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==Causes == In 2017, a Canadian government Task Force on Environmental Health said that there had been very little rigorous peer-reviewed research into MCS and almost a complete lack of funding for such research in North America.<ref name=":7" />{{Rp|53}} "Most recently," it said, "some peer-reviewed clinical research has emerged from centres in Italy, Denmark and Japan suggesting that there are fundamental neurobiologic, metabolic, and genetic susceptibility factors that underlie ES (Environmental Sensitivities)/MCS."<ref name=":7" />{{Rp|53}} When speaking at an Australian federal parliamentary inquiry into environmental illness, in 2018, Dr Graeme Edwards, the inquiry's representative of Royal Australasian College of Physicians<ref name=":40">''[https://www.racp.edu.au/docs/default-source/advocacy-library/racp-submission-to-the-australian-parliament-s-health-aged-care-and-sport-committee-inquiry-into-biotoxin-related-illnesses-in-australia.pdf?sfvrsn=7ae3131a_4 Royal Australasian College of Physicians' Submission to the Australian Parliament’s Health, Aged Care and Sport Committee Inquiry into Biotoxin-related Illnesses in Australia]'', Aug 2018. ''“Dr Graeme Edwards represented the RACP at this public hearing and we trust the Committee benefited from his contribution to the discussions.”'' p.1.</ref> said that there was "relatively good consensus" that causation was multifactorial. "There is no single causative factor," he said. "It is a combination of factors ... unless you have all the pieces of the puzzle lining up, you actually don't get the disease. And because we are talking about multi-dimensional triggers, any one individual, at any one point in time, may not have exposure to all of those triggers to get a pathological result. And therein lies the complexity."<ref name="Hansard9Aug2018">{{citation|url=https://parlinfo.aph.gov.au/parlInfo/download/committees/commrep/e7694a12-573a-4e51-933d-46fe0f9a9a3d/toc_pdf/Standing%20Committee%20on%20Health,%20Aged%20Care%20and%20Sport_2018_08_09_6406_Official.pdf;fileType=application%2Fpdf#search=%22committees/commrep/e7694a12-573a-4e51-933d-46fe0f9a9a3d/0001%22|title=Biotoxin related illnesses in Australia, comments by Dr Graeme Edwards, Official Committee of the House of Representatives Standing Committee on Health, Aged Care and Sport|date=Aug 9, 2018|location=Canberra|publisher=House of Representatives, Hansard Records}}</ref>{{Rp|11}} These recent statements suggest that earlier depictions of MCS as being ''either'' biologically or psychologically caused likely set up a false dichotomy or dilemma. === Toxicological === It has been hypothesized that MCS is caused by exposure to particular chemicals—most commonly certain pesticides. Professor [[Martin Pall|Martin L. Pall]] proposed that MCS had a toxicological and biochemical cause, and that "seven individual chemicals or chemical classes—organophosphorus/carbamate, organochloride and pyrethroid pesticides, organic solvents, carbon monoxide, hydrogen sulphide and mercury/mercurial compounds—could initiate MCS through their ability to increase N-methyl-D-aspartate (NMDA) receptor activity."<ref name=":9">{{citation|chapter=1.2 Scatenamento della MCS|trans-chapter=1.2 Triggering of MCS|url=https://www.infoamica.it/wp-content/uploads/2019/07/Consenso-MCS-20-giugno-2019.pdf|title=Consenso Italiano sulla Sensibilita Chimica Multipla (MCS). Documento di consenso e linee guida sulla Sensibilita Chimica Multipla (MCS) del Gruppo di Studio Italiano sulla MCS|trans-title=Italian Consensus on Multiple Chemical Sensitivity (MCS) -- Consensus Document and Guidelines on Multiple Chemical Sensitivity (MCS) by the Italian Workgroup on MCS | last =Grouppo di Italiano Studio MCS|location=Università degli Studi di Milano, Italy|date=2019-05-23}}</ref><ref name=":5">{{Cite book | chapter=What are the symptoms of MCS|isbn=978-0-9807221-4-7|url=http://test.nicnas.gov.au/Media/Latest_News/MCS.asp|title=A Scientific Review of Multiple Chemical Sensitivity: Identifying Key Research Needs|date=2010 | last =National Industrial Chemicals Notification and Assessment Scheme | last2=Office of Chemical Safety and Environmental Health|location=Canberra, Australia||dead-url=y|archive-date=Nov 2010|archive-url=https://web.archive.org.au/awa/20160615131255mp_/https://www.nicnas.gov.au/__data/assets/word_doc/0015/17223/MCS-Final-Report-for-publication-November-2010-hardcopy-version.docx}}</ref> Pall hypothesized that overactivity of the NMDA receptors, coupled with stress-related increases in [[nitric oxide]] and the oxidative product [[peroxynitrite]] (known as the [[Nitric oxide hypothesis|NO/ONOO cycle]]) caused MCS symptoms and worsened the condition.<ref name=":15">{{Cite book | title=[[Explaining "Unexplained Illnesses"|Explaining "Unexplained illnesses": Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, Gulf War Syndrome and Others]] | last =Pall| first = Martin L.|publisher=Routledge & Harrington Park Press|year=2007|isbn=978-0789023896|location=New York}}</ref><ref>{{Cite journal|vauthors=Pall ML, Satterlee JD|date=2001|title=Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome, and Post Traumatic stress disorder|url=https://semanticscholar.org/paper/d804ba7af6079f3d70cf1f4feb43d17d4e22a021|journal=Annals of the New York Academy of Sciences|volume=933|issue=1|pages=323–9|via=|doi=10.1111/j.1749-6632.2001.tb05836.x|pmid=12000033|bibcode=2001NYASA.933..323P}}</ref> He suggestedthat hypersensitivity occurred because of limbic kindling, neural sensitization, and/or neurogenic inflammation—processes which could be driven by the NO/ONOO cycle.<ref name=":5" /> A 2019 scientific review said that while further research was required to confirm Pall's theory, that his hypothesis "had found broad consensus in the scientific community” and was compatible with previous hypotheses,<ref name=":4">{{citation|trans-chapter=1.4 Proposed mechanisms for MCS|chapter=1.4 Meccanismo proposti per la MCS|url=https://www.infoamica.it/wp-content/uploads/2019/07/Consenso-MCS-20-giugno-2019.pdf|title=Consenso Italiano sulla Sensibilita Chimica Multipla (MCS). Documento di consenso e linee guida sulla Sensibilita Chimica Multipla (MCS) del Gruppo di Studio Italiano sulla MCS|trans-title=Italian Consensus on Multiple Chemical Sensitivity (MCS) -- Consensus Document and Guidelines on Multiple Chemical Sensitivity (MCS) by the Italian Workgroup on MCS | last =Grouppo di Italiano Studio MCS|location=Università degli Studi di Milano, Italy|date=2019-05-23}}</ref> including Dr. Iris Bell's theory of neuronal sensitization<ref name=":17">{{Cite journal | last =Bell | first = Iris R. | last2=Baldwin | first2=Carol M. | last3 = Fernandez | first3 = Mercedes | last4 = Schwartz | first4 = Gary E.R.|date=1999-04-01|title=Neural sensitization model for multiple chemical sensitivity: overview of theory and empirical evidence|url=https://doi.org/10.1177/074823379901500303|journal=Toxicology and Industrial Health|language=en|volume=15|issue=3-4|pages=295–304|doi=10.1177/074823379901500303|issn=0748-2337}}</ref><ref name=":18">{{Cite journal | last =Bell | first = IR|author-link= | last2=Rossi | first2=J|author-link2= | last3 = Gilbert | first3 = ME|author-link3= | last4 = Kobal | first4 = G|author-link4= | last5 = Morrow | first5 = LA | authorlink5 = | last6 = Newlin | first6 = DB|author-link6= | last7 = Sorg | first7 = BA | last8 = Wood|first8 = RW|date=1997-03-01|title=Testing the neural sensitization and kindling hypothesis for illness from low levels of environmental chemicals.|url=https://ehp.niehs.nih.gov/doi/abs/10.1289/ehp.97105s2539|journal=Environmental Health Perspectives|volume=105|issue=suppl 2|pages=539–547|doi=10.1289/ehp.97105s2539|pmc = 1469815|pmid=9167993|access-date=|quote=|via=}}</ref> and William Meggs’ theory of neurogenic inflammation.<ref name=":16">{{Cite journal | last =Meggs | first = William J.|date=2017-05-09|title=The Role of Neurogenic Inflammation in Chemical Sensitivity|url=https://www.liebertpub.com/doi/full/10.1089/eco.2016.0045|journal=Ecopsychology|volume=9|issue=2|pages=83–89|doi=10.1089/eco.2016.0045}}</ref> It also said that Pall's theory may explain the comorbidity of MCS and other pathologies hypothesized to be related to the same mechanism, including [[fibromyalgia]] (FM) and [[ME/CFS]], and that it might be why MCS symptoms tend to lessen after exposure to inhibitors and/or antagonists of NMDA receptors.<ref name=":4" />The review also said that "pesticides, including herbicides, insecticides and agricultural chemicals, are among the substances most commonly implicated in the activation of MCS cases in the United States."<ref name="4.3">{{citation|chapter=4.3|trans-chapter=4.3 Reduction of risk|url=https://www.infoamica.it/wp-content/uploads/2019/07/Consenso-MCS-20-giugno-2019.pdf|title=Consenso Italiano sulla Sensibilita Chimica Multipla (MCS). Documento di consenso e linee guida sulla Sensibilita Chimica Multipla (MCS) del Gruppo di Studio Italiano sulla MCS|trans-title=Italian Consensus on Multiple Chemical Sensitivity (MCS) -- Consensus Document and Guidelines on Multiple Chemical Sensitivity (MCS) by the Italian Workgroup on MCS | last =Grouppo di Italiano Studio MCS|location=Università degli Studi di Milano, Italy|date=2019-05-23}}</ref> Pall's theory has also been used to explain why Gulf War veterans, particularly those who were exposed to [[organophosphate]] pesticides, have been found to be more likely to have MCS than the general population<ref>{{cite journal|vauthors=Reid S, et al|year=|title=Multiple Chemical Sensitivity and Chronic Fatigue Syndrome in British Gulf War Veterans|url=https://doi.org/10.1093%2Faje%2F153.6.604|journal=American Journal of Epidemiology|volume=153|issue=6|pages=604–9|doi=10.1093/aje/153.6.604|pmid=11257069 | last = | first = | last2= | first2=|date=2001|pmc=|quote= | last3 = | first3 = | last4 = | first4 = | last5 = | first5 = | last6 = | first6 = | last7 = | first7 = | last8 = |first8 = |author-link= | authorlink5 = |via=}}</ref><ref name=":15" /> as well as the fact that chemical sensitivities are a known symptom reported in Gulf war syndrome or post-deployment syndrome.<ref>[https://europepmc.org/abstract/med/15757795 Gronseth GS. Gulf war syndrome: A toxic exposure? A systematic review. ''Neurol Clin''. May 2005;23(2):523-540.]</ref><ref name=":48">{{Cite web|url=https://www.healthquality.va.gov/guidelines/MR/cmi/VADoDCMICPG2014.pdf|title=Clinical practice guideline for the management of chronic multisystem illness | last =U.S. Department of Veterans Affairs, Department of Defense|date=Oct 2014}}</ref><ref>{{Cite journal | last =Spelman | first = Juliette F. | last2=Hunt | first2=Stephen C. | last3 = Seal | first3 = Karen H. | last4 = Burgo-Black | first4 = A. Lucile|date=2012-09-01|title=Post Deployment Care for Returning Combat Veterans|url=https://doi.org/10.1007/s11606-012-2061-1|journal=Journal of General Internal Medicine|language=en|volume=27|issue=9|pages=1200–1209|doi=10.1007/s11606-012-2061-1|issn=1525-1497|pmc = 3514997|pmid=22648608}}</ref> The U.S. Department of Veterans Affairs concluded that "risk factors that may be associated with predisposing, precipitating, and perpetuating chronic multi system illnesses [including MCS] among veterans" included chemical exposure, and notably chemical exposure in the Gulf War, where some military personel were exposed to nerve agents (like sarin and cyclosarine) and toxic smoke.<ref name=":48" /> [[Mold]] and mycotoxin exposures have also been hypothesized to trigger the onset of MCS.<ref name="Rea2010">{{Cite journal | last =Rea | first = William J.|date=2018-06-01|title=A Large Case-series of Successful Treatment of Patients Exposed to Mold and Mycotoxin|url=http://www.sciencedirect.com/science/article/pii/S0149291818301899|journal=Clinical Therapeutics|language=en|volume=40|issue=6|pages=889–893|doi=10.1016/j.clinthera.2018.05.003|issn=0149-2918}}</ref><ref>{{Cite journal | last =Lieberman | first = Allan | last2=Rea | first2=William | last3 = Curtis | first3 = Luke|date=2006-09-01|title=Adverse health effects of indoor mold exposure|url=https://www.jacionline.org/article/S0091-6749(06)01396-0/abstract|journal=Journal of Allergy and Clinical Immunology|language=English|volume=118|issue=3|pages=763|doi=10.1016/j.jaci.2006.06.037|issn=0091-6749|pmid=16950304}}</ref><ref>{{Cite journal | last =Vojdani | first = Aristo | last2=Thrasher | first2=Jack D. | last3 = Madison | first3 = Roberta A. | last4 = Gray | first4 = Michael R. | last5 = Heuser | first5 = Gunnar | last6 = Campbell | first6 = Andrew W.|date=2003-07-01|title=Antibodies to Molds and Satratoxin in Individuals Exposed in Water-Damaged Buildings|url=https://doi.org/10.1080/00039896.2003.11879143|journal=Archives of Environmental Health: An International Journal|volume=58|issue=7|pages=421–432|doi=10.1080/00039896.2003.11879143|issn=0003-9896|pmid=15143855}}</ref><ref name="Hansard9Aug2018" /> Exposure to mold has already been associated with initiating inflammation and higher incidences of certain chronic conditions (like asthma), which are common symptoms of MCS.<ref>{{Cite book | last=Hänninen | first = Otto O.|author-link= | last2= | first2=|author-link2=|date=2011|editor-last=Adan|editor-first=Olaf C. G. |editor2-last=Samson|editor2-first=Robert A.|title=Fundamentals of mold growth in indoor environments and strategies for healthy living.|url=https://doi.org/10.3920/978-90-8686-722-6_10|journal=|chapter=World Health Organisation (WHO) Guidelines for Indoor Air Quality: dampness and mold.|language=en|location=Wageningen|publisher=Academic Publishers|pages=277–302|doi=10.3920/978-90-8686-722-6_10|isbn=978-90-8686-722-6|access-date=|quote=Toxicological evidence obtained in vivo and in vitro supports these findings, showing the occurrence of diverse inflammatory and toxic responses after exposure to microorganisms – including their spores, metabolites and components isolated from damp buildings. The increasing prevalence of asthma and allergies in many countries increase the number of people susceptible to the effects of dampness and mould in buildings.|via=|ISBN=}}</ref><ref name=":40" /><ref name="Knibbs2018">{{Cite journal | last =Knibbs | first = Luke D.|author-link= | last2=Woldeyohannes | first2=Solomon|author-link2= | last3 = Marks | first3 = Guy B.|author-link3= | last4 = Cowie | first4 = Christine T.|author-link4= | last5 = | first5 = | authorlink5 = | last6 = | first6 = |author-link6= | last7 = | first7 = | last8 = |first8 = |date=2018|title=Damp housing, gas stoves, and the burden of childhood asthma in Australia|url=https://onlinelibrary.wiley.com/doi/abs/10.5694/mja17.00469|journal=Medical Journal of Australia|language=en|volume=208|issue=7|pages=299–302|doi=10.5694/mja17.00469|issn=1326-5377|pmc=|pmid=|access-date=|quote=Exposure to damp housing and gas stoves is common in Australia, and is associated with a considerable proportion of the childhood asthma burden.|via=}}</ref><ref>{{Cite journal | last =Quansah | first = Reginald | last2=Jaakkola | first2=Maritta S. | last3 = Hugg | first3 = Timo T. | last4 = Heikkinen | first4 = Sirpa A M. | last5 = Jaakkola | first5 = Jouni J.K.|date=2012-11-07|title=Residential Dampness and Molds and the Risk of Developing Asthma: A Systematic Review and Meta-Analysis|url=https://journals.plos.org/plosone/article/file?type=printable&id=10.1371/journal.pone.0047526|journal=PLoS ONE|volume=7|issue=11|pages=e47526|doi=10.1371/journal.pone.0047526|issn=1932-6203|pmc = 3492391|pmid=23144822}}</ref><ref>{{Cite journal | last =Mendell| first = Mark J|author-link= | last2=Mirer | first2=Anna G|author-link2= | last3 = Cheung | first3 = Kerry | author-link3= | last4 = Tong | first4 = My | author-link4= | last5 = Douwes | first5 = Jeroen | authorlink5 = | last6 = | first6 = |author-link6= | last7 = | first7 = | last8 = |first8 = |date=2011-06-01|title=Respiratory and Allergic Health Effects of Dampness, Mold, and Dampness-Related Agents: A Review of the Epidemiologic Evidence|url=https://ehp.niehs.nih.gov/doi/full/10.1289/ehp.1002410|journal=Environmental Health Perspectives|volume=119|issue=6|pages=748–756|doi=10.1289/ehp.1002410|pmc = 3114807|pmid=21269928|access-date=|quote=The authors reported evidence from epidemiologic studies and meta-analyses showed indoor dampness or mould to be associated consistently with increased asthma development and exacerbation, current and ever diagnosis of asthma, dyspnoea, wheeze, cough, respiratory infections, bronchitis, allergic rhinitis, eczema, and upper respiratory tract symptoms. Associations were found in allergic and non-allergic individuals. Evidence strongly suggested causation of asthma “exacerbation” in children.|via=}}</ref> {{See also|Mold illness}} === Neurological === Many common symptoms of MCS are neurological<ref name="Rossi2018" /><ref name="pmid30088144" /><ref name=":0">{{citation|chapter=1. Sensibilitá Chimica Multipla (MCS): Definizione di Caso|trans-chapter=1. Clinical features of the disease|url=https://www.infoamica.it/wp-content/uploads/2019/07/Consenso-MCS-20-giugno-2019.pdf|title=Consenso Italiano sulla Sensibilita Chimica Multipla (MCS). Documento di consenso e linee guida sulla Sensibilita Chimica Multipla (MCS) del Gruppo di Studio Italiano sulla MCS|trans-title=Italian Consensus on Multiple Chemical Sensitivity (MCS) -- Consensus Document and Guidelines on Multiple Chemical Sensitivity (MCS) by the Italian Workgroup on MCS | last =Grouppo di Italiano Studio MCS|location=Università degli Studi di Milano, Italy|date=2019-05-23}}</ref> (for example, "dizziness, seizures, head pain, fainting, loss of coordination"<ref name="Steinemann2018" />). And neurogenic inflammation and sensitization are widely thought to be mechanisms involved in causing, perpetuating and worsening MCS.<ref name=":0" /><ref name=":17" /><ref name=":18" /><ref name=":16" /> William Meggs said that [[Neuroinflammation|neurogenic inflammation]] was a well-defined pathophysiological process, in which chemical irritants triggered nerve fibers to release inflammatory mediators, which led to disease. In a 2017 review, he said that with MCS, an initiating chemical exposure (commonly a respiratory irritant or pesticide) was usually identified in association with the onset of the disease.<ref name=":16" /> Iris Bell researched brain-wave patterns in people with MCS. He showed, in several studies using [[Electroencephalography]] (EEG), that people with MCS often had certain abnormal brain wave patterns.<ref name=":4" /><ref>[https://europepmc.org/abstract/med/7778120 Schwartz GE, Bell IR, Dikman ZV, et al. EEG responses to low-level chemicals in normals and cacosmics. ''Toxicol Ind Health'' 1994; 10(4-5): 633-43.]</ref> For example, he found that women with MCS were more likely to have greater resting alpha waves than controls, which he said suggested the possibility of central nervous system hypo-activation.<ref>[https://www.sciencedirect.com/science/article/pii/S000632239700245X Bell IR, Schwartz GE, Hardin EE, Baldwin CM, Kline JP. Differential resting quantitative electroencephalographic alpha patterns in women with environmental chemical intolerance, depressives, and normals. ''Biol Psychiatry'' 1998; 43(5): 376-88.]</ref> Multiple neuro-imaging studies have shown that people with MCS often have other neurological abnormalities, including abnormal cerebral perfusion patterns, especially in the [[Autonomic nervous system|autonomic nervous system areas]].<ref name=":4" /><ref>[https://www.tandfonline.com/doi/abs/10.1080/15287399409531843 Callender TJ, Morrow L, Subramanian K. Evaluation of chronic neurological sequelae after acute pesticide exposure using SPECT brain scans. ''Toxicol Environ Health'' 1994; 41(3): 275-84.]</ref><ref>[https://www.sciencedirect.com/science/article/pii/B9780120597857500478 Callender TJ, Morrow L, Subramanian K, Duhon D, Ristov M. Three dimensional brain metabolic imaging in patients with toxic encephalopathy. ''Environ Res'' 1993; 60(2): 295-319.]</ref><ref>[https://europepmc.org/abstract/med/7778114 Heuser G, Mena I, Alamos F. NeuroSPECT findings in patients exposed to neurotoxic chemicals. ''Toxicol Ind Health'' 1994; 10(4-5): 561-71.]</ref><ref>[https://onlinelibrary.wiley.com/doi/abs/10.1002/hbm.20266 Hillert L, Musabasic V, Berglund H, Ciumas C, Savic I. Odor processing in multiple chemical sensitivity. ''Hum Brain Mapp'' 2006; 28(3): 172-82.]</ref><ref>[https://journals.sagepub.com/doi/abs/10.1177/074823379901500316 Ross GH, Rea WI, Johnson AR, Hickey DC, Simon TR. Neurotoxicity in single photon emission computed tomography brain scans of patients reporting chemical sensitivities. ''Toxicol Ind Health'' 1999; 15(3-4): 415-20.]</ref> These abnormalities have been documented both in studies using [[Positron emission tomography]] (PET) and [[Single-photon emission computed tomography]] (SPECT) scans.<ref name=":4" /><ref>[https://link.springer.com/article/10.1007/s10548-015-0453-3 Alessandrini M, Micarelli A, Chiaravalloti A, et al. Involvement of Subcortical Brain Structures During Olfactory Stimulation in Multiple Chemical Sensitivity. ''Brain Topogr 2'' 016; 29(2): 243-52.]</ref><ref>[https://link.springer.com/article/10.1007/s00259-014-2969-2 Chiaravalloti A, Pagani M, Micarelli A, et al. Cortical activity during olfactory stimulation in multiple chemical sensitivity: a (18)F-FDG PET/CT study. ''Eur J Nucl Med Mol Imaging'' 2015; 42(5): 733-40]</ref> In addition to people with MCS having documented neurological abnormalities, neuroplasticity is thought by some researchers to be an important mechanism in the disease. In 2018, a representative of the Royal Australasian College of Physicians said: “It could be a multiple chemical sensitivity phenomenon. It could be an irritable bowel phenomenon. It could be fibromyalgia... The common unifying features in all of these conditions is related to what we do know is happening, which is neuroplasticity in the nervous system. We know that, regardless of the initiating trigger—whether it was an overwhelming infection of a mould related organism or some other viral infection—it sets up, within the biological system called the nervous system, neuroplastic changes. They can be, and have been, documented by evidence based research. We can document that there are changes in the nervous system, and that change in the nervous system results in a change in the sensitivity and responsiveness of the human being.”<ref name="Hansard9Aug2018" />{{Rp|12}}<ref name=":40" /> ===Immunological=== MCS is not an allergy, and subjects with MCS having adverse reactions do not routinely exhibit the immune markers associated with allergies.<ref name="NICNAS" />{{Rp|21}} Nevertheless, certain immune irregularities have been identified in subjects with MCS in a range of studies.<ref name="Rossi2018" /><ref name=":4" /><ref name="NICNAS" />{{Rp|22}} In the 1980s and 1990s, some researchers hypothesized that these immune irregularities suggested that MCS was caused by a chemically induced disturbance of the immune system, which resulted in chronic immune dysfunction.<ref name="NICNAS" />{{Rp|22}}<ref name="Genuis2013" /> While others concluded that allergic or immunotoxicological reactions could be contributing factors in at least a subset of MCS patients.<ref name="NICNAS" />{{Rp|22}}<ref>Albright JF, Goldstein RA. Is there evidence of an immunologic basis for multiple chemical sensitivity? Toxicol Ind Health 1992; 8(4): 215-9.</ref><ref>Meggs WJ (1992) MCS and the immune system. Toxicol Ind Health 8(4):203-214.</ref> As more studies were conducted, however, some argued that there was no consistent pattern of immunological reactivity or abnormality in MCS.<ref name="NICNAS" />{{Rp|22}}<ref name="Graveling1999">{{cite journal|vauthors=Graveling RA, Pilkington A, George JP, Butler MP, Tannahill SN|year=1999|title=A review of multiple chemical sensitivity|url=https://www.ncbi.nlm.nih.gov/pubmed/10448311|journal=Occupational and Environmental Medicine|volume=56|issue=2|pages=73–85|doi=10.1136/oem.56.2.73|pmc=1757696|pmid=10448311}}</ref><ref>[https://link.springer.com/article/10.1023/A:1026460726965 Labarge XS & McCaffrey RJ (2000) Multiple chemical sensitivity: a review of the theoretical and research literature. Neuropsychol Rev 10(4):183-211.]</ref> More recently, a French study found that subjects with MCS had higher levels of histamine than controls.<ref name=":4" /><ref name=":26">[https://www.degruyter.com/view/j/reveh.2015.30.issue-4/reveh-2015-0027/reveh-2015-0027.xml Belpomme D, Campagnac C, Irigaray P. Reliable disease biomarkers characterizing and identifying electrohypersensitivity and multiple chemical sensitivity as two etiopathogenic aspects of a unique pathological disorder. Rev Environ Health 2015; 30(4): 251-71.]</ref> It also identified damage to the blood-brain barrier in MCS subjects, the production of antibodies against myelin and evidence of inflammatory processes involving the limbic system and thalamus.<ref name=":4" /><ref name=":26" /> These findings led the research team to conclude that some level of immune activation was likely occurring in the condition.<ref name=":4" /><ref name=":26" /> There is also evidence that subjects with MCS are more likely than controls to have real allergies<ref name="Valderrama2015" />{{Rp|16}} and autoimmune diseases. And the 2019 consensus on MCS notes an association between the condition and [[Hashimoto's thyroiditis|Hashimoto's Thyroiditis]], [[Systemic lupus erythematosus|Systemic Lupus Erythematosus (SLE)]], [[psoriasis]] and atopic [[eczema]].<ref>{{citation|trans-chapter =3.11 Rheumatological evaluation|chapter=3.11|url=https://www.infoamica.it/wp-content/uploads/2019/07/Consenso-MCS-20-giugno-2019.pdf|title=Consenso Italiano sulla Sensibilita Chimica Multipla (MCS). Documento di consenso e linee guida sulla Sensibilita Chimica Multipla (MCS) del Gruppo di Studio Italiano sulla MCS|trans-title=Italian Consensus on Multiple Chemical Sensitivity (MCS) -- Consensus Document and Guidelines on Multiple Chemical Sensitivity (MCS) by the Italian Workgroup on MCS | last =Grouppo di Italiano Studio MCS|location=Università degli Studi di Milano, Italy|date=2019-05-23}}</ref><ref>[https://www.ncbi.nlm.nih.gov/pubmed/20588228 Hybenova M, Hrda P, Prochazkova J, Stejskal V, Sterzl I. The role of environmental factors in autoimmune thyroiditis. Neuro Endocrinol Lett 2010; 31(3): 283-9.]</ref><ref>[https://ehp.niehs.nih.gov/doi/abs/10.1289/ehp.97105s2417 Ziem G, McTamney J. Profile of patients with chemical injury and sensitivity. Environ Health Perspect 1997; 105 Suppl 2: 417-36.]</ref><ref>[https://europepmc.org/abstract/med/17594860 Nogué S, Fernandez-Sola J, Rovira E, Montori E, Fernandez-Huerta JM, Munne P. Multiple chemical sensitivity: study of 52 cases. Med Clin (Barc) 2007; 129(3): 96-8; quiz 9.]</ref> === Psychological === It has also been hypothesized that multiple chemical sensitivity is a psychological disorder. Psychsomatic, psychiatric and psychological theories of MCS, however, have not been accepted by the most recent medical consensus document on MCS,<ref name=":12">{{citation|chapter=2. Epidemiologia|trans-chapter=2. Epidemiology|url=https://www.infoamica.it/wp-content/uploads/2019/07/Consenso-MCS-20-giugno-2019.pdf|title=Consenso Italiano sulla Sensibilita Chimica Multipla (MCS). Documento di consenso e linee guida sulla Sensibilita Chimica Multipla (MCS) del Gruppo di Studio Italiano sulla MCS|trans-title=Italian Consensus on Multiple Chemical Sensitivity (MCS) -- Consensus Document and Guidelines on Multiple Chemical Sensitivity (MCS) by the Italian Workgroup on MCS | last =Grouppo di Italiano Studio MCS|location=Università degli Studi di Milano, Italy|date=2019-05-23}}</ref> and the hypothesis that MCS has a psychological cause has attracted considerable criticism.<ref name=":7" /><ref name=":4" /><ref name="Genuis2013" /><ref>[https://journals.lww.com/joem/FullText/2018/08000/Multiple_Chemical_Sensitivity___Review_of_the.23.aspx Tuuminen, Tamara "Review of the State of the Art in Epidemiology, Diagnosis, and Future Perspectives" Journal of Occupational and Environmental Medicine: August 2018 - Volume 60 - Issue 8 - p e429 doi: 10.1097/JOM.0000000000001369]</ref><ref name="Davidoff1994">{{Cite journal | last =Davidoff | first = A.L. | author-link= | last2=Fogarty| first2 = L.|author-link2= | last3 = | first3 = |author-link3= | last4 = | first4 = |author-link4= | last5 = | first5 = | authorlink5 = | last6 = | first6 = |author-link6= | last7 = | first7 = | last8 = |first8 = |date=Sep 1994|title=Psychogenic origins of multiple chemical sensitivities syndrome: a critical review of the research literature|url=https://www.ncbi.nlm.nih.gov/pubmed/7944561|journal=Archives of Environmental Health|volume=49|issue=5|pages=316–325|doi=10.1080/00039896.1994.9954981|issn=0003-9896|pmc=|pmid=7944561|access-date=|quote=|via=}}</ref><ref>[https://www.mdpi.com/548534 Bransfield RC, Friedman KJ. Differentiating Psychosomatic, Somatopsychic, Multisystem Illnesses, and Medical Uncertainty. ''Healthcare'' (Basel). 2019 Oct 8;7(4). pii: E114. doi: 10.3390/healthcare7040114.]</ref><ref name="SBS">Cunich, Simon. [https://www.sbs.com.au/news/the-feed/mcs-the-condition-that-affects-one-million-australians-but-is-dismissed-by-doctors MCS--the condition that affects one million Australia] SBS television. Sydney, Australia. Updated 14 Aug 2018. [ Is multiple chemical sensitivity real? / Is MCS real?] Prof. Anne Steinemann of Melbourne University: ''"MCS is a very real physical disease".''</ref><ref name="Davidoff1996">{{Cite journal | last =Davidoff | first = A.L. | author-link= | last2=Keyl | first2=P.M. | author-link2= | last3 = | first3 = |author-link3= | last4 = | first4 = |author-link4= | last5 = | first5 = | authorlink5 = | last6 = | first6 = |author-link6= | last7 = | first7 = | last8 = |first8 = |date=May 1996|title=Symptoms and health status in individuals with multiple chemical sensitivities syndrome from four reported sensitizing exposures and a general population comparison group|url=https://www.ncbi.nlm.nih.gov/pubmed/8687241|journal=Archives of Environmental Health|volume=51|issue=3|pages=201–213|doi=10.1080/00039896.1996.9936017|issn=0003-9896|pmc=|pmid=8687241|access-date=|quote=|via=}}</ref> The main arguments used to support the is that MCS has psychological causes have been: # there is no certainty about biological causes of MCS, therefore it must be psychological<ref>{{Cite journal | last =Gots | first = Ronald E.|date=1995-01-01|title=Editorial Commentary: Multiple Chemical Sensitivities–Public Policy|url=https://doi.org/10.3109/15563659509000459|journal=Journal of Toxicology: Clinical Toxicology|volume=33|issue=2|pages=111–113|doi=10.3109/15563659509000459|issn=0731-3810|pmid=7897748}}</ref><ref>{{citation|first =Kimberly | last =Hainge|url=https://www.ncagr.gov/SPCAP/pesticides/UpdateFall03.pdf|work=Pesticide Update|publisher=Florida Department of Agriculture & Consumer Services|volume=XXI|issue=1|date=Fall 2003|title=Multiple chemical sensitivity}}</ref> # that nocebo responses may operate in MCS,<ref>{{Cite journal | last =Binkley | first = K|author-link= | last2=Kutcher | first2=S|author-link2= | last3 = | first3 = |author-link3= | last4 = | first4 = |author-link4= | last5 = | first5 = | authorlink5 = | last6 = | first6 = |author-link6= | last7 = | first7 = | last8 = |first8 = |date=Apr 1997|title=Panic response to sodium lactate infusion in patients with multiple chemical sensitivity syndrome|url=https://doi.org/10.1016/s0091-6749(97)70086-1|journal=Journal of Allergy and Clinical Immunology|volume=99|issue=4|pages=570–574|doi=10.1016/s0091-6749(97)70086-1|issn=0091-6749|pmc=|pmid=|access-date=|quote=|via=}}</ref> and # that people with MCS are more likely than controls to have anxiety, depression and the personality trait absorption.<ref>[https://doi.org/10.1016%2Fs0091-6749%2897%2970086-1 10.1016/s0091-6749(97)70086-1 Witthöft M, Rist F, Bailer J (2008). "Evidence for a specific link between the personality trait of absorption and idiopathic environmental intolerance". ''J. Toxicol. Environ. Health Part A''. '''71''' (11–12): 795–802. doi: 10.1080/15287390801985687. PMID 18569578]</ref><ref>[http://www.psychosomaticmedicine.org/cgi/pmidlookup?view=long&pmid=16314597 Bailer J, Witthöft M, Paul C, Bayerl C, Rist F (2005). "Evidence for overlap between idiopathic environmental intolerance and somatoform disorders"]. ''Psychosom Med''. '''67''' (6): 921–9. doi: 10.1097/01.psy.0000174170.66109.b7. PMID 16314597]</ref> The 2019 Italian consensus on MCS concluded that the studies that hypothesize that the condition has a psychological cause "have been the object of strong criticism, both for methodological deficiencies as well as for the conflict of interests of the scientists who propose this thesis."<ref name=":4" /> It said there was consensus that MCS reactions could cause psychiatric symptoms through biological processes (eg. neurogenic inflammation) and that symptoms of the condition should not be mistaken for the cause.<ref name=":4" /> It also highlighted that "it was researchers at Johns Hopkins University who pointed out that it is ineffective to use personality tests such as MMP2 (i.e. Minnesota Multiphasic Personality Inventory 2) for the study of the pathogenesis of environmental diseases...concluding that the presence of psychological-psychiatric symptoms in patients with MCS was compatible with the objective limitations imposed by the disease, rather than being the cause."<ref name=":4" /><ref name="Davidoff1994" /><ref name="Davidoff1996" /> Other researchers have emphasized that the psychosocial impacts of the disease (especially isolation and stigmatization) are likely to have significant impacts on mental health.<ref name=":7" />{{Rp|48}}<ref name="Davidoff1996" /><ref name="Davidoff1994" /><ref>[http://downloads.hindawi.com/journals/isrn.nursing/2011/838930.pdf Gibson PR, Lindberg A. Physicians' perceptions and real practices regarding patient reports of multiple chemical sensitivity. ISRN Nurs 2011; 2011: 838930.]</ref><ref name="Gibson2009" /><ref>"MCS and EI [Multiple Chemical Sensitivities and Environmental Illness]", [https://counselingatcela.com/ The Counseling Center at CELA] blog. "Is MCS a mental illness? MCS is not a mental illness." Accessed 18 Feb 2020.</ref><ref name="PMC2821254">{{Cite journal | last =Lavergne| first = M. Ruth|author-link= | last2=Cole | first2=Donald C.|author-link2= | last3 = Kerr | first3 = Kathleen|author-link3= | last4 = Marshall | first4 = Lynn M.|author-link4= | last5 = | first5 = | authorlink5 = | last6 = | first6 = |author-link6= | last7 = | first7 = | last8 = |first8 = |date=Feb 2010|title=Functional impairment in chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2821254/|journal=Canadian Family Physician|volume=56|issue=2|pages=e57–e65|doi=|issn=0008-350X|pmc=2821254|pmid=20154232|access-date=|quote=|via=}}</ref> One study showed that anxiety and depression typically started in people with MCS post onset of the condition.<ref>{{Cite journal | last =Caress | first = Stanley M|author-link= | last2=Steinemann | first2=Anne C|author-link2= | last3 = | first3 = |author-link3= | last4 = | first4 = |author-link4= | last5 = | first5 = | authorlink5 = | last6 = | first6 = |author-link6= | last7 = | first7 = | last8 = |first8 = |date=2003-09-01|title=A review of a two-phase population study of multiple chemical sensitivities.|url=https://ehp.niehs.nih.gov/doi/10.1289/ehp.5940|journal=Environmental Health Perspectives|volume=111|issue=12|pages=1490–1497|doi=10.1289/ehp.5940|pmc = 1241652|pmid=12948889|access-date=|quote=The study found that while 37.7% of respondents said that they experienced mental health symptoms after developing sensitivities; only 1.4% (n =1) said that they had had mental health problems prior to becoming sensitive, and 5.8% said they didn’t know whether they had had mental health problems prior.|via=}}</ref> The presence of [[nocebo]] responses in MCS does not indicate that it is the cause of the disease.<ref>''[http://eceri-institute.org/fichiers/1441982765_Statement_EN_DEFINITIF.pdf Brussels International Scientific Declaration on EHS and MCS] (2015).'' Declaration from the 5th Paris Appeal Congress of 18 May 2015 at the Royal Academy of Medicine, Brussels, Belgium. ''"The nocebo effect is not a relevant nor a valid explanation when considering scientifically valuable blind provocation studies, since objective biological markers are detectable in patients as well as in animals."'' </ref> Nocebo responses are found in many biologically caused conditions,<ref>{{citation|url =https://www.health.harvard.edu/newsletter_article/The_nocebo_response|title = The nocebo response|website=Harvard Health. Harvard Medical School blog|date =Mar 2014|access-date=Feb 12, 2020}}</ref> including asthma, and they have been shown to be especially pronounced in neurological conditions (including [[migraine]] and chronic pain).<ref>{{Cite journal | last =Bittar | first = Caroline|author-link= | last2=Nascimento | first2=Osvaldo J.M. | author-link2= | last3 = | first3 = |author-link3= | last4 = | first4 = |author-link4= | last5 = | first5 = | authorlink5 = | last6 = | first6 = |author-link6= | last7 = | first7 = | last8 = |first8 = |date=Jan 2015|title=Placebo and nocebo effects in the neurological practice|url=https://www.ncbi.nlm.nih.gov/pubmed/25608129|journal=Arquivos De Neuro-Psiquiatria|volume=73|issue=1|pages=58–63|doi=10.1590/0004-282X20140180|issn=1678-4227|pmc=|pmid=25608129|access-date=|quote=|via=}}</ref> It is noteworthy that psychological approaches to care in MCS patients have had “very limited success,”<ref name=":7" />{{Rp|48}} and that neither MCS, MCS/ES nor IEI have been included in any edition of the DSM (''American Psychiatric Association Diagnostic and Statistical Manual''<ref>{{Cite book | title=Diagnostic and Statistical Manual of Mental Disorders (DSM-5)|pages=|isbn=978-0890425541|edition=5th|volume=|language=|title-link=|url=|access-date=|date=May 15, 2014|publisher=American Psychiatric Association | last =American Psychiatric Association | first = |author-link= | last2= | first2=|author-link2= | last3 = | first3 = |author-link3= | last4 = | first4 = |author-link4= | last5 = | first5 = | authorlink5 = | last6 = | first6 = |author-link6= | last7 = | first7 = |author-link7= | last8 = |first8 = |author-link8= | last9 = | first9 = |author-link9=|veditors=|others=|doi=|oclc=|quote=|archive-url=|archive-date=|location=|editor-last=|editor-first=|editor1-link=|editor-last2=|editor-first2=}}</ref>) nor have they been listed among somatoform disorders in the [[ICD-10|International Classification of Diseases]].<ref>[https://www.icd10data.com/ICD10CM/Codes/F01-F99/F40-F48/F45-/F45.8 "Other somatoform disorders". 2020 ICD-10-CM Diagnosis Code F45.8]</ref> In Canada, in 2017, following a three-year government inquiry into environmental illness, it was recommended that a public statement be made by the health department dispelling the misperception that MCS/ES is psychological.<ref name=":7" />{{Rp|17}} === Genetic === The 2019 consensus on MCS said that the condition could, at least in part, be caused by genetic alterations affecting detoxification pathways—something which in combination with toxin exposures could make some people more vulnerable to developing MCS than the rest of the population.<ref name=":4" /> Recent Italian studies found that compared to controls, patients with MCS had higher levels of the nitrites and nitrates that are involved in oxidative stress and inflammatory processes, including those that contribute to the oxidative damage of DNA.<ref name=":4" /> They also found that the presence of the following genetic polymorphisms were more likely in people with MCS than controls: NOS3, NOS2 and GPX1.<ref name=":4" /><ref name=":23">[https://www.hindawi.com/journals/mi/2015/245308/abs/ De Luca C, Gugliandolo A, Calabro C, et al. Role of polymorphisms of inducible nitric oxide synthase and endothelial nitric oxide synthase in idiopathic environmental intolerances. Mediators Inflamm 2015; 2015: 245308.]</ref><ref name=":24">[https://www.sciencedirect.com/science/article/pii/S0024320515301211 Gugliandolo A, Gangemi C, Calabro C, et al. Assessment of glutathione peroxidase-1 polymorphisms, oxidative stress and DNA damage in sensitivity-related illnesses. Life Sci 2016; 145: 27-33. 78.]</ref> Other genetic markers known to affect detoxification pathways have been identified as being more common in subjects with MCS than controls,<ref name=":4" /><ref name=":23" /><ref name=":24" /><ref name="DeLuca2011">[https://www.mdpi.com/1660-4601/8/7/2770 De Luca C, Raskovic D, Pacifico V, Thai JC, Korkina L. The search for reliable biomarkers of disease in multiple chemical sensitivity and other environmental intolerances. Int J Environ Res Public Health 2011; 8(7): 2770-97.]</ref><ref>[http://downloads.hindawi.com/journals/oximed/2013/831969.pdf Caccamo D, Cesareo E, Mariani S, et al. Xenobiotic sensor- and metabolism related gene variants in environmental sensitivity-related illnesses: a survey on the Italian population. Oxid Med Cell Longev 2013; 2013: 831969.]</ref><ref>[https://www.hindawi.com/journals/mi/2014/924184/abs/ De Luca C, Thai JC, Raskovic D, et al. Metabolic and genetic screening of electromagnetic hypersensitive subjects as a feasible tool for diagnostics and intervention. Mediators Inflamm 2014; 2014: 924184.]</ref> including polymorphisms and differences in expression of the following: [[CYP2D6]], [[MTHFR]], [[NAT1]], [[NAT2]], [[GSTM1]], and [[PON1]] and [[PON2]].<ref>{{Cite web|url=https://www.karger.com/Article/FullText/497322|title=Assessment of CYP2C9, CYP2C19, and CYP2D6 Polymorphisms in Allergic Patients with Chemical Sensitivity | last =D’Attis | first = S|authorlink= | last2=Massari | first2=S | authorlink2=|date=2019|website=|pages=173–186|doi=10.1159/000497322|archive-url=|archive-date=|dead-url=|access-date=2020-05-14 | last3 = Mazzei | first3 = F | last4 = Maio | first4 = D | last5 = Bozzetti | first5 = MP | last6 = Vergallo | first6 = I | last7 = Mauro | first7 = S | last8 = Minelli|first8 = M|journal=Int Arch Allergy Immunol|volume=179|issue=}}</ref><ref name="McKeown et al. 2004">{{cite journal |vauthors=McKeown-Eyssen G, Baines C, Cole DE, Riley N, Tyndale RF, Marshall L, Jazmaji V | title = Case-control study of genotypes in multiple chemical sensitivity: CYP2D6, NAT1, NAT2, PON1, PON2 and MTHFR | volume = 33| issue = 5 | pages = 971–8 | pmid = 15256524 | doi = 10.1093/ije/dyh251 | journal = Psychosomatic Medicine |url=https://doi.org/10.1093%2Fije%2Fdyh251 | last = | first = | last2= | first2=|date=2004|pmc=|quote= | last3 = | first3 = | last4 = | first4 = | last5 = | first5 = | last6 = | first6 = | last7 = | first7 = | last8 = |first8 = |via= }}</ref><ref name="Schnackenberget">{{Cite journal | last =Schnakenberg | first = Eckart | last2=Fabig | first2=Karl-Rainer | last3 = Stanulla | first3 = Martin | last4 = Strobl | first4 = Nils | last5 = Lustig | first5 = Michael | last6 = Fabig | first6 = Nathalie | last7 = Schloot | first7 = Werner|date=2007-02-10|title=A cross-sectional study of self-reported chemical-related sensitivity is associated with gene variants of drug-metabolizing enzymes|url=https://doi.org/10.1186/1476-069X-6-6|journal=Environmental Health|volume=6|issue=1|pages=6|doi=10.1186/1476-069X-6-6|issn=1476-069X}}</ref> These findings could support the hypothesis that MCS is caused by a synergy of environmental exposures to toxic substances and the impaired ability to metabolize toxic substances, due to factors related to genetic predisposition.<ref name=":4" />
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