Multiple Chemical Sensitivity - The End of Controversy

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Multiple Chemical Sensitivity - The End of Controversy

 

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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 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).

 

Table 1

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 levels.

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.

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.

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.

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.

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.

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 (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.

 

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.

 

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 term.

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.

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.

 

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., 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 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., 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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