Multiple Chemical Sensitivity
Diseases

Multiple Chemical Sensitivity (MCS)

DEFINITION

Multiple Chemical Sensitivity(MCS) or Idiopathic Environmental Intolerance (IEI) is a chronic medical condition characterized by symptoms that the affected person attributes to exposure to low levels of chemicals. Commonly suspected substances include smoke, pesticides, plastics, synthetic fabrics, scented products, petroleum products and paints. Symptoms may be vague and non-specific, such as nausea, fatigue and headaches but also commonly include inflammation of skin, joints, gastrointestinal tract and airways. Multiple chemical sensitivity (MCS) can be considered an environmental illness (see the site on The Environmental Illness Resource at http://www.ei-resource.org/), term generally used to describe a number of mild to severe health responses to toxins and chemical products.

HISTORICAL NOTES

The first description of a similar disease was given by Edgar Allan Poe in 1839 (Symptoms in the stories of E.A. Poe; The tell-tale face of CO poisoning). The American author was, in fact, repeatedly poisoned by exposure to carbon monoxide (CO) from illuminating gas, which was made from coal and contained extremely high levels of CO.
It was then medically definited as a symptom fo neurasthenia in 1869, and rediscovered as allergic toxemia in 1945. In 1987, after been proposed not as symptom but as a distinct desease, was redefined in MCS. Finally in the 1990s it was associated with chronic fatigue syndrome, fibromyalgia, and Gulf War syndrome as a syndrome with no certain or unkonwn etiology. In fact, MCS is not recognized as an organic, chemical-caused illness by the American Medical Association and some other Us based organisations because of the lack of scientific evidence that supports a cause-and-effect relationship between exposure to low levels of chemicals and the symptoms.

On the recognition of MCS in medical literature and government policy, 1999
Multiple chemical sensitivities - public policy, 1995

EPIDEMIOLOGY

According to avaiable informations about American population (Prevalence of multiple chemical sensitivities: a population-based study in the southeastern United States, 2004) 12.6% of Americans have reported an unusual hypersensitivity to common chemical products such as perfumes, fresh paint, pesticides, and other petrochemical-based substances, and 2.5% reported they had been medically diagnosed with MCS. Additionally, 31.1% of those sampled reported adverse reactions to fragranced products, and 17.6% experienced breathing difficulties and other health problems when exposed to air fresheners. Although chemical hypersensitivity was more common in women¹ it is experienced by both men and women of a variety of ages² and educational levels. A population-based, cross-sectional epidemiological study (MCS. Symptom Prevalence and Risk Factors in a Military Population, 2000) involving American veterans of the Gulf War and non-Gulf War veterans concluded that the prevalence of MCS-type symptoms in Gulf War veterans was somewhat higher than in the other. A more recent study (Prevalence and interannual changes in multiple chemical sensitivity in Japanese workers, 2014) has shown that MCS exists among Japanese workers and that prevalence rate has been higher in 2011 than in 2003.

SYMPTOMS

MCS is characterised by recurrent, vague and aspecific symptoms referrable to multiple organ systems (Clinical features of multiple chemical sensitivity, 1997). They occur in response to demonstrable exposure to chemical compounds at doses far below those known to cause harmful effects in the general population. No one available test of organ system function can explain the symptoms. The wide heterogeneity of symptoms between individual people make it difficult to define a typical symptoms pattern for MCS.

• GENERAL SYMPTOMS:
  • sickness, weakness, low energy
  • dizziness
  • anorexia
  • suppression of immune system
  • dry mouth, dry eyes

• PHYSICAL SYMPTOMS:
  • Respiratory tract: difficulty breathing, asthma, nasal congestion, throat soreness, chest tightness
  • Osteomuscular system: joint pains, muscle discomfort, tendinitis
  • Gastrointestinal and urinary system: digestive difficulties, abdominal pain, nausea, vomiting, diarrhea, gastrointestinal and/or urinal disturbance, overactive bladder
  • Nervous system: headache, visual disturbances (blurring, halo effect, inability to focus), nerve pain, paresthesia, trembling, restless leg syndrome
  • Dermatological disorders: skin rash, urticaria, contact dermatitis

• PSYCHOLOGICAL SYMPTOMS:
  • inability to concentrate
  • memory problems
  • sense of discomfort, restlessness
  • sleep disturbance, insomnia
  • anxiety, panic attacks

It is also reported an acute sense of smell (hyperosmia) and sensitivity to natural plant fragrance and natural pine terpenes (Odor processing in multiple chemical sensitivity, 2006; Multiple chemical sensitivity worsens quality of life and cognitive and sensorial features of sense of smell, 2014).

A review of multiple chemical sensitivity, 1999
Sickness-related dysfunction in persons with self-reported multiple chemical sensitivity at four levels of severity, 2009

CHEMICAL TRIGGERS

There are a lot of chemical agents that can induce the wide variety of sympotms above reported. In particular have to be mentioned:

1. cleaning agents and laundry detergents
2. pesticides, insecticides, herbicides, fertilizers and other agricoltural chemicals
3. perfumes and beauty products.

But also a lot of other toxic agents: agricultural chemicals, gasoline (or diesel fuel), petroleum-based products (e.g. asphalt), formaldehyde, glues, varnishes, nail polishes, paints, solvents, paint thinners, volatile organic compounds (VOCs), lotion, aftershave lotions, skin care products, air fresheners, deodorizers and scented candles, shampoos, hairsprays and hair care products, dishwashing liquid and dishwasher detergent, marking pens (e.g. highlighters).

A review of a two-phase population study of multiple chemical sensitivities, 2003
Multiple chemical sensitivity: a diagnosis not to be missed, 2013

DIAGNOSIS

Diagnosis of multiple chemical sensitivity is clinical, based on symptoms described by patients. Cullen's criteria refer to a multiorgan syndrome, not explained on the basis of any known organic cause, and acquired following an exposure to airborne environmental noxiae of chemically defined structure. Symptoms can be foreseen and have to occur regularly, in concomitance with any exposure at subliminar levels (below 1% of the dose normally eliciting a toxicological response in normal individuals) of chemical trigger/s. They also have to improve considerably or heal completely after trigger withdrawal. If the diagnosis is suspected clinically it can be (at least partially) confirmed:

• using the Quick Environmental Exposure and Sensitivity Inventory (QEESI) , a self-questionnaire that asks individuals to rank their responses to exposures from 0 to 10 in four scales: symptom severity, chemical intolerances, other intolerances, and life impact³;
• testing patients response to the random introduction of chemicals that they have self-identified as relevant (e.g. scented soaps, detergents, etc.).

It is often shown comorbidity with chronic fatigue syndrome, fibromyalgia and a lot of other disorders, such as anxiety and depression. (Functioning in individuals with chronic fatigue syndrome, 2007)

Misdiagnosis

MCS is frequently misdiagnosed as asthma, allergic conditions and mast cell activation diseases such as mastocytosis where symptoms such as brain fog and headaches can be triggered by chemicals or inhalants. So patients are frequently referred to respiratory and allergy specialists. Most often the syndrome is regarded as a phsychiatric disorder (above all anxiety disorders) or diagnosed with somatoform disorder and mood disorder.

Multiple chemical sensitivity: a diagnosis not to be missed, 2013
Psychiatric and somatic disorders and multiple chemical sensitivity (MCS) in 264 environmental patients, 2002; Psychiatric and somatic morbidity of patients with suspected multiple chemical sensitivity syndrome, 2000; New aspects of psychiatric morbidity in idiopathic environmental intolerances, 2006;

PATHOGENESIS

MCS is a poorly understood condition and there is no univoque theory about its pathogenesis. However many hypothesis have been proposed.

Psychological

Chemical sensitivity: pathophysiology or pathopsychology? 2013

Neurological

Brain dysfunction in multiple chemical sensitivity,2009
Increased capsaicin-induced secondary hyperalgesia in patients with multiple chemical sensitivity. 2011
Changes in cerebral blood flow during olfactory stimulation in patients with multiple chemical sensitivity, 2013

GENETICAL

Some studies show that genetic polymorphisms relating to the body's detoxification processes have a statistically significant role in determining MCS prevalence⁴. In particular, biochemists have paid attention on genes encoding proteins that metabolize chemicals previously implicated in MCS:

• Paraoxonase, a group of a group of enzymes involved in the hydrolysis of OPs pesticides :
  • PON1
  • PON2

• Arylamine N-acetyltransferase , that catalyzes the transfer of acetyl groups from acetyl-CoA to aromatic amines in organic solvents:
  • NAT1
  • NAT2

• Cytocrome p450 , the terminal oxidase enzymes in electron transfer chains:
  • CYP2D6

As a consequence of these polymorfism, people with MCS may show genetically determined impairments of detoxification enzymes, CNS sensitization (Multiple chemical sensitivity: potential role for neural sensitization, 1999) and an elevation of nitric oxide/peroxynitrite (Elevated nitric oxide/peroxynitrite theory of multiple chemical sensitivity, 2003). Latest theories regarding MSC pathogenesis (A cross-sectional study of self-reported chemical-related sensitivity is associated with gene variants of drug-metabolizing enzymes, 2007 ; Biological definition of multiple chemical sensitivity, 2010) emphasize decreased levels of reduced and oxidized glutathione (GSH/GSSG), as well as of glutathione-metabolizing enzymes activities.

The genetic variants analyzed regard glutathione S-transferases(GST). GST is a family of conjugating enzymes playing a key role in the biotransformation of organic xenobiotics, in the metabolism of endogenous electrophiles (e.g. HNE) and in the deactivation of reactive oxygen species. The GST isozyme polymorphisms is considered implicated in the risk of environment associated tumors and other environment related human pathologies (such as MCS, systemic lupus erythematosus and vitiligo and MCS) as well as cellular processes of inflammation and degenerative diseases).

• GST isozymes evaluated:
  • GSTM1 (related in possible changes in individual's susceptibility to carcinogens and toxins)
  • GSTT1
  • GSTP1

Individuals with self-reported chemical-related sensitivity were more frequent carriers of genetic variants (especially homozigous deletions) of GSTM1, GSTT1, GSTP1 and NAT2. In all of these mechanisms, excessive ROS are involved.

So in MCS patients exist serious and multiple dysfunctions of chemical defensive system. They can depend on genetic defects and modifications of metabolizing/antioxidant enzyme expression or activity mediated by redox active agents such as NO and inflammatory cytokines (e.g. IFN-γ and IL-10). The polymorphism also regards genes encoding the receptors and transcriptional factors regulating metabolizing enzymes.

Recently have been studied metabolic redox parameters in erythrocytes of individuals with MCS and have been founded the following data:

• decrease in erythrocyte catalase activity;
• decrease in GST activity;
• up-regulation of the erythrocyte GPX activity;
• low levels of reduced and oxidized glutathione;
• elevated plasma levels of NO2−/NO3−;

A possible MSC pathogenesis

• Dysfunction or depletion of GSH, GST and catalase leads to severe oxidative stress due to an insufficient elimination of oxidation metabolites.

• Excessive amount of hydrogen peroxide and other free radical initiates a non-enzymatic reaction of lipid peroxidation resulting in the decomposition of PUFA to form a broad array of aldehydes such as malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE). These aldeydes easily react with proteins and DNA⁵, affecting enzyme gene expression, enzymatic activity, and forming autoantigens.

This chain is confirmed by significantly low content of PUFA founded in the erythrocyte membrane and increased levels of HNE-protein levels in MCS plasma.

• Additionally, elevated levels of NO2-/NO3-, H2O2 and low activity of catalase stimulate the expression and action of pro-inflammatory redox-dependent cytokines as the chemokines IL-8 and MCP-1 and the growth factors PDGF and VEGF. So there are abnormal levels of several immune-modulating cytokines in un-stimulated MCS individuals⁶, expecially for the ratio of IL-4/IL-13, that are Th2 associated cytokines. In particular, there is an important up-regulation of IL-4 and a down-regulation of IL-13 (An elevated pro-inflammatory cytokine profile in multiple chemical sensitivity, 2013).

• Cytokines enhance COX-2 and LOX genes expression, that rapidly oxidize products of PUFA peroxidation_ forming respectively prostaglandins and leukotrienes, that are potent biological effectors.

In conclusion, in MCS un-stimulated people seems to be an elevated immune activation and chronic low-grade inflammation. It is important to take in consideration that there is no alteration in IgE plasma levels: the symptoms experienced after inhalation of common volatile chemicals are not mediated by enhanced IgE . Therefore there is an individual peculiarity of adaptive or not adaptative response to chemical stressors, so that an exposure to those products could exasperate a an already compromised condition.

Exposure to chemical agents may induces a further increase of IL-4 plasma level due to IL-4 producing cells (as eosinophils or mast cells) in lungs and nasal lamina propria. For what concerns IL-13, it changes the mucosal epithelium of the respiratory trat from an absorptive barrier to a mucus secreting one by stimulating mucus production, and it is also involved in suppression of cytokines production. Because of the low level of IL-13 in MCS people, their mechanisms of protection may be less functional.

Responses of MSC people to chimical agents exposure can be related to a further, sudden and abnormal elevation:

1. of ROS (due to a deficient detoxification system)
2. of cytokines and inflammatory molecules

This mechanism could (partially) explain the wide range of symptoms after exposure and also the high comorbidity with psychiatric disorders (From inflammation to sickness and depression, 2008).

THERAPY

Because of the uncertain pathogenesis of MCS there is no a gold standard therapy and the only certain preventive measure is to avoid known irritants. Nonetheless several treatments have been proposed in order to relieve MCS symptoms such as psycotherapy (expecially mindfullness-based cognitive therapy), antidepressant (Zoloft, Sertraline), anxiolytics, nutritional support (vitamins), antioxidant etc.
In relation to glutathione depletion, a recent study hypothesizes that intranasal administration⁷ of GSH could be a good solution. In fact, the patients who have been administrated inGSH has reported an improvement in MCS symptoms, probably because it can improve detoxification and lead to a decreasing ROS levels. Moreover, equally important, inGSH therapy is well tolerated, non-invasive, can be self-administered and is inexpensive (∼$50/month).

Even though (in)GSH holds promise for future treatment of MCS an other respiratory and CNS diseases (where free-radical burden is a suspected contributor to disease progression) it should be further evaluated by clinical trials.

Currently additional studies are certainly needed for a better understanding of Multiple Chemical Sensitivity, as well as other Environmental Illnesses. Meanwhile we can all contribute to improve our health and that of environment, for example using organic products rather than chemicals.

--------------------------------------------------------------------------------------------------------------------------------------

¹ Some studies reported that most patients with MCS are women between the ages of 30 and 50 years (Multiple Chemical Sensitivity, 2012; Clinical features of multiple chemical sensitivity, 1997).

² Multiple chemical sensitivities following intolerance to azo dye in sweets in a 5-year-old girl, 2006

³ QUEESI test

⁴ Also of several related conditions, including fibromyalgia, post-traumatic stress disorder, Gulf War syndrome, and chronic fatigue syndrome.

⁵ See also Calcium and Colorectal Cancer

⁶ IL-1, IL-2, IL-4, IL-6 and TNFalfa found to be statistically significantly increased and IL-13 down-regulated. The cytokine differences in MCS seen in this study are in line with findings from other medically unexplained disorders often associated with MCS, such as FMS, CFS and GWS.

⁷ Because of the target tissue is the brain or the respiratory tract, the best method of administration is intranasal.

--------------------------------------------------------------------------------------------------------------------------------------

- MCS
- American Academy of Environmental Medicine
- Occupational and Environmental Medicine