (Holroyd et al 1997), and diesel exhaust (Ichinose et al 1997, Miyabara et al 1998)..."
"...In conclusion, we found an increased familial occurrence of perfume-related respiratory symptoms where 35% of phenotypic variation was due to additive genetic effects and 65% was due to individual specific environmental effects...".
Often occurring with MCS - introverted intuition may be the noblest gift - but with greater sensitivity to the ambient environment.
"...Intuition, on the other hand, receives from sensation only the impetus to its own immediate activity; it peers behind the scenes, quickly perceiving the inner image that gave rise to the particular form of expression...introverted intuition perceives all the background processes of consciousness with almost the same distinctness as extraverted sensation registers external objects...
...Introverted intuition apprehends the images arising from the a priori inherited foundations...
...introverted intuition, through its perception of these inner processes, can supply certain data which may be of the utmost importance for what is going on in the world. It can even foresee new possibilities in more or less clear outline, as well as events which later actually do happen...
...an extraordinary dependence on sense-impressions. This compensates the rarified air of the intuitive's conscious attitude, giving it a certain weight, so that complete "sublimation" is prevented...hypersensitivity of the sense organs..."
V. MCS 3ad: MCS Genetics - Likely a Neural Portrait
Outline
A. Genetics in Detox Enzymes Not Majority Etiology
B. Inflammatory Cause of Detox Enzyme Dysfunction
C. A Genetic Neuroinflammatory Portrait
A. Genetics in Detox Enzymes Not Majority Etiology
Several studies have been widely misreported by the MCS Community: Haley 1999 concerned gulf war veterans and PON 1; McKeown- Eyssen 2004 CYP2D6, NAT1,2, and PON1,2 - warning caution the numbers are small; and Schnakenberg 2007 GSTM1 and GSTT1 results applied to 50% of the population.
MCKEOWN-EYSSEN 2004 disputed that of Haley:
"...However our findings differ from those of Haley et al who also observed an association of Gulf War Syndrome with the homozygous R genotype, as we found no corresponding significant association with MCS for the homozygous I. genotype (I.I.) of PON1 55 or for the homozygous R genotype of PON1-192...
...Neither were there differences between cases and controls in the frequency of the 55I. allele (seen in 66.3% of chromosomes for cases and 63.8% for controls in Table 2, P=0.52 from Fisher's exact test)..."
Berg 2010, with MCS subjects diagnosed by Cullen criteria, found no association of PON1 with MCS.
Concerning other enzymes, MCKEOWN-EYSSEN 2004:
"...our results suggest that individuals with higher CYP2D6 activity (homozygous active) are at increased risk for MCS compared with individuals with two non-functional alleles...however in view of the small numbers , such an association must be viewed cautiously...while differences in NAT2 allele distribution were only marginally significant (table 2), when alleles combine into genotype, rapid acetylators were found at increased risk (table 3)...in view of the small numbers such an association must be viewed cautiously..."
Berg 2010 sank the ship of Haley and Mckeown-Eyssen misapplication to MCS.
"...In conclusion, based upon a considerable number of study participants, we were not able to confirm previous findings of substantial importance of gene variants in CYP2D6, NAT2, PON1, MTHFR, and CCK2R to MCS and self-reported chemical sensitivity..."
"...GSTs are a family of phase 2 enzymes found in all eukaryotic species. They play a critical role in detoxifying both naturally occurring and xenobiotic compounds, including carcinogens, environmental toxins, and reactive oxygen species, by catalyzing the transfer and conjugation of glutathione (Manfredi 2009, Hayes 1995)..."
Over 50% of the population have one or both of the GSTM1 and GSTT1 deletions (Piacentini 2011, Block 2011, Ginsberg 2009, Hayes 1995).
The Schnakenberg study had 521 subjects. None were known to have diagnosed MCS. The subjects filled out a form having 3 choices: not at all a problem, moderate symptoms, or disabling symptoms; in describing their reaction to 10 different exposures: exhaust, smoke, insecticide, gasoline, etc. They were awarded 1, 2, or 3 points in order of severity for each choice so maximum score was 30 and minimum 10.
Those scoring more than 20 were defined as chemically sensitive so that 273 wound up in the "chemically sensitive" group and 248 in the less sensitive group.
Schnakenberg 2007 stated: "...our study subjects were identified by a questionnaire asking for chemical hypersensitivity and not for symptoms of MCS..."
DELUCA 2010 whose case group was diagnosed MCS by Cullen criteria (Cullen 1987), found no significant differences in allele and genotype frequencies of CYP's, UGT, GSTM, GSTT, and GSTP between the MCS and control groups and refer to the studies of Mckeown 2004 and Schnakenberg 2007 as follows:
DELUCA C. ET AL BIOLOGICAL DEFINITION OF MULTIPLE CHEMICAL SENSITIVITY FROM REDOX STATE AND CYTOKINE PROFILING AND NOT FROM POLYMORPHISMS OF XENOBIOTIC- METABOLIZING ENZYMES. TOX AND APPL PHARM 248:285-292 2010:
"...Mckeown-Eyssen et al (2004) suggested also a possible gene-gene interaction between CYP2D6 and N-acetyl transferase 2 (NAT2), with rapid metabolizers for both enzymes showing a substantially elevated risk to develop MCS. The results concerning NAT2 alone or its combination with CYPs found no confirmation in later studies (Schnakenberg et al 2007; Weismuller et al., 2008; Berg et al 2010).
On contrast Schnakenberg et al (2007) suggested that individuals being slow acetylators, and those with homozygously deleted GSTM1 and GSTT1 genes, are significantly more likely to develop MCS syndrome. We did not confirm Schnakenberg's findings, as we did not find any significant differences in GSTs allele or genotype distribution between patients as compared with data previously published in healthy volunteers (table 4) (Garte et al., 2001)..."
In summary, Berg 2010 and Deluca 2010 with diagnosed MCS subjects found genetic variants in detox the same among MCS people as in the general population.
DELUCA 2010 conclude:
"... there exist serious and multiple dysfunctions of chemical defensive systems in MCS patients. These dysfunctions may mainly depend not on genetic defects but on non-genetic modifications of metabolizing/antioxidant enzyme expression and/or activity, mediated by redox active agents such as NO and inflammatory cytokines..."
"...the current research into the genetic contribution to MCS and chemical sensitivity has yielded inconsistent findings, and no result seems to offer an etiologic explanation for a large proportion of patients. A recent finding that the heritability of respiratory symptoms related to perfume, a main complaint in MCS, was 0.35 (Elberling 2009), however encourages further research into the subject... "
B. Inflammatory Cause of Detox Enzyme Dysfunction
"...Phase I reactions form a new or modified functional group or a cleavage (oxidation, reduction, hydrolysis). These are non synthetic - the most important are cytochrome P450 isoenzymes (CYPs) that transfer electrons and catalyze oxidation.
Phase II reactions are synthetic - involving conjugation with an endogenous compound forming metabolites more polar and readily excreted by the kidneys and liver in urine and bile..."
"...(i) LPS (bacterial lipopolysaccharides) induces the release of intermediary cytokines, which, in turn, induce NOS activity in Kupffer cells and hepatocytes; (ii) NO binds to heme iron in cytochromes P450 and prevents oxygen binding, thereby blocking enzyme activity; (iii) NO may also enhance degradation of cytochromes P450 by nitrosylation of heme or thiols in P450 apoprotein or impair transcriptional activation of P450...
...In summary, cytokine induced overproduction of NO could explain attenuation of activity, content, and transcription of cytochromes P450 by a diverse array of immunostimulants..."
STADLER 1994:
"...Inflammatory stimulation of the liver leads to the induction of nitric oxide (NO) biosynthesis. Because NO binds to the catalytic heme moiety of cytochromes P450 (CYPs), we investigated whether NO interferes with specific CYP-dependent metabolic pathways...
...NO synthesis was induced in rat hepatocytes by incubation with a mixture of cytokines and endotoxin. Concurrently, as NO production in hepatocytes increased within 24 hr, a decrease in CYP1A1 dependent benzo[a]pyrene turnover was observed to almost undetectable levels...the inhibition of benzo[a]pyrene turnover by endogenous NO must have been predominantly due to functional inhibition of CYP activity...
...Inhibition of hepatocellular CYP activity by NO was predominantly due to a direct effect on the enzymes. However, NO-dependent inhibition of CYP expression at a transcriptional level was also demonstrated..."
TERLECKY S. ET AL. PEROXISOMES AND AGING. 1763;12:1749-54 2006:
"...there are circumstances in which the tightly regulated balance of hydrogen peroxide producing and degrading activities in peroxisomes is upset - leading to the net production and accumulation of hydrogen peroxide and downstream reactive oxygen species. The factor most essentially involved is catalase, which is missorted in aging, missing or present at reduced levels in certain disease states, and inactivated in response to exposure to specific antibiotics...
...Many individuals worldwide are hypocatalasemic, not due to aging's effects, but rather to a reduction in cellular catalase expression (Eaton 1995, Wen 1988) or stability (Eaton 1995, Crawford 1988)...
...Cells from a hypocatalasemic patient (expressing approximately 25% of normal catalase levels) were found to have accumulated hydrogen peroxide and harbored age-associated pathologies (Wood 2006)..." Deluca 2010 found catalase activity 30% of normal in MCS patients.
Proatherogenic conditions of severe oxidative stress were found in MCS patients due to inflammatory stimulation of blood cell populations with cytokines: elevated NO, glutathione depletion, catalase deficiency, and a fatty acid profile indicating lipid peroxidation - increased SFA with losses in PUFA, N-6, N-3, arachidonic acid and omega 3 (Deluca 2010).
Sensory receptor activation and alveolar macrophage involvement in damaged airway epithelium due to ACA PM - changes in the innate inflammatory immune system (Hogg 2009, Abbas 2007) - result in release of mediators: neuropeptides, cytokines, chemokines, and growth factors (Dantoft 2014, Maes 2012, Deering-Rice 2011, Hazari 2011, Costa 2010, Deluca 2010, Taylor-Clark 2010, Caceres 2009, Anand 2008, Bessac 2008), Nassenstein 2008, Bautista 2006, Inoue 2005, Kobayashi 2005, Veronesi 2001); increased circulating leukocytes, production of acute phase proteins (Hiraiwa 2014, 2013, Hogg 2009, Goto 2004, Mukae 2001); nitric oxide overproduction (Maes 2012, Deluca 2010, Calderon-Garciduenas 2008); and dysfunction of Phase I and II xenobiotic and antioxidant enzymes in a systemic condition of severe oxidative stress (Deluca 2010, Liptrott 2009, Oslund 2008, Chun 2002, Sterner-Kock 1999, Tinel 1999, Tanabe 1996, Tapner 1996, Nadin 1995, Stadler 1994, Khatsenko 1993).
C. A Genetic Neuroinflammatory Portrait
"...DRG neurons, cultured from BALB/c and B6 neonates, were loaded with Fluo-3 AM and exposed to the prototype irritants, acid pH (5.0, 6.5), or capsaicin (3, 10 μM). Analysis of their increases in intracellular calcium showed that significantly higher numbers of BALB/c neurons responded to these prototype irritants, relative to B6 neurons.
Morphometric analysis of BALB/c neurons, histochemically stained with cobalt to label neurons bearing capsaicin-sensitive receptors, showed a significantly higher level of stained neurons relative to B6 neurons.
Finally, semiquantitative RT-PCR showed a higher expression of VR1 receptor mRNA in DRG and spinal cord taken from neonatal BALB/c mice relative to B6 mice.
Taken together, these data suggest that capsaicin and acid-sensitive irritant receptors, located on somatosensory cell bodies and their nerve fiber terminals, subserve PM-induced airway inflammation and are quantitatively different in responsive and nonresponsive mouse strains..."
"...We have previously shown that the BALB/c mouse strain is responsive to PM-inflammation in contrast to the non-responsive C57/blk (B6) mouse strain.
This differential sensitivity is retained in PM exposed cultures of somatosensory neurons from the dorsal root and trigeminal ganglia that innervate the airways in terms of inflammatory cytokine release.
In the present study, we use RT-PCR, cobalt histochemistry and immunocytochemical techniques to show that the expression of capsaicin (VR1) and Substance P (NK-1) receptors and the release of inflammatory cytokines and neuropeptides are higher in sensory neurons from BALB/c mice relative to the B6 strain.
These data suggest that the strain-specific inflammatory response to PM and other irritants (i.e. capsaicin, acid sensitive) seen in vivo and in vitro models of PM inflammation is subserved by sensory and neuropeptide receptors..."
"...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..."
"...The mechanism by which inflammatory conditions are provoked by chemicals is via chemoreceptors on sensory nerve C-fibers with the release of substance P and other mediators of neurogenic inflammation...progression of inflammation to organ damage is possible to those who continue to be exposed..."
"...after capsaicin provocation the patients showed a significant increase in NGF which was related to capsaicin cough sensitivity...SHR (sensory hypereactivity) is real and measurable, demonstrating a pathophysiology in the airways of these patients compared to healthy subjects..."
"...The findings of the present study indicate that the mechanisms underlying MCS may originate in the sensory nervous system..." - MCS cough occurring in response to capsaicin at concentrations far less (.150) than both the control group (1.120) and the chronic cough group (.630).
"...taken together, the above in vivo and in vitro studies suggested that the variable inflammatory sensitivity to PM observed in different mouse strains (ie Balb/C, B6) related to quantitative differences in the neuropeptide, VR1 (now TRP) receptors 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 et al 1995), nitrogen dioxide (Holroyd et al 1997), and diesel exhaust (Ichinose et al 1997, Miyabara et al 1998)..."
Heritability of respiratory symptoms has been shown.
"...In conclusion, we found an increased familial occurrence of perfume-related respiratory symptoms where 35% of phenotypic variation was due to additive genetic effects and 65% was due to individual specific environmental effects..."
As mentioned above in Appendix IV, C.G. Jung's Psychological Types (1921) R.F.C. Hall translation published by Princeton University Press, early but highly regarded - written by a principle founder of modern Psychology - and from which can be attributed wide use of the terms introversion and extraversion - is an organization of 8 principle types according to dominance of the feeling, thinking, intuition, or sensation function in either the introverted or extraverted attitude.
Jung further refines the types by recognizing a function of secondary importance - for example introverted intuition (a perceptive function) if in the primary dominant position is paired to either introverted thinking or feeling as the secondary complementary judgement function - making a total of 16 types.
A psychological portrait emerges - cumulative image of typical characteristics - while individual features are effaced.
Occurring with randomly equal distribution and distinctness - Jung concluded the type phenomenon must have a genetic foundation.
Jung 1921 reported hypersensitivity of the sense organs only among the genetically determined introverted intuitives - strongly indicating a shared genetic basis of physiological and psychological features.
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..."
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