etiology and pathogenesis are not well established, but there is no dearth of hypotheses guiding research. With fibromyalgia and chronic fatigue syndrome, several biological abnormalities have been detected in both sets of patients, including dysfunction of the HPA (hypothalamic–pituitary–adrenal) axis, leading to hypocortisolism (Demitrack and Crofford, 1998). Some observers postulate that the chain of causation begins with dysfunction of the central nervous system, which in turn triggers changes in immune function and changes in pain processing pathways (Clauw and Chrousos, 1997). Other biological correlates of chronic fatigue syndrome include anatomical abnormalities in subcortical white matter of the brain (via neuroimaging), chronic activation of the immune system, and reactivation of several latent viruses (Komaroff and Buchwald, 1998). With multiple chemical sensitivity, the etiology and pathogenesis are unclear. The model considered to have the strongest empirical support focuses on dysfunction of the mesolimbic pathway of the central nervous system (Graveling et al., 1999). Proposed by Bell and colleagues (1998a), the model posits that exposure to a host of exogenous and/or endogenous agents can elicit sensitization of neurons in the mesolimbic pathway. Because this pathway mediates autonomic, endocrine, and cognitive function, perturbations could lead to a broad array of seemingly unrelated symptoms. The model relates to chemical intolerance,18 an unpleasant subjective sensation evoked by low-level exposures, rather than to multiple chemical sensitivity per se, which is a severe form of chemical intolerance. Since chemical intolerance also is common to chronic fatigue syndrome and fibromyalgia, Bell and colleagues (1998a) postulate that their model may also apply to these conditions.


This appendix highlights the process of how a new disease comes to be recognized in medicine. The objective of this usually protracted process is to demonstrate through research that patients are affected by a unique clinical entity, one that is distinct from all other established clinical entities. The strength and coherence of research findings are not the only determinants of whether a new disease gains recognition by the medical establishment. Social factors, including culture and economics, also contribute to decisions, which are made by medical professionals. Professionals are convened under the auspices of the World Health Organization and the American Psychiatric Association, which publish their listings in the International Classification of Diseases and the Diagnostic and Statistical Manual of Mental Disorders, respectively.


The advantage of studying chemical intolerance is that it can be measured in animal models. Other attributes of medically unexplained illnesses, such as fatigue, pain, and headache, are far more difficult to measure in animal behavior. Multiple chemical sensitivity is one of the few medically unexplained conditions for which an animal model has been developed (Table D.1).

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