Multiple chemical sensitivity: towards the end of controversy

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

There are four classes of chemicals reported to commonly produce MCS and also trigger symptoms in those already sensitized. These are the organophosphate/carbamate pesticides, volatile organic solvents, pyrethroid pesticides, and organochlorine (chlordane and lindane) pesticides. The three groups of pesticides acting at their major site of action can each initiate a control sequence that leads to increases in NMDA activity and consequent increases in nitric oxide. (4-6,14,16) The putative target for organic solvents, the vanilloid receptor, (7) is also known to be able to produce increases in NMDA activity and nitric oxide. (7) Thus, we see a common response to each of these four classes of chemicals as possibly being central to the action of these chemicals in MCS. How then, might this response lead to an understanding of chemical sensitivity? Apparently through a striking convergence of this mechanism with that proposed earlier by Dr. Iris Bell. (17-20) Bell proposed that MCS is centered on the process of neural sensitization, providing substantial support for this view. Her ideas were the focus of a New York Academy of Science meeting (Ann N Y Acad Sci, vol. 933). The major mechanism of neural sensitization is thought to be long-term potentiation (LTP), a mechanism thought to be involved on a highly selective basis, in strengthening of synaptic transmission in the central nervous system, during learning and memory. LTP is known to involve NMDA receptors in the postsynaptic cell and also nitric oxide which diffuses back to the presynaptic cell, acting as what is known as a retrograde messenger (%%) to increase release of glutamate neurotransmitter. (5) Thus, immediately you can see a striking convergence of these two theories. Each class of chemicals can act to stimulate the neural sensitization process proposed to be central to MCS. In addition, it is possible to propose a vicious cycle mechanism (actually part of the larger mechanism diagrammed in Fig. 1) that involves both excessive nitric oxide through the retrograde messenger role already discussed and peroxynitrite, through its ability to inhibit mitochondrial function and therefore ATP generation. (5) It is known that when cells containing NMDA receptors become energy-deprived, those receptors become hypersensitive to stimulation. (5) ATP-depletion in the glial cells may also have a role in increasing NMDA activity because of decreased transport of extracellular glutamate, the main NMDA agonist acting in the brain.

It can be seen from the above, how high level chemical exposure may initiate a vicious cycle mechanism involving excessive NMDA activity, nitric oxide and peroxynitrite that would render areas of the brain hypersensitive to further chemical exposure. There are also three other well-documented mechanisms that may also have a role: Increased vanilloid activity due to oxidants (7); breakdown of the blood-brain-barrier (BBB) due to the action of peroxynitrite, (5) thus allowing increased chemical access to the brain; and decreased chemical metabolism due to inhibition of cytochrome P450 activity by nitric oxide. (5,6) The notion is that the total of six proposed mechanisms will act synergistically with each other to produce the exquisite sensitivity reported in MCS. Of these mechanisms, there is experimental support for a role of the NMDA receptors and of nitric oxide, (4-6) for the breakdown of the BBB in both an animal model of MCS and in humans, (6,13) and for excessive vanilloid activity in MCS. (7) The overall mechanism is supported by at least 38 different types of observations, 24 documented in ref. 5, 12 more in ref. 7 and two additional ones in ref. 13.