Several studies have been referenced in support of the incorrect conclusion that most MCS people have genetics in detox enzymes as cause of the disease:
HALEY R.W. ET AL. ASSOCIATION OF LOW PON1 TYPE Q (TYPE A) ARLESTERASE ACTIVITY WITH NEUROLOGIC SYMPTOM COMPLEXES IN GULF WAR VETERANS. TOXICOL APPLIED PHARMACOL 157: 227-33 1999
MCKEOWN-EYSSEN G. ET AL. CASE CONTROL STUDY OF GENOTYPES IN MULTIPLE CHEMICAL SENSITIVITY: CYP2D6, NAT1, NAT2, PON1, PON2 AND MTHFR. INT J EPIDEM 33:971-78 2004
SCHNAKENBERG E. ET AL. A CROSS SECTIONAL STUDY OF SELF- REPORTED CHEMICAL-RELATED SENSITIVITY IS ASSOCIATED WITH GENE VARIANTS OF DRUG METABOLIZING ENZYMES. ENV H 6:6 2007
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..."
In contrast Schnakenberg 2007 report members of their "chemically sensitive" group - most of whom did not have MCS - were more frequently slower acetylators. and also report that GSTM1 and GSST1 genes were more often homozygously deleted. They conclude by saying that more observations need to be made to confirm their results.
BLOCK G. ET AL. SERUM VITAMIN C AND OTHER BIOMARKERS DIFFER BY GENOTYPE OF PHASE 2 ENZYME GENES GSTM1 AND GSTT1. AM J CL NUTR 94:929-37 2011:
"...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). It is conceivable that an effect would be reflected upon filling out a questionnaire that might be interpreted as a degree of sensitivity (Schnakenberg 2007) but the evidence shows these deletions occur no more often among MCS patients than controls (Berg 2010, Deluca 2010).
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. Considering at most 15% of the population have MCS then no more than 78 of the 273 in the more "chemically sensitive" group can be expected to have MCS.
Schnakenberg 2007 stated: "...our study subjects were identified by a questionnaire asking for chemical hypersensitivity and not for symptoms of MCS..."
Because both groups are mostly normal in that they don't have MCS - associations cannot be used to draw conclusions unless you believe 52% of the population have 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)..."
The studies of McKeown Eyssen 2004 and Schnakenberg 2007 have been misleading - and both cautioned against drawing conclusions from their results.
Referring to those studies as proof that genetic variants in detox enzymes dictate intolerance of specific chemicals as causative in Multiple Chemical Sensitivity in most cases presents a fiction.
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..."
BERG N.D. GENETIC SUSCEPTIBILITY FACTORS FOR MULTIPLE CHEMICAL SENSITIVITY REVISITED. Int J Hyg Env H 213: 131-39 2010:
"...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...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 (Eberling 2009), however encourages further research into the subject... "
Berg 2010 and Deluca 2010 with diagnosed MCS subjects found genetic variants in detox the same among MCS people as in the general population.
Though genetics in detox may have effect - there is no evidence they could account for the airway tissue damage, immediate and extended neuro-immune inflammatory symptoms, secretion of cytokines, chemokines, and growth factors - and wide ranging fine particle combustion byproduct, volatile organic compound, and other chemical intolerance involved with MCS.
Comparing diagnosed MCS patients with controls - Kimata 2004 reported 3, 4, and 7 times plasma substance P, VIP, and nerve growth factor increasing to 4, 6, and 11 fold higher than controls whose levels remained unchanged after exposure to a painted room.
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..."
Deluca 2010 found MCS people had nearly 3 times plasma cytokines IFN-y, IL-8, and IL-10, double the chemokine MCP-1, over twice growth factor PDGF, and 8 times VEGF - along with a 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, N-6, N-3, arachidonic acid, and omega 3.
Deluca 2010 state: "... dysfunction of two major antioxidant enzymes and depletion of glutathione leads to severe oxidative stress and impaired elimination of phase I oxidation metabolites. Excessive amount 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. This kind of enzymatic oxidation could reasonably occur upon pro-inflammatory stimulation of blood cell populations with cytokines..."
Systemic inflammatory products - such as cytokines released by neuro-immune activity in the airway - result in dysfunction of detox enzymes - placing the etiology as genetic differences in receptors , pathways, and neuropeptide release on airway C-fiber sensory nerves - the fine peripheral network of the trigeminal nervous system lining the nasal and upper pulmonary airway.
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 an association - not an established causative factor - it is not known whether these variants confer protection or increase harmful effects - if the latter they may be of significance regarding certain intolerances 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 as mentioned above: 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 47% 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).
The etiology of MCS - concerns genetics in the airway epithelium and its sensory innervation - as evidenced by Veronesi 2001, 2000, Roy 2000, Jung 1921.
Also pointing in the airway direction is the heritability mentioned by Berg 2010 above - found by ELBERLING J. ET AL. A TWIN STUDY OF PERFUME- RELATED RESPIRATORY SYMPTOMS. INT J ENV H 212: 670-78 2009:
"...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..."
MCS people are not so much of genetic defect - as genetically sensitive - unless you think at least 12% of the population are naturally defective so they can't breathe the air. At fault is the general air quality.
MCS is usually genetic vulnerability in the 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 - which become altered to a proinflammatory condition - airway damage and exposed c-fiber nerves - in a continuous combustion byproduct aerosol including particle agglomerates with adsorbed hydrocarbons and singlet nonagglomerated nanoparticles - resulting in elevated plasma levels of chemokines, cytokines, growth factors, and nitric oxide that mediate serious and multiple dysfunction of chemical defense systems.
Postscript: Glutathione and Nutrition
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 Schnakenberg study - 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 2004, Lyons 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).
Sekhar 2011 reported that by supplementing elderly volunteers with glycine and approx 1000 mg cysteine in the form of n-acetylcysteine per 150 lb body weight (.81 mmol kg-1 d-1) - GSH levels improved and oxidant concentrations decreased -
GSH: 39 yr old controls 2.08 mmol/L RBC, elderly before supplement 1.12 after 2.18 mmol/L RBC.
Oxidant Concentrations: isoprostanes controls 97.2, elderly before 136.3 after 84.8, lipid peroxides controls 1.86, elderly before 6.03 after 3.00.
These oxidant concentrations are expected elevated in MCS (MCS acc, Deluca 2010, Terlecky 2006, Kennedy 2005).
The 1000 mg / 150 lb body weight n-acetylcysteine supplementation of Sekhar 2011 is nearly the combined total of cysteine (273mg) and methionine (755mg) in 3 1/2 oz 100% light tuna in water (no added soy). The elderly often consume less total protein than those younger and recent research using the indicator amino acid method holds that the RDA/DRI for protein has been 30% underestimated (Elango 2011, (Humayan 2007, Jackson 2004).
Earlier estimates of adult protein requirement at 55 grams/day include 2000-3000 mg cysteine and methionine. An improved intake of 80-100 provide 3200-4200 - similar to the 1000mg supplement difference in the Sekhar study.
3 1/2 oz tuna rather than a supplement increases total protein (25 grams), adds 3 mcg B-12 (Hermann 2008) which exceeds the RDA and approaches the optimal 4-7mcg suggested by Vakur Bor 2010, provides iron absorption enhancement (Hurrell 2010, Navas Carraterro 2008), may prevent loss of skeletal muscle carnitine transport capacity (Stephens 2011), and contains 300mg of preformed EPA and DHA omega-3 fatty acids.
Ramon 2009 indicated that much toxicity of fish may have to do with ocean contaminants- other than mercury - found in fatty fish - with lean fish producing better birth outcomes than diets not containing fish.
Lowest tuna mercury levels are of canned light from the Indian and Pacific Oceans (Sunderland 2007) such as Natural Sea, Natural Value , and Ocean Naturals (Thailand). Canned white (albacore) has nearly 3 fold the mercury of light (skipjack and yellowfin - with skipjack the least) and fresh tuna from the Atlantic have 2-5 times higher levels depending on the variety. Cod and haddock are lean and relatively low in mercury (USDA 2010).
Beef, pork, and poultry have cysteine and methionine amounts similar to that of fish - though contain higher saturated fat and cholesterol. Pork and poultry are low in B-12 (USDA).
Brown rice has nearly as much methionine - but is lower in cysteine - compared to wheat - but the greater fiber and digestion resistant starch of whole wheat limits its consumption due to excess bulk - so that prepared breads typically consumed - not 100% whole wheat - have little more cysteine per calorie than rice.
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