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Multiple Chemical Sensitivities Syndrome (MCSS)

Question: What is it and What is Known About MCSS?

Answer: Actually, the preferred medical term is Idiopathic Environmental Intolerance (IEI), which can be defined as a "chronic, recurring disease caused by a person's inability to tolerate an environmental chemical or class of foreign chemicals."

IEI thus represents a complex gene-environment interaction, the true cause of which is currently unknown. There is almost always a precipitating event, usually associated with the smell of a chemical, and a response involving one or more organ systems. Once the imitating event has passed, the same response or even an exaggerated occurs each time the stimulus is encountered again. Often the initiating stimulus is a higher dose or an overwhelming dose, but subsequently much lower doses can trigger the symptoms. A number of unrelated chemicals (e.g. insecticides, antiseptic cleaning agents) might precipitate the same response. Because the syndrome is similar to certain allergic conditions and to certain organ-system responses caused by emotional disturbances, IEI has often been confused with allergy (atopy) or psychiatric illness. Disagreement among physicians and medical researchers - as to what IEI really is - has, of course, made research funding difficult ("is this a real syndrome, or is this a mental problem or a simple allergy?") In fact, in an environmental health sciences meeting in Brisbane, Australia, several years ago, there was an old-fashioned debate on MCSS, and the proponents who believed that it was simply a psychiatric disorder won the debate!

Six criteria of IEI
Several years ago a committee of experts in thie field decided upon a consensus as to what "qualifies" the patient as truly having IEI [Arch Environ Health 1999; 54: 147]. Six criteria were decided upon:

  1. Symptoms are reproducible with repeated (chemical) exposures.
  2. The condition is chronic.
  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).

Several medical conditions appear to be related to, or overlap with, IEI - such as sick-building syndrome (SBS), food intolerance syndrome (FIS), and perhaps the Gulf War Illness (GWI). In each of these, a chemical (smell usually, or taste) appears to precipitate one or more organ-system responses. The initiating culprit might be: chemicals in a new rug, cockroach dander, or freon circulating in a closed-ventilation building (SBS); chemicals in wine, processed corn products, or sulfites consumed (FIS); or nerve gas, organophosphates, or pesticides to which soldiers were exposed during the brief 1991 was in the Middle East (GWI). Additional conditions (of discomfort, pain or dysfunction) that might have a genetic component but also seem to have an environmental stimulus include: chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, atypical connective tissue disease after silicone breast implants, chronic hypoglycemia (low blood sugar), drug-induced autoantibodies/hepatitis (liver toxicity), illness while living near a toxic waste dump site, dental amalgam disease, and MTBE (methyl-tert-butyl ether, a gasoline additive)-associated symptoms. Inflammation of the lungs caused by diesel exhaust particles (DEPs) is of particular interest, since it illustrates the potential for the drug-biotransformation and immune systems (which protect us from small and large foreign compounds, respectively) to interact and contribute to the disease process. In this situation, cellular processes regulated by the aryl hydrocarbon receptor (AHR) apparently activate an inflammatory response involving TH2 helper cells, subsequently increasing immunoglobulin E (IgE) production.

How might we dissect this complex disease?
Frequently, individuals with IEI present with symptoms of rhinitis (runny nose), along with other diffuse systemic complaints. First, the physician must determine whether the patient has a runny nose due to an allergy problem (allergic rhinitis) or not an allergy problem (nonallergic rhinitis).

Seasonal allergic rhinitis refers to patients with allergy symptoms triggered by pollen or mold-spore allergens. "Triggering stimuli" occur when the patient is outdoors during the pollen seasons. Symptoms can include sneezing fits (i.e. 5-10 sneezes in succession), itching of the eyes/ears/nose/throat/roof of the mouth, runny nose, watery/puffy eyes, nasal stuffiness, post-nasal drip, sinus pressure, and fatigue. Perennial allergic rhinitis refers to year-round hay fever symptoms that are triggered by indoor allergens such as dust mites, cockroaches, mold-spores, feathers, and animal dander. Perennial allergens may be difficult to identify by history alone; skin testing is necessary to confirm sensitization to these allergens but does not indicate that the individual is currently being exposed.

A patient with nonallergic rhinitis is one who has had an allergic component ruled out by skin tests. Nonallergic rhinitis can be further divided into inflammatory (nonallergic rhinitis with eosinophilic syndrome, NARES) and noninflammatory (vasomotor rhinitis, VMR) subtypes. Nonallergic rhinitis is an organ-specific disorder of unknown etiology (cause not understood) that is aggravated by strange chemical smells and weather changes. The noninflammatory form of nonallergic rhinitis, VMR, satisfies the first five of the above criteria, suggesting that this disorder is a potential model (Ann Alergy Asthma Immunol 2001: 86;494] for investigating the genetic etiology of the more global disease, IEI.

Nonallergic VMR can mimic allergic rhinitis. Patients with nonallergic VMR experience nasal congestion, postnasal drip, headaches/sinus pressure and ear-plugging. Skin testing to seasonal and perennial allergens is negative (i.e. non-atopic). "Triggering stimuli" for nonallergic VMR include weather changes (temperature or barometric pressure changes), postural changes, and irritants such as smoke, perfumes, potpourris, solvents, cleaning agents, incense, and soaps and detergents (to name a few).

Is IEI associated with mutations in olfactory receptor (OR) genes?
The field of olfaction (ability to smell distinct classes of things) has recently exploded with the advent of genomics and the Human Genome Project. A superfamily of ~1000 odorant receptor (OR) genes has been discovered, located in multiple clusters on all but two of the 24 human chromosomes (22 autosomes, X Y chromosome). These OR clusters comprise 17 gene families, four of which contain >100 members each [Genome Res 2001; 11;685]. Interestingly, 64% of the human's OR genes are nonfunctional (pseudogenes). The fact that apes have a greater percentage of functional OR genes - is strong evidence that the evolving human species has lost its need for maintaining a very keen sense of smell. The OR gene superfamily comprises 1-3% of the entire genomic complement of genes, and is likely to be the largest gene superfamily in the genome of any species.

Other clusters of human chemosensory genes include the vomeronasal receptors, related to an accessory olfactory organ thought to be largely inactive in primates. The OR genes are members of the 7-transmembrane domain G-protein-coupled receptor (GPCR) superfamily. In situ hybridization studies indicate that each OR gene is expressed in ~1 per 1000 olfactory epithelial (OE) neurons, suggesting that each OE neuron expresses only one OR gene [Cell 2000;100:611]. People clearly have very different abilities to sense smells. Polymorphisms in many of these genes have been reported, implying a mechanism for interindividual variation in olfactory responses [Gene 2000; 260:87]-and perhaps to diseases triggered by olfactory stimuli.

Conclusions
IEI is a complex disease involving gene-environment interactions [Environ Health Perspect 2000; 108:1219]. Perhaps one place to begin, in dissecting this complex disease, would be to study nonallergic VMR because it can be more precisely defined. Would polymorphisms, in particular functional OR genes, be responsible for nonallergic VMR? Could nonallergic VMR be a sufficient phenotypic end-point such that it could be examined in a phenotype-genotype association study involving a candidate-gene approach, a candidate-gene-region approach, or a total genome scan?

It seems tempting to postulate that nonallergic VMR might be a sufficiently quantitative trait that it can be used first in attempting to dissect the very complex disease syndromes associated with IEI, SBS, FIS and GWI. Anyway, this is the approach that is being taken by three University of Cincinnati CEG researchers-Jonathan Bernstein, Dan Nebert, and Li (Felix) Jin. Given the exploding advances in our knowledge about the human genome, it seems that the time to tackle this complicated (and very common) environmental disease is now.

--Contributed by Dan Nebert, with help from Steve Leeder, and Jonathan Bernstein.

Courtesy of Interface: Genes and the Environment - published by the University of Cincinnati Center for Environmental Genetics

For more information - see also Multiple Chemical Sensitivity Syndrome (American Family Physician: September 1, 1998) , by Michael K. Magill, M.D., and Anthony Suruda, M.D., M.P.H., University of Utah School of Medicine, Salt Lake City, Utah

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