Multiple chemical sensitivity: towards the end of controversy

Townsend Letter for Doctors and Patients, August-Sept, 2005 by Martin L. Pall

There are nine well accepted paradigms of human disease. The tenth may explain the features of multiple chemical sensitivity (MCS) and a group of related illnesses including chronic fatigue syndrome (CFS), fibromyalgia (FM) and post-traumatic stress disorder (PTSD); Gulf War syndrome appears to be a combination of all four. The elevated nitric oxide/peroxynitrite vicious cycle paradigm explains most of the puzzling features of this group of previously unexplained illnesses (1-16) that afflict tens of millions of people in the US and elsewhere. These illnesses have multiple overlaps with each other. (2-5,13,16) They share many common symptoms and signs. They are repeatedly reported to be comorbid conditions. Cases of each of them typically show a common pattern of case initiation, with cases being preceded by and presumably induced by a short-term stressor, only to be followed by a chronic illness that usually persists for life. These similarities have led many different researchers to propose that two, three or all four of them may share a common etiologic mechanism (3,5,16) but they were unable to suggest what that mechanism might be.

The short term stressors reported to initiate these illnesses are very diverse. Six have very well-documented roles as initiators, viral infection, bacterial infection, physical trauma (particularly head and neck trauma), organophosphate/carbamate pesticide* exposure, volatile organic solvent exposure and severe psychological stress. There are six additional stressors that are less well documented as initiators of these illnesses and thus may be viewed as candidate initiators. These latter six include pyrethroid pesticide exposure, organochlorine (chlordane or lindane) pesticide exposure, a protozoan infection (toxoplasmosis), ciguatoxin poisoning (#), carbon monoxide poisoning and thimerosal exposure. All 12 of these are known to be able to initiate a sequence of events leading to increases in nitric oxide levels. Thus they all have a common biochemical end point, suggesting that they may act to initiate these illnesses through a common mechanism. (1-5,7,13,16) The three classes of infection all act to raise nitric oxide levels primarily by inducing the inducible nitric oxide synthase (iNOS) whereas most of the others are known to act by increasing NMDA (a) receptor activity and such NMDA activity is known to produce, in turn, increases in nitric oxide and its oxidant product, peroxynitrite. The NMDA activity is known to act by allowing an influx of calcium into the cell, leading to increased activity of the calcium dependent neural nitric oxide synthase (nNOS) activity. (5) Thus the stressors do not all share a common pathway or common enzyme producing nitric oxide. What they do appear to share is a common response of increased nitric oxide and its oxidant product peroxynitrite (b).

So how might elevated levels of nitric oxide and peroxynitrite** initiate these chronic illnesses? The proposed mechanism is that they initiate a biochemical/physiological vicious cycle mechanism which is responsible for both the chronic nature of these illnesses and is responsible for generating their diverse symptoms and signs. That vicious cycle mechanism is diagrammed in figure 1. The arrows in the figure represent a total of 22 distinct mechanisms, 18 of which are quite well documented. (1,5,7,13,16) The other 4 are based on what appear to be solid data, but are less established. The overall vicious cycle is quite plausible but what needs to be questioned is its physiological significance to these illnesses. One needs to focus, then, on the role of the various elements of this cycle in the chronic phases of these illnesses and that has been the focus of many of my papers on this subject. (1-7,10,12,13,16) Each of the following has been reported to occur in from two to four of these illnesses and typically when it has not been reported, it has not been studied: Elevated levels of nitric oxide, oxidative stress, elevated NF-kB activity, elevated levels of inflammatory cytokines, elevated NMDA activity, and increased vanilloid sensitivity (#&). Intracellular calcium levels have not been studied but some properties produced by such calcium increase have been reported. A pattern of mitochondrial dysfunction characteristic of peroxynitrite-mediated damage has been reported in CFS and FM. (1,16) So although it may certainly be argued that further studies are needed on many of these areas, the pattern of evidence that is available is supportive of the predictions of the vicious cycle mechanism. Many of the predictions of the cycle are also supported by studies of certain animal models of these illnesses. There is, for example, convincing published evidence for a key role of both NMDA activity and nitric oxide in certain animal models of MCS and substantial but less convincing evidence in PTSD models as well. There is an animal model of CFS that fits very well with the proposed mechanism but where some of the important predictions have never been tested. While there is no explicitly stated animal model for FM, whose characteristic symptom is widespread pain hypersensitivity, the mechanism of hyperalgesia in animals is known to involve all of the elements of the proposed vicious cycle. (16) So in general, although the biochemical and physiological experimental data on these illnesses is limited, what data is available is in good agreement with the predictions of the cycle.