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Multiple Chemical Sensitivities: A Workshop Developing Clinical Research Protocols for Studying Chemical Sensitivities William J. Meggs The decade of the eighties brought progress in identifying and quantifying the low level exposures to volatile organic compounds found in the indoor air of homes, schools, and offices. In addition, some data is now available on both endogenous and added low molecular weight organic chemicals in food and water. Claims of adverse health effects from these exposures are far-ranging, and the challenge is now upon the clinical investigator to scientifically determine if there are adverse health effects associated with these exposures. There are specific difficulties associated with the development of research protocols in this area, and issues that must be addressed include: (a) Determination of patient populations to be studied, (b) the determination of proper control groups, (c) proper techniques for blinding challenges with odorous substances, (d) assessing psychiatric problems, (e) allowing for ''adaptative'' phenomena, (g) designing which will simultaneously establish if stimulus-response relationships exist while investigating possible underlying mechanisms and perhaps most difficult, (f) desiring studies that will be definitive in a highly controversial and politicized area of investigation. There are three approaches to defining patient populations to be studied. In the first circumstance, patients are recruited on the basis of reactivity to chemicals, either by meeting a case definition for multiple chemical sensitivity syndrome or claimed reactivity to multiple chemicals, with the focus on the etiological agents which may or may not reproduce the syndrome. In the second approach patients are recruited that have specific diseases such as asthma, rheumatoid arthritis, or depression, with effects of withdrawing and re-exposing patients to specific chemicals determined. In the third design, a given population such as a group of workers in a specific factory are sampled for response. In all three approaches, studies must be designed employing objective parameters to measure disease activity. Studies on patient populations with polysomatic complaints and no objective findings is not likely to yield definitive data. Patients with both objective illness and alleged chemical reactivity are available and are preferred patients for study. Diseases are potentially induced or exacerbated by environmental chemicals if: (a) the disease incidence has increased in recent years, (b) occupational exposure induces or exacerbates the disease, (c) there are case reports or anecdotal data relating the disease to chemical exposures, (d) the disease activity is linked to pharmaceuticals, as in drug-induced
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Multiple Chemical Sensitivities: A Workshop autoimmune hemolytic anemia, and (e) if animal models of the disease show induction by chemical exposure. Using these criteria, a group of diseases that need to be studied is given in Table 1. We do not claim that all of these diseases rigorously meet each of the above criteria. Common features of these diseases are a waxing and waning course, localized tissue inflammation, and ultimately tissue destruction. They are candidates for Stage 2 and Stage 3 illnesses of the Hypothetical Chemical Stress Syndrome, discussed elsewhere in these proceedings. TABLE 1 Some of the Diseases Whose Relationship to Environmental Chemicals Needs Clarification Asthma Autoimmune hemolytic anemia Crohn's Disease Depression Manic depressive illness Multiple sclerosis Rheumatoid Arthritis Schizophrenia Systemic Lupus Erythematosis Ulcerative Colitis Clinical research protocols must be designed to incorporate suitable control groups. Investigators must recognize that the entire population is exposed to low-level volatile organic chemicals (VOC's), and there is data suggesting that normal volunteers exposed in challenge chambers to mixtures of VOC's can become symptomatic. Some effects of chronic low-level VOC exposure may be seen in both normal individuals and patients. Clinical studies of adverse effects of chemicals must be double-blinded, but unique difficulties arise in the case of odorous inhalants. Odor masking by exposing the subject to a high dose chemical considered innocuous and a low dose chemical to be tested presents unique problems in this setting and will require systematic study. Anesthetizing the olfactory bulb may mask olfactory mediated physiologic reactions. The experience of blinding techniques in the study of food allergy and food intolerance should be heeded, and these investigators have found that blinding techniques should not be accepted a priori, but should be subjected to scientific scrutiny. Exposures of patients during sleep may be the most effective technique, but will need controlled investigation due to altered physiology during sleep. Clinical studies must allow for psychiatric illnesses in the patient population. It is recognized that there are behavioral aspects to this illness. In the original description of the multiple chemical sensitivity syndrome, it was claimed that psychiatric symptoms including depression, hallucinations, and manic states can be induced in some patients by chemical
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Multiple Chemical Sensitivities: A Workshop exposure. A contrary view is that this population consists of psychiatric patients with somatization and chemical phobias. Clinical studies can address this controversy by assessing the psychiatric state of patients in the presence and absence of chemical exposures. Great care must be employed in the design of double-blinded psychiatric evaluations. In the original clinical description of the multiple chemical sensitivity syndrome, it was claimed that chemically sensitive patients chronically exposed to chemical inhalants do not react acutely to chemical challenges and go through a withdrawal phase lasting approximately five days when removed from the chemical environment. Chronic symptoms are said to resolve after withdrawal, but the patients develop acute symptoms when rechallenged with chemicals. Clinical studies must allow for this adaptation mechanism in order to be accepted. Considerations of possible adaptative phenomena will require residential clinical research units in which indoor air can be controlled. A further consideration during the period of study includes monitoring for reactivity to both endogenous and added organic chemicals in food, and contaminants of water. Study design should include specific laboratory studies to objectively address defined questions. Though the pathogenesis of this syndrome has not been established, proposed mechanisms should be considered and used as a basis to design a laboratory panel to be followed as patients enter the protocol, undergo withdrawal from the chemical environment in a clinical research unit, and then are reexposed to specific agents. For instance, Are there changes in helper and suppresser lymphocyte numbers, or lymphocyte activation, during this process? Following acute challenge, are substances such as histamine or metabolites of neurotransmitters released into the blood or urine? In summary, scientific understanding in this area of clinical medicine will only develop with the establishment of clinical research units designed to minimize volatile organic chemicals in the air, staffed with multidisciplinary teams of specialists, and employing well-designed clinical protocols. Patients should be studied in defined populations such as those characterized by quantifiable, objective diseases. Disease activity and laboratory parameters should be followed from entry through withdrawal from organic chemicals, and then upon reexposure. Trials must be double-blinded, with careful assessment for changes in disease activity and in laboratory parameters. Normal volunteers should undergo identical evaluations. Costs of this research and potential sources of funding will be discussed.
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