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Environ Health Prev Med. 2014 Dec 11
The correlation between mental health and multiple chemical sensitivity: a survey study in Japanese workers.

Cui X1, Lu X, Hisada A, Fujiwara Y, Katoh T.
Faculty of Life Science (Medical Sciences/Basic research), Kumamoto University, Japan

OBJECTIVE: This study was designed to determine the correlation between mental health and multiple chemical sensitivity (MCS).

METHOD: The present study was conducted at two companies in 2011; both in Kyushu, Japan. The "subjective symptoms" subscale of the "Self-diagnosis Checklist for Assessment of Workers' Accumulated Fatigue" was used as a mental health subscale. To determine if multiple chemical exposure has an impact on mental health, we composed an original path model using structural equation analysis.

RESULT: Our final path model can be regarded as good: CMIN/DF = 1.832, CFI = 0.996, and RMSEA = 0.038, AIC = 71.158. As expected, chemical sensitivity and other chemical sensitivity scores predicted the health effects of multiple chemical exposure (ß = 0.19, 0.64). Mental health was predicted by symptom severity and life impact (ß = 0.56 and 0.12), which were both affected by multiple chemical exposure (ß = 0.38 and 0.89, respectively).

CONCLUSION: As far as we are aware, this is the first study using path analysis to explore whether MCS can indicate mental health in worker populations worldwide, and we found a significant causal relationship between them. This could indicate that more focus should be placed on the impact of MCS on mental health in future investigations.

Oxford University Press on behalf of the British Journal of Anaesthesia. 2011 Aug 10
Xenon anaesthesia for laparoscopic cholecystectomy in a patient with multiple chemical sensitivity

Christian Stoppe, Jan Cremer, Steffen Rex, Gereon Schaelte, Astrid Fahlenkamp, Rolf Rossaint, Raphael Rosch, Dirk O. Bauerschlag, and Mark Coburn
Department of Anaesthesiology, University Hospital, RWTH Aachen, Germany. mcoburn@ukaachen.de

The management of general anaesthesia in patients suffering from multiple chemical sensitivity (MCS) poses a challenge. MCS has been described first in the 1940s (1, 2). It occurs in response to diverse stimuli and emerges after exposure to usually harmless doses of environmental chemicals or medications. The pathophysiology of MCS is still only poorly understood. Possible hypotheses include triggers from unspecific allergic or toxic exposure and neurobiological sensitization (3, 4). Therefore patients are exposed to a significant risk of adverse drug interactions while undergoing general anaesthesia (5). The noble gas xenon offers many characteristics of an ideal anaesthetic including hemodynamic stability and rapid induction and emergence from anaesthesia, regardless of its duration (6-8). Furthermore, as an inert gas, xenon is known to be independent of the patients` metabolism and biotransformation, hence interacting less putatively with mechanisms possibly involved in the triggering of MCS. Therefore we applied xenon anaesthesia in a patient with MCS undergoing laparoscopic cholecystectomy.

Here, we report the case of a 53-year-old woman (1.68m and 68.5 kg), who presented with increasing pain due to chronic cholecystolithiasis and a persistent ovarian cyst. The patient was scheduled for elective cholecystectomy and cyst enucleation. Since the early 1980s, the patient has suffered from MCS symptoms with high sensitivity to environmental chemicals, intermittent restlessness and unspecific breathing problems. Since that time, the patient manifested multiple sensitivities to various drugs, which led to her abstinence of all medication for more than 15 years. Preoperative evaluation classified the patient in the ASA II risk category and in a postoperative nausea and vomiting risk score of III (Apfel score). The patient did not receive premedication. In the operation theatre, routine monitoring - consisting of 3-lead-ECG, pulse oxymetry and intermittent blood pressure measurements - was instituted according to our clinical standards. The patient received 100% oxygen for 3 minutes and subsequently a bolus of fentanyl 0.15mg. Induction of anaesthesia was started with a dose of 150mg disoprivan followed by a repeated bolus of 100 mg, while the use of muscle relaxant was avoided. After tracheal intubation, the patient was ventilated with a closed-circuit anaesthetic machine (TAEMA Felix Dual; ALMS, France) using volume control. After denitrogenation had been completed, xenon application was started aiming at a target concentration of 54%. Two additional doses of fentanyl were applied i.v., 0.1mg prior to incision and 0.05mg 45 minutes after start of surgery. During surgery, neither heart rate nor blood pressures indicated anaphylaxis. At end of surgery (185 min) the xenon application was stopped. The patient opened her eyes 150 s after termination of xenon, and adequate reaction on verbal command as well as spontaneous breathing were observed 20 seconds later, resulting in extubation 3 minutes after stop of xenon application. The patient was transferred to the post-anaesthesia care unit (PACU) and discharged 2 hours later to the surgical standard care unit. The patient did not show any signs of PONV and Aldrete Score was > 9 throughout the first 6 hours after end of surgery. Likewise, postoperative visits on the 1st and 2nd postoperative day did not show any adverse events or signs of intolerance and the patient`s recovery was appropriate. A fortnight after discharge, the patient was again interviewed. The patient complained about difficulties regarding full mobilization, which she attributed to the surgery procedure but did not exhibit any signs of chemical sensitivity or intolerance during the whole postoperative course. At present there is no gold standard for general anaesthesia in patients with MCS. The special characteristics of the noble gas xenon may offer a new approach for safe anaesthesia in patients with MCS.

Toxicol Appl Pharmacol. 2010 Nov 1;248(3):285-92. Epub 2010 Apr 27.
Biological definition of multiple chemical sensitivity from redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes.

De Luca C, Scordo MG, Cesareo E, Pastore S, Mariani S, Maiani G, Stancato A, Loreti B, Valacchi G, Lubrano C, Raskovic D, De Padova L, Genovesi G.
Laboratory of Tissue Engineering & Skin Pathophysiology, Dermatology Institute (IDI IRCCS), Rome, Italy.

BACKGROUND: Multiple chemical sensitivity (MCS) is a poorly clinically and biologically defined environment-associated syndrome. Although dysfunctions of phase I/phase II metabolizing enzymes and redox imbalance have been hypothesized, corresponding genetic and metabolic parameters in MCS have not been systematically examined.

OBJECTIVES: We sought for genetic, immunological, and metabolic markers in MCS.

METHODS: We genotyped patients with diagnosis of MCS, suspected MCS and Italian healthy controls for allelic variants of cytochrome P450 isoforms (CYP2C9, CYP2C19, CYP2D6, and CYP3A5), UDP-glucuronosyl transferase (UGT1A1), and glutathione S-transferases (GSTP1, GSTM1, and GSTT1). Erythrocyte membrane fatty acids, antioxidant (catalase, superoxide dismutase (SOD)) and glutathione metabolizing (GST, glutathione peroxidase (Gpx)) enzymes, whole blood chemiluminescence, total antioxidant capacity, levels of nitrites/nitrates, glutathione, HNE-protein adducts, and a wide spectrum of cytokines in the plasma were determined.

RESULTS: Allele and genotype frequencies of CYPs, UGT, GSTM, GSTT, and GSTP were similar in the Italian MCS patients and in the control populations. The activities of erythrocyte catalase and GST were lower, whereas Gpx was higher than normal. Both reduced and oxidised glutathione were decreased, whereas nitrites/nitrates were increased in the MCS groups. The MCS fatty acid profile was shifted to saturated compartment and IFNgamma, IL-8, IL-10, MCP-1, PDGFbb, and VEGF were increased.

CONCLUSIONS: Altered redox and cytokine patterns suggest inhibition of expression/activity of metabolizing and antioxidant enzymes inMCS. Metabolic parameters indicating accelerated lipid oxidation, increased nitric oxide production and glutathione depletion in combination with increased plasma inflammatory cytokines should be considered in biological definition and diagnosis of MCS.

J Neurol Sci. 2009 Dec 15;287(1-2):72-8. Epub 2009 Oct 3.
Brain dysfunction in multiple chemical sensitivity

Orriols R, Costa R, Cuberas G, Jacas C, Castell J, Sunyer J. rorriols@vhebron.net
Servei de Pneumologia, Hospital Universitari Vall d' Hebron, Barcelona, Catalonia, Spain.

Multiple Chemical Sensitivity (MCS) is a chronic acquired disorder of unknown pathogenesis. The aim of this study was to ascertain whether MCS patients present brain single photon emission computed tomography (SPECT) and psychometric scale changes after a chemical challenge. This procedure was performed with chemical products at non-toxic concentrations in 8 patients diagnosed with MCS and in their healthy controls. 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<or=0.01). By contrast, controls showed hyperperfusion in the cingulus, right parahippocampus, left thalamus and some cortex regions (p<or=0.01). The clustered deactivation pattern in cases was stronger than in controls (p=0.012) and the clustered activation pattern in controls was higher than in cases (p=0.012). In comparison to controls, cases presented poorer quality of life and neurocognitive function at baseline, and neurocognitive worsening after chemical exposure. Chemical exposure caused neurocognitive impairment, and SPECT brain dysfunction particularly in odor-processing areas, thereby suggesting a neurogenic origin of MCS.

Ugeskr Laeger. 2006 Mar 13;168(11):1116-9
Multiple chemical sensitivity: a well-defined illness?

Kolstad HA, Silberschmidt M, Nielsen JB, Osterberg K, Andersen JH, Bonde JP, Fink P.
Arhus Universitetshospital, Arbejdsmedicinsk Klinik, Arhus C. hkols@as.aaa.dk

Some people react to smells or chemicals at levels far below toxicological thresholds with nonspecific symptoms, fear and social isolation. They may be diagnosed with multiple chemical sensitivity. There is no empirical evidence indicating that this condition is explained by toxicological mechanisms, even though a number of theories have been proposed. The authors of this review conclude that this is a functional condition. These patients need information and treatment in accordance with this fact. Instead of being advised how to avoid exposure to chemicals, they should be properly trained in appropriate confrontation with the chemicals encountered in everyday life.

Toxicology. 2005 Oct 5
Low level lindane exposure alters extinction of conditioned fear in rats.

Cloutier S, Forquer MR, Sorg BA.
Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, Washington 99164-6520, USA.

Gamma-hexachlorocyclohexane (lindane) is a pesticide with the potential to produce long-term effects on fear or anxiety due to its targeting of the GABA(A) receptor in the brain. Multiple chemical sensitivity (MCS) is a human condition that has been attributed to repeated chemical exposures, with pesticides heavily implicated in the initiation of MCS. The symptoms in MCS patients are wide ranging but prominent among these in a subset of patients is increased evoked panic responses. Drawing a parallel between these responses in MCS patients and a panic model in rats, these studies explored a potential animal model for MCS. The effects of repeated lindane exposure on conditioned fear behavior was examined in adult male Sprague-Dawley rats. Animals were administered vehicle or lindane (intraperitoneally) for either 3days/week (1, 2 or 5mg) or 5days/week (2mg) over 2 weeks, and 18 days later were examined for anxiety levels on an elevated plus-maze. One day later, animals were trained for fear conditioning to an odor conditioned stimulus (CS). Freezing behavior was measured 1 day later in the context where pairing occurred, and then for a total of 6 days in a different environment in which either no CS or the CS was presented. After a second 18-day period of no treatment, rats were again tested for their freezing response to the CS for 2 days. Lindane pretreatment did not alter elevated plus-maze performance, nor did it alter contextual freezing behavior. However, pretreatment with lindane decreased the extinction of fear conditioning to the CS such that freezing behavior in controls was significantly lower than in lindane-pretreated rats, and this effect persisted during testing 18 days later. The results indicate that repeated low-level lindane exposure may produce long-lasting changes in anxiety-related neural circuitry. This suggests that odor-triggered symptoms associated with an aversive event may persist in MCS patients because of the ability of some chemicals to alter fear or anxiety circuitry in the brain.

Med Clin (Barc). 2005 Apr 2;124(12):451-3
Chronic fatigue syndrome and multiple chemical hypersensitivity after insecticide exposition.

Fernandez-Sola J, Lluis Padierna M, Nogue Xarau S, Munne Mas P.
Servicio de Medicina Interna. Unidad Multidisciplinar de Fatiga Cronica. Hospital Clinic de Barcelona. IDIBAPS. Universitat de Barcelona. Barcelona. Spain.

Background and objective: Chronic Fatigue Syndrome (CFS) and Multiple Chemical Sensitivity (MCS) are well-defined illnesses that may appear after some toxic exposures. Patients and method: We report a consecutive series of 26 patients who developed CFS after exposure to insecticide products. It was associated with MCS in a third of cases. RESULTS: Toxic exposure was of labour origin after returning to usual work place after a process of fumigation. In 42% of cases there was no fulfilment of fumigation safety rules. The majority of patients were mean-aged women who developed an acute upper airway inflammatory syndrome, without muscarinic or nicotinic manifestations, followed by digestive syndrome, neurocognitive, fibromyalgic and chronic fatigue manifestations. The course of disease was shorter than 1 year in 5 cases (19%), longer than 1 year in 15(58%), and disabling in 6 cases (23%).

CONCLUSIONS: Due to the possible prevention of this toxic exposure, it is very important to carefully follow measures of environment isolation and ventilation after insecticide use in order to avoid the development of these diseases.

Umweltbundesamt, WaBuLu-Heft 01/05 - Umweltforschungsplan des Bundesministeriums für Umwelt, Naturschutz und Reaktorsicherheit
Studie zum Verlauf und zur Prognose des MCS-Syndroms

Eis D, Wiesmüller A, Worm M, Schwarz E, Eikmann Th, Nowak D, Renner B, Brockmöller J
Robert Koch Institut Berlin, Bereich Umweltmedizin - Universitätsklinikum Aachen - Charitè-RKI-Verbund - Fachkrankenkaus Nordfriesland Bredstedt - Universitätsklinikum Giessen - LMU München Klinikum Innenstadt - Universität Erlangen-Nürnberg - Universitätsklinikum Göttingen

An der Basiserhebung waren sechs umweltmedizinsiche Zentren beteiligt (Aachen, Berlin, Bredstedt, Freiburg, Giessen, München). An der zweiten Erhebung nahmen fünf Zentren Teil (ohne Freiburg). Die Gesamtstichprobe umfasste 291 Patienten.

Die multivariate Datenanalyse ergab keinen Anhalt für Zusammenhänge zwischen Beschwerden und Noxen, weder für die Gesamtgruppe der Umweltambulanzpatienten noch für die MCS-Patienten.

Nach wie vor konkurrieren drei Arten von MCS/IEI-Therorien:

1. Toxikogene MCS-Theorien (toxikogen-somatische MCS-Konzepte)
2. Psychogene MCS-Therorien (psychosomatische MCS-Konzepte)
3. Integrative MCS-Theorien

Die Ergebnisse der MCS-Verbundstudie sprechen nicht für die mit Bezug auf ein toxikogen-somatologisches Konzept formulierten Hypothesen. Es gibt gute Gründe sich einer im erweiterten Sinne psychosomatischen bzw. integrativ-medizinischen Theorie von IEI (oder spezieller, MCS) zuzuwenden.

Wir plädieren für die Variante 3, da ätiologische Präjudizierungen, wie die Psychogenese angesichts der noch bruchstückhaften Erkenntnislage noch nicht genügend abgesichert sind.

Mit Nachdruck weisen wir darauf hin, dass in die Differentialdiagnostik beim MCS-Syndrom nicht nur somatische, sondern stets auch psychische Gesundheitsstörungen einzubeziehen sind, damit den Patienten eine der Diagnose adäquate medizinische Versorgung zuteil werden kann.

Nuklearmedizin. 2002 Dec;41(6):233-9
PET in patients with clear-cut multiple chemical sensitivity (MCS).

Bornschein S, Hausteiner C, Drzezga A, Bartenstein P, Schwaiger M, Forstl H, Zilker T.
Toxikologische Abteilung der II. Medizinischen Klinik und Poliklinik, Technische Universitat Munchen, Klinikum rechts der Isar, Munchen

AIM: Multiple chemical sensitivity (MCS) is a controversially discussed symptom complex. Patients afflicted by MCS react to very low and generally non-toxic concentrations of environmental chemicals. It has been suggested that MCS leads to neurotoxic damage or neuroimmunological alteration in the brain detectable by position emission tomography (PET) and single photon emission computer tomography (SPECT). These methods are often applied to MCS patients for diagnosis, although they never proved appropriate.

METHOD: We scanned 12 MCS patients with PET, hypothesizing that it would reveal abnormal findings.

RESULTS: Mild glucose hypometabolism was present in one patient. In comparison with normal controls, the patient group showed no significant functional brain changes.

CONCLUSION: This first systematic PET study in MCS patients revealed no hint of neurotoxic or neuroimmunological brain changes of functional significance.

Arbeitsmed Sozialmed Umweltmed. 40 (2005) 251–257
Untersuchungen zur Suszeptibilität bei multipler Chemikalienüberempfindlichkeit (MCS)

Robert Koch Institut Berlin, Bereich Umweltmedizin - Universitätsklinikum Göttingen, Abteilung Klinische Pharmakologie, Direktor: Prof. Dr. med. J. Brockmöller

Im Rahmen einer Studie wurden eine Reihe von Polymorphismen in Genen analysiert, die fur die enzymatische Bildung reaktiver Substanzen aus Fremdstoffen verantwortlich sind oder die eine Entgiftung reaktiver Fremdstoff-Folgeprodukte katalysieren oder die Entzündungsreaktionen vermitteln können. Auf der Seite der detoxifizierenden Enzyme, also Enzyme, die in der Lage sind, insbesondere oxidativen Schäden vorzubeugen, wurden die Paraoxonase, die Glutathion-S-Transferasen M1 und T1, die Arylamin-N-Acetyltransferase Typ 2 sowie die Glukuronosyl- transferase Typ 1A1 gemessen. Seitens der Mediatoren von Entzündungsreaktionen wurden eine Reihe von Genen untersucht, die möglicherweise ebenfalls mit besonderer Empfindlichkeit einhergehen (wie dies bereits für Überempfindlichkeiten im Bereich der Atemwege belegt ist).

In die molekulargenetische Untersuchung konnten 205 konsekutiv gesammelte Blutproben aus fünf umweltmedizinischen Ambulanzen einbezogen werden.

Die Gruppe der Umweltambulanz-Patienten zeigte in ihren Allelhäufigkeiten bei adäquater Alpha-Fehler-Adjustierung keine signifikanten Unterschiede zu den aus anderen Studien für die kauka- sische/europäische Bevölkerung bekannten Allelhäufigkeiten. Auch bestanden keine statistisch signifikanten Genotyp-Unterschiede zwischen der Umweltambulanz-Patientengruppe mit selbstberichteter MCS (sMCS) und der Nicht-sMCS-Gruppe unter den Umweltambulanz-Patienten.

Die Studie liefert keine Anhaltspunkte für eine diagnostisch verwertbare Häufung bestimmter Genvarianten bei Umweltambulanz-Patienten oder bei Personen, die sich selbst als an „MCS"erkrankt einstufen. Eine diagnostische Relevanz von derartigen molekulargenetischen Untersuchungen ist daher im Allgemeinen bei Patienten umweltmedizinischer Ambulanzen, soweit Expositionen im Niedrigdosisbereich vorliegen, zum gegenwärtigen Zeitpunkt nicht zu erkennen.

Expo Anal Environ Epidemiol. 2004 Jan;14(1):84-91.
Identification of responsible volatile chemicals that induce hypersensitive reactions to multiple chemical sensitivity patients.

Shinohara N, Mizukoshi A, Yanagisawa Y.
Graduate School of Frontier Sciences, Institute of Environmental Studies, The University of Tokyo, Japan.

Multiple chemical sensitivity (MCS) has become a serious problem as a result of airtight techniques in modern construction. The mechanism of the MCS, however, has not been clarified. Responsible chemicals and their exposure levels for patient's hypersensitive reactions need to be identified. We measured the exposure of 15 MCS patients to both carbonyl compounds and volatile organic compounds (VOCs) that may induce hypersensitive reactions. The exposures of those not suffering from MCS (non-MCS individuals) were also measured at the same time. To characterize the chemicals responsible for MCS symptoms, we applied a new sampling strategy for the measurement of carbonyls and VOCs using active and passive sampling methods. The results of our study clearly demonstrated that the chemicals responsible for such hypersensitive reactions varied from patient to patient. Moreover, the concentrations during hypersensitive symptoms, which were apparent in some of the MCS patients, were far below both the WHO and the Japanese indoor guidelines. The average exposure levels of MCS patients within a 7-day period were lower than those of paired non-MCS individuals except for a few patients who were exposed to chemicals in their work places. This result indicates that the MCS patients try to keep away from exposures to the chemical compounds that cause some symptoms.Journal of Exposure Analysis and Environmental Epidemiology (2004) 14, 84-91.

Clin Diagn Lab Immunol. 2003 Nov;10(6):1029-36.
Reproducibility of immunological tests used to assess multiple chemical sensitivity syndrome.

Hoover DR, Donnay A, Mitchell CS, Ziem G, Rose NR, Sabath DE, Yurkow EJ, Nakamura R, Vogt RF, Waxdal M, Margolick JB.
Department of Statistics and Institute for Health, Health Care Policy and Aging Research, Rutgers University, Piscataway, New Jersey, USA.

Whether persons with multiple chemical sensitivity syndrome (MCS) have immunological abnormalities is unknown. To assess the reliability of selected immunological tests that have been hypothesized to be associated with MCS, replicate blood samples from 19 healthy volunteers, 15 persons diagnosed with MCS, and 11 persons diagnosed with autoimmune disease were analyzed in five laboratories for expression of four T-cell surface activation markers (CD25, CD26, CD38, and HLA-DR) and in four laboratories for autoantibodies (to smooth muscle, thyroid antigens, and myelin). For T-cell activation markers, the intralaboratory reproducibility was very good, with 90% of the replicates analyzed in the same laboratory differing by < or = 3%. Interlaboratory differences were statistically significant for all T-cell subsets except CD4+ cells, ranging from minor to eightfold for CD25+ subsets. Within laboratories, the date of analysis was significantly associated with the values for all cellular activation markers. Although reproducibility of autoantibodies could not be precisely assessed due to the rarity of abnormal results, there were inconsistencies across laboratories. The effect of shipping on all measurements, while sometimes statistically significant, was very small. These results support the reliability of fresh and shipped samples for detecting large (but perhaps not small) differences between groups of donors in the T-cell subsets tested. When comparing markers that are not well standardized, it may be important to distribute samples from different study groups evenly over time.

Int J Hyg Environ Health. 2003 Oct;206(6):531-8.
Multiple chemical sensitivity in male painters; a controlled provocation study.

Georgellis A, Lindelof B, Lundin A, Arnetz B, Hillert L.
Department of Occupational and Environmental Health, Stockholm County Council, Stockholm, Sweden.

The purpose of the present study was to examine whether male painters reporting multiple chemical sensitivity (MCS) differ from their matched controls (male painters without such sensitivity) during controlled chamber challenges to singular and mixtures of odorous chemicals with respect to: (1) Subjective rating of symptoms (i.e., symptoms related to central nervous system (CNS) and symptoms related to irritation) and sensations of smell elicited by low-level chemical exposures. (2) Changes in serum prolactin and cortisol levels, changes in nasal cavity and eye redness as a result of the various exposures. Moreover, background assessments were made regarding mental well-being, sense of coherence (SOC) as well as state of anxiety and depression in both groups. The MCS and control group consisted of 14 and 15 male painters respectively. Regarding background assessments of mental well-being, anxiety, depression and SOC, statistically significant differences were obtained between painters with MCS and their controls. During the controlled chamber challenges, neither difference regarding sensations of smell nor development of CNS related symptoms were seen between MCS and control group. In contrast, subjective rating of symptoms related to irritation (i.e., eyes, nose, throat, skin, and breathing difficulties) was significant higher in subjects with MCS. No differences between the groups as a result of the different exposures were seen concerning nasal cavity, eye redness and serum cortisol levels. However, a trend (P = 0.056) between the groups was measured regarding a decline of serum prolactin levels in the MCS group. This is a relatively small study with a limited number of volunteers; and no definitive conclusions can be drawn concerning the above findings. But it is the first controlled challenge study that incorporates similarly exposed groups (painters) recruited from a community rather than from a clinical population.

Occup Med (Lond). 2003 Oct;53(7):479-82.
Central neurological abnormalities and multiple chemical sensitivity caused by chronic toluene exposure.

Lee YL, Pai MC, Chen JH, Guo YL.
Department of Environmental and Occupational Health, National Cheng Kung University Medicine College, Tainan, Taiwan.

Multiple chemical sensitivity (MCS) is a syndrome in which multiple symptoms occur with low-level chemical exposure; whether it is an organic disease initiated by environmental exposure or a psychological disorder is still controversial. We report a 38-year-old male worker with chronic toluene exposure who developed symptoms such as palpitation, insomnia, dizziness with headache, memory impairment, euphoria while working, and depression during the weekend. Upon cessation of exposure, follow-up neurobehavioural tests, including the cognitive ability screening instrument and the mini-mental state examination, gradually improved and eventually became normal. Although no further toluene exposure was noted, non-specific symptoms reappeared whenever the subject smelled automotive exhaust fumes or paint, or visited a petrol station, followed by anxiety with sleep disturbance. During hospitalization for a toluene provocation test, there was no difference between pre-challenge and post-challenge PaCO(2), PaO(2), SaO(2) or pulmonary function tests, except some elevation of pulse rate. The clinical manifestations suggested that MCS was more relevant to psychophysiological than pathophysiological factors.

FASEB J. 2002 Sep;16(11):1407-17.
NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as the mechanism of chemical sensitivity in multiple chemical sensitivity.

Pall ML.
School of Molecular Biosciences, Washington State University, Pullman, Washington 99164-4660, USA.

Multiple chemical sensitivity (MCS) is a condition where previous exposure to hydrophobic organic solvents or pesticides appears to render people hypersensitive to a wide range of chemicals, including organic solvents. The hypersensitivity is often exquisite, with MCS individuals showing sensitivity that appears to be at least two orders of magnitude greater than that of normal individuals. This paper presents a plausible set of interacting mechanisms to explain such heightened sensitivity. It is based on two earlier theories of MCS: the elevated nitric oxide/peroxynitrite theory and the neural sensitization theory. It is also based on evidence implicating excessive NMDA activity in MCS. Four sensitization mechanisms are proposed to act synergistically, each based on known physiological mechanisms: Nitric oxide-mediated stimulation of neurotransmitter (glutamate) release; peroxynitrite-mediated ATP depletion and consequent hypersensitivity of NMDA receptors; peroxynitrite-mediated increased permeability of the blood-brain barrier, producing increased accessibility of organic chemicals to the central nervous system; and nitric oxide inhibition of cytochrome P450 metabolism. Evidence for each of these mechanisms, which may also be involved in Parkinson's disease, is reviewed. These interacting mechanisms provide explanations for diverse aspects of MCS and a framework for hypothesis-driven MCS research.

Med Hypotheses. 2000 May;54(5):734-8
Chemical sensitivity and fatigue syndromes from hypoxia/hypercapnia

Ross PM.
The American Health Foundation, New York, USA.

The multiple chemical sensitivities syndrome (MCS) and other chronic syndromes causing fatigue, headache and other protean CNS symptoms without observable signs, are proposed to result from hypoxia/hypercapnia (H/H) due to disturbed breathing. The concept is explained in terms of sleep apnea (SA), although H/H could result from causes other than SA. Reasons for considering this etiologic linkage are as follows: 1. MCS symptoms resemble those of SA. 2. The only physical signs associated with MCS (upper airway inflammation and obstruction) can aggravate SA. 3. The only neuropsychiatric finding common among MCS symptomatics, reduced verbal recall, is associated with SA. 4. Many MCS symptomatics attribute onset of their condition to a pesticide or solvent exposure. Solvent neurotoxicity may cause cacosmia, a symptom of MCS and SA. 5. Improved upper airway patency, a first-line therapy in SA, may improve symptoms in some MCS-like conditions. Implications for diagnosis and treatment of MCS are discussed. Copyright 2000 Harcourt Publishers Ltd.

Toxicol Ind Health. 1999 Apr-Jun;15(3-4):403-9
Odor sensitivity and respiratory complaint profiles in a community-based sample with asthma, hay fever, and chemical odor intolerance

Baldwin CM, Bell IR, O'Rourke MK.
Respiratory Sciences Center, University of Arizona, Tucson, USA.

This is a community-based study of odor sensitivity and respiratory complaints for persons reporting asthma (n = 14/141), hay fever (n = 72/140), and chemical odor intolerance (CI) (n = 41/181). CI, a symptom of multiple chemical sensitivity (MCS), was determined from self-ratings of feeling 'moderately' to 'severely' ill using the Chemical Odor Intolerance Index (CII). Index odors included perfume, pesticide, drying paint, new carpet odor, and car exhaust. Six additional odors [natural gas, disinfectants, chlorinated water, room deodorizers, and environmental tobacco smoke (ETS)] were also assessed in the health and environment survey. Asthmatics reported feeling 'frequently' to 'almost always' ill from the CII index odors of drying paint, new carpet odor, perfume, and cleaning agents compared to nonasthmatics. People with hay fever documented feeling 'frequently' to 'almost always' ill from pesticides, drying paint, and car exhaust compared to individuals without hay fever. The CI cited illness from air freshener, natural gas and chlorinated water, in addition to the index odors of perfume, paint, pesticides, new carpeting and auto exhaust. All three groups were significantly more likely to report feeling ill from ETS. People with asthma were significantly more likely to report lower lung complaints, such as wheeze and dyspnea. People with hay fever cited more chest tightness. The CI were significantly more likely to report upper and lower respiratory symptoms. Given this overlap in respiratory complaints, it could be that CI may serve to amplify these traditional immune-related disorders and/or suggest that having asthma or hay fever could make one more vulnerable to CI.Toxicol Ind Health. 1999 Apr-Jun;15(3-4):295-304

Toxicol Ind Health. 1999 Apr-Jun;15(3-4):295-304
Neural sensitization model for multiple chemical sensitivity: overview of theory and empirical evidence.

Bell IR, Baldwin CM, Fernandez M, Schwartz GE.
Department of Psychiatry, University of Arizona, Tucson 85723, USA.

This paper summarizes theory and evidence for a neural sensitization model of hyperresponsivity to low-level chemical exposures in multiple chemical sensitivity (MCS). MCS is a chronic polysymptomatic condition in which patients report illness from low levels of many different, structurally unrelated environmental chemicals (chemical intolerance, CI). Neural sensitization is the progressive host amplification of a response over time from repeated, intermittent exposures to a stimulus. Drugs, chemicals, endogenous mediators, and exogenous stressors can all initiate sensitization and can exhibit cross-sensitization between different classes of stimuli. The properties of sensitization overlap much of the clinical phenomenology of MCS. Animal studies have demonstrated sensitization to toluene, formaldehyde, and certain pesticides, as well as cross-sensitization, e.g., formaldehyde and cocaine. Controlled human studies in persons with self-reported CI have shown heightened sensitizability in the laboratory to nonspecific experimental factors and to specific chemical exposures. Useful outcome measures include spectral electroencephalography, blood pressure, heart rate, and plasma beta-endorphin. Findings implicate, in part, dopaminergic mesolimbic pathways and limbic structures. A convergence of evidence suggests that persons with MCS or with low-level CI may share some characteristics with individuals genetically vulnerable to substance abuse: (a) elevated family histories of alcohol or drug problems; (b) heightened capacity for sensitization of autonomic variables in the laboratory; (c) increased amounts of electroencephalographic alpha activity at rest and under challenge conditions over time. Sensitization is compatible with other models for MCS as well. The neural sensitization model provides a direction for further systematic human and animal research on the physiological bases of MCS and CI.

Med Pr. 1998;49(5):473-81
Multiple chemical sensitivity: a new type of toxicity?

Gralewicz S.
Zakladu Toksykologii i Kancerogenezy, Instytutu Medycyny Pracy, Lodzi.

Multiplechemical sensitivity (MCS) is a chronic condition manifested by the appearance of variable symptoms, involving many systems and organs, after exposure to extremely low levels of chemicals, mainly pesticides and solvents. The paper discusses briefly the main hypotheses concerning causes and mechanisms of MCS development. It was emphasized that during neurotoxicity assessment is necessary to pay more attention to these aspects of toxic effects of chemicals likely to generate MSc.

Environ Health Perspect. 1997 Mar;105 Suppl 2:515-9
Empirical approaches for the investigation of toxicant-induced loss of tolerance

Miller C, Ashford N, Doty R, Lamielle M, Otto D, Rahill A, Wallace L.
Department of Family Practice, University of Texas Health Science Center at San Antonio, 78284-7794, USA.

It has been hypothesized that sensitivity to low-level chemical exposures develops in two steps: initiation by an acute or chronic chemical exposure, followed by triggering of symptoms by low levels of previously tolerated chemical inhalants, foods, or drugs. The Working Group on Toxicant-induced Loss of Tolerance has formulated a series of research questions to test this hypothesis: Do some individuals experience sensitivity to chemicals at levels of exposure unexplained by classical toxicological thresholds and dose-response relationships, and outside normally expected variation in the population? Do chemically sensitive subjects exhibit masking that may interfere with the reproducibility of their responses to chemical challenges? Does chemical sensitivity develop because of acute, intermittent, or continuous exposure to certain substances? If so, what substances are most likely to initiate this process? An experimental approach for testing directly the relationship between patients' reported symptoms and specific exposures was outlined in response to the first question, which was felt to be a key question. Double-blind, placebo-controlled challenges performed in an environmentally controlled hospital facility (environmental medical unit) coupled with rigorous documentation of both objective and subjective responses are necessary to answer this question and to help elucidate the nature and origins of chemical sensitivity.

Environ Health Perspect. 1997 Mar;105 Suppl 2:437-41
Clinical characteristics of chemical sensitivity: an illustrative case history of asthma and MCS

Ross GH.
Environmental Health Center-Dallas, Texas 75231, USA.

A case history of the induction of asthma and chemical sensitivity in a 42-year-old registered nurse illustrates several of the characteristic features of multiple chemical sensitivity (MCS). This patient's problems started shortly after moving into a new home under construction, with associated chemical exposures. Other MCS patients report the onset of the condition with other chemical exposures such as those encountered at their places of work or use of pesticides at their residences. Patients often describe a spreading phenomenon of increasing intolerance to commonly encountered chemicals at concentrations well tolerated by other people. Symptoms usually wax and wane with exposures, and are more likely to occur in patients or families with preexisting histories of migraine or with classical allergies. Idiosyncratic medication reactions (especially to preservative chemicals) are common in MCS patients, as are dysautonomia symptoms (such as vascular instability) and poor temperature regulation. Myalgia and joint pains and food intolerance are common features as well. Contamination with xenobiotic chemicals is frequently found in these patients when they are tested. Reactive airways dysfunction syndrome is a recently identified condition that exhibits features of both asthma and chemical sensitivity. MCS patients frequently have patterns of neurotoxic brain metabolism that can be confirmed on single photo emission computed tomography imaging.