Multiple chemical sensitivity

Multiple Chemical Sensitivity (MCS), also known as Idiopathic Environmental Intolerances (IEI) and Environmental Sensitivities/Multiple Chemical Sensitivities (ES/MCS), was defined in a 2017 scientific review as "a complex syndrome that manifests as a result of exposure to a low level of various common contaminants."

A 2019 review described the condition as an "acquired disorder characterized by recurrent symptoms, affecting multiple organs and systems, which arise in response to a demonstrable exposure to chemicals, even at low doses, much lower than those that would cause a reaction in the general population."

Chemicals that are common triggers for MCS symptoms include pesticides, petrochemicals, formaldehyde, and perfumed products. Natural irritants like mold and woodfire smoke are also common incitants.

The etiology, diagnosis, and treatment of MCS are still being researched and debated.

MCS is not recognized as a separate, discrete disease by the World Health Organization (WHO), but a 2017 review said that it can be codified as a clinical condition using existing disease codes in WHO's 2010 International Classification of Diseases (ICD10). It also said that it is recognized as a discrete pathology in some countries' indexes of disease and by some government agencies.

Signs and symptoms
In 1999, an International Consensus on MCS was published in ''The Archives of Environmental Health. '' The Consensus was the conclusion of a ten-year study by an international multidisciplinary team of 89 clinicians and researchers, with different points of view about MCS. What they agreed was that the clinical characteristics of MCS should be defined as follows: “[1] a chronic condition, [2] with symptoms that recur reproducibly, [3] in response to low levels of exposure, [4] to multiple and unrelated chemicals, and [5] improve or resolve when incitants are removed, [6] MCS involves symptoms in different organs.” 

The symptoms of MCS affect multiple organs and body systems,   range from mild to disabling and decrease quality of life.

Common symptoms of MCS include headache, migraine, neurocognitive deficits, dizziness, fatigue, cardiac arrhythmia, tachycardia, hypotension, hypertension, gastrointestinal problems, nausea, vomiting, muscle and joint pain, skin rashes, visual disturbances, seizures, asthma and anaphylaxis.  

A 2017 review of MCS studies said: “MCS is a syndrome that progresses to increasingly serious stages, with the gradual onset of multiple pathologies”.

Causes
There is a lack of agreement among MCS researchers on the cause or causes of the condition.

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. "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/MCS."

One of the most thorough academic reviews of MCS research to be undertaken was published in Italy in May 2019. It said that the current predominant hypotheses about the causes of MCS were: biochemical, neuro-physiological and related to the limbic system and genetic predisposition.

Some researchers say a consensus that the causes are multifactorial has been reached.

In 2018, when speaking at an Australian federal parliamentary inquiry into environmental illness, In 2018, Dr Graeme Edwards, a representative of the Royal Australasian College of Physicians, 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.”

Toxicological
Professor 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.”

Pall hypothesized that overactivity of the NMDA receptors, coupled with stress-related increases in nitric oxide and the oxidative product peroxynitrite (known as the NO/ONOO cycle) caused MCS symptoms and worsened the condition. He suggested that hypersensitivity occurred because of limbic kindling, neural sensitization, and/or neurogenic inflammation—processes which can be driven by the NO/ONOO cycle.

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, including Dr. Iris Bell's theory of neuronal sensitization and William Meggs’ theory of neurogenic inflammation. 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 Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS), and it might be why MCS symptoms tend to reduce after exposure to inhibitors and/or antagonists of NMDA receptors. The 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.

The 2019 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."

Dr. William J. Rea and other researchers   also concluded that mold and mycotoxin exposures could trigger the onset of the condition, suggesting that pesticides are not the only class of chemicals associated with triggering the onset of MCS.

Neurological
Many common symptoms of MCS are neurological (for example, "dizziness, seizures, head pain, fainting, loss of coordination" ). And neurogenic inflammation and sensitization are widely thought to be mechanisms involved in causing, perpetuating and worsening MCS.

William Meggs said that 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.

Iris Bell researched brain-wave patterns in people with MCS. He showed, in several studies using Electroencephalograms (EEG), that people with MCS often had certain abnormal brain wave patterns. 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.

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 areas. These abnormalities have been documented both in studies using PET (Positron Emission Tomography) and SPECT (Single Photon Emission Computed Tomography) scans.

In addition to people with MSC having documented neurological abnormalities, neuroplasticity is thought by some researchers to be an important mechanism in the disease. In 2018, an official 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.”

Immunological
MCS is not an allergy, and subjects with MCS having adverse reactions do not routinely exhibit the immune markers associated with allergies. Nevertheless, certain immune irregularities have been identified in subjects with MCS in a range of studies.

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. While others concluded that allergic or immunotoxicological reactions could be contributing factors in at least a subset of MCS patients. As more studies were conducted, however, some argued that there was no consistent pattern of immunological reactivity or abnormality in MCS.

More recently, a French study found that subjects with MCS had higher levels of histamine than controls. 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. These findings led the research team to conclude that some level of immune activation was likely occurring in the condition.

There is also evidence that subjects with MCS are more likely than controls to have proper allergies and autoimmune diseases, and the 2019 consensus on MCS notes an association between the condition and Hashimoto's Thyroiditis, Systemic Lupus Erythematosus (SLE), Psoriasis and Atopic eczema.

Psychological
Several mechanisms for a psychological etiology of the condition have been proposed, including theories based on misdiagnoses of an underlying mental illness, stress, or classical conditioning. Many people with MCS also meet the criteria for major depressive disorder or anxiety disorder. Other proposed explanations include somatic symptom disorder, panic disorder,  migraine, chronic fatigue syndrome, or fibromyalgia, where symptoms such as brain fog and headaches can be triggered by chemicals or inhalants. Through behavioral conditioning, it has been proposed that people with MCS may develop real, but unintentionally psychologically produced, symptoms, such as anticipatory nausea, when they encounter certain odors or other perceived triggers. It has also been proposed in one study that individuals may have a tendency to "catastrophically misinterpret benign physical symptoms"  or simply have a disturbingly acute sense of smell. The personality trait absorption, in which individuals are predisposed to becoming deeply immersed in sensory experiences, may be stronger in individuals reporting symptoms of MCS. In the 1990s, behaviors exhibited by MCS sufferers were hypothesized by some to reflect broader sociological fears about industrial pollution and broader societal trends of technophobia and chemophobia.

These theories have attracted considerable criticism.

The most recent scientific review and consensus on MCS, from May 2019, said 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."

It is noteworthy that psychological approaches to care in MCS patients have had “very limited success,” and that neither MCS, ES nor IEI have been included in any edition of the DSM (the American Psychiatric Association Diagnostic and Statistical Manual ) nor have they been listed among somatoform disorders in the International Index Code of Diseases.

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.

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.

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. They also found that the presence of the following genetic polymorphisms were more likely in people with MCS than controls: NOS3, NOS2 and GPX1.

Other genetic markers known to affect detoxification pathways have been identified as being more common in subjects with MCS than controls,    including polymorphisms and differences in expression of the following: CYP2D6, NAT2, GSTM1, and PON1 and PON2.

These findings could support the hypothesis that MCS is caused by a synergy of environmental exposures to toxic substances and the impaired ability to metabolise toxic substances, due to factors related to genetic predisposition.

International Classification of Diseases
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 discrete 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 MCS. The US Occupational Safety and Health Administration (OSHA) indicates that MCS is highly controversial and that there is insufficient scientific evidence to explain the relationship between the suggested causes of MCS and its symptoms. OSHA recommends evaluation by a physician knowledgeable of the symptoms presented.

Treatment and management
At this time, there is no clinically proven cure for MCS. There is also no scientific consensus on supportive therapies for MCS, "but the literature agrees on the need for patients with MCS to avoid the specific substances that trigger reactions for them and also on the avoidance of xenobiotics in general, to prevent further sensitization."

There is also consensus that a multidisciplinary approach is required for adequately managing the health of someone with MCS. And some studies suggest a special focus on correcting any nutritional deficiencies may be beneficial.

There is also evidence that some patients with MCS have poor tissue oxygenation when exposed to triggers, likely because of oxidative stress or because neural inflammation has reduced blood flow. Breathing medical oxygen following accidental chemical exposures is a suggested remedy for these patients.

The 2019 consensus and clinical guidelines on MCS said that people with MCS "must be guaranteed, according to their individual needs and level of disability" medical Oxygen and the necessary equipment to use it (that is, tubing and a mask from non-triggering materials).

The other aids the 2019 consensus said were necessary for patients with MCS to manage the functional impacts of their condition were: face masks (with HEPA and VOC filters), portable air purifiers for the home and for inside vehicles (made of metal, with HEPA and activated carbon filters) and water purifiers.

Epidemiology
Prevalence rates for MCS vary according to the diagnostic criteria used. What is clear is that the condition is reported across industrialised countries and it affects women more than men.

The most extensive epidemiological study into MCS in the United States was in 2005. It found that the national prevalence rate for MCS diagnosed by a doctor was 2.5% and self-reported MCS was 11.2%.

In 2018, the same researchers reported that the prevalence rate of diagnosed MCS had increased by more than 300% and self-reported chemical sensitivity by more than 200% in the previous decade. They found that 12.8% of those surveyed reported medically diagnosed MCS and 25.9% reported having chemical sensitivities.

A 2014 study by the Canadian Ministry of Health estimated, based on its survey, that 0.9% of Canadian males and 3.3% of Canadian females had a diagnosis of MCS by a health professional.

While a 2018 study at the University of Melbourne found that 6.5% of Australian adults reported having a medical diagnosis of MCS and that 18.9 per cent reported having adverse reactions to multiple chemicals. The study also found that for 55.4 per cent of those with MCS, the symptoms triggered by chemical exposures could be disabling.

These findings demonstrate that in the above countries MCS is not a rare disease.

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 (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.

History
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). In the 1990s, an association was noted with chronic fatigue syndrome, fibromyalgia, and Gulf War syndrome.

In 1994, the AMA, American Lung Association, US EPA and the 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.

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 because of budgetary constraints and the allocation of funds to other, extensively overlapping syndromes with unknown cause, 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.

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.

A 1997 U.S. 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.

In 2007, the Australian Human Rights and Equal Opportunity Commission referenced chemical sensitivities, in a publication about access guidelines. It said “a growing number of people report being affected by sensitivity to chemicals used in the building, maintenance and operation of premises. This can mean that premises are effectively inaccessible to people with chemical sensitivity.”

In 2014, a task force into Environmental Health was established in Canada by the Ministry of Health and Long-Term Care to take an evidence-based approach to investigating ES/MCS and chronic fatigue syndrome and fibromyalgia. In 2017, the task force issued its first report which recommended that the Minister of Health make a statement "reinforcing the serious debilitating nature of these conditions," "dispelling the misperception that they are psychological," and that hospitals and long-term care homes be made safe for people with these conditions, complying "as quickly as possible, with relevant accessibility and accommodation legislation." The basis for these recommendations, the report said, was that “there is [was] lack of understanding and recognition about these conditions,” and that sufferers faced "significant stigma and discrimination within the health care system” and “overwhelming barriers accessing high quality, appropriate patient-centred care”. It concluded that they "were more likely to have unmet health needs” than the rest of the population.

In response to a WHO call for papers at the 5th Paris Appeal Congress of Environmental Idiopathic Intolerance conference that took place in Belgium on 18 May 2015, a submission signed by 25 scientists from different countries, working in the field of environmental medicine, supported a statement that said that MCS ought "to be fully recognized by international and national institutions with responsibility for human health". This submission was provisionally accepted by the Spanish health ministry and was later cited by a Spanish judge as a legal document in a case related to MCS.

In February 2018, the Journal of Occupational and Environmental Medicine published "Multiple Chemical Sensitivity: Review of the State of the Art in Epidemiology, Diagnosis, and Future Perspectives" covering 17 years of literature internationally on the topic.

In popular culture
Safe (1995), a cult film by director Todd Haynes, is an iconic depiction of MCS.

Voted best film of the nineties by The Village Voice Film Poll , and described by critics as ”the scariest film of the year”, “a mesmerizing horror movie” and “a work of feminist counter-cinema,” Safe depicts MCS as a profoundly destabilising and alienating condition.

Protagonist Carol White, played by Julianne Moore, is a homemaker who suddenly develops a range of symptoms following the renovation of her home, in an affluent suburb of polluted Los Angeles. As Carol’s symptoms worsen, the chemicals that are triggering them seem ubiquitous. Her husband is skeptical; her community indifferent and unsupportive. She realises there is no place for her in society. So, like a refugee, she leaves her home, possessions and world behind. Without her husband, she moves to an eerie desert community for people with environmental illness.

“She is so excruciatingly alone”, Moore said of her character at the end of the film. While Haynes said Carol’s isolation was both the answer and the problem for her.

Twenty years after the film’s release, Haynes said its themes—disease and immunity in a post-industrial landscape and how recovery is a burden often put on victims of illness—were even more relevant than they were when he made the film.