Multiple Chemical Sensitivity - The End of Controversy
chemical sensitivity (MCS), where people report being exquisitely
sensitive to a wide range of organic chemicals, is almost always
described as being "controversial." The main source of this supposed
controversy is that there has been no plausible physiological mechanism
for MCS and consequently, it was difficult to interpret the puzzling
reported features of this condition. As discussed below, this is no
longer true and consequently the main source of such controversy has
been laid to rest. There still are important issues such as how it
should be diagnosed and treated and these may also be allayed by further
studies of the mechanism discussed below.
The descriptions of MCS made by a several different research groups are
remarkably consistent. MCS sufferers report being hypersensitive to a
wide variety of hydrophobic organic solvents, including gasoline vapor,
perfume, diesel or jet engine exhaust, new or remodeled buildings where
building materials or carpeting has outgassed various solvents, vapors
associated with copy machines, many solvents used in industrial
settings, cleaning materials and cigarette and other smoke. Each of
these is known to have volatile hydrophobic organic compounds as a
prominent part of its composition. The symptoms of MCS sufferers report
having on such solvent exposure include multiorgan pain typically
including headache, muscle pain and joint pain, dizziness, cognitive
dysfunction including confusion, lack of memory, and lack of
concentration. These symptoms are often accompanied by some of a wide
range of more variable symptoms. The major symptoms reported on chemical
exposure in MCS are strikingly similar to the chronic symptoms in
chronic fatigue syndrome (CFS) and may be explained by mechanisms
previously proposed for the CFS symptoms (1). Perhaps the best source of
information on the properties and science of MCS is the Ashford and
Miller book (2). Many individual accounts of MCS victims have been
presented in an interesting book edited by Johnson (3). Most MCS
sufferers trace their sensitivity to chemicals to a chemical exposure at
a particular time in their life, often a single, high level exposure to
organic solvents or to certain pesticides, notably organophosphates or
carbamates. Some MCS cases are traced to a time period where the person
lived or worked in a particular new or newly remodeled building ("sick
building syndrome") where the outgassing of the organic solvents may
have had a role in inducing MCS. One of the most interesting examples of
MCS/sick building syndrome occured about 15 years ago when the U. S.
Environmental Protection Agency remodeled its headquarters and some 200
of its employees became chemically sensitive. The obvious interpretation
of this pattern of incidence of MCS is that pesticide or high level or
repeated organic solvent exposure induces cases of MCS. This
interpretation has been challenged by MCS skeptics but they have, in my
judgement, no plausible alternative explanation.
MCS in the U. S. appears to be surprisingly common. Epidemiologists have
studied how commonly MCS occurs in the U. S. and roughly 9 to 16 %
having more modest sensitivity. Thus we are talking about perhaps 10
million severe MCS sufferers and perhaps 25 to 45 million people with
more modest sensitivity. From these numbers, it appears that MCS is the
most common of what are described as "unexplained illnesses" in the U.
S. Those suffering from severe MCS often have their lives disrupted by
their illness. They often have to move to a different location, often
undergoing several moves before finding an tolerable environment. They
may have to leave their place of employment, so many are unemployed.
Going out in public may expose them to perfumes that make them ill. They
often report sensitivity to cleaning agents used in motels or other
commercial locations. Flying is difficult due to jet fumes, cleaning
materials, pesticide use and perfumes.
The exquisite sensitivity of many MCS people is most clearly seen
through their reported sensitivity to perfumes. MCS people report
becoming ill when a person wearing perfumes walks by or when they are
seated several seats away from someone wearing perfume. Clearly the
perfume wearer is exposed to a much higher dose than is the MCS person
and yet the perfume wearer reports no obvious illness. This strongly
suggests that MCS people must be at least 100 times more sensitive than
are normal individuals and perhaps a 1000 or more times more sensitive.
Thus a plausible physiological model of MCS must be able to explain each
of the following: How can MCS people be 100 to 1000 times more sensitive
to hydrophobic organic solvents than normal people? How can such
sensitivity be induced by previous exposure to pesticides or organic
solvents? Why is MCS chronic, with sensitivity typically lasting for
life? How can the diverse symptoms of MCS be explained? Each of these
questions is answered by the model discussed below.
Elevated Nitric Oxide/Peroxynitrite/NMDA Model of MCS:
My own interest in MCS stems from the reported overlaps among MCS and
chronic fatigue syndrome (CFS), fibromyalgia (FM) and posttraumatic
stress disorder (PTSD). These have overlapping symptoms, many people are
diagnosed as having more than one of these and cases of each of these
are reported to be preceded by and presumably induced by a short term
stressor such as infection in CFS and chemical exposure in MCS. The
overlaps among these have led others to suggest that they may share a
common causal (etiologic) mechanism. Having proposed that elevated
levels of nitric oxide and its oxidant product, peroxynitrite are
central to the cause of CFS, it was obvious to raise the question of
whether these might be involved in MCS. We proposed such a role in a
paper published in the Annals of the New York Academy of Sciences (4)
and in a subsequent paper, I list 10 different types of experimental
observations that provide support for the view that elevated levels of
these two compounds have an important role in MCS (5). These 10
observations are listed in the table below (from ref. 5).
Types of Evidence Implicating Nitric Oxide/Peroxynitrite in MCS
Several organic solvents thought to be able to induce MCS,
formaldehyde, benzene, carbon tetrachloride and certain
organochlorine pesticides all induce increases in nitric oxide
sequence of action of organophosphate and carbamate insecticides is
suggested, whereby they may induce MCS by inactivating
acetylcholinesterase and thus produce increased stimulation of
muscarinic receptors which are known to produce increases in nitric
Evidence for induction of inflammatory cytokines by organic
solvents, which induce the inducible nitric oxide synthase (iNOS).
Elevated cytokines are an integral part of a proposed feedback
mechanism of the elevated nitric oxide/peroxynitrite theory.
Neopterin, a marker of the induction of the iNOS, is reported to be
elevated in MCS.
Increased oxidative stress has been reported in MCS and also
antioxidant therapy may produce improvements in symptoms, as
expected if the levels of the oxidant peroxynitrite are elevated.
a series of studies of a mouse model of MCS, involving partial
kindling and kindling, both excessive NMDA activity and excessive
nitric oxide synthesis were convincingly shown to be required to
produce the characteristic biological response.
symptoms exacerbated on chemical exposure are very similar to the
chronic symptoms of CFS (1) and these may be explained by several
known properties of nitric oxide, peroxynitrite and inflammatory
cytokines, each of which have a role in the proposed mechanism.
These conditions (CFS, MCS, FM and PTSD) are often treated through
intramuscular injections of vitamin B-12 and B-12 in the form of
hydroxocobalamin is a potent nitric oxide scavenger, both in vitro
and in vivo.
Peroxynitrite is known to induce increased permeabilization of the
blood brain barrier and such increased permeabilization is reported
in a rat model of MCS.
types of evidence implicate excessive NMDA activity in MCS, an
activity known to increase nitric oxide and peroxynitrite levels.
although one can make a substantial case for this theory for an elevated
nitric oxide/peroxynitrite etiology (cause) in MCS, this does not
explain how the exquisite chemical sensitivity may be produced - which
has to be viewed as the most central puzzle of MCS. By what mechanism or
set of mechanisms can such exquisite sensitivity to organic chemicals be
Another theory of MCS was proposed earlier by Iris Bell (6,7) and
coworkers and adopted with modifications by numerous other research
groups. This was the neural sensitization theory of MCS. What this
theory says is that the synapses in the brain, the connections between
nerve cells by which one nerve cell stimulates (or in some cases
inhibits) another become hypersensitive in MCS. This neural
sensitization theory is supported by observations that many of the
symptoms of MCS relate directly to brain function and that a number of
studies have shown that scans of the brains of MCS people, performed by
techniques known as PET scanning or SPECT scanning are abnormal. There
is also evidence that electrical activity in the brains of MCS people,
measured by EEG's, is also abnormal. Neural sensitization is produced by
a mechanism known as long term potentiation, a mechanism that has a role
in learning and memory. Long term potentiation produces neural
sensitization but in the normal nervous system, it does so very
selectively - increasing the sensitivity of certain selected synapses.
In MCS, it may be suggested, that a widespread sensitization may be
involved that is somehow triggered by chemical or pesticide exposure.
This leaves open the question as to why specifically hydrophobic organic
solvents or certain pesticides are involved and, most importantly, how
these can lead to such exquisite chemical sensitivity as is seen in MCS.
So the neural sensitization theory is a promising one but it leaves
unanswered the central puzzles of MCS.
The question that I raised in my key paper (5), published in the
prestigious publication of the Federation of American Societies for
Experimental Biology, The FASEB Journal, is what happens if both of
these theories are correct? The answer is that you get a fusion theory
that, for the first time, answers all of the most puzzling questions
about MCS. The fusion theory is supported by all of the observations
supporting the nitric oxide/peroxynitrite theory, all of the
observations supporting the neural sensitization theory plus several
additional observations that relate specifically to the fusion.
How can we understand this fusion theory? When you look at the two
precursor theories together, you immediately see ways in which they
interact with each other. Long term potentiation, the mechanism behind
neural sensitization, involves certain receptors at the synapses of
nerve cells called NMDA receptors. These are receptors that are
stimulated by glutamate and aspartate and when these receptors are
stimulated to be active, they produce in turn, increases in nitric oxide
and its oxidant product, peroxynitrite. So immediately you can see a
possible interaction between the two theories. Furthermore, nitric oxide
can act in long term potentiation, serving as what is known as a
retrograde messenger, diffusing from the cell containing the NMDA
receptors (the post-synaptic cell) to the cell that can stimulate it
(the pre-synaptic cell), making the pre-synaptic cell more active in
releasing neurotransmitter (glutamate and aspartate). In this way, NMDA
stimulation increases the activity to the pre-synaptic cell to stimulate
more NMDA activity. Thus we have the potential for a vicious cycle in
the brain, with too much NMDA activity leading to too much nitric oxide
leading to too much NMDA activity etc (see Figure 1, below). There is
also a mechanism by which peroxynitrite may act to exacerbate this
potential vicious cycle. Peroxynitrite is known to act to deplete energy
(ATP) pools in cells by two different mechanisms and it is known that
when cells containing NMDA receptors are energy depleted, the receptors
become hypersensitive to stimulation. Consequently nitric oxide may act
to increase NMDA stimulation and peroxnitrite may act to increase the
sensitivity to such stimulation. With both nitric oxide and
peroxynitrite levels increased by NMDA receptor activity, an overall
increase in these activities may lead to a major, sustained increase in
neural sensitivity and activity. The only thing left is to explain how
hydrophobic organic chemicals or pesticides can stimulate this whole
response. I'll discuss that below.
also proposed two additional, accessory mechanisms in MCS. One is that
peroxynitrite is known to act to break down the blood brain barrier -
the barrier that minimizes the access of chemicals to the brain. By
breaking down this barrier, more chemicals may accumulate in the brain,
thus producing more chemical sensitivity. It has been reported that an
animal model of MCS shows substantial breakdown of the blood brain
barrier. Nitric oxide is also known to inhibit the activity of certain
enzymes that degrade hydrophobic organic solvents, known as cytochrome
P-450's. By inhibiting these enzymes, nitric oxide will cause more
accumulation of these compounds because they are broken down much more
slowly. Consequently there are four distinct mechanisms proposed to
directly lead to chemical sensitivity:
Nitric oxide acting as a retrograde messenger, increasing release of
neurotransmitters (glutamate and aspartate) that stimulate the NMDA
Peroxynitrite depleted energy (ATP) pools, thus making the NMDA
receptors more sensitive to stimulation.
Peroxynitrite acts to break down the blood brain barrier, thus
allowing greater chemical access to the brain.
Nitric oxide inhibits cytochrome P-450 activity, thus slowing
degradation of hydrophobic organic chemicals.
proposed to be the combination of all four of these mechanisms, each
acting at a different level and therefore expected to act
synergistically with each other, that produces the exquisite chemical
sensitivity reported in MCS.
So how do organophosphate pesticides or hydrophobic organic chemicals
initiate this sensitivity and trigger symptoms of MCS? Both are proposed
to stimulate the potential vicious cycle involving too much nitric
oxide/peroxynitrite and too much NMDA activity (figure 1).
Organophosphates and carbamate pesticides, often reported to be involved
in inducing cases of MCS, are both acetylcholinesterase inhibitors,
acting to increase acetylcholine levels which stimulate muscarinic
receptors in the brain. It is known that stimulating of certain
muscarinic receptors produces increases in nitric oxide! Thus these two
pesticides should be able to act to stimulate the proposed nitric oxide/peroxynitrite/NMDA
vicious cycle mechanism. Hydrophobic organic solvents are proposed to
act by three possible mechanisms, two producing increases in nitric
oxide and one producing energy depletion and therefore NMDA stimulation.
These three mechanisms are documented in the scientific literature but
none have been tested yet for involvement in MCS. So both the
pesticides, organophosphates and carbamates, and the hydrophobic organic
solvents have known mechanisms which should be able to initiate the
proposed vicious cycle centered on excessive NMDA/nitric oxide/peroxynitrite
and thus initiate MCS. Once MCS has been initiated, by simulating this
same cycle, they are predicted to produce the symptoms of chemical
Explanations for the most puzzling features reported for MCS:
If this theory is correct, it provides answers to all of the most
difficult questions about MCS.
do pesticides (organophosphates and carbamates) and hydrophobic
organic solvents act to induce cases of MCS? Each acts to initiate a
vicious cycle mechanism involving NMDA receptors, nitric oxide and
peroxynitrite in the brain, with organophosphates/carbamates acting
via one known mechanism and hydrophobic organic solvents acting by
do hydrophobic organic solvents act to trigger the symptoms of MCS?
They act by the same mechanism proposed for such solvents in #1
is MCS chronic? Presumably for two reasons: Because of the several
positive feedback loops that maintain the elevated nitric oxide/peroxynitrite/NMDA
activity and also because changes in the synapses of the brain may
be long term.
can MCS victims be so exquisitely sensitive to organic solvents?
Because there are four different mechanisms by which nitric oxide or
peroxynitrite act to produce the response, with the combination of
all four acting synergistically to produce such exquisite
sensitivity. The mechanisms of all four are well documented although
their relevance to MCS can be questioned.
are the symptoms of MCS generated? Possibly by the same mechanisms
proposed earlier for the symptoms of chronic fatigue syndrome.
can we explain the overlaps of MCS with chronic fatigue syndrome,
fibromyalgia, posttraumatic stress disorder and Gulf War syndrome?
All of these are proposed to involve excessive nitric oxide and
peroxynitrite and all may also involved excessive NMDA activity.
1. .Pall M. L. (2000) Elevated peroxynitrite as the cause of chronic
fatigue syndrome: other inducers and mechanisms of symptom generation. J
Chronic Fatigue Syndr 7(4),45-58.
2. Ashford N.A., Miller C. (1998) Chemical Exposures: Low Levels and
High Stakes, John Wiley and Sons, Inc., New York.
3. Johnson A., ed. (2000) Casualties of Progress. MCS Information
Exchange, Brunswick ME.
4. Pall M. L., Satterlee J. D. (2001) Elevated nitric oxide/peroxynitrite
mechanism for the common etiology of multiple chemical sensitivity,
chronic fatigue syndrome and posttraumatic stress disorder. Ann NY Acad
5. Pall M. L. (2002) NMDA sensitization and stimulation by peroxynitrite,
nitric oxide and organic solvents as the mechanism of chemical
sensitivity in multiple chemical sensitivity. FASEB J 16,1407-1417.
6. .Bell I. R., Miller C. S., Schwartz G. E. (1992) An olfactory-limbic
model of multiple chemical sensitivity syndrome: possible relationships
to kindling and affective spectrum disorders. Biol Psychiatry
7. Bell I. R., Baldwin C. M., Fernandez M., Schwartz G. E. (1999) Neural
sensitization model for multiple chemical sensitivity: overview of
theory and empirical evidence. Toxicol Ind Health 15,295-304.