TAR syndrome

Multiple chemical sensitivity (MCS) has been described under various names since the 1940s.[1,2] MCS syndrome is characterized by the patient's belief that his or her symptoms are caused by very low-level exposure to environmental chemicals. The term "chemical" is used to refer broadly to many natural and man-made chemical agents, some of which have several chemical constituents. Health care professionals who focus on MCS often refer to themselves as practicing "clinical ecology." MCS syndrome has led to great controversy among clinicians, researchers, patients, lawyers, legislators and regulatory agencies. The absence of scientific agreement on MCS has contributed to the development of emotionally charged, extreme and entrenched positions. Gots[2] summarized the controversy as follows:

"[MCS] has been rejected as an established organic disease by the American Academy of Allergy and Immunology, the American Medical Association, the California Medical Association, the American College of Physicians, and the International Society of Regulatory Toxicology and Pharmacology. It may be the only ailment in existence in which the patient defines both the cause and the manifestations of his own condition. Despite this, it has achieved credibility in workmen's [sic] compensation claims, tort liability, and regulatory actions."

Position statements from a variety of medical and governmental organizations on MCS and clinical ecology are shown in Table 1.[3-8] No consensus has been reached as to whether MCS is a new illness or has a biologic basis, what causes it or how it should be treated. As we await answers to these questions, clinicians must care responsibly and compassionately for patients experiencing this syndrome.[9]

TABLE 1 Statements from Medical and Governmental Organizations About MCS Syndrome and Clinical Ecology

American Medical Association, 1992: "No evidence based on well-controlled clinical trials is available that supports a cause-and-effect relationship between exposure to very low levels of substances and the myriad symptoms reported by clinical ecologists to result from such exposure.... Until such accurate, reproducible, and well-controlled studies are available, the American Medical Association Council on Scientific Affairs believes that multiple chemical sensitivity should not be considered a recognized clinical syndrome."[3]

American College of Physicians, 1989: "Review of the clinical ecology literature provides inadequate support for the beliefs and practices of clinical ecology The existence of an environmental illness as presented in clinical ecology theory must be questioned because of the lack of a clinical definition. Diagnoses and treatments involve procedures of no proven efficacy."[4]

American College of Occupational and Environmental Medicine, 1993: "The science is indeterminate about MCS as a specific entity and the cause and effect relationships have not been clearly established."[5]

American Academy of Allergy and Immunology, 1986: "An objective evaluation of the diagnostic and therapeutic principles used to support the concept of clinical ecology indicates that it is an unproven and experimental methodology."[6]

American Lung Association, Environmental Protection Agency, Consumer Product Safety Commission and American Medical Association, 1994: "The diagnostic label of multiple chemical sensitivity (MCS)--also referred to as `chemical hypersensitivity' or `environmental illness'--is being applied increasingly, although definition of the phenomenon is elusive and its pathogenesis as a distinct entity is not confirmed."[7]

Environmental Protection Agency, 1996: "There is at present no medical consensus concerning the definition or nature of this disorder."[8]

MCS = multiple chemical sensitivity

Definitions

Several definitions have been proposed for MCS.[1] Cullen's[10] definition is widely used. It includes four elements: (1) the syndrome is acquired after a documentable environmental exposure that may have caused objective evidence of health effects; (2) the symptoms are referable to multiple organ systems and vary predictably in response to environmental stimuli; (3) the symptoms occur in relation to measurable levels of chemicals, but the levels are below those known to harm health; and (4) no objective evidence of organ damage can be found.

Cullen's definition has the practical advantage of describing a syndrome without specifying individual symptoms or mechanisms of disease. Other definitions have been proposed that describe specific symptoms or postulate disease mechanisms.[1] These definitions are reflected in the other names that have been used for MCS and overlapping conditions, such as environmental illness, chemical AIDS, 20th century disease, total allergy syndrome, sick building syndrome, chemophobia, immune dysregulation and others.

In this article, the term "MCS" refers to the clinical syndrome without implying a mechanism of disease, in recognition of the lack of reliable scientific evidence to clarify such a mechanism. Indeed, the syndrome of MCS is likely heterogeneous, with multiple etiologic contributors in individual patients or different patterns of illness in response to a single mechanism of disease, or both.[11] MCS may represent a new, yet-to-be determined mechanism of disease.[11] If so, it would have in common with previous "new" mechanisms of disease, such as infection and malignancy, an apparent chaos of symptoms that begin to make sense only after elucidation of the common underlying pathology.

Symptoms

Patients with MCS syndrome can have severe symptoms that interfere with daily life and work. They often report that they had no symptoms before a single large exposure, which is then followed by exacerbation of symptoms in response to previously tolerated low-level exposures. Virtually any symptom has been attributed to the syndrome, but the symptoms generally occur in one of three categories: central nervous system symptoms, respiratory and mucosal irritation, or gastrointestinal problems.

Common symptoms include fatigue, difficulty concentrating, depressed mood, memory loss, weakness, dizziness, headaches, heat intolerance and arthralgias.[12] The typical patient with MCS presents with a firmly stated belief that the symptoms result from chemical exposure. Symptoms are precipitated by a wide array of common environmental agents, as listed in Table 2.[12] Patients exposed to pesticides have been reported to have more severe symptoms than those exposed to chemicals during a building remodeling?

MCS = multiple chemical sensitivity.

Adapted with permission from Lax MB, Henneberger PK. Patients with multiple chemical sensitivities in an occupational health clinic: presentation and follow-up. Arch Environ Health 1995; 50:425-31.

Patients often significantly alter their behavior in an attempt to avoid presumed precipitants of symptoms. They may have withdrawn from activities, friends and family in an attempt to eliminate chemical exposures. In one study[12] of 35 patients with occupationally related MCS evaluated in an occupational medicine clinic, 97 percent of the patients had stopped activities outside the home, 91 percent had limited their travel, 89 percent had limited their contact with friends and 77 percent had left a job. Many changed home routines: 97 percent had stopped using cleaning compounds, 69 percent removed home furnishings and 63 percent limited their contact with family members. In their personal care, 94 percent stopped using fragrances, 91 percent changed their diet and 86 percent changed the type of clothing they wore.

Illustrative Case

A 50-year-old woman was seen as a new patient by a family physician. She complained of back and chest pain, poor concentration, difficulty recalling names and an intermittent shuffling gait. Her past history included sleep apnea, diabetes, hypertension, depression, remote lumpectomy for breast cancer, gastric bypass surgery for obesity, and chemical exposure.

Her exposure history began 20 years previously. She had worked for 15 years in a factory where she was repeatedly exposed to paint fumes. Five years before her initial visit to the new physician, she had collapsed at work and was taken to a hospital by an ambulance. She had became totally disabled since that time.

She was previously seen by a physician who specializes in chemical sensitivity, and laboratory tests at that time showed an elevated erythrocyte sedimentation rate, serum titers of antibodies to myelin and a serum level of trimethylbenzenes. In an inhalation challenge test, she reacted to toluene but not to ethanol or formaldehyde. That physician reported his opinion that the patient had chemical hypersensitivity from her workplace exposures. He specified that she "must never be again exposed to any quantity of chemicals."

The patient had been followed for several years by a psychiatrist, who also believed she was totally disabled. His diagnoses included post-traumatic stress disorder, major depression, generalized anxiety and panic attacks.

The patient requested that her new physician confirm that chemicals caused her illness.

Epidemiology

Most patients (85 to 90 percent) complaining of MCS syndrome are women. Most present between the ages of 30 and 50 years. Much additional basic descriptive and epidemiologic information is still unknown. The incidence and prevalence are unknown. The question of whether MCS is becoming more or less common is unanswered, as is the question of whether it is preventable. The natural history and biologic outcomes of MCS are unknown, and descriptions of MCS in primary care settings have not been reported. Selected patients from specialty settings comprise reports of the syndrome.[14]

Proposed Mechanisms

Theories of the etiology of MCS can be grouped into four broad categories: physical, stress, misdiagnosis and illness belief.[15]

Physical

Three basic physical mechanisms have been proposed to explain MCS: allergy, direct toxic effects and neurobiologic sensitization.

Allergy. Followers of the clinical ecology movement believe chemical exposure causes the development of allergy to low levels of many chemicals, not just the initiating one. Supporters point to a spectrum of immune system tests that have been found to be abnormal in patients with MCS syndrome.

However, there are many problems with these tests, such as wide natural variation in the test results, few reference standards to determine what statistically "normal" is and lack of reproducibility. Finally, careful studies comparing patients with MCS and control patients have found no differences on immunologic testing.[16] Thus, it is not possible to rely on immunologic testing to demonstrate the etiology of MCS.

Toxicologic Effects. Others propose a toxicologic effect of low-dose exposure--in effect, poisoning. However, objective evidence for such an effect is lacking.[17] Patients with MCS experience symptoms at levels of chemical exposure far lower than those considered toxic.

Neurobiologic Sensitization. The third proposed physical mechanism is that affected persons develop increasing neurologic sensitivity to the adverse effects of chemicals.[18,19] Animal models for such neurologic changes include limbic kindling and time-dependent neurologic sensitization. In these models, animals repeatedly exposed to seizure-inducing chemicals or electrical stimulation have been found to develop lower thresholds for seizure induction than the thresholds observed before exposure. With other stimuli, animals have been found to have an amplification of the response to the stimulus over time.[20] How ever, these events have been documented only with pharmacologic doses and only in animals, not in humans and not at the low doses purported to cause MCS.

Stress

About one half of the patients with MCS in various studies meet the criteria for depressive and anxiety disorders.[21] Many patients meet the diagnostic criteria for somatoform disorders. There are marked similarities between MCS and post-traumatic stress disorder.[18] Therefore, generalized "stress" or anxiety and depression have been suggested as precipitants of MCS, but studies suggesting causality, rather than merely an association between MCS and psychiatric problems, are fraught with methodologic problems.[22]

Clearly, patients with MCS have a higher prevalence of psychiatric conditions such as somatization, depression and anxiety. It is not clear whether psychiatric conditions cause MCS, are caused by it or are simply associated with MCS. It is possible, for example, that both MCS and psychiatric illness are results of a common underlying neurobiologic mechanism.

Misdiagnosis

Some believe that MCS is not a syndrome separate from the psychiatric disorders but just a variant presentation of them.

Illness Belief

Whatever its physiologic, toxic or psychiatric origins are, MCS has become the focus for great efforts to support a particular set of beliefs about its mechanism and manifestations. MCS is discussed in an array of patient support groups and clinics, by clinicians, hotlines and lawyers, in journals and other media, and on World Wide Web sites. It has become the subject of disability laws and settlements.

Differential Diagnosis

The differential diagnosis for MCS includes various psychiatric and somatic illnesses. Psychiatric illnesses that may coexist with MCS, present as MCS or mimic MCS include somatoform disorders, panic and other anxiety disorders, depression and personality disorders. Malingering and factitious illness may also be considered. However, stable MCS might be a relatively unusual presentation for malingering, and factitious illness usually has associated objective findings, which are absent in MCS.

It has been suggested that Gulf War syndrome may be a variant of MCS. However, the etiology of Gulf War syndrome and the potential relationship between it and MCS are unclear. Symptoms of MCS may also overlap with chronic fatigue syndrome, but the diagnostic criteria for chronic fatigue syndrome differ from those for MCS. A major distinction is that the patient with MCS has a history of chemical exposure before the onset of symptoms.

Somatic illnesses that can mimic MCS include those with vague or subtle presentations, such as hypercalcemia, hypothyroidism, systemic lupus erythematosus and fibromyalgia.

Evaluation

A careful initial history, physical examination and basic laboratory investigation at the outset of providing medical care to a patient with MCS syndrome will substantially improve the physician-patient relationship and the quality of care. These patients are truly suffering as a result of their symptoms and deserve compassionate evaluation and management from a clinician who is sympathetic to their plight, but who also will protect them from unwarranted, dangerous, expensive or unproven evaluation and management.

The physician should empathetically confirm that he or she recognizes the intensity and reality of the symptoms while being clear about the degree to which a biologic relationship to chemical exposures can or cannot be confirmed. Not all data necessarily need to be obtained at the first visit, but this visit should initiate a shared plan for a systematic and thorough initial evaluation of the patient's problems.[23]

The initial history should include a thorough review of each of the many symptoms that may be present. Information should be obtained about the initial and subsequent exposures thought to exacerbate symptoms. This information should include specific chemicals or other agents to which the patient was exposed, the mechanism and duration of exposure, protective measures, symptoms, other workers exposed and their symptoms, and nonoccupational exposures. A psychiatric history should be a standard part of the evaluation. Records of previous medical evaluations and treatment should be obtained and reviewed before embarking on an extensive subsequent evaluation.

The physical examination should focus particularly on organ systems with referable symptoms. Laboratory testing should be limited to standard basic testing as indicated to evaluate specific historical items and abnormal physical findings.

Laboratory evaluation by "challenge testing" refers to having the patient inhale low concentrations of the offending chemical(s). Unfortunately, truly "blind" challenges may often not be possible because of the smell of the agent(s).[24] It is difficult to separate reactions to the smell of the chemicals from physiologic effects. The biologic basis of reactions in patients with MCS appears similar to those occurring in panic disorder.[25] Although many patients report cognitive impairment between exposures, this effect is not reproducible on neuropsychologic testing.[26]

Tests that are not recommended for routine evaluation of MCS include environmental challenge testing, quantitative encephalography, brain electrical activity mapping, neuropsychologic testing, brainstem evoked potentials, positron emission tomography, immunologic testing and determination of blood levels of trace volatile organic compounds or pesticides.[23]

Management

A huge array of treatment strategies for MCS have been proposed, including antifungal therapies, diets rotated to avoid the offending agents and the "radical separatist avoidance approach,"[9] which is an attempt to avoid all exposures to man-made chemicals. However, randomized controlled trials of the treatment of MCS are lacking. Therefore, the clinician should be cautious in supporting any untested management plan.

The principle goals of treatment are summarized in Table 3. The first goal of management is to establish an effective physician-patient relationship.[27] This is possible if the physician is respectful of the patient, compassionate about the symptoms and genuinely interested in helping to evaluate and manage the patient's problems. The overall goal of treatment is to maximize rehabilitation and to control, not cure, the patient's symptoms.

NOTE: If consultation is desired, contact an occupational and environmental health physician or the Association of Occupational and Environmental Clinics (telephone: 202-347-4976).

MCS = multiple chemical sensitivity

Information from reference 27.

Standard treatment should be provided for identified psychiatric and physical disorders. Treatment of psychiatric and non-MCS somatic disorders does not imply that MCS is either "all in the patient's head" or entirely explained by concomitant somatic illness. Rather, treatment of these problems can reduce the patient's total burden of suffering and may improve his or her ability to cope with the MCS symptoms and to achieve maximal function.

The patient should be encouraged to work and to socialize despite the symptoms. The major disability from MCS is often the isolation and withdrawal experienced as the patient seeks to avoid chemical exposures. Yet there is no evidence that such avoidance is effective or that continued exposure leads to any adverse biologic effects. Therefore, the physician should not encourage the patient to avoid low-dose exposure to a variety of chemicals. Indeed, according to Sparks and associates,[23] "[a] recommendation for long-term avoidance of chemical exposures is contraindicated. It is also impossible to accomplish?

The patient should be encouraged to increase activity gradually, while keeping anxiety or other symptoms at tolerable levels. This can be accomplished by following a systematic plan of behavioral treatment, desensitizing the patient to the distress experienced in symptom-producing situations. Relaxation or breath-control exercises may be helpful, as well as teaching the patient that autonomic symptoms of arousal, such as palpitations and tremor, are not dangerous and that activity can persist despite their occurrence.[27,28]

The authors thank Frank Mitchell, D. O., for helpful review of the manuscript.

REFERENCES

[1.] Miller CS. White paper. Chemical sensitivity: history and phenomenology. Toxicol Ind Health 1994; 10(4-5):253-76.

[2.] Gots RE. Multiple chemical sensitivities--public policy [Editorial]. J Toxicol Clin Toxicol 1995;33:111-3.

[3.] American Medical Association Council on Scientific Affairs. Clinical ecology. JAMA 1992;268:3465-7.

[4.] American College of Physicians. Clinical ecology. Ann Intern Med 1989;111:168-78.

[5.] American College of Occupational and Environmental Medicine. Position statement. Multiple chemical sensitivities, environmental tobacco smoke, and indoor air quality. Retrieved March 1998 from the World Wide Web: http://www. acoem.org/paprguid/papers/mcs.htm.

[6.] Executive Committee of the American Academy of Allergy and Immunology. Clinical ecology. J Allergy Clin Immunol 1986;78:269-71.

[7.] Environmental Protection Agency, American Lung Association, Consumer Product Safety Commission, American Medical Association. Indoor air pollution: an introduction for health professionals. U.S. Government Printing Office Publication no. 1994-523-217/81322; 1994. Retrieved March 1998 from the World Wide Web: http://www. epa.gov/iaq/pubs/hpguide.html.

[8.] Environmental Protection Agency. Hazardous air pollutant list. Federal Register 1996;61(118):30816-23. Retrieved March 1998 from the World Wide Web: http://frwebgate1.access.gpo.gov/cgi-bin... cID=1332623988+30+2+0&WAISaction=retrieve

[9.] Rest KM. Advancing the understanding of multiple chemical sensitivity (MCS): overview and recommendations from an AOEC workshop. Toxicol Ind Health 1992;8(4):1-13.

[10.] Cullen MR. The worker with multiple chemical sensitivities: an overview. Occup Med 1987;2:655-61.

[11.] Miller CS. Chemical sensitivity: symptom, syndrome or mechanism for disease? Toxicology 1996;111:69-86.

[12.] Lax MB, Henneberger PK. Patients with multiple chemical sensitivities in an occupational health clinic: presentation and follow-up. Arch Environ Health 1995;50:425-31.

[13.] Miller CS, Mitzel HC. Chemical sensitivity attributed to pesticide exposure versus remodeling. Arch Environ Health 1995;50:119-29.

[14.] Neutra RR. Some preliminary thoughts on the potential contribution of epidemiology to the question of multiple chemical sensitivity. Public Health Rev 1994;22:271-8.

[15.] Sparks P J, Daniell W, Black DW, Kipen HM, Airman LC, Simon GE, et at. Multiple chemical sensitivity syndrome: a clinical perspective. I. Case definition, theories of pathogenesis, and research needs. J Occup Med 1994;36:718-30 [Published erratum in J Occup Med 1994;36:1334].

[16.] Simon GE, Daniell W, Stockbridge H, Claypoole K, Rosenstock L. Immunologic, psychological, and neuropsychological factors in multiple chemical sensitivity. A controlled study. Ann Intern Med 1993; 119:97-103.

[17.] Wolf C. Multiple chemical sensitivities. Is there a scientific basis? Int Arch Occup Environ Health 1994;66:213-6.

[18.] Friedman MJ. Neurobiological sensitization models of post-traumatic stress disorder: their possible relevance to multiple chemical sensitivity syndrome. Toxicol Ind Health 1994;10(4-5):449-62.

[19.] Bell IR. White paper. Neuropsychiatric aspects of sensitivity to Low-level chemicals: a neural sensitization model. Toxicol Ind Health 1994;10(4-5):277-312.

[20.] Bell IR, Miller CS, Schwartz GE, Peterson JM, Amend D. Neuropsychiatric and somatic characteristics of young adults with and without self-reported chemical odor intolerance and chemical sensitivity. Arch Environ Health 1996;51:9-21.

[21.] Simon GE. Psychiatric symptoms in multiple chemical sensitivity. Toxicol Ind Health 1994;10(45):487-96.

[22.] Davidoff AL, Fogarty L. Psychogenic origins of multiple chemical sensitivities syndrome: a critical review of the research literature. Arch Environ Health 1994;49:316-25.

[23.] Sparks P J, Daniell W, Black DW, Kipen HM, Altman LC, Simon GE, et al. Multiple chemical sensitivity syndrome: a clinical perspective. II. Evaluation, diagnostic testing, treatment, and social considerations. J Occup Med 1994;36:731-7.

[24.] Staudenmayer H. Multiple chemical sensitivities or idiopathic environmental intolerances: psychophysiologic foundation of knowledge for a psychogenic explanation [Editorial]. J Allergy Clin Immunol 1997;99:434-7.

[25.] Binkley KE, Kutcher S. Panic response to sodium lactate infusion in patients with multiple chemical sensitivity syndrome. J Allergy Clin Immunol 1997;99:570-4.

[26.] Fiedler N, Kipen HM, DeLuca J, Kelly-McNeil K, Natelson B. A controlled comparison of multiple chemical sensitivities and chronic fatigue syndrome. Psychosom Med 1996;58:38-49.

[27.] Simon GE. Psychiatric treatments in multiple chemical sensitivity. Toxicol Ind Health 1992;8(4):67-72.

[28.] Guglielmi RS, Cox DJ, Spyker DA. Behavioral treatment of phobic avoidance in multiple chemical sensitivity. J Behav Ther Exp Psychiatry 1994; 25:197-209.

MICHAEL K. MAGILL, M.D., is professor and chairman of the Department of Family and Preventive Medicine and director of the Utah Area Health Education Centers Program, University of Utah School of Medicine, Salt Lake City. A graduate of Duke University School of Medicine, Durham, N.C., Dr. Magill completed a family medicine residency and a faculty development fellowship at the Duke-Watts Family Medicine Program, Durham, N.C.

ANTHONY SURUDA, M.D., M.RH, is clinical associate professor in the Department of Family and Preventive Medicine and director of the occupational medicine residency program at the University of Utah School of Medicine. Dr. Suruda graduated from Johns Hopkins University School of Medicine, Baltimore, and completed an internal medicine residency at the University of Connecticut and a residency in preventive medicine at Johns Hopkins University.

Address correspondence to Michael K. Magill, M.D., Department of Family and Preventive Medicine, University of Utah School of Medicine, 50 N. Medical Dr., 1C26SOM, Salt Lake City, UT 84132.

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