Multiple Chemical Sensitivity (MCS) - Martin Pall

[Guest guest]

Multiple Chemical Sensitivity (MCS)

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_mcs.htm)

Martin L. Pall, Professor

_http://molecular.biosciences.wsu.edu/Faculty/pall/pall_mcs.htm_

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_mcs.htm)

 

_Main web page_

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_main.htm)

_Chronic fatigue syndrome web page_

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_cfs.htm)

_Fibromyalgia web page_

(http://molecular.biosciences.wsu.edu/Faculty/pall/pall_fibro.htm)

MCS is the most complex of these illnesses and has been the most challenging

of them to explain. Among its most puzzling features is the following:

Cases are reported to be initiated by four distinct classes of organic

chemicals: Volatile organic solvents and related compounds and three

classes of pesticides. The pesticides include organophosphorus/carbamate

pesticides, the organochlorine pesticides and the pyrethroid pesticides.

Previous

exposure to one or more of these classes of chemicals initiates high level

sensitivity to all of these classes of chemicals. Clearly one of the challenges

is

to explain how one can have a common response to these diverse classes of

chemicals. My solution to this puzzle is diagrammed in Figure 1 below:

 

The organophosphorus/carbamate pesticides and the organic solvents are known

to be able to increase NMDA activity, apparently through the pathways

diagrammed above (1-6). They have also been shown to increase nitric oxide

levels

(5,7). The organochlorine and pyrethroid pesticides are known to be able to

increase NMDA activity (8-11), as well and NMDA stimulation is known to be able

to produce increases in nitric oxide and its oxidant product, peroxynitrite

(2,3). Thus the ability of organochlorine and pyrethroid pesticides to

increase nitric oxide and peroxynitrite levels is inferred from these pathways.

It

can be seen, then, from Figure 1 that each of these classes of chemicals can

produce a common response, involving increased NMDA activity and nitric oxide

levels. The nitric oxide response predicts that this mode of action is

consistent with a NO/ONOO- cycle mechanism.

Certain additional types of chemicals may also act via this common

mechanism, including certain oxidants such as chlorine gas and certain mold

toxins,

both of which may act via vanilloid receptor stimulation to increase NMDA

activity (5).

Several of the MCS skeptics have argued that there cannot possibly be a mode

of action by which such diverse chemicals can produce a common biological

response. The evidence summarized in Figure 1 shows that they are wrong about

this.

Neural Sensitization and the NO/ONOO- Cycle

While the NO/ONOO- cycle explains why these illnesses are chronic and how

they may be initiated by various short-term stressors that increase nitric

oxide levels, it does not, by itself, provide an explanation for the exquisite

chemical sensitivity found in MCS patients. Thus the NO/ONOO- cycle described

on my main web page, may be part of the explanation of MCS, but only part. The

chemical sensitivity has been estimated in some patients to be on the order

of 1000-fold higher than that found in normals clearly requires an

explanation. Indeed, this high level sensitivity to many chemicals can be argued

to be

the most puzzling feature of MCS and any explanation for its etiology must

include an explanation for this feature.

A key inference initially made by Dr. Iris Bell (12-16) and supported by

Rossi (17) and others (18) is that chemical sensitivity in the brain involves

neural sensitization. Neural sensitization if the process by which the synapses

in the brain, the connections between neurons, become more sensitive to

stimulation. Neural sensization increases the stimulation of one neuron (the

post-synaptic neuron) by another (the pre-synaptic neuron). Neural

sensitization

is a process that is stimulated in a highly controlled fashion during the

process of learning and memory. The question raised by this view is how can

chemical exposure lead to a massive stimulation of neural sensitization, rather

than the limited and precisely controlled process involved in learning and

memory?

The most important process involved in neural sensitization is thought to be

a process known as long term potentiation (LTP), a process by which previous

neuronal activity may lead to increased neural sensitization. LTP is a very

complex process, involving on the order of 100 different variables, two of

the most important of which are the NMDA receptors and nitric oxide. NMDA

activity of the post-synaptic neuron has a key role, leading to increased nitric

oxide synthesis also in the post-synaptic cell. The nitric oxide can diffuse

back to the pre-synaptic cell, changing its properties and increasing its

activity in releasing the neural transmitter, L-glutamate. The glutamate

release,

will act to stimulate the NMDA receptors again the post-synaptic cell

(discussed in reference 2).

The pattern of control here is diagrammed in Figure 2 below:

* figure coming soon *

The pattern shown in Fig. 2 shows a potential vicious cycle where increased

NMDA activity leads to increased nitric oxide, acting as a retrograde

messenger to stimulate further NMDA activity. This cycle is part of the

NO/ONOO-

cycle mechanism and may be expected, therefore, to have a key role in

up-regulating cycle activity. There are other important actions diagrammed in

Fig. 2,

based on the ability of increased peroxynitrite activity to lower energy

metabolism and therefore deplete ATP levels. The ATP depletion can increase NMDA

activity in two ways: ATP depletion will cause the NMDA receptors in cells to

be more sensitive to stimulation (2,6). Furthermore, because the neural

transmitter glutamate is lowered by being transported into cells (mainly glial

cells), and because such transport is an energy-dependent process, depletion of

energy will also lead to the prolonged presence of glutamate such that it can

further stimulate NMDA receptors (6).

It follows that NO/ONOO- cycle biochemistry will be expected to stimulate

neural sensitization via three processes, one involving nitric oxide

(retrograde messenger activity) and two involving peroxynitrite and consequent

energy

depletion.

There are three additional mechanisms that are expected to be involved, all

increasing the action of chemicals in stimulating these processes. These are

as follows:

It is known that peroxynitrite can lead to a permeabilization (or partial

breakdown) of the blood brain barrier, the barrier that helps prevent the

access of many types of chemicals into the brain. Thus peroxynitrite will act

to

increase access of such chemicals to the brain, increasing their effect on the

brain. Dr. Bodo Kuklinski has reported such blood brain barrier in MCS

patients (19) and Dr. Abou-Donia (20) has also reported such breakdown in

animal

models of MCS, providing support for this mechanism in MCS.

Nitric oxide inhibits the metabolism of chemicals via enzymes known as

cytochrome P450’s, the main enzymes involving in the initial detoxification

of

many chemicals. Thus nitric oxide inhibition of cytochrome P450 activity will

be

expected to produce increased sensitivity to those chemicals (2,6).

The vanilloid receptors are the receptors thought to be involved in the

action of volatile organic solvents and some other chemicals in MCS (5).

Vanilloid receptor activity is reported to be increased by oxidants and

specifically

by superoxide and consequently these NO/ONOO- cycle components are expected

to produce increased chemical sensitivity via this pathway.

It follows that there are six distinct mechanisms each of which is expected

to increase neural stimulation in response to chemical exposures, with each

acting in distinct ways. These will be expected to act synergistically with

each other and it is reasonable, therefore that a combination of such

mechanisms may well lead to the circa 1000-fold increase in sensitivity reported

in

MCS patients.

Figure 2 also shows (lower section) how organophosphorus pesticides and

other toxicants can stimulate the entire cycle shown in the figure. Similarly,

other chemicals (solvents and two other classes of pesticides) should be able

to stimulate this same cycle by stimulating both NMDA activity and increasing

nitric oxide and peroxynitrite levels, as suggested from Fig. 1.

Sensitivity in Peripheral Tissues

Meggs and others have described sensitivity to essentially these same

diverse groups of chemicals in peripheral tissues (21-25). These include

sensitivity in the lungs, upper respiratory tract, skin and gastro-intestinal

tract

(21-25). The lung sensitivity, often called RADS for reactive airways

dysfunction syndrome can be initiated by chemical exposure which produces, in

turn

cases of asthma or an asthma-like disease. Asthmatics are not only sensitive to

antigens but also to organic chemicals, to cold air and to excessive exercise.

Clearly the chemically initiated chemical sensitivity in these peripheral

organs shows many similarities to the central (brain) sensitivity symptoms

described above, suggesting similarities in mechanism. While some parts of the

apparent mechanism for central sensitivity, breakdown of the blood brain

barrier and possibly retrograde messenger function for nitric oxide may not be

expected to occur in these peripheral tissues, the other mechanisms discussed

above may be expected to occur peripherally as well as centrally. Other

mechanisms may contribute to these peripheral sensitivities, including

neurogenic

inflammation (21-44) and mast cell activation (6).

In these peripheral sensitivities, the sensitivity mechanisms must be

determined by local changes in each impacted tissue, such that affected

individuals

may show sensitivity in some tissue regions but not in others. Thus the

local nature of the NO/ONOO- cycle is needed to explain the variations of MCS

symptoms from one individual to another, just as it is to explain the

variability of the other multisystem illnesses.

Puzzles about MCS

There are 40 distinct observations that provide experimental support for one

or more of the components of the MCS model outlined here (1-6). Each of

these is potentially important and certainly the entire pattern of evidence is

substantial. But what is more important as a test of any new disease paradigm,

is how well it explains each of the puzzling observations about the disease.

I will finish this web page, then, as I started by discussing the various

puzzles that have made MCS such a challenging illness to understand. It is

these many puzzles about MCS that have made it possible for some to continue to

argue that it cannot have a physiological explanation despite clear and

compelling physiological and genetic evidence to the contrary. We have needed

plausible explanations for each of these puzzles and fortunately, the fusion of

the NO/ONOO- cycle mechanism with neural sensitization, pesticide action

mechanisms, neurogenic inflammation and vanilloid receptor mechanisms have

provided

just that.

In Chapter 7 of my book (6), the chapter on MCS, I list 11 challenging

puzzles about MCS as follows:

* How can so many diverse chemicals initiate a common sensitivity

mechanism and trigger sensitivity responses? Each of them acts to stimulate a

pathway that leads to NMDA stimulation and increases in nitric oxide and

peroxynitrite.

* Why is MCS chronic? The NO/ONOO- cycle makes it chronic, as do the

long-term changes in the synapses in the brain that are part of the chemical

sensitivity mechanism.

* How can MCS sufferers be so exquisitely sensitive to chemicals, on

the order of a thousand times more sensitive than normals? Six distinct

mechanisms acting synergistically with each other, can produce this high-level

sensitivity.

* How can diverse volatile organic solvents initiate and trigger

sensitivity responses? They appear to act by stimulating the vanilloid receptor

to

increase NMDA activity, nitric oxide and peroxynitrite levels.

* Why are the symptoms of MCS patients so diverse? Because of the

local nature of the NO/ONOO- cycle, different tissues may be impacted in

different individuals.

* Why is MCS comorbid with CFS and FM and why is it part of Gulf War

syndrome? These are all NO/ONOO- cycle diseases and the common etiology

produces the comorbidity.

* How can MCS patients show desensitization/masking in response to

repeated or chronic low level chemical exposure? We proposed (5) that

desensitization/masking which has been reported to occur with organic solvents

and

similar chemicals is caused by the properties of the vanilloid receptor, such

that exposure to many but not all vanilloid agonists, leads to lowered

vanilloid

receptor activity.

* How can molds in some “sick building syndrome†situations produce

MCS? Mold toxins may also act by stimulating the vanilloid receptor (5).

* Why is neurogenic inflammation found in peripheral chemically

sensitive tissues? Because neurogenic inflammation can be stimulated by both

vanilloid activity and nitric oxide (3), both NO/ONOO- cycle elements.

* How can mast cell activation be involved? Same answer as for 9,

because both vanilloid activity and nitric oxide can stimulate mast cell

activation (6).

* How can the reported changes in the porphyrin biosynthetic pathway

be produced? The synthesis of the porphyrin biosynthetic enzymes has been

reported to be lowered by nitric oxide (3). In addition, the last enzyme in

this

pathway is structurally similar to proteins inactivated by peroxynitrite (3).

The combination of these two mechanisms may be involved here.

We now have solutions for each of these puzzles, the first five of which

have already been discussed on this web page. While I am not claiming that we

have proven all of these explanations, there are plausible physiological

explanations for each of them. MCS can no longer be claimed to be unexplained.

References:

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for the common etiology of multiple chemical sensitivity, chronic fatigue

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2. Pall ML. 2002 NMDA sensitization and stimulation by peroxynitrite, nitric

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chemical sensitivity: central role on N-methyl-D-aspartate receptors in the

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in press.

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