Multiple Chemical Sensitivity - The End of Controversy? (fwd)

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Multiple Chemical Sensitivity - The End of Controversy? Chronic Fatigue

Syndrome & Fibromyalgia News

ImmuneSupport.com

03-05-2003

By L. Pall

Professor of Biochemistry and Basic Medical Sciences

Washington State University

Source: http://molecular.biosciences.wsu.edu/Faculty/pall.html

Multiple 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 book (2).

Many individual accounts of MCS victims have been presented in an

interesting book edited by (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

occurred 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 judgment, 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 ls 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: 1.

Several organic solvents thought to be able to induce MCS, formaldehyde,

benzene, carbon tetrachloride and certain organochlorine pesticides all

induce increases in nitric oxide levels.

2. A 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.

3. 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.

4. Neopterin, a marker of the induction of the iNOS, is reported to be

elevated in MCS.

5. 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.

6. 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.

7. The 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.

8. 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.

9. Peroxynitrite is known to induce increased permeabilization of the

blood brain barrier and such increased permeabilization is reported in a

rat model of MCS.

10. 5 types of evidence implicate excessive NMDA activity in MCS, an

activity known to increase nitric oxide and peroxynitrite levels.

However, 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 (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.

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 peroxynitrite 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.

I have 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

receptors.

• 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.

It is 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

sensitivity.

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.

1. 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.

2. 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.

3. 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 term.

4. 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 questioned.

5. How are the symptoms of MCS generated? Possibly by the same mechanisms

proposed earlier for the symptoms of chronic fatigue syndrome.

6. 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.

References:

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., C. (1998) Chemical Exposures: Low Levels and High

Stakes, Wiley and Sons, Inc., New York.

3. 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

Sci 933,323-329.

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., 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.

For more information please visit

http://molecular.biosciences.wsu.edu/Faculty/pall.html. Reprinted with

author's permission.