Multiple Chemical Sensitivity, Part 1


Multiple Chemical Sensitivity:

Toxicological and Sensitivity Mechanisms


Martin L. Pall

Professor Emeritus of Biochemistry and Basic Medical Sciences, Washington State University and Research Director, The Tenth Paradigm Research Group

638 NE 41st Ave.

Portland, OR 97232-3312 USA






Cases of multiple chemical sensitivity (MCS) are reported to be initiated by seven classes of chemicals.  Each of the seven acts along a specific pathway, indirectly producing increases in NMDA activity in the mammalian body.  Members of each of these seven classes have their toxicant responses lowered by NMDA antagonists, showing that the NMDA response is important for the toxic actions of these chemicals. The role of these chemicals acting as toxicants, in initiating cases of MCS has been confirmed by genetic evidence showing that six genes that influence the metabolism of these chemicals, all influence susceptibility to MCS.  It is likely that chemicals act along these same pathways, leading to increased NMDA activity when they trigger sensitivity responses in MCS patients.


The chronic nature of MCS and also related multisystem illnesses is thought to be produced by a biochemical vicious cycle mechanism, the NO/ONOO- cycle, which is initiated by various stressors that increase nitric oxide and peroxynitrite levels (with some but not others acting via NMDA stimulation).  The NO/ONOO- cycle is based on well documented individual mechanisms.  The interaction of this cycle with previously documented MCS mechanisms, notably neural sensitization and neurogenic inflammation, explains many of the previously unexplained properties of MCS.  This overall mechanism is also supported by physiological correlates found in MCS and related multisystem illnesses, objectively measurable responses to low level chemical exposure in MCS patients, many studies of apparent animal models of MCS and also evidence from therapeutic trials of MCS-related illnesses.  Some have argued that MCS is a psychogenic illness, but this view is completely inconsistent with this diverse data on MCS and related illnesses and the literature claiming psychogenesis of MCS is deeply flawed.  In addition, two rare predictions that can be used to test psychogenesis both lead to rejection of the psychogenic hypothesis.  While the NO/ONOO- cycle mechanism for MCS is supported by many different observations, there are also multiple areas where further study is needed.


Key Words:  Peroxynitrite; oxidative stress; excitotoxicity; mitochondrial dysfunction; long term potentiation; chronic fatigue syndrome/myalgic encephalomyelitis; fibromyalgia




Multiple chemical sensitivity (1) (MCS), also known as chemical intolerance, multiple chemical sensitivities, chemical sensitivity, or toxicant induced loss of tolerance (TILT) is an illness or disease where previous chemical exposure appears to initiate the wide ranging sensitivities characteristic of MCS.  The inference that cases of MCS are initiated by previous chemical exposure is implied by the TILT name (2). Case initiation by such previous chemical exposure was also a requirement for a person to fit the Cullen case definition (3) for MCS.  The role of previous chemical exposures is widely discussed in the influential Ashford and Miller book which reviewed MCS (4) and at least 50 studies have shown that such previous chemical exposure is characteristic of and appears to initiate most MCS cases (reviewed in 1,4-6).  Some have claimed that MCS is a psychogenic illness and have advocated the name idiopathic environmental intolerance (IEI).  This name argues, in essence, that chemical exposure is not involved in initiating such sensitivity and that we have no idea what the cause may be, that is that it is idiopathic.  Both of these contentions have been vigorously challenged (1).  This paper is primarily a separately written and much shorter version of reference 1 and the reader is referred to that study for a much more extensive documentation of many of the observations contained below.


What Types of Chemicals Initiate Cases of MCS and How Can They Act as Toxicants?


Perhaps the largest single challenge in understanding MCS is how can the diverse chemicals implicated in initiating cases of MCS and triggering sensitivity symptoms in those already sensitive act to produce a common response in the body?  The MCS skeptic, Ronald Gots has challenged MCS researchers, arguing that the diverse types of chemicals reportedly involved cannot possibly produce a common response (7).  Certainly in order to develop a compelling model for MCS, we need to meet this challenge (Fig. 1).


           Figure 1



Each of the arrows represents a mechanism whereby one element of the figure stimulates another.  The upside down T’s represent inhibitory mechanisms.  It can be seen that each of the four classes of compounds leads to increased NMDA activity via the pathways diagrammed above.  The specific mechanisms diagrammed in this figure are discussed in some detail in references 1 and 5.


The main classes of chemicals that initiate cases of MCS are the very large class of organic solvents and related compounds and three classes of pesticides (1,4,5,6,8).  The pesticides include the often reported classes of organophosphorus and carbamate pesticides (1,4,5,8), the organochlorine pesticides (1,4) and the pyrethroid pesticides (1,4).  These four classes of compounds can all produce a common response in the body, increasing the activity of the NMDA receptors (Fig. 1 and refs. 1,5). 


Other types of chemicals reported to initiate cases of MCS include mercury, hydrogen sulfide and carbon monoxide (reviewed in 1).  These three (with mercury acting through its product methylmercury) all produce increases in NMDA activity, as well (1).  Furthermore, there is data from animal models that members of all seven of these classes of chemicals can have their toxic responses greatly lowered by using NMDA antagonists (1).  This shows that not only do members of these classes of chemicals act to produce an increase in NMDA activity, but that the increase has a major role, probably the major role, in the toxic response to these chemicals.


So there is a compelling solution to what is arguably the largest single challenge in understanding the mechanism of MCS, namely that all seven classes of these chemicals act to produce a common response in the body, increased activity of the NMDA receptors.


There are six other types of evidence implicating elevated NMDA activity in MCS (1,5,9,10).  These include clinical observations that the NMDA antagonist dextromethorphan can substantially lower reactions of MCS cases to chemical exposure (1,9,10).  This specific observation suggests that in people who have become chemically sensitive, chemicals triggering such sensitivity reactions also act to increase NMDA activity.  In other words, both initiating chemicals and chemicals triggering sensitivity responses may well act along exactly the same pathways.  The sensitivity of MCS patients to monosodium glutamate (9,10), an NMDA agonist, also suggests a role of elevated sensitivity to agents acting via the NMDA receptors, in the chronic phase of MCS.


Is There Other Evidence that Initiating Chemicals Act as Toxicants in MCS?


We have, then, compelling evidence that chemicals act to initiate cases of MCS and that each class of such chemicals produces a common toxic response in the body, characterized by elevation of NMDA activity. 


Table 1.  Genetic Polymorphisms Influencing MCS Susceptibility



Function- chemical metabolism




Detoxification of organophosphorus toxicants including pesticides




Hydroxylation of hydrophobic compounds

May be expected to increase activity of strictly hydrophobic solvents on the TRPV1 receptor




May produce more or less activity, depending on substrate



Provides reduced glutathione for conjugation

Should increase detoxification and excretion



Glutathione conjugation

Should increase detoxification and excretion



Glucuronidation, leading to increased excretion


H=Haley et al, 1999 (11); M=McKeown-Eyssen et al, 2004 (12); S=Schnakenberg et al, 2007 (13); M&S= Müller and Schnakenberg, 2008 (14).


The role of chemicals acting as toxicants in MCS has been confirmed by a series of compelling studies showing that genes that help determine the metabolism of such chemicals influence susceptibility to MCS (reviewed in 1), see Table 1.


In these four studies (11-14), a total of six genes whose products have roles in the metabolism of organic solvents and related compounds, and in some cases the metabolism of pesticides, influence susceptiblity (Table 1).  The data showing that four of these genes, studied in the S and M&S papers (13,14) help determine susceptibility  and have very high levels of statistical significance, strongly arguing that these associations are not caused by a statistical fluke.  The data from the other two studies, implicating three genes, are statistically significant, as well (Table 1).  There is only one interpretation that is compatible with such a role for all six of these genes.  It is that chemicals act as toxicants in the initiation of MCS and that consequently, enzymes that influence the metabolism of these compounds, converting them into either less or more active compounds, determine how susceptible each individual is to being initiated with a case of MCS (1,4).  These are all apparent gene X environment interactions such that the role of specific polymorphic genes will be influenced by the chemical exposure of specific populations.  Consequently, we should not expect that all populations will show the same patterns of genetic susceptibility because they differ from one another in chemical exposure patterns.


Since the Nobel prize winning studies of Beadle and Tatum in the 1940’s it has been clear that genetics is THE most powerful approach towards determining biological mechanism.  It follows from the genetic studies summarized in Table 1, and the common action of apparent initiating chemicals producing a toxic response (via increased NMDA activity) that is otherwise implicated in MCS, that the role of chemicals acting as toxicants in MCS is undeniable.


MCS Is a Reaction to Chemicals, Not Odors


It should be clear from the above, that chemicals acting in MCS are not acting on the classic olfactory receptors (15,16), but rather are acting as toxicants.  This is opposite many published but undocumented claims that MCS is a response to odors.  There is additional evidence arguing against the view that MCS is a reaction to odors.  MCS sufferers who are acosmic, having no sense of smell, people who have intense nasal congestion and people whose nasal epithelia have been blocked off with nose clips can all be highly chemically sensitive (1,4).  This does not necessarily mean that MCS never impacts the olfactory system.  It simply  means that MCS is not primarily an olfactory response.  A recent study, confirmed this view, showing that the olfactory center in the brain in people with MCS was less sensitive to activation by chemical exposure than in normal controls, rather than being more sensitive (17).


What Causes the Chronic Nature of MCS ?


The initiation of cases of MCS via chemicals acting to increase excessive NMDA activity is important, and it raises two additional important questions:  Why is MCS chronic?  And how does this chronic illness generate the symptoms of MCS including the exquisite high level sensitivity to this group of chemicals?  Let’s consider the first question first.


Figure 2.  Updated version of NO/ONOO- cycle

Each arrow represents one or more mechanisms by which the variable at the foot of the arrow can stimulate the level of the variable at the head of the arrow.  It can be seen that these arrows form a series of loops that can potentially continue to stimulate each other.  An example of this would be that nitric oxide can increase peroxynitrite (abbreviated PRN) which can stimulate oxidative stress which can stimulate NF-kappa B which can increase the production of iNOS which can, in turn increase nitric oxide.  This loop alone constitutes a potential vicious cycle and there are a number of other loops, diagrammed in the figure that can collectively make up a much larger vicious cycle. You will note that the cycle not only includes the compounds nitric oxide, superoxide and peroxynitrite but a series of other elements, including the transcription factor NF-kappa B,  oxidative stress, inflammatory cytokines (in box, upper right), the three different forms of the enzymes that make nitric oxide (the nitric oxide synthases iNOS, nNOS and eNOS), and two types of neurological receptors, some of the TRP group of receptors and the NMDA receptors.  Central to the figure are the reciprocal interactions between peroxynitrite, abbreviated as PRN and tetrahydrobiopterin (BH4) depletion.  Also indicated is the ATP (energy) depletion produced by the impacts of peroxynitrite, superoxide and nitric oxide on mitochondrial function.

Increased NMDA activity is known to produce increased calcium influx into cells, leading to increased activity of two calcium-dependent nitric oxide synthases, nNOS and eNOS, which produce, in turn increased nitric oxide (1,18,19).  Nitric oxide reacts with superoxide to form peroxynitrite, a potent oxidant (1,18,19).  Peroxynitrite is thought to initiate a complex biochemical vicious cycle, known as the NO/ONOO- cycle (Fig. 2), which is responsible for the etiology of not only MCS, but also such related and comorbid diseases as chronic fatigue syndrome, fibromyalgia and post-traumatic stress disorder (1,5,20,21).  The cycle is named for the structures of nitric oxide (NO) and peroxynitrite (ONOO-) but is pronounced “no, oh no!” because this is the way sufferers feel when they are afflicted by these chronic diseases.  The latest version of the cycle is diagrammed in Fig.2 (1, 21).  It can be seen (Fig.2) that the NO/ONOO- cycle is actually an interacting series of cycles, and the combination of all of these cycles is thought to make the NO/ONOO- cycle difficult to down-regulate, thus producing challenges for therapy that aims at lowering the basic cause.


The basic concept here, is actually quite simple.  Initiating stressors act mainly through peroxynitrite, to initiate the cycle and once the cycle is initiated, IT IS the CAUSE of ILLNESS.  That is these diseases, which typically last for decades and often for life, are produced by the NO/ONOO- cycle, with the initiating stressor often being long gone.  While there are some chronic stressors involved in initiating these diseases, most are short-term stressors whose role is to initiate the cycle.


The various elements of the cycle are linked to each other by arrows, with each arrow representing one or more mechanisms by which one element of the cycle increases another.  Each of these mechanisms, and 30 are represented in Fig. 2 (1,5,21), are well-documented mechanisms, most of which have been demonstrated to have measurable roles in genuine pathophysiological conditions.  Thus there is nothing new in terms of individual mechanisms in the cycle, and the only new inferences seen here are a consequence of their various interactions seen in the NO/ONOO- cycle.


Initiating Stressors


A series of initiating stressors that are reported to initiate cases of MCS and also three other related multisystem illnesses are listed in Table 2.  These four illnesses, chronic fatigue syndrome/myalgic encephalomyelitis, MCS, fibromyalgia and post-traumatic stress disorder all share many symptoms in common, are commonly comorbid and all share a common pattern of case initiation, with cases initiated by several short term stressors which produce, then, subsequent chronic illness.  Many scientists have suggested that two, three or all four of these these may share a common etiology (1,5) and it is argued here and elsewhere (1,5,20,21), that what we call the NO/ONOO- cycle is the etiologic mechanism.



Table 2The Stressors Implicated in the Literature in the initiation of these illnesses.

  Illness                               Stressors Implicated in Initiation of Illness

Chronic fatigue syndrome/myalgic encephalomyelitis


Viral infection, bacterial infection, organophosphorus pesticide exposure, carbon monoxide exposure, ciguatoxin poisoning, physical trauma, severe psychological stress, toxoplasmosis (protozoan) infection, ionizing radiation exposure

Multiple chemical sensitivity

Volatile organic solvent exposure, organophosphorus/carbamate pesticide exposure, organochlorine pesticide exposure, pyrethroid exposure; hydrogen sulfide; carbon monoxide; mercury


Physical trauma (particularly head and neck trauma), viral infection, bacterial infection, severe psychological stress, pre-existing autoimmune disease

Post-traumatic stress disorder

Severe psychological stress, physical (head) trauma

The stressors indicated in bold are the ones most commonly implicated for that specific disease/illness.  It should be noted that the majority of such stressors are implicated in the initiation of more than one illness. 



It has already been noted that all of the chemicals implicated in MCS initiation act to increase nitric oxide levels via increased NMDA activity.  However, several initiators for CFS/ME and fibromyalgia do not act to increase NMDA activity.  Specifically the infections which are commonly involved in initiating cases of CFS/ME and also fibromyalgia act via induction of the inducible nitric oxide synthase (iNOS) (5).   Ionizing radiation which also initiates cases of CFS/ME-like illness also act via iNOS induction (20).  It follows that increased NMDA activity is not apparently required to initiate the NO/ONOO- cycle but nitric oxide and especially its product peroxynitrite increases may be required.


This pattern suggests that there may be a specific requirement for increased NMDA activity for MCS initiation but not for CFS/ME or fibromyalgia initiation.  We will return to why this may be the case below.


Five Principles


There are five principles underlying the NO/ONOO- cycle as an explanatory model:


Short-term stressors that initiate cases of multisystem illnesses act by raising nitric oxide and/or other cycle elements.


Initiation is converted into a chronic illness through the action of vicious cycle mechanisms, through which chronic elevation of peroxynitrite and other cycle elements is produced and maintained.  This principle predicts that the various elements of the NO/ONOO- cycle will be elevated in the chronic phase of illness.


Symptoms and signs of these illnesses are generated by elevated levels of nitric oxide and/or other important consequences of the proposed mechanism, i.e. elevated levels of peroxynitrite or inflammatory cytokines, oxidative stress, elevated NMDA and TRPV1 receptor activity, ATP and BH4 depletion and others.


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Multiple Chemical Sensitivity is “a diagnostic label for people who suffer multi-system illnesses as a result of contact with, or proximity to, a variety of airborne agents and other substances." (EPA)


General Information


Multiple Chemical Sensitivities (MCS) was identified in a 1989 multidisciplinary survey of 89 clinicians and researchers, and modified in 1999.  Top consensus criteria (Multiple chemical sensitivity: a 1999 consensus, 1999) for MCS define the condition by these criteria:


A chronic condition.

Symptoms recur reproducibly.

Symptoms recur in response to low levels of chemical exposure.

Symptoms occur when exposed to multiple unrelated chemicals.

Symptoms improve or resolve when trigger chemicals are removed.

Multiple organ systems are affected.


Toxic substances that people with MCS become disabled by include any quantity of exposures to pesticides, secondhand smoke, alcohol, fresh paint, scented products and perfumes, candles, fragrances, food preservatives, flavor enhancers, aerosols, tap water, cosmetics, personal care products, new carpets, petroleum products, formaldehyde, outdoor pollutants, newspaper ink, cleaning compounds, printing and office products, and other synthetically derived chemicals.  Some also become ill from natural products that are highly concentrated such as natural orange cleaners due to high volatile organic compound and pesticide concentration.  Symptoms can range from minor annoyances (headache, runny nose) to life-threatening reactions (seizures, anaphalaxis).