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Multiple chemical sensitivity (MCS) is a chronic medical condition characterized by symptoms that the affected person attributes to low-level chemical exposure. Commonly accused substances include smoke, pesticides, plastics, synthetic fabrics, scented products, petroleum products, and paint fumes. Symptoms are often vague and non-specific, such as nausea, fatigue, dizziness and headaches, but also commonly include inflammation of skin, joints, gastrointestinal tract and airways.

MCS is not recognized as an organic, chemical-caused illness by the American Medical Association and some other US based organisations. Blinded clinical trials have shown MCS patients react as often and as strongly to placebos, including clean air, as they do to the chemicals they say harm them. This has led some in the healthcare profession to believe MCS symptoms are due to odor hypersensitivity or are mainly psychological. Regardless of the etiology, some people with severe symptoms are disabled as a result.

History
Edgar Allan Poe published a description consistent with MCS in 1839, it was given a medical definition as a symptom of neurasthenia in 1869, and rediscovered as allergic toxemia in 1945. MCS was first proposed as a distinct disease by Theron G. Randolph in 1950. In 1965, Randolph founded the Society for Clinical Ecology as an organization to promote his ideas about symptoms reported by his patients. As a consequence, clinical ecology emerged as a non-recognized medical specialty. In 1984, the Society for Clinical Ecology changed its name to American Academy of Environmental Medicine (AAEM), but soon, other societies, such as the National Center for Environmental Health Strategies surpassed it in number of members. MCS was redefined in 1987 as multiple chemical sensitivity (MCS), and in the 1990s associated with chronic fatigue syndrome, fibromyalgia syndrome, and Gulf War syndrome (GWS).

Definition
Six consensus criteria were identified by researchers for the diagnosis and definition of MCS in 1989 (later edited in 1999):


 * 1) Symptoms are reproducible with repeated (chemical) exposures.
 * 2) The condition has persisted for a significant period of time.
 * 3) Low levels of exposure (lower than previously or commonly tolerated) result in manifestations of the syndrome (i.e. increased sensitivity).
 * 4) The symptoms improve or resolve completely when the triggering chemicals are removed.
 * 5) Responses often occur to multiple chemically unrelated substances.
 * 6) Symptoms involve multiple-organ symptoms (runny nose, itchy eyes, headache, scratchy throat, ear ache, scalp pain, mental confusion or sleepiness, palpitations of the heart, upset stomach, nausea and/or diarrhea, abdominal cramping, aching joints).

The National Institute of Environmental Health Sciences defines MCS as a "chronic, recurring disease caused by a person's inability to tolerate an environmental chemical or class of foreign chemicals". MCS has also been described as a group of "sensitivities to extraordinarily low levels of environmental chemicals" appearing "to develop de novo in some individuals following acute or chronic exposure to a wide variety of environmental agents including various pesticides, solvents, drugs, and air contaminants", including those found in sick buildings.

Environmental medicine specialists claim MCS causes negative health effects in multiple organ systems, and respiratory distress, seizures, cognitive dysfunction, heart arrhythmia, nausea, headache, and fatigue can result from exposure to levels of common chemicals that are normally deemed as safe.

Controversy
Official recognition is generally limited to an agreement that affected people are clinically sick rather than malingering, without consensus that the symptoms are caused by chemicals. For example, Australia, which funds some MCS-related research, falls into the group of countries that recognize the existence of the syndrome but are unable to establish consensus that the symptoms are necessarily caused by or related to chemical exposures.

In 1997, U.S. Social Security Administration Commissioner John Callahan issued a court memorandum officially recognizing MCS "as a medically determinable impairment" on an agency-wide basis. That is, without making any statement about the cause of MCS or the role of chemicals in MCS, the Social Security administration agrees that some MCS patients are too disabled to be meaningfully employed.

In 1995, an Interagency Workgroup on Multiple Chemical Sensitivity was formed under the supervision of the Environmental Health Policy Committee within the United States Department of Health and Human Services to examine the body of research that had been conducted on MCS to that date. The work group included representatives from the Centers for Disease Control and Prevention, United States Environmental Protection Agency, United States Department of Energy, Agency for Toxic Substances and Disease Registry, and the National Institutes of Health. The Predecisional Draft document generated by the workgroup in 1998 recommended additional research in the basic epidemiology of MCS, the performance of case-comparison and challenge studies, and the development of a case definition for MCS. However, the workgroup also concluded that it was unlikely that MCS would receive extensive financial resources from federal agencies due to budgetary restraints and the allocation of funds to other, extensively overlapping syndromes with unknown etiology, such as chronic fatigue syndrome, fibromyalgia, and Gulf War syndrome. The Environmental Health Policy Committee is currently inactive, and the workgroup document has not been finalized.

With regard to the potential for exposure to chemicals in the workplace and MCS, the U.S. Occupational Safety and Health Administration (OSHA) has indicated that MCS is highly controversial and that there is insufficient scientific evidence to explain the relationship between the theorized causes of MCS and its symptoms. However, OSHA recommends that "…an evaluation must be performed by a physician knowledgeable of the symptoms of this condition."

A 1997 court decision held that MCS "is untested, speculative, and far from generally accepted in the medical or toxicological community," and thus cannot be used as the basis for disability claims. Furthermore, accommodations sought for MCS are sometimes denied as being unreasonable as a matter of law.

The International Statistical Classification of Diseases and Related Health Problems (ICD), maintained by the World Health Organization, does not recognize multiple chemical sensitivity or environmental sensitivity as a valid diagnosis.

The American Medical Association (AMA) has stated that because of the lack of scientific evidence, based on well-controlled clinical trials, that supports a cause-and-effect relationship between exposure to very low levels of chemicals and the myriad symptoms reported by clinical ecologists, MCS is not recognized as an established organic disease. The American Academy of Allergy, Asthma, and Immunology, the California Medical Association, the American College of Physicians, and the International Society of Regulatory Toxicology and Pharmacology also do not recognize it. In 1994, the AMA, American Lung Association, US EPA and US Consumer Product Safety Commission published a booklet on indoor air pollution that discusses MCS, among other issues. The booklet further states that a pathogenesis of MCS has not been definitively proven, and that symptoms that have been self-diagnosed by a patient as related to MCS could actually be related to allergies or have a psychological basis, and recommends that physicians should counsel patients seeking relief from their symptoms that they may benefit from consultation with specialists in these fields.

Ronald E. Gots, M.D., an environmental toxicologist and frequent defense consultant in toxic tort litigation, describes MCS as "a label given to people who do not feel well for a variety of reasons and who share the common belief that chemical sensitivities are to blame. ... It has no consistent characteristics, no uniform cause, no objective or measurable features. It exists because a patient believes it does and a doctor validates that belief." In editorial in the Journal of Toxicology - Clinical Toxicology Gots wrote, "The phenomenon of multiple chemical sensitivities is a peculiar manifestation of our technophobic and chemophobic society. ... It may be the only ailment in existence in which the patient defines both the cause and the manifestations of his own condition."

Clinical trials
Some trials support and some don't support the claim that the symptoms of multiple chemical sensitivity are caused by chemicals.

A double-blind inhalant challenge in 1991 concluded, "The conclusion of the study is that in these patients, chemical sensitivity clearly does exist (pulse rate differences between positive responses and placebo - p .001)"

A 1991 controlled comparison of symptoms and chemical intolerances reported by Gulf War veterans, implant recipients and persons with multiple chemical sensitivity suggests that "some patients with antecedent chemical exposures, whether exogenous (chemical spill, pesticide application, indoor air contaminants) or endogenous (implant), develop new chemical, food, and drug intolerances."

A 1993 double-blind study suggested that MCS subjects could not discriminate between their chemical triggers and clean air when an olfactory masker was introduced that eliminated the ability to discriminate on the basis of odor.

In a 2008 double-blind study, a variety of responses, including the subjective perception of being exposed to solvents, increases in blood pressure or heart rate, or increased symptom severity, were measured following the double-blind exposure to several solvents. People with an MCS diagnosis showed no differences in these parameters when they were exposed to clean air or to solvents at a concentration too low to smell. The trial did not support the hypothesis that MCS is directly related to the effects of chemical exposures. Since MCS sufferers seem to have symptoms only when they perceive exposure to chemicals, the syndrome is proposed to be a result of odor hypersensitivity in which individuals have an exaggerated response to scents, or psychological factors.

A 2010 Italian study that genotyped patients diagnosed with MCS, with suspected MCS, and healthy controls suggested inhibition of expression and activity of metabolizing and antioxidant enzymes in MCS, accelerated lipid oxidation, increased nitric oxide production and glutathione depletion and increased plasma inflammatory cytokines.

Symptoms
Symptoms of MCS may be mild to disabling. Symptoms may be physical or psychological in nature and are essentially those that are disruptive to the individuals’ mental or physical wellness and that the individual attributes to exposure to a chemical or scent.

By far, the most common symptoms are vague, non-specific complaints: feeling tired, "brain fog" (short-term memory problems, difficulty concentrating) and muscle pain. These complaints are common to a large number of medical conditions, from psychiatric conditions, such as major depressive disorder, to neurological conditions, such as orthostatic intolerance, to sleep disorders, high blood pressure, autoimmune diseases and cancer.

A partial list of other symptoms patients have attributed to MCS include difficulty breathing, pains in the throat, chest, or abdominal region, asthma, skin irritation, contact dermatitis, and hives or other forms of skin rash, headaches, neurological symptoms (nerve pain, pins and needles feelings, weakness, trembling, restless leg syndrome, etc.), tendonitis, seizures, visual disturbances (blurring, halo effect, inability to focus), extreme anxiety, panic and/or anger, sleep disturbance, suppression of immune system, digestive difficulties, nausea, indigestion/heartburn, vomiting, diarrhea, joint pains, vertigo/dizziness, abnormally acute sense of smell (hyperosmia), sensitivity to natural plant fragrance or natural pine terpenes, insomnia, dry mouth, dry eyes, and an overactive bladder.

Causes
There is no clear consensus as to what causes the symptoms of MCS; there may be several causes.

Misdiagnosis
More than half of 54 people from one study about MCS instead had somatoform disorder or panic disorder. However, diagnosis of somatoform disorders is not without controversy, being unreliable due the reliance on diagnosis by exclusion.

Other possible explanations include migraine, anxiety disorder, lupus, postural orthostatic tachycardia syndrome or other forms of orthostatic intolerance, hay fever and other allergies, hypercalcemia, hypothyroidism, chronic fatigue syndrome, fibromyalgia, or mast cell activation diseases such as mastocytosis, where symptoms such as brain fog and headaches can be triggered by chemicals or inhalants. Sufferers may also have a tendency to "catastrophically misinterpret benign physical symptoms" or simply have a disturbingly acute sense of smell.

Psychological
More than half of over 500 peer-reviewed articles on MCS support an organic basis for MCS, whereas less than one-quarter support a psychiatric basis. A psychogenic interpretation of MCS also is specifically rejected in the 1994 consensus position statement of the American Lung Association, American Medical Association (AMA), U.S. Environmental Protection Agency (US EPA), and U.S. Consumer Product Safety Commission (US CPSC) (U.S. Government Printing Office 1994–523–217/81322).

Several mechanisms for psychological etiology have been proposed, including theories based on stress, Pavlovian conditioning, or misdiagnoses of an underlying mental illness. Behavior exhibited by MCS sufferers may reflect broader sociological fears about industrial pollution.

The distinction between physiological and psychological causes is often difficult to test, and it is particularly challenging for MCS because substances used to test for sensitivity can often be detected by scent. Odor cues make double blind studies of MCS patients difficult, and scents might provoke a psychosomatic response.

A review of 37 provocation studies concluded "persons with MCS do react to chemical challenges; however, these responses occur when they can discern differences between active and sham substances, suggesting that the mechanism of action is not specific to the chemical itself and might be related to expectations and prior beliefs".

An alternative psychological cause has been suggested by a recent case-control study in which MCS was associated with a personality trait called absorption, in which individuals are predisposed to becoming deeply immersed in sensory experiences, leading to self-altered states of consciousness (see Flow). When 54 MCS sufferers were compared to 44 subjects with a somatoform disorder and 54 normal individuals, only those with MCS had increased absorption scores, leading the authors to suggest absorption contributes to MCS by making individuals more susceptible to harboring beliefs in MCS, and these beliefs are reinforced by conditioning.

The cause and existence of MCS are disputed. In particular, doctors disagree about whether symptoms are physiologically or psychologically generated, or both. United States courts and several medical organizations reject MCS as a physiological disease. An approach called clinical ecology attempts to treat the disease, but this work is controversial. Critics charge: These claims are challenged, particularly (1) and (2), insofar as both definitions and physiological pathways have actually been proposed. The scientific community remains divided, however, with many proponents of the psychosomatic school rejecting physiological explanations outright.
 * 1) MCS has never been clearly defined,
 * 2) no scientifically plausible mechanism has been proposed for it,
 * 3) no diagnostic tests have been substantiated, and
 * 4) not a single case has been scientifically validated.

Neurological
One of the first studies on MCS (1993) focused on possible long-term potentiation in the hippocampi and neural sensitization as a central mechanism. Later studies examined the role of the inflammatory process, and found brain inflammation was correlated with symptoms of MCS. In 1999, Meggs proposed MCS is caused by low molecular weight-chemicals that bind to chemoreceptors on sensory nerve C-fibres, leading to the release of inflammatory mediators.

MCS people may have some neurological dysfunction in the odor-processing areas of the brain.

Genetic differences in metabolism
In 2004, McKeown-Eyssen and colleagues showed polymorphisms in the CYP2D6 allele responsible for variation in toxicant metabolism pathways may cause differences in susceptibility to MCS. Pall has suggested elevated nitric oxide and peroxynitrite (NO/ONOO-) as the etiology for MCS and several related conditions, including fibromyalgia, posttraumatic stress disorder, Gulf War syndrome, and chronic fatigue syndrome. This seems to be supported by a study by Reid et al. (2001) into the prevalence of MCS amongst British Gulf War syndrome sufferers. This study concluded veterans who had used personal organophosphate pesticides during the second Gulf War were 12 times more likely to develop MCS. Many observable and empirical, scientific facts can help identify MCS, including SPECT scans and chemical encephalopathy, vitamin deficiencies, mineral deficiencies, excess amino acid deficiency, and disturbed lipid and carbohydrate metabolism.

McKeown-Eyssen studied 203 MCS sufferers and 162 controls; blood tests revealed genetic differences relating to the body's detoxification processes were present more often in those with MCS than those without. The data showed five genetic polymorphisms have a statistically significant role in determining MCS prevalence. Each of these genes encode proteins that metabolize chemicals previously implicated in MCS, notably the organophosphate pesticides (PON1 and PON2 genes) and the organic solvents (CYP2D, NAT1 and NAT2 genes). People with a high expression of two specific genes (CYP2D6 and NAT2) were 18 times more likely to have MCS than those without. They concluded "a genetic predisposition for MCS may involve altered biotransformation of environmental chemicals." Haley found similar, confirmatory results with the PON1 gene in studies of the Gulf War syndrome veterans. A new study by Schnakenberg et al. (2006) confirmed the genetic variation previously found by McKeown-Eyssen and Haley. A total of 521 unrelated individuals participated in the study. Genetic variants of four genes were analyzed: NAT2, GSTM1, GSTT1, and GSTP1. The researchers concluded the individuals who are NAT2 slow acetylators and those with homozygously deleted GSTM1 and GSTT1 genes are significantly more likely to develop chemical sensitivity. According to the study, the glutathione S-transferases act to inactivate chemicals, so people without these GSTM1 and GSTT1 genes are less able to metabolize environmental chemicals, because "glutathione S-transferases play an important role in the detoxification of chemicals". The deletion of another gene, the GSTP1 gene, leaves individuals more susceptible to developing these diseases, as lack of these genes means a loss of protection from oxidative stress.

A specific laboratory rat, the Flinders Sensitive line, has been bred by Dr. Overstreet to be sensitive to an organophosphate, and displays "Increased sensitivity to cholinergic agents [that] has also been observed in several human populations, including individuals suffering from chemical intolerance." In particular, Flinders Sensitive rats show increased responses to nicotine, alcohol, and other chemicals known to act on acetylcholine, dopamine, and serotonin receptors. However, these rats have not reacted abnormally to other chemicals thought to trigger MCS, such as perfume, in any known studies. Study of these rats may therefore provide useful clues about the mechanisms involved in some, but not all, forms of chemical intolerance in humans.

Miscellaneous theories
It has been shown that MCS individuals have differences in their systemic immune mediator profiles. A study done in 2013 showed abnormalities in the levels of various inflammatory cytokines in those with MCS, when compared to controls.
 * Immune Dysregulation

People who have stronger emotional states will react more strongly to a smell. The brain's emotional regions do not discriminate well between the different odors. That discrepancy between brain regions may relate to anxiety disorders. If the olfactory region does not distinguish a dangerous odor signal from a benign smell, the brain's fight-or-flight region can overreact. There has been some suggestion that the hypothalamic-pituitary-adrenal axis ("stress axis" may be blunted in persons highly sensitive to chemicals, such as MCS, Addison's disease, chronic fatigue syndrome, and seasonal affective disorder.
 * Emotional stresses

Chemical triggers
Multiple chemicals have been reported to trigger MCS symptoms. In addition to anything which is perfumed or scented, complaints are commonly formed about everyday items:


 * Food
 * Tartrazine (a.k.a. FD&C Yellow #5 or E102), and other azo dyes (true allergy must first be excluded)
 * Caffeine
 * Monosodium glutamate

Multiple food intolerances can be masked by a delayed reaction. These are not allergic reactions, and cannot be tested, only discovered by an elimination diet.

In a review of a two-phase population study, respondents with MCS indicated cleaning agents (88.4%), pesticides (81.2%), perfumes (81.2%), vehicle exhaust (72.5%), the products used in barber shops and beauty salons (60.9%), new carpeting (53.6%), new furniture (39.1%), chlorine in drinking water (29.1%), and fresh ink (26.1%) were the products most often reported to trigger reactions in the respondents. They also indicated smoke from a fireplace, wood stove, or barbecue grill, and secondhand tobacco smoke were triggers for reactions.
 * Substances with strong scents

Other reported chemical triggers include:
 * Gasoline (petrol) or diesel fuel
 * Petroleum-based products, including petroleum jelly, tar, or asphalt
 * Pesticides, herbicides, fertilizers, and other agricultural chemicals
 * Industrial cleaning chemicals, such as dry cleaning fluid
 * Formaldehyde
 * Glues, varnishes, polishes, paints, solvents, paint thinners, and volatile organic compounds (VOCs)
 * Bleach, fabric softeners, wool-wash, and laundry detergents
 * Perfumes, lotion, aftershave lotion, nail polish, or skin care products
 * Air fresheners, deodorizers and scented candles
 * Shampoos, hairsprays and hair care products
 * Dishwashing liquid and dishwasher detergent
 * Marking pens, such as highlighters

Diagnosis
People who have developed symptoms of MCS have attributed a wide assortment of symptoms to chemical exposure, though symptoms are generally consistent for each individual. The first step in diagnosing a potential MCS sufferer is to identify and treat all other conditions which are present and which often explain the reported symptoms. For example, true allergy, thyroid disorders, orthostatic syndromes, anxiety, and depression need to be carefully evaluated and, if present, properly treated.

The "gold standard" procedure for identifying a person who has MCS is to test his or her response to the random introduction of chemicals the patient has self-identified as relevant, such as scented soaps or dryer sheets. This may be done in a carefully designed challenge booth to eliminate the possibility of contaminants in the room. Chemicals and controls, sometimes called prompts, are introduced in a random method, usually scent-masked. The test subject does not know when a prompt is being given. Objective and subjective responses are measured. Objective measures, such as the galvanic skin response electrodermal response, indicate psychological arousal, such as fear, anxiety, or anger. Subjective responses include patient self-reports. A diagnosis of MCS can only be justified when the subject cannot consciously distinguish between chemicals and controls, and when responses are consistently present with exposure to chemicals and consistently absent when prompted by a control.

Investigators in Japan, Spain, Germany and the United States have used the Quick Environmental Exposure and Sensitivity Inventory (QEESI) as a self-screening questionnaire in their research on MCS. The QEESI is a shortened version of the Environmental Exposure and Sensitivity Inventory developed by Dr. Claudia S. Miller. The QEESI asks individuals to rank their responses to exposures from 0 to 10 in four scales: symptom severity, chemical intolerances, other intolerances, and life impact.

Treatment
In various studies, about one half of the patients who present with symptoms of MCS meet the criteria for depressive and anxiety disorders, and these conditions must be treated when present. The use of SSRI antidepressants with a 53-year-old man with multiple chemical sensitivities showed a dramatic improvement, which suggests, as with the general population, a subgroup of MCS patients may have an atypical depression and should be evaluated for this condition.

Another study showed psychotherapy resulted in significant, long-term improvement in MCS symptoms, although there was no control group to which to compare results.

While patients typically resist the potentially stigmatizing diagnosis of an anxiety disorder, many MCS sufferers benefit strongly from lifestyle changes. A 2003 survey of 917 MCS patients revealed the two most effective treatments for MCS, in order of self-perceived harm/benefit ratio, were a chemical-free living space and chemical avoidance. Next came prayer and meditation, which presumably did no harm. By comparison, two-thirds of patients who had tried Zoloft thought it was harmful. Other treatments with perceived harm included other pharmaceutical drugs, provocative neutralization, hydrogen peroxide, Metagenics' UltraClear medical food, and microhydrin antioxidants. Overall, one or more antidepressants and anxiolytics were rated harmful by about half of survey respondents who had tried them, and as either harmless or helpful by the remaining respondents.

Other treatment modalities variably consist of the avoidance of known irritants, nutritional support to purge the body of its toxic load, sauna detoxification and autolymphycyte factor treatment.

Because many people eliminate whole categories of food in an effort to reduce symptoms, a complete review of the patient's diet may be needed to avoid nutritional deficiencies.

Epidemiology
Epidemiological data from three states puts the prevalence of chemical sensitivity at 16 to 33% of the general population, 2 to 6% of whom have already been diagnosed with MCS.

As Magill and Seruda report: "Most patients (85 to 90 percent) complaining of MCS syndrome are women. Most present between the ages of 30 and 50 years. Much additional basic descriptive and epidemiologic information is still unknown. The incidence and prevalence are unknown. The question of whether MCS is becoming more or less common is unanswered, as is the question of whether it is preventable. The natural history and biologic outcomes of MCS are unknown, and descriptions of MCS in primary care settings have not been reported. Selected patients from specialty settings comprise reports of the syndrome."

Relationship to Gulf War syndrome
Several clinical and epidemiological studies conducted in the United States and in the United Kingdom have investigated the occurrence of MCS in military personnel deployed to the Persian Gulf during the 1990s. Some of the health complaints and symptoms reported by veterans of the Gulf War attributed to Gulf War syndrome are similar to those reported for MCS, including headache, fatigue, muscle stiffness, joint pain, inability to concentrate, sleep problems, and gastrointestinal issues.

A population-based, cross-sectional epidemiological study involving American veterans of the Gulf War, non-Gulf War veterans, and non-deployed reservists enlisted both during Gulf War era and outside the Gulf War era concluded the prevalence of MCS-type symptoms in Gulf War veterans was somewhat higher than in non-Gulf War veterans. After adjusting for potentially confounding factors (i.e., age, sex, and military training), there was a robust association between individuals with MCS-type symptoms and psychiatric treatment (either therapy or medication) before deployment and, therefore, before any possible deployment-connected chemical exposures.

The odds of reporting MCS or chronic multiple-symptom illness was 3.5 times greater for Gulf War veterans than non-Gulf veterans.

Gulf War veterans have an increased rate of multiple-symptom conditions compared to military personnel deployed to other conflicts, and although it is unexplained, Gulf War syndrome is not considered distinct from other medically unexplained syndromes observed in civilian populations, including MCS.

In media

 * The 1995 film Safe, starring Julianne Moore and directed by Todd Haynes, is about a woman who develops MCS. It was voted the best film of the 1990s in the 1999 Village Voice Film Poll.
 * The 2008 work Tilt, by Italian writer Caterina Serra, reports and narrates the lives of many patients affected by MCS.
 * Anne Lipscomb's 2009 memoir Poisoned by Pollution: An Unexpected Spiritual Journey details the author's struggles with MCS.
 * In a 2009 episode of the TV series Bones, MCS patients are scammed and murdered.
 * John Stossel's 1994 TV special The Blame Game, which chronicles cultural victimization and lack of responsibility in American society, includes a group of four employees of Tompkins County, New York's Social Services Department who claimed to have been rendered disabled by MCS caused by the chemicals in their building.
 * In the TV series Northern Exposure, the character Mike Monroe is portrayed as suffering from MCS.