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Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms

Environmental and Ecotoxicology

  1. Martin L. Pall PhD

Published Online: 15 DEC 2009

DOI: 10.1002/9780470744307.gat091

General, Applied and Systems Toxicology

General, Applied and Systems Toxicology

How to Cite

Pall, M. L. 2009. Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms. General, Applied and Systems Toxicology. .

Author Information

  1. Washington State University, Professor Emeritus of Biochemistry and Basic Medical Sciences and Research Director, Tenth Paradigm Research Group, Portland, Oregon, USA

Publication History

  1. Published Online: 15 DEC 2009


Cases of multiple chemical sensitivity (MCS) are initiated by exposure to organic solvents and three classes of pesticides. Each of these can act indirectly to increase NMDA activity and the toxic effects of members of each of these classes can be lowered by using NMDA antagonists. Other chemicals, mercury, H2S and CO exposure may also initiate cases of MCS and have toxic responses mediated through increased NMDA activity. Thus each of these types of chemicals appears to act as a toxicant through increased NMDA activity. Six additional types of evidence suggest roles for elevated NMDA activity in MCS, suggesting that this response is involved, not only in MCS case initiation, but also in response to low-level chemicals in those who are already sensitive. The inference that chemicals act as toxicants in MCS is confirmed by three genetic studies showing that five genes that encode enzymes that metabolize these chemicals act to determine MCS susceptibility.

The chronic nature of MCS is thought to be produced by a local biochemical vicious cycle mechanism, the NO/ONOO cycle, which is initiated by nitric oxide acting through its oxidant product peroxynitrite, which are both produced in MCS in response to excessive NMDA activity. Cycle elements, including NMDA activity, intracellular calcium, nitric oxide and peroxynitrite are thought to interact with other mechanisms, including neural sensitization in the brain and neurogenic inflammation in peripheral tissues to produce the high-level chemical sensitivity that is the hallmark of MCS. This complex model of MCS is supported by the following types of observations: MCS correlates in the chronic phase of illness, extensive animal model studies implicating almost all NO/ONOO cycle elements, clinical trial data in the related illnesses chronic fatigue syndrome and fibromyalgia, and a variety of objectively measurable responses to low-level chemical exposure in MCS patients, responses that should be further studied as possible specific biomarker tests for MCS. While plausible mechanisms are proposed for the generation of both shared and specific symptoms and signs in MCS, there are little data on whether these mechanisms are actually involved in generating these symptoms and signs in MCS. Previous claims that MCS is produced by some sort of psychogenic mechanism have multiple flaws and are inconsistent with the various types of evidence discussed above. Several areas of research are discussed in which the author argues that research will be richly rewarded.


  • N-methyl-d-aspartate (NMDA) receptors;
  • oxidative stress;
  • nitrosative stress;
  • chronic inflammatory biochemistry;
  • local vicious cycle mechanism;
  • prevalence of multiple chemical sensitivity;
  • sick building syndrome;
  • moulds and mycotoxins;
  • multiple chemical sensitivity case definitions