Multiple Chemical Sensitivity, Part 2
Because the compounds involved, nitric oxide, superoxide and peroxynitrite have quite limited diffusion distances in biological tissues and because the mechanisms involved in the cycle act at the level of individual cells, the fundamental mechanisms are local.* The consequences of this primarily local mechanism show up in the multisystem illnesses through the stunning variations one sees in symptoms and signs from one patient to another. Different tissue impact of the NO/ONOO- cycle mechanism is predicted to lead to exactly such variations in symptoms and signs.
One also sees evidence for this fourth principle in MCS and related multisystem illnesses from published brain scan studies (17,22-26) where one can directly visualize the variable tissue distribution in the brains of patients suffering from MCS or one of these related illnesses (1,5,20). This principle also explains the stunning variation that sufferers of each of these illnesses report in severity and also in their symptoms and signs (1,4, 27).
Therapy should focus on down-regulating the NO/ONOO- cycle biochemistry. In other words, we should be treating the cause, not just the symptoms
It can be seen that these five principles collectively produce a nearly complete explanatory model of NO/ONOO- cycle diseases. We have already discussed, above, evidence for fit to the first principle in the case of MCS. Evidence for a fit to all five principles for MCS is provided in 1,9,10,28 and also Chapter 7, ref. 5. Such evidence will be discussed more briefly below.
The fit to each of these five principles, for a specific disease/illness, provides a very distinct type of evidence that that disease/illness is a NO/ONOO- cycle disease. Because of this, each of the five principles serve as a criterion for deciding whether a specific disease/illness is a good candidate for inclusion under the NO/ONOO- cycle disease mechanism. In this way, the five principles serve for NO/ONOO- cycle diseases, somewhat like Koch’s postulates do for infectious diseases.
There has been a lot of interest in case definitions for MCS because of concern about whether different studies of “MCS” are studying the same patient population. In a review of different case definitions (29), it appeared that the 1999 consensus case definition (30) was probably the best available such case definition but two modest changes may be improvements (1). Having said that, the most important thing about standardizing patient studies may be to limit the huge range of severity among cases of MCS in such studies and possibly also the variation of tissue impact of sensitivity responses. It can be argued that studies should focus on the most sensitive quarter of MCS patients because differences of less severely affected patients when compared with controls will be more difficult to measure (1).
There have been a number of prevalence estimates of MCS that have been reviewed elsewhere (1,5,27). The prevalence of severe MCS in the U.S, is approximately 3.5% of the population, with much larger numbers, possibly 12 to 25% moderately affected (1,5). The most extensive such studies have been published in a series of papers by Caress and Steinemann (31). Studies from Canada, Germany, Denmark and Sweden have produced similar to somewhat lower estimated prevalences, roughly 50 to 100% of the U.S. estimates (1). From these various studies, MCS appears to have a very high prevalence, even higher than that of diabetes. Four studies report that there is also high comorbidity between MCS and important chronic diseases (32-35), providing further evidence that the public health impact of MCS is immense.
Some Possible Mechanisms for Shared Symptoms and Signs
While the symptoms of MCS, CFS/ME, fibromyalgia and PTSD are highly variable from one patient to another, these four illnesses share a series of symptoms and signs that were reviewed earlier (5). Each of them can be explained as being a consequence of NO/ONOO- cycle elements, in many cases as a consequence of their impact on certain regions of the body (Table 3).
Table 3 Explanations for Symptoms and Signs
It should be noted that while each of these are plausible mechanisms and, in most cases well-documented mechanisms under some pathophysiological circumstances, in most cases their role in generating these symptoms in these multisystem illnesses is not established.
The mechanisms outlined in Table 3 are not established mechanisms in these illnesses. Nevertheless, they provide evidence that there are such plausible mechanisms for the generation of these symptoms and signs that are consistent with the NO/ONOO- cycle mechanism.
Neural Sensitization and a Fusion Model of MCS
Dr. Iris Bell and her colleagues (36-39) and also others (27,40,41) have proposed that neural sensitization in response to chemical exposure may be the central mechanism of chemical sensitivity coming from the brain, acting especially in the limbic system. The ten “striking similarities” between neural sensitization and MCS discussed in Ashford and Miller (4) may be the best summary of the types of evidence originally supporting this view.
The probable mechanism of such neural sensitization, known as long term potentiation (LTP), is known to involve elevated NMDA activity, as well as several consequences of such NMDA elevation, all NO/ONOO- cycle elements, including elevated intracellular calcium levels, nitric oxide and peroxynitrite (reviewed in 1). It can be argued that the fact that several key elements of the NO/ONOO- cycle have very important roles in LTP is not likely to be coincidental, but rather that what we have acting here is a fusion model of the NO/ONOO- cycle mechanism with the neural sensitization mechanism which explains the properties of central sensitization much better than does either one alone (1,9,10). Increased chemical sensitivity of certain regions of the limbic system has been reported in a recent SPECT scan study comparing MCS patients and controls (17).
The key role of NMDA elevation in LTP and the ability of the various classes of chemicals that initiate cases of MCS to increase NMDA activity must be viewed as a central unifying concept in MCS. High level chemical exposure leading to massive increases in NMDA activity in regions of the brain, as well as massive increases in downstream responses in intracellular calcium, nitric oxide and peroxynitrite, will be expected collectively to produce massive stimulation of LTP. Whereas LTP stimulation is very selectively involved in increasing the sensitivity of specific synapses in learning and memory, such massive stimulation by chemical exposure will be expected to produce pathophysiological responses. Because such massive responses will directly occur only in regions of the brain where such chemical exposure can produce NMDA stimulation, this will lead to high level chemical sensitivity because these are exactly the regions of the brain that will be stimulated by subsequent chemical exposure in those that have been sensitized. One of the assumptions of this model is that there must be substantial overlap in the brain regions stimulated by different classes of chemicals that act along different pathways to produce increases in NMDA activity.
Energy depletion produced by mitochondrial dysfunction as a consequence of elevated levels of peroxynitrite, superoxide and nitric oxide (1,5,9,20) is expected to have a key role in such MCS-related neural sensitization whereas it may have only minor effects in normal LTP as it acts in learning and memory. When whole regions of the brain are impacted by the the NO/ONOO- cycle, the massive elevation of these compounds over such regions of the brain will be expected to produce much more substantial energy depletion. Energy depletion is known to produce increased NMDA sensitivity via two well established mechanisms. When cells containing such NMDA receptors have lowered energy metabolism, the lowered membrane potential of the cell produces large increases in NMDA sensitivity (9,42-44). Furthermore glutamate, the major physiological NMDA agonist has its extracellular levels lowered after release of the neurotransmitter by transport into glial cells, an energy requiring process (45,46). It follows that energy depletion also produces increased and prolonged NMDA stimulation. These roles of energy depletion may be expected, therefore, to have major roles in MCS but to have little if any role in normal LTP.
The confluences of these NO/ONOO- cycle elements as important influences on LTP produces what has been called a fusion model of MCS (9,10). This fusion model is our best understanding of how the central nervous system-related chemical sensitivity is generated.
MCS patients often report exquisite chemical sensitivity, on the order of 1000 times the sensitivity of normals (5,9) and such high level sensitivity has also been reported in a study of measured sensitivity responses (47). How, then, can such a high level of sensitivity be generated by this fusion model mechanism?
It has been proposed that the cycle acts at several different levels to produce such high level central sensitivity, possibly involving the following mechanisms (1,5):
Chemical exposure will stimulate regions of the brain with already existing neural sensitization, with that neural sensitization maintained both by the standard LTP mechanism and by the local elevation of the NO/ONOO- cycle. This combination may be exacerbated by a series of mechanisms each involving elements of the NO/ONOO- cycle, as follows:
Nitric oxide acting as a retrograde messenger will act to stimulate further glutamate release by the presynaptic neurons.
Energy metabolism dysfunction produced by peroxynitrite, superoxide and nitric oxide, will cause NMDA receptors to be hypersensitive to stimulation. It is known that energy metabolism dysfunction produces a decreased membrane potential which acts, in turn, to cause the NMDA receptors in such cells to be hypersensitive to stimulation (reviewed in 9, 42-44).
Energy metabolism dysfunction also acts on glial cells which normally rapidly lower extracellular glutamate via energy dependent glutamate transport. Lowered energy metabolism will then lead to increased extracellular glutamate, leading in turn to increased NMDA stimulation (45,46).
Peroxynitrite leads to a partial breakdown of the blood-brain barrier, leading to increased chemical access to the brain (reviewed in 9,10,48). Kuklinski et al (49) have reported blood-brain barrier breakdown in MCS patients and there is also an animal model of MCS in which similar breakdown has been observed (50-52).
Many of the chemicals implicated in MCS are metabolized via cytochrome P450 activities and these enzymes are known to be inhibited by nitric oxide, thus possibly leading to increased accumulation of the active chemical forms (reviewed in 9).
TRPV1, TRPA1 and some other TRP receptors are activated through the action of oxidants, as discussed above, and organic solvents and other agents that act via these TRP receptors such as some mold toxins may be expected to have increased activity due to such TRP receptor activation (1,62).
These are all known mechanisms but they have to be considered as hypothetical here because their roles as important causal mechanisms in producing MCS has not been established.
It should be noted, however, that these various mechanisms will be expected to act in multiplicative fashion, such that relatively modest changes at each level, perhaps on the order of perhaps two-fold to five-fold increases at each level, will when multiplied by each other to easily produce a 1000-fold increase in sensitivity. For example, a three-fold increase of each will produce an increased sensitivity of 37=2187, substantially larger than 1000.
Furthermore, one sees huge ranges in apparent sensitivities in MCS patients, ranges that can be explained by being produced by relatively modest differences in NO/ONOO- cycle activities. Environmental medicine physicians have emphasized for many years, the importance of avoiding chemical exposure in order to avoid up-regulating the MCS mechanism and one can see from the multiplicative nature of these presumed mechanisms, why even minor up-regulation of the NO/ONOO- cycle may be able to produce major increases in sensitivity.
Peripheral Sensitivity Mechanisms
The fourth principle underlying the NO/ONOO- cycle mechanism, discussed above, is that the basic mechanism is local, such that up-regulation of the cycle will impact different tissues in different individuals. In the case of MCS, different patients often show different patterns of sensitivity. For example, Sorg states in her review (27) that “Patients with MCS generally experience a reproducible constellation of symptoms but each patient may have a different set of symptoms to the same chemical.”#* In addition to the central sensitivity, discussed in the previous section, peripheral sensitivities occur, involving the upper respiratory tract, asthma-type symptoms, GI tract sensitivities, skin sensitivities and sometimes additional organ sensitivities. Sensitivities to chemicals and other agents in the respiratory tract has often been referred to as reactive airways disease. These all appear to be local mechanisms and the mechanisms of such peripheral sensitivities have been most studied by Meggs and his coworkers (53-57). Meggs has reported a role of neurogenic inflammation in peripheral sensitivity (53-57). Such neurogenic inflammation may be a substantial portion of the NO/ONOO- cycle mechanism. It can be triggered by NO/ONOO- cycle elements including the NMDA and TRPV1 receptors (58-63). Because it produces inflammatory responses, it may be expected to up-regulate the cycle as well (1,5). Neurogenic inflammation stimulation by the NMDA receptors may explain the role of chemicals acting to increase NMDA activity in initiating cases involving peripheral sensitivity. Such NMDA stimulation may be able to increase neurogenic inflammation, thus triggering NO/ONOO- cycle elevation in peripheral tissues.
Peripheral chemical sensitivity and perhaps central sensitivity as well may involve mast cell activation (64-66), a process that is stimulated by two NO/ONOO- cycle elements, TRPV1 activation and NF-kappaB stimulation (67-69).
In general, when one looks at the possible (probable?) mechanisms leading to high level peripheral sensitivity, many of the mechanisms proposed above for central sensitivity may be expected to be involved. However clearly the blood brain barrier has no role in peripheral sensitivity and the role of nitric oxide acting as a retrograde messenger may be unlikely to have a role. However, neurogenic inflammation and mast cell activation may have substantial roles. So again, sensitivity mechanisms acting multiplicatively at multiple levels may be responsible for the apparent high level sensitivity associated with peripheral tissues.
Summary of Animal Model Data
Ref. 1 reviewed 39 different apparent animal model studies of MCS. A surprisingly large number of NO/ONOO- cycle elements as it is proposed to play out in MCS have been implicated in such animal models (citations provided in reference 1). NO/ONOO- cycle elements as well as their interactions with neural sensitization and neurogenic inflammation mechanisms have been reported to be involved in one or more such animal models:
Neural sensitization and cross sensitization (where sensitization to one chemical also produces sensitization to a second chemical).
Progressive sensitization, where sensitivity progresses with increasing numbers of chemical exposures.
Chemical agents acting via decreased acetylcholinesterase or GABAA activity or via increased TRPV1 activity or sodium channel activity (see Fig. 1).
Increased NMDA activity.
Increased nitric oxide.
Elevated inflammatory cytokine levels or levels of other inflammatory markers.
Elevated levels of intracellular calcium.
Breakdown of the blood brain barrier.
Airways sensitivity (reactive airways disease).
Chemical linkage to the sensory irritation response (thought to involve a number of TRP receptors including TRPV1).
While only a limited number of these have been measured in each animal model, so that one cannot determine whether all of these may be implicated in any single animal model, it is surprising how many aspects of the NO/ONOO- cycle as it is predicted to play out in MCS, are implicated in one or more animal models. In fact, the only major part of the cycle that is not implicated in one or more animal models is BH4 depletion, which has never been measured.
One can, therefore, make a substantial case for the NO/ONOO- cycle as the mechanism of MCS from animal model data alone.
Putative Specific Biomarker Tests Via Objectively Measurable Responses to Chemical Exposure
There are quite a number of studies where objectively measurable responses to chemical exposure differs in comparing MCS patients with controls. In most cases, these involve tests of responses to low level chemical exposure. Clearly one needs to develop specific biomarker tests for MCS, so that tentative diagnoses based on self-reported symptoms can be objectively confirmed via one or more objectively measurable tests. Thus the literature on objectively measurable responses to chemical exposure, where MCS patients differ from normal controls, is of great importance because such responses may be viewed as putative specific biomarker tests.
Table 3, below, summarizes a number of such studies. Only one citation is provided for each type of study and other relevant citations are provided in ref. 1.
Table 3. Possible Specific Biomarker Tests
Of these tests, the capsaicin cough response test, the blood histamine, nerve growth factor and other inflammatory marker test of Kimata (66) and the nasal lavage tests may be the easiest to apply in a clinical setting and therefore may be the best as practical specific biomarker tests. Having said that, both the cough response test and the nasal lavage test may only pick up MCS patients with substantial respiratory tract involvement and so may not be helpful in testing for the minority of MCS patients lacking such involvement. The Kimata (66) approach, while promising, has only been studied in one published paper, so clearly we need much more information to determine how reproducible it may be.
The various possible specific biomarker tests summarized in Table 3, all appear to be consistent with the NO/ONOO- cycle mechanism for MCS, as outline elsewhere in this paper. Several of them are consistent with the inflammatory aspects of that mechanism, several appear to be consistent with neural sensitization and one involves the pathway of action predicted for the action of organic solvents in MCS.
The Pattern of Evidence
In (1), evidence is summarized supporting various aspects of the NO/ONOO- cycle as it is thought to play out in MCS. Specifically evidence is summarized providing support for each of the following:
Excessive NMDA activity
Elevated levels of nitric oxide
Elevated iNOS induction
Breakdown of the blood brain barrier
Elevated levels of inflammatory cytokines
Elevated TRPV1 activity
Mitochondrial/energy metabolism dysfunction
In total there are 51 distinct types of evidence for involvement of one of these. Although there are quite a number of areas where more research is needed, the total of evidence supporting this model for MCS is quite impressive.
Occupational Chemical Exposure and MCS
There have been very few studies of occupational chemical exposure and MCS. This should not be surprising, because corporations have often been opposed to studies of their employees because such studies might document their potential liability. Nevertheless, there have been a number of such studies that have been published.
Morrow et al (77) reported that approximately 60% of organic solvent exposed workers had MCS-like symptoms. In an important study, occupational medicine patients differed from general patients in responses to the Toronto MCS questionnaire in much the same way that self identified MCS patients did, albeit to a lesser extent (78), suggesting that chemical exposure in the occupational environment may initiate substantial numbers of MCS cases. Zibrowski and Robertson (79) reported increased prevalence of MCS-like symptoms among laboratory technicians exposed to organic solvents as compared with similar laboratory technicians with no apparent exposure. An epidemiological study, estimating the prevalence of MCS in various occupations including those expected to have substantial chemical exposure to classes of chemicals implicated in MCS as a consequence of the occupation, reported increased prevalence of MCS in several occupations involving such chemical exposure, again suggesting a causal role of chemical exposure (80,81). Yu et al (82) found high prevalences of MCS-like symptoms among solvent exposed printing workers as compared with non-chemically exposed controls. Moen et al (83) reported high prevalences of neurological sympoms including MCS-like symptoms among mercury exposed dental technicians. There are at least a dozen studies reporting high prevalences of reactive airways disease, a common aspect of MCS, among workers occupationally exposed to organic solvents.
There has been much more study of therapy of the related illnesses, CFS/ME and fibromyalgia than for MCS. Within the CFS /fibromyalgia group of illnesses, there is evidence for roles of each of the following mechanisms based on the probable mechanisms of action of individual agents in clinical trials (1,5,20):
Elevated levels of nitric oxide
Excessive NMDA activity
Tetrahydrobiopterin (BH4) depletion
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