Multiple Chemical Sensitivity Syndrome Research Articles

Sensitization induced by kindling and kindling-related phenomena as a model for Multiple Chemical Sensitivity

It has been suggested that the neurobehavioral dysfunction observed in persons presenting with symptoms of Multiple Chemical Sensitivity (MCS) syndrome involves sensitization of neural circuits. Two hypotheses for the route of exposure in induction of neural sensitization in MCS are: (a) direct chemical stimulation of olfactory processes, or (b) general systemic response to inhaled chemicals. In either case, the mechanism of action may involve chemical kindling or kindling-related phenomena. A neural sensitization mechanism based on kindling or kindling-related phenomena is attractive and has been previously demonstrated in both in vitro and in vivo animal models. Without a testable animal model for chemically mediated induction of MCS, however, any argument that MCS is mediated by kindling or kindling-related phenomena is reduced to the circular argument “the mechanism of sensitization is sensitization.” The present survey provides an overview of the experimental paradigms that result in sensitization, differentiated on the basis of probable neurophysiological and neurochemical mechanisms. Neurophysiological potentiation, electrical kindling, chemical kindling and behavioral sensitization are evaluated and discussed in relationship to MCS.

Nasal Pathology and infrastructure in Patients with Chronic Airway Inflammation (RADS and RUDS) Following an Irritant Exposure

Reactive airways dysfunction syndrome is a chronic asthma-like condition developing after an acute irritant exposure, and chronic inflammation has been seen on endobronchial biopsy. Reactive upper-airways dysfunction syndrome is chronic rhinitis developing in temporal association with a toxic inhalation exposure, but the pathophysiology is unknown. To study biopsies of the nasal mucosa in patients with reactive upper-airways dysfunction syndrome and in some cases reactive airways dysfunction syndrome developing in temporal association with a chlorine dioxide exposure, to see if a histologic basis for the persistent rhinitis and sensitivity to chemical irritants could be determined. Specimens were stained with hematoxylin-eosin and immunoperoxidase stains for substance P, vasointestinal peptide, and S-100 (nerve fibers), and fixed in glutaraldehyde for electron microscopy. Biopsies of three nonexposed subjects were performed for comparison. A pathologist blinded to clinical data interpreted the specimens. Inflammation ratings of exposed individuals were higher than for the nonexposed individuals. The number of nerve fibers stained was greater for patients vs controls. Substance P and vasointestinal peptide staining was nonspecific. Electron microscopy showed desquamation of the epithelium and permeability of epithelial cell junctions. This study suggests a mechanism by which ongoing low level exposures perpetuate airway inflammation after an inducing toxic inhalation. A possible overlap between reactive airways dysfunction syndrome, reactive upper-airway dysfunction syndrome and the multiple chemical sensitivity syndrome is suggested.

Neurogenic switching: a hypothesis for a mechanism for shifting the site of inflammation in allergy and chemical sensitivity.

Neurogenic switching is proposed as a hypothesis for a mechanism by which a stimulus at one site can lead to inflammation at a distant site. Neurogenic inflammation occurs when substance P and other neuropeptides released from sensory neurons produce an inflammatory response, whereas immunogenic inflammation results from the binding of antigen to antibody or leukocyte receptors. There is a crossover mechanism between these two forms of inflammation. Neurogenic switching is proposed to result when a sensory impulse from a site of activation is rerouted via the central nervous system to a distant location to produce neurogenic inflammation at the second location. Neurogenic switching is a possible explanation for systemic anaphylaxis, in which inoculation of the skin or gut with antigen produces systemic symptoms involving the respiratory and circulatory systems, and an experimental model of anaphylaxis is consistent with this hypothesis. Food-allergy-iducing asthma, urticaria, arthritis, and fibromyalgia are other possible examples of neurogenic switching. Neurogenic switching provides a mechanism to explain how allergens, infectious agents, irritants, and possibly emotional stress can exacerbate conditions such as migraine, asthma, and arthritis. Because neurogenic inflammation is known to be triggered by chemical exposures, it may play a role in the sick building syndrome and the multiple chemical sensitivity syndrome. Thus neurogenic switching would explain how the respiratory irritants lead to symptoms at other sites in these disorders.

Does Amalgam Affect the Immune System? A Controversial Issue (Part 2 of 2)

Although in use for more than 150 years, dental amalgam has been questioned more or less vigorously as a dental restoration material due to its alleged health hazard. Humans are exposed to mercury and the other main dental amalgam metals (Ag, Sn, Cu, Zn) via vapour, corrosion products in swallowed saliva, and direct absorption into the blood from the oral cavity. Dental amalgam fillings are the most important source of mercury exposure in the general population. Local, and in some instances, systemic hypersensitivity reactions to dental amalgam metals, especially mercury, occur at a low frequency among amalgam bearers. Experimental and clinical data strongly indicate that these and other subclinical systemic adverse immunological reactions to dental amalgam metals in humans will be linked to certain MHC genotypes, and affect only a small number of the exposed individuals. These individuals will be very difficult to detect in a mixed population of susceptible and resistant individuals, including persons with alleged symptoms due to dental amalgam fillings, where many of the individuals are likely to suffer from conditions with no proven immunological background such as multiple chemical sensitivity syndrome. Intensified studies should be performed to identify such susceptible MHC genotypes, taking advantage of the reported cases of more heavily metal-exposed humans with systemic autoimmune reactions. Further studies will also be needed to ascertain whether the combined exposure to the metals in dental amalgam may lower the threshold for adverse immunological reactions, since recent studies have shown that the metals in alloy, especially silver, may induce autoimmunity in genetically susceptible mice.

Does amalgam affect the immune system? A controversial issue.

Although in use for more than 150 years, dental amalgam has been questioned more or less vigorously as a dental restoration material due to its alleged health hazard. Humans are exposed to mercury and the other main dental amalgam metals (Ag, Sn, Cu, Zn) via vapour, corrosion products in swallowed saliva, and direct absorption into the blood from the oral cavity. Dental amalgam fillings are the most important source of mercury exposure in the general population. Local, and in some instances, systemic hypersensitivity reactions to dental amalgam metals, especially mercury, occur at a low frequency among amalgam bearers. Experimental and clinical data strongly indicate that these and other subclinical systemic adverse immunological reactions to dental amalgam metals in humans will be linked to certain MHC genotypes, and affect only a small number of the exposed individuals. These individuals will be very difficult to detect in a mixed population of susceptible and resistant individuals, including persons with alleged symptoms due to dental amalgam fillings, where many of the individuals are likely to suffer from conditions with no proven immunological background such as multiple chemical sensitivity syndrome. Intensified studies should be performed to identify such susceptible MHC genotypes, taking advantage of the reported cases of more heavily metal-exposed humans with systemic autoimmune reactions. Further studies will also be needed to ascertain whether the combined exposure to the metals in dental amalgam may lower the threshold for adverse immunological reactions, since recent studies have shown that the metals in alloy, especially silver, may induce autoimmunity in genetically susceptible mice.

Multiple Chemical Sensitivities–Syndrome and Solution

After describing two patients seen by the author, we define multiple chemical sensitivities and discuss the scope of the problem and the epidemiology. Although the incidence of multiple chemical sensitivities is not known, the demographics are similar to that of agoraphobia. The classical conditioning model is proposed as a useful description of multiple chemical sensitivities. The desensitization approach to the diagnosis and treatment is proposed. Results with three patients were encouraging and the approach seems worthy of further evaluation and refinement.

Psychogenic origins of multiple chemical sensitivities syndrome: a critical review of the research literature.

The purpose of this review was to critically evaluate research on the psychogenic origins of multiple chemical sensitivities (MCS) syndrome. Using as keywords environmental illness, multiple chemical sensitivities, and clinical ecology, two databases--PsychLit and Medline--were searched by computer; reference lists of all articles located were also searched manually. Ten articles meeting three criteria were selected for review. Five sample selection problems, seven measurement problems, and three study design problems were common in all but one of the articles reviewed. Current studies investigating psychogenic hypotheses of MCS syndrome are methodologically problematic and their conclusions questionable. Studies of psychiatric profiles observed in MCS syndrome need to be designed to differentiate between competing psychogenic and biogenic hypotheses.

Building- and home-related complaints and illnesses: “Sick building syndrome”

Building- and home-related complaints and illnesses: “Sick building syndrome”

Low-Level Chemical Sensitivity: A Perspective from Behavioral Toxicology

Low-level chemical sensitivity is hardly a new issue in environmental toxicology. It is, in fact, the focus of risk assessment. The risk assessment process is designed explicitly to estimate the health threats posed by low exposure levels, typically by extrapolating from high experimental or environmental levels. The conventional risk assessment structure, however, was designed primarily around cancer. It is only awkwardly applicable to neurobehavioral toxicants because of the multiplicity of endpoints that have to be considered in evaluating neurotoxicity. At the same time, neurotoxic risk assessment maintains certain advantages over cancer risk assessment because of diminished uncertainties over dose extrapolation. It does not have to depart as far from the range of observable data. The main problem with extending the risk assessment model to issues such as Multiple Chemical Sensitivity (MCS) and Sick Building Syndrome (SBS) is the absence of a specific chemical whose concentration can be measured and then manipulated. A prototypical agent, however, such as a volatile organic solvent, might be selected and studied. Beyond the choice of agent, however, is the question of which behavioral criteria are likely to yield the most useful information. Although neuropsychological test batteries provide one source of data, they typically are administered in a setting other than the one allegedly provoking the syndrome. A different approach invokes what might be called a miniature work situation. Here, a test subject is evaluated in a setting that emphasizes sustained performance testing in the presence of target chemicals. Experimental design is another factor to be considered. Two features are especially critical. The most sensitive design, at least for the current stage of knowledge, would probably emphasize consistency of response, and would choose as subjects individuals who claim to be afflicted with low-level sensitivity. Consistency in a single individual may be more informative than significance tests in a large sample. In addition, consistency as a criterion helps overcome the problem that, in any such sample, only a minor proportion of the subjects may truly exhibit such sensitivity. At a later stage, a broader range of subjects might be targeted. Research on behavioral disorders evoked by food additives illustrates the importance of such questions. It also demonstrates that the methods currently used to assess the potential toxicity of many substances, including food additives, typically ignore subtle, and often sensitive, neurobehavioral measures.

Neurobiological Sensitization Models of Posttraumatic Stress Disorder: Their Possible Relevance to Multiple Chemical Sensitivity Syndrome

Neurological sensitization has been proposed as a model for post-traumatic stress disorder (PTSD) (Lipper et al., 1986; van der Kolk, 1987; Friedman, 1988; Post et al., 1988, 1994; Charney et al., 1993). Laboratory paradigms in which repeated exposure to a discrete stimulus is associated with progressive intensification of a neurophysiologic, behavioral, or pharmacologic response has many parallels with the sequence of events that precipitates PTSD. Investigators with other clinical interests have also been attracted to sensitization models. Specifically, Bell and associates (1992) have proposed that olfactory-limbic kindling is a very good model for understanding the etiology of multiple chemical sensitivity (MCS) syndrome. A number of articles in this volume have addressed the goodness-of-fit between this model and MCS. My major assignment is to review laboratory data and clinical observations pertinent to sensitization models of PTSD. I will show that although there are intriguing parallels between the two phenomena, one must have great respect for the complexity and polymorphism of both sensitization and PTSD before grasping for simplistic theoretical conclusions. Secondly, I will address the following question; if both PTSD and MCS can be understood as sensitization phenomena, are PTSD patients at greater risk to develop MCS and vice versa? This article is divided into four sections: a) a description of three distinct sensitization phenomena; b) a description of the symptoms of PTSD; c) a review of the applicability of sensitization models to the clinical phenomenology of PTSD; and d) a review of the hypothesis that PTSD patients might be more vulnerable to MCS.

RADS and RUDS--the toxic induction of asthma and rhinitis.

Inhalation exposures can produce asthma and rhinitis by several mechanisms. Sensitization with the production of IgE specific for a substance can lead to symptoms on reexposure via mast cell degranulation and the release of inflammatory mediators. Some substances, known as environmental adjuvants, enhance the immune response to concomitant exposures with the environmental adjuvant. Respiratory irritants can lead to asthma and rhinitis through interaction with chemical irritant receptors in the airway, leading to release of substance P from sensory nerves and neurogenic inflammation. The reactive airways dysfunction syndrome is a chronic asthma-like syndrome resulting from a single acute exposure to a respiratory irritant, while the reactive upper-airways dysfunction syndrome is chronic rhinitis stemming from an irritant exposure. The dysregulation of neurogenic inflammation by chemical exposures may be an important mechanism in the toxic induction of reactive airways dysfunction syndrome and reactive upper-airways dysfunction syndrome and may play a role in understanding the sick building syndrome and the multiple chemical sensitivity syndrome.

Neurogenic Inflammation and Sensitivity to Environmental Chemicals

Neurogenic inflammation as a pathway distinct from antigen-driven, immune-mediated inflammation may play a pivotal role in understanding a broad class of environmental health problems resulting from chemical exposures. Recent progress in understanding the mediators, triggers, and regulation of neurogenic inflammation is reviewed. Evidence for and speculations about a role for neurogenic inflammation in established disorders such as asthma, rhinitis, contact dermatitis, migraine headache, and rheumatoid arthritis are presented. The sick building syndrome and multiple chemical sensitivity syndrome have been defined as clinical entities in which exposure to chemical inhalants gives rise to disease. Current data on the existence of chemical irritant receptors in the airway and skin are discussed; neurogenic inflammation arising from stimulation of chemical irritant receptors is a possible model to explain many of the aspects of chemical sensitivities.

Neurogenic inflammation and sensitivity to environmental chemicals.

Neurogenic inflammation as a pathway distinct from antigen-driven, immune-mediated inflammation may play a pivotal role in understanding a broad class of environmental health problems resulting from chemical exposures. Recent progress in understanding the mediators, triggers, and regulation of neurogenic inflammation is reviewed. Evidence for and speculations about a role for neurogenic inflammation in established disorders such as asthma, rhinitis, contact dermatitis, migraine headache, and rheumatoid arthritis are presented. The sick building syndrome and multiple chemical sensitivity syndrome have been defined as clinical entities in which exposure to chemical inhalants gives rise to disease. Current data on the existence of chemical irritant receptors in the airway and skin are discussed; neurogenic inflammation arising from stimulation of chemical irritant receptors is a possible model to explain many of the aspects of chemical sensitivities.

Rhinolaryngoscopic examination of patients with the multiple chemical sensitivity syndrome.

Ten patients who met the Cullen case definition for the multiple chemical sensitivity syndrome were evaluated; a history was taken, and physical examination and fiberoptic rhinolaryngoscopy were performed. All patients had an initial chemical exposure, which was followed by multiple physical and mental complaints in response to subsequent exposure to a variety of odorous organic chemicals. Rhinitis was a prominent complaint in nine patients, but one patient denied any nasal symptoms. Rhinolaryngoscopic findings were abnormal in all patients; edema, excessive mucus, a cobblestone appearance of the posterior pharynx and base of the tongue, and mucosal injection were observed frequently. A particularly striking finding was focal areas of blanched mucosa that surrounded a prominent vessel. These results suggest that nasal pathology may be a prominent feature of this disorder.

Multiple Chemical Sensitivities Syndrome: Toward a Working Case Definition

A study was conducted to identify clinical diagnostic criteria that experts regarded as major for categorizing patients as having multiple chemical sensitivities (MCS) syndrome. A cross-sectional survey of 148 medical practitioners with an interest in, or familiarity with, the condition was performed scoreable questionnaires were returned by 60.1% of those surveyed. The following five criteria, all based on self-reports, were selected as major for diagnosing the syndrome by more than 50% of the respondents: (1) symptoms are reproducible with exposure; (2) condition is chronic; (3) low levels of exposure result in manifestations of the syndrome; (4) symptoms resolve with removal of incitants; and (5) responses occur to multiple, chemically unrelated substances. It is proposed that the major criteria accepted by the majority of survey respondents be used provisionally as the basis for categorizing cases in investigations of MCS syndrome.

Clinical Ecology

PHYSICIANS who practice clinical ecology believe that exposure to low levels of environmental substances present in the air or ingested from food and liquids causes in susceptible individuals a variety of ill-defined symptoms affecting nearly every organ system. MULTIPLE CHEMICAL SENSITIVITY SYNDROME Most physicians who practice clinical ecology (clinical ecologists) maintain that a number of patients have the multiple chemical sensitivity syndrome (MCSS) (also called clinical ecological illness, environmental illness, chemical AIDS [acquired immunodeficiency syndrome], 20th-century disease, environmental hypersensitivity disease, total allergy syndrome, and cerebral allergy). 1-10 Clinical ecology has been defined as the orientation in medicine in which physicians primarily work with patients to uncover the cause-and-effect relationship between their ill health and food or low-level chemical exposure. 9 Other definitions have been offered and no general agreement exists that clinical ecology and MCSS are synonymous. 8-10 The lack of a clear definition or diagnostic test for MCSS has

An olfactory-limbic model of multiple chemical sensitivity syndrome: Possible relationships to kindling and affective spectrum disorders

This paper reviews the clinical and experimental literature on patients with multiple adverse responses to chemicals (Multiple Chemical Sensitivity Syndrome-MCS) and develops a model for MCS based on olfactory-limbic system dysfunction that overlaps in part with Post's kindling model for affective disorders. MCS encompasses a broad range of chronic polysymptomatic conditions and complaints whose triggers are reported to include low levels of common indoor and outdoor environmental chemicals, such as pesticides and solvents. Other investigators have found evidence of increased prevalence of depression, anxiety, and somatization disorders in MCS patients and have concluded that their psychiatric conditions account for the clinical picture. However, none of these studies has presented any data on the effects of chemicals on symptoms or on objective measures of nervous system function. Synthesis of the MCS literature with large bodies of research in neurotoxicology, occupational medicine, and biological psychiatry, suggests that the phenomenology of MCS patients overlaps that of affective spectrum disorders and that both involve dysfunction of the limbic pathways. Animal studies demonstrate that intermittent repeated low level environmental chemical exposures, including pesticides, cause limbic kindling. Kindling (full or partial) is one central nervous system mechanism that could amplify reactivity to low levels of inhaled and ingested chemical and initiate persistent affective, cognitive, and somatic symptomatology in both occupational and nonoccupational settings. As in animal studies, inescapable and novel stressors could cross-sensitive with chemical exposures in some individuals to generate adverse responses on a neurochemical basis. The olfactory-limbic model raises testable neurobiological hypotheses that could increase understanding of the multifactorial etiology of MCS and of certain overlapping affective spectrum disorders.

Multiple Chemical Sensitivities: A Practicing Clinician's Point of View Clinical and Immunologic Research Findings

The multiple chemical sensitivities syndrome is a symptom complex characterized by emotional depression, short-term memory loss, acquired intolerance to environmental agents such as aerosolized petrochemicals and foods, and alteration in metabolic rate associated with increased body mass. This syndrome can be caused by multiple etiologic agents. With careful evaluation, it is rare that a causal agent can not be identified in this syndrome. Our treatment regimens include combinations of diet and environment control as well as antiviral, antifungal, and immune modulator therapy. We find that the majority of patients can, through time and appropriate treatment, be restored to a normal and productive lives.