Multiple Chemical Sensitivity
Because of the pervasive
use of toxins in our society, a new disease has emerged known as Multiple
Chemical Sensitivity (MCS). Environmental physician Grace Ziem has proposed
a working definition: "Multiple chemical sensitivity (MCS) is defined as
illness reactions associated with exposure to more than one chemical, at
significantly lower exposure levels than one would cause noticeable illness
in the general population, not mediated solely by known immune mechanisms,
often accompanied with unusual fatigue, involving symptoms in multiple organ
systems, and usually including symptoms of the central nervous system."
If you are a person who is severely
chemically sensitive, you are a person with serious problems in living.
If you have a job, you will probably not be able to give it up for financial
reasons; you may have to move; you may lose friends and family; you will
probably have less energy; for a while you will need more money; you may not
be able to go to stores and other public buildings; you may even become
completely homebound. In short, you will have to give up a great
deal---or experience the continued deterioration of your health as you go on
living as you have been.
As you give up these things, you will
probably begin feeling better. In time, you may feel fairly well.
You may begin feeling almost “cured,” though you will have to be careful
about chemical exposures the rest of your life
Many disabled people look to social
security disability benefits as their first hope. For people with
EI/MCS, however, obtaining such benefits has not been easy. Often it
has required legal action. In 1979 the U.S. Department of Health,
Education, and Welfare (now Health and Human Services) to provide social
security disability benefits to a woman named Marna Slocum. (She now
maintains a toxin-free rental apartment in Hawaii for recovering EI/MCS
patients who are able to travel. Renters are asked to use washable
luggage that they must wash in an outdoor wash machine before entering the
apartment, to rid it of possible contamination from the plane trip.)
In 1988 the Social Security Administration
(SSA) added a section on multiple chemical sensitivities to its disability
manual, thus giving official recognition to the illness and opening the way
for more of environmentally injured to obtain social security benefits.
While chemical exposure
affects all of us to one degree or another, people with MCS are severely
affected. People with chemical sensitivity often become ill from being in
the presence of only infinitesimal amounts of a chemical. To them, a faint
of gasoline fumes can cause devastating symptoms of fatigue. Unfortunately,
others around them who cannot smell the odors label them as hypochondriacs,
often noting, “If I can’t smell it you must be imagining it.” This is far
from the truth, and chemically sensitive people can take some comfort in the
fact that the health effects of low level chemical exposure are becoming
For example, Dr. Donald
Dudley, at the Washington Institute of Neurosciences in Seattle, found that
when patients were exposed to chemicals to which they reported sensitivity,
they showed significant changes in their visual and auditory evoked
potential readings – a measure of the ray at which nerves transmit messages
from the eyes and ears to the brain. Gary Schwartz, Ph.D., and his research
team at the University of Arizona showed that the brain registers exposure
to a chemical odor even though the nose does not sense its presence. Russell
Jaffe, M.D., of Reston, Virginia, has demonstrated that a variety of immune
reactions to chemicals occur in people with chronic illness.
Psychological and behavioral factors are known to play a
significant role in initiating or perpetuating symptoms in some
persons with these illnesses. In the field of pain research, the
interrelationship between physiologic and psychological factors
in symptom expression has been well studied. Using both established
and novel methodologies, studies have suggested that psychological
factors such as hyper vigilance and expectancy are playing a
relatively minor role in most individuals with Fibromyalgia and
that clear evidence exists of physiologic amplification of
Sometimes such persons
acquire MCS after an acute or traumatic experience to one or more toxic
substances. After that experience they become acutely "sensitized" to
very low levels of many chemicals, perhaps permanently. The former
head of the Chicago Art Institute, Tony Jones, is an example of this type of
"sensitizing." Once a sculptor creating large pieces of outdoor art from
synthetic resin and fiberglass, Jones lost consciousness one day from
breathing the toxic resin fumes, even though he was fully geared up in a
double cartridge gas mask. As luck would have it, one of his students
who was sharing his studio discovered him to give him necessary first-aid.
Now, extremely sensitive to all plastics, Jones has exchanged sculpting for
It is of note, though, that
existing data on this spectrum of illnesses would suggest that
there may be greater psychological contributions to
symptomology if an illness is defined in part by behavior
(e.g., avoidance of chemical exposures) rather than on the basis
of symptoms alone.
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.
Types of Evidence Implicating Nitric Oxide/Peroxynitrite in MCS
organic solvents thought to be able to induce MCS, formaldehyde, benzene,
carbon tetrachloride and certain organochlorine pesticides all induce
increases in nitric oxide levels.
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 oxide.
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
a marker of the induction of the iNOS, is reported to be elevated in MCS.
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.
- In 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.
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.
- 5 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 generated?
Another theory of MCS was proposed earlier by Iris Bell 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 was raised, 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.
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.
- How 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 another mechanism.
- How do
hydrophobic organic solvents act to trigger the symptoms of MCS? They act
by the same mechanism proposed for such solvents in #1 above.
- Why 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
- How 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
- How are
the symptoms of MCS generated? Possibly by the same mechanisms proposed
earlier for the symptoms of chronic fatigue syndrome.
- How 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,
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 Sci
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 32,218-242.
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.
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