Robert J. Harrison, MD, MPH
Clinicians have been challenged by the individual with multiple complaints relating to low-level occupational or environmental exposures. Patients report respiratory, central nervous system, musculoskeletal, gastrointestinal, and systemic symptoms after exposure to common environmental irritants such as perfumes, cigarette smoke, home or office furnishings, household cleaners, and a host of other petrochemical products. Upper respiratory (eg, nasal congestion, dryness, or burning), central nervous system (eg, concentration problems, memory difficulties, insomnia, drowsiness, irritability, and depression), and vegetative (eg, fatigue, headache, arthralgias, and myalgias) symptoms predominate. Symptoms occur with exposures well below thresholds permitted by federal or state regulatory agencies as causing acute adverse effects in humans, resulting in significant impairment, lost work time, complete job loss, or major alterations in social and family functions. Individuals may report symptom onset following acute or chronic low-level occupational or environmental exposures, with persistent symptoms that are triggered by subsequent environmental contaminants. Often patients seek help from multiple health care providers who suggest psychiatric etiologies or treatment, obtain toxicologic or immunologic test batteries, or initiate a variety of empirical treatments. Workers’ compensation or disability claims often are disputed, and employers may have difficulty accepting or accommodating clinician or patient requests for alternative work environments. As a result, frustration, anger, hostility, and suspicion may confront the clinician when significant impairment continues despite lengthy and expensive consultations.
Some controversy continues to surround the etiology, case definition, diagnosis, and treatment of individuals with multiple chemical sensitivity (MCS). The specialty of clinical ecology that emerged in the 1960s adopted theories of causation that differ from those of traditional allergy, immunology, and toxicology, thereby laying the basis for medical and legal disputes regarding legitimate or acceptable forms of treatment, medical or workers’ compensation insurance reimbursement, and disability benefits. As a result, some clinicians believe that etiologic theories, diagnosis, and the clinical management of MCS are inconsistent with sound medical science. In more recent years, however, important progress has been made in elucidating and defining the nature of this condition. The combined efforts of several disciplines, including toxicology, psychology, and physiology, have suggested a multifactorial explanatory model for this condition. To guide the clinical evaluation of individuals with this disorder or to respond to requests for epidemiologic investigation, the health care practitioner should be aware of current controversies, including knowledge gaps and the need for further research.
EPIDEMIOLOGY & CASE DEFINITIONS
The term “multiple-chemical sensitivity” was defined in 1987 as an acquired disorder characterized by recurrent symptoms, referable to multiple organ systems, occurring in response to demonstrable exposure to many chemically unrelated compounds at doses far below those established in the general population to cause harmful effects. These seven criteria should be met:
1. The disorder is acquired in relation to some documentable environmental exposure(s), insult(s) or illness(es).
2. Symptoms involve more than one organ system.
3. Symptoms recur and abate in response to predictable stimuli.
4. Symptoms are elicited by exposures to chemicals of diverse structural classes and toxicologic modes of action.
5. Symptoms are elicited by exposures that are demonstrable (albeit at low level).
6. Exposures that elicit symptoms must be very low, by which is meant standard deviations below “average” exposures known to cause adverse human responses.
7. No single, widely available test of organ function can explain the symptoms.
Previous terms for this disorder included environmental hypersensitivity and environmental illness. Environmental hypersensitivity was defined as a chronic (ie, continuing for more than 3 months) multisystem disorder usually involving symptoms of the central nervous system and at least one other system. Affected persons are frequently intolerant to some foods and react adversely to some chemicals and to environmental agents, singly or in combination, at levels generally tolerated by the majority. Affected persons have varying degrees of morbidity, from mild discomfort to total disability. On physical examination, the patient usually is free from any abnormal objective findings. Improvement is associated with avoidance of suspected agents, and symptoms recur with reexposure. The term “environmental illness” (EI) has been described as an acquired disease characterized by a series of symptoms caused and/or exacerbated by exposure to environmental agents. Symptoms involve multiple organs in the neurologic, endocrine, genitourinary, and immunologic systems.
A panel of the World Health Organization (WHO) recommended that the terms MCS and EI be replaced by idiopathic environmental intolerance (IEI), arguing that use of the word sensitivity may be construed as connoting an allergic cause and that the link between symptoms and exposure is unproven. Other names for this disorder have been used in the published literature, including chemical intoleranceand toxicant-induced loss of tolerance. However, none of these terms has been adopted universally.
Patients with MCS should be distinguished from those with acute occupational diseases such as acute solvent intoxication, occupational asthma, and allergic rhinitis/sinusitis. In these conditions, there usually are objective findings, and the relationship between the condition and exposure is more readily apparent. Several medical organizations, including the American Academy of Allergy and Immunology, the American College of Physicians, the American College of Occupational and Environmental Medicine, and the Council of Scientific Affairs of the American Medical Association, have issued position statements about the causal etiology of MCS. These organizations have not found evidence to link MCS with toxic chemical exposures and have suggested that MCS is primarily a psychological or behavioral disorder.
The epidemiologic and clinical case definitions for MCS have been refined by researchers over the past few years, and certain subsets of questions can provide high specificity for the diagnosis. In one study, combinations of four symptoms (having a stronger sense of smell than others, feeling dull/ groggy, feeling “spacey,” and having difficulty concentrating) successfully discriminated MCS patients from controls. In another study, self-reported reactions to copy machine emissions, marking pens, aftershave, window cleaner, nylon fabric, pine-scented products, and rayon material were significant in a discriminant matched-pair analysis of MCS cases and controls. Other studies report overlap between these symptoms and those reported by patients with other conditions of unexplained etiology, such as chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and temporomandibular disorder. The Quick Environmental Exposure and Sensitivity Inventory (QEESI) can be used to assess chemical intolerance. In one study of a primary care population, one of five respondents met criteria for chemical intolerance using the QEESI. These individuals had significantly higher rates of comorbid allergies and possible major depressive, panic, generalized anxiety, alcohol abuse, and somatization disorders. The Idiopathic Environmental Intolerance Symptom Inventory (IEISI) has also been suggested as a reliable, valid, and fast tool for the study of specific symptom prevalence in IEI.
A population-based survey in California found that 6.3% reported physician-diagnosed “environmental illness” or “multiple chemical sensitivity,” and 15.9% reported being “allergic or unusually sensitive to everyday chemicals.” Hispanic ethnicity was associated with physician-diagnosed MCS, and female gender was associated with self-reported sensitivity. Significant functional impairment in terms of physical, occupational, and social functioning was reported among individuals with MCS. Another population-based survey in Georgia found that 12.6% reported increased sensitivity. Among these individuals reporting hypersensitivity to common chemical products, the most common triggers of symptoms were cleaning products, tobacco smoke, perfume, pesticides, and car exhaust. Lifestyle modifications were reported frequently, including change in household cleaning/personal hygiene products, home water- and/or airfiltration systems, and location of residence. Self-reported chemical sensitivity was found among 9% of respondents in a population-based survey in Germany.
No single chemical exposure or workplace process is more prevalent in association with the onset of MCS. Records-based reports from an allergy practice, academic occupational medicine clinic, and environmental health center suggest that individuals with MCS are predominantly women (70–80%) in the 30- to 40-year-old age range, with a disproportionate number from service industries. MCS patients in these reports tend to be of higher socioeconomic status, more highly educated, and had a diversity of both occupational and environmental exposures. In a Canadian survey, symptoms such as difficulty concentrating, fatigue, forgetfulness, and irritability were reported at the start of illness. Symptoms related to respiratory irritation such as sneezing, itchy or burning eyes, and hoarseness or loss of voice were reported commonly after subsequent exposure to environmental irritants. Several populations have been identified that may develop symptoms of MCS, including industrial workers, occupants of “tight buildings” such as office workers and school children, residents of communities whose air or water is contaminated by chemicals, and individuals with unique, personal exposures to various chemicals in domestic indoor air, pesticides, drugs, or consumer products. Workplace exposures to poor indoor air quality, pesticide exposure, and remodeling have been associated with the onset of MCS. Other diagnostic subsets have been reported among individuals with solvent-associated psycho-organic syndrome, chemical headaches, and intolerance to solvents.
Symptoms of MCS also resemble those of sick-building syndrome, a constellation of excessive work-related symptoms related to an indoor office environment (eg, headache; eye, nose and throat irritation; fatigue; and dizziness) without an identifiable etiology. MCS has been reported to follow pesticide exposure among employees in a casino and among several office workers following a large-scale outbreak of sick building syndrome. Several symptoms included in the Centers for Disease Control and Prevention (CDC) case definition of chronic fatigue syndrome (ie, fatigue, confusion, memory loss, sleep difficulties, myalgias, and headaches) also are common among individuals with MCS, and affected individuals may be concerned about occupational or environmental etiologies for chronic fatigue syndrome. Aside from symptom overlap, there is currently no evidence linking chronic fatigue syndrome to occupational or environmental chemical exposures.
A number of epidemiologic surveys have been performed among symptomatic veterans of the Gulf War and Cambodia peacekeeping operations. In most studies, veterans report poorer general health, more cognition difficulties, and a higher prevalence of chronic fatigue syndrome, posttraumatic stress disorder, irritable bowel syndrome, and MCS. One study reported a prevalence of symptoms consistent with MCS in 13.1% of Gulf War veterans. Another study of Gulf War veterans found a higher prevalence of MCS than among non–Gulf War military personnel (5.4% vs 2.6%), with greater sensitivity to organic chemicals, vehicle exhaust, cosmetics, and smog. The prevalence of MCS among British Gulf War veterans was significantly associated with exposure to pesticides. Among Cambodian peacekeeping operations veterans, significantly more MCS subjects reported having used insect repellants that contained N,N-diethyl-metatoluamide (DEET). However, the proportion of Cambodia peacekeeping veterans with symptoms of MCS was relatively low.
In a prospective panel survey of a Swedish population sample, elevated subjective health complaints, high stress in daily life and a strained work situation increased the risk of developing annoyance to environmental factors. These results of this survey suggest that that reduced subjective health, over the course of time, may be attributed to environmental factors. Several clinical surveys also demonstrate marked functional impairment in MCS patients, consistent with reported difficulties working and caring for their homes and families, and support the concept of comprehensive assessment, medical management, and social and financial support to avoid the deterioration of function associated with prolonged illness.
ETIOLOGY
The major theories of pathogenesis of MCS can be divided into those that center on a physiologic or toxicologic mechanism and those that ascribe MCS to psychological or behavioral determinants.
Toxicologic Mechanisms
Studies of symptoms in MCS patients are focused on responses below those seen with classic higher-dose exposures as workplace or environmental exposures in this population are considerably lower than those expected to cause end-organ toxicity based on known dose-response relationships. In some studies, no specific reactions to the type or level of chemical exposures have been found in controlled environments, suggesting that autonomic arousal mechanisms in response to odors may play an important role in mediating symptoms. In these studies, MCS subjects do not demonstrate lower olfactory threshold sensitivity or enhanced ability to identify odors accurately. This suggests that nonsensory factors (eg, attention, bias, and personality) can alter the self-reported impact of exposure to volatile chemicals. In a recent study of Gulf War veterans with chemical sensitivity compared with healthy veterans, MCS subjects exposed to low levels of chemicals (ie, diesel vapor with acetaldehyde) reported significantly increased symptoms such as disorientation, respiratory discomfort, and malaise.
To examine genetic and metabolic parameters in MCS, MCS patients and population controls were divided into four severity groups of chemical sensitivity. When genotyping was performed for variants in the genes encoding cytochrome P450 2D6, arylamine N-acetyltransferase 2, paraoxonase 1, methylene tetrahydrofolate reductase, and the cholecystokinin 2 receptor, no significant differences were consistently confirmed.
Psychiatric Mechanisms
Several studies suggest that anxiety and depression are significant contributors to the physical and cognitive symptoms of MCS subjects. Data from some clinical and epidemiologic studies show an association between lifetime psychiatric disorder, particularly mood, anxiety, somatoform, and personality disorders. Many patients with MCS are reported to have psychiatric conditions (eg, psychoses, affective or anxiety disorders, or somatoform disorders—somatization, conversion, and hypochondriases) with symptoms well before their diagnosis of environmentally related illness. Some patients with persistent or recurrent medically unexplained symptoms may have an atypical posttraumatic stress disorder, where specific and recurrent somatic symptoms follow acute or chronic chemical exposures, with subsequent experience of symptoms repeatedly triggered by low-level environmental irritants.
Patients with MCS display high anxiety sensitivity and in response to laboratory carbon dioxide inhalation tend to experience heightened anxiety and panic attacks. Patients with self-identified chemical sensitivity exhibited a positive symptomatic response to sodium lactate compared with placebo infusion, suggesting that MCS may have a neurobiologic basis similar to that of panic disorder. MCS subjects in one study scored significantly higher than controls on standardized psychological questionnaires for agoraphobic conditions and agoraphobia. One study has shown a significantly higher prevalence of the panic disorder–associated CCK-B allele 7 in subjects with MCS. In a recent Danish study, there were positive and statistically significant associations between psychological distress and IEI, which remained statistically significant after adjusting for major life events and social support.
Prolonged physical symptoms and sensitivity to common environmental irritants have been described as a behavioral conditioned response or an “odor-triggered panic attack.” Several authors suggest that the development of MCS in some individuals may be a result of, at least in part, pavlovian conditioning processes in which the expression of overt symptoms to certain substances reflects classically conditioned responses to previously neutral olfactory and contextual stimuli. Specific cognitive and behavioral interventions such as systematic desensitization, relaxation techniques, self-hypnosis, and biofeedback have been suggested as treatment strategies for these patients. Some MCS patients have been described as primarily ideational (obsessive-compulsive) or phobic in character, requiring a different psychotherapeutic approach focusing on the effect of physical symptoms on psychological function, stress associated with physical and interpersonal isolation, or the frustration of multiple physician consultations.
Neuropsychological measures (eg, electroencephalography [EEG], scalp electromyography, and skin resistance) during relaxation in individuals who attribute medical and psychological symptoms to chemical exposures have been compared with subjects with primary psychological disorders and with a control group. MCS patients did not differ from psychological subjects, and both were significantly different from controls, suggesting that individuals with MCS may have primary emotional, anxiety, attentional, or personality disorders. The MCS group had a higher somatization score on a standard self-report symptom inventory, and a subset of these patients had a history of early childhood sexual abuse. Patients recruited from the practice of a community allergist with a reported diagnosis of chemical sensitivity were compared with control patients from a university-based occupational musculoskeletal and back-injury clinic. Patients with MCS reported a higher prevalence of current psychological distress (ie, depression, anxiety, and somatization) and somatization symptoms preceding the onset of sensitivity symptoms. Neuropsychological performance did not differ when adjusted for the level of psychological distress.
In one case series of patients referred for outpatient evaluation for MCS, three-quarters met DSM-IV criteria for at least one psychiatric disorder, and over one-third had somatoform disorders. Subjects with a diagnosis of environmental illness had a higher prevalence of affective disorders (particularly major depression), anxiety, and somatoform disorders compared with controls, and more environmental illness subjects met lifetime criteria for a major mental disorder. Both asthmatics and MCS subjects performed significantly higher than controls on scales of chemical odor intolerance and anxiety sensitivity, and anxiety and depression were significant contributors to the physical and cognitive symptoms of MCS subjects. Individuals with environmental illness filing workers’ compensation claims had a greater prevalence of prior psychiatric morbidity (ie, anxiety, depression, and somatization trait) and higher self-reported measures of somatization and hypochondriasis.
Although many studies find that MCS is a psychological disorder with a belief system characterized by the toxic attribution of symptoms and disability, some studies suggest that psychiatric and psychological disorders may be a consequence, rather than a cause, of MCS. Among subjects referred to an occupational medicine clinic who met the case definition for MCS, psychiatric evaluation did not suggest any premorbid psychiatric diagnosis or a premorbid tendency toward somatization. Clinically significant psychiatric symptoms of depression and anxiety were present among most subjects, with a subset performing poorly on tests of verbal performance. Despite a preponderance of psychiatric symptoms among MCS patients, psychiatric diagnoses were uncommon, and most did not suffer from a diagnosable psychiatric disease. In a population-based survey of Georgia residents, among individuals reporting hypersensitivity to common chemicals, only 1.4% had a history of prior emotional problems, whereas 37.7% developed these problems after physical symptoms began. In a study designed to test the hypothesis that IEI symptoms result from learning via classical conditioning of odors to fear, the fear conditioning account of IEI was only partially satisfactory as an explanation of symptoms.
Immunologic Mechanisms
Environmental and occupational chemical exposures may affect the immune system, with a variety of cellular and cell-mediated immunologic effects established in both animals and humans. Xenobiotics may produce immunosuppression and alter host resistance in experimental animals following acute or subchronic exposure, and immunologic effects in humans have been reported in association with dusts (eg, silica and asbestos), polyhalogenated aromatic hydrocarbons (eg, dioxins, furans, and polychlorinated biphenyls), pesticides, metals (eg, lead, cadmium, arsenic, and methyl mercury), and solvents. However, neither experimental immune dysfunction nor epidemiologic evidence of altered immunity has been correlated with clinical disease.
MCS has been postulated to be an immunologic disorder, with generalized immune dysregulation as a result of free-radical generation and alkylation, structural alteration of antigens, or hapten/carrier reactions. Chemicals are hypothesized to alter immune responses, triggering lymphokines and leading to clinical symptoms of cell-mediated immune response. Chemically sensitive patients are reported to have altered T- and B-lymphocyte counts, abnormal helper-suppresser ratios, and antibodies to a variety of chemicals. Patients with building-related illness have been reported to have an abnormal antibody response and altered cellular immunity to formaldehyde, although these findings have not been confirmed using controls, and clinical correlation is absent. MCS also has been hypothesized to be the result of an interaction between the immune and nervous systems.
Studies of patients with MCS have found no consistent abnormalities in immunoglobulins, complement, lymphocytes, or B- or T-cell subsets. A study of patients with MCS found no evidence of increased autoantibodies, lymphocyte count, helper or suppresser cells, B or T cells, or TAI- or interleukin-2-positive cells compared with control subjects. Absence of objective evidence for immunologic abnormality distinguishes patients with MCS from those with other allergic disorders, autoimmune diseases, and congenital or acquired immunodeficiencies.
Respiratory Mechanisms
Many individuals with MCS report a heightened sense of smell or develop symptoms at low levels of environmental irritant exposure. MCS has been hypothesized to represent an amplification of the nonspecific immune response to low-level irritants. Altered function of C-fibers, respiratory epithelium, or neuroepithelial interaction is postulated to result in increased symptom reporting correlated with physiologic abnormality. Neurogenic inflammation mediated by cell-surface enzymes could play a role in upper respiratory symptoms reported by MCS patients. Subjects with MCS were reported to have a significant decrease in flow values with anterior rhinomanometry, independent of substance or doses, compared with controls. Subjects with MCS showed greater respiratory symptom scores with controlled exposures to test irritants. Capsaicin inhalation provoked more respiratory symptoms in subjects with MCS than controls, suggesting that neurogenic factors may be of importance. Patients with MCS were found with rhinolaryngoscopy to have marked cobblestoning of the posterior pharynx, base of the tongue, or both. In a study of environmental chemosensory responsivity (CR) and the relationship to personality traits, affective states, and odor perception, CR and odor thresholds predicted perceptual ratings of odors and high CR was associated with nonchemosensory affective traits. To test the concept that MCS might be a function of symptom learning, experimental evidence on healthy volunteers suggested that conscious expectancy, which may be modulated by odor quality, determined whether learned symptoms develop in response to a specific odor or to the general context.
Olfactory-Limbic Mechanisms
MCS has been postulated to be the result of environmental chemical exposure, with the triggering or perpetuation of affective and cognitive disorders as well as somatic dysfunction in vulnerable individuals via sensitization of the central nervous system. The neural sensitization model may incorporate both physical and psychological stressors that are elicited following chemical exposure. This theory proposes that MCS may result from neural sensitization, with excessive or altered neurotransmitter activity and/or alterations of the blood-brain barrier. There are anatomic links between the olfactory nerve, limbic system, and hypothalamus that could explain how odor or irritation of the respiratory tract indirectly results in multiorgan symptoms. Animal models have been developed recently to study the effects of repeated formaldehyde exposure on the hypothalamus-pituitary-adrenal axis and behavioral sensitization. Interactions between environmental chemicals and the vomeronasal organ also have been postulated to play a role in altered chemosensory function.
Kindling is a type of time-dependent sensitization of olfactory-limbic neurons by drug or nondrug stimuli, with activation of neural structures such as the amygdala and hypothalamus. Limbic structures are among the most susceptible to kindling-induced seizures, and persistent cognitive and emotional sequelae have been associated with temporal lobe epilepsy in humans and kindling in animals. The vanilloid receptor also has been proposed a possible CNS target in MCS. In this model of MCS, sensitization to food or chemicals parallels the phenomenon of time-dependent sensitization from drugs or nondrug stressors, with heightened sensitivity to stimuli, gradual improvement following withdrawal, and reactivation of symptoms following reexposure. Time-dependent sensitization has been studied as a possible model for cacosmia (subjective sense of feeling ill from odors) among nonpatient populations, which may have relevance to similar symptoms reported by MCS patients. It also has been hypothesized that shy individuals may have hyperreactive limbic systems and may self-report greater symptoms of illness owing to chemical exposures. Laboratory studies have demonstrated sensitization in individuals with MCS for variables such as electroencephalographic activity and increased heart rate and blood pressure. In a small study, chemical exposure caused neurocognitive impairment, and SPECT brain dysfunction particularly in odor-processing areas. In this model, low-level chemical exposure among susceptible individuals could result in affective spectrum disorders with various cognitive and somatic symptoms. This theory attempts to unify physiologic and psychological theories, suggesting that altered neurotransmitter activity may be the underlying mechanism for both affective and somatic symptoms seen among MCS patients.
CLINICAL MANAGEMENT
History & Physical Examination
A careful, thoughtful, and compassionate exposure and psychosocial history is critical. Although the etiology of MCS is controversial, the patient may be suffering from disabling symptoms and frustrated by the lack of definitive answers from clinicians and sometimes is desperately seeking advice and counsel regarding treatment. Approaching the history with the suspicion that the patient with MCS is suffering from a psychiatric disorder, is malingering, or is seeking monetary benefits is not helpful in establishing a therapeutic relationship. Acknowledgment of symptoms and the establishment of a trusting relationship should not necessarily be avoided because the etiology is uncertain or patient motivation is suspect. Where the diagnosis is suspect or contested, an adversarial relationship sometimes may emerge in the provider-patient context that may erode trust, challenge the provider’s capacity to treat the patient, and interfere with the therapeutic goals.
A history should be obtained of symptom onset in relationship to acute or chronic exposures. One standardized questionnaire called the Quick Environment Exposure Sensitivity Inventory (QEESI) has been developed that can assist clinicians in evaluating patients and populations for chemical sensitivity. Attention should be paid to respiratory, dermal, neurologic, and systemic symptoms. Most patients with MCS report general systemic symptoms such as difficulty concentrating, fatigue, lethargy, forgetfulness, and irritability. Myalgias, gastrointestinal complaints, headache, burning eyes, and hoarseness or loss of voice also are reported commonly. These various symptoms are provoked by exposure to low-level airborne contaminants such as perfumes, colognes, cleaning solutions, smoke, gasoline, exhaust fumes, and printing inks. Duration and severity of symptoms should be recorded, particularly in relationship to repeated exposures in the workplace or environment (eg, improvement away from work or on weekends/vacations with worsening symptoms at work). An occupational history should be obtained, including past employment and exposure to chemicals, dusts, or fumes. Recent and past chemical exposures should be identified by product names or material safety data sheets, and any environmental monitoring data should be reviewed if available.
Symptoms of headache, fatigue, lethargy, myalgias, and trouble concentrating may persist for hours to days or even weeks, with typical “reactions” reported after exposures to airborne chemicals. Often the individual with MCS will have already identified a variety of chemicals that result in symptoms and will have initiated an avoidance regimen. Varying degrees of restrictions in social and work activities may be reported, including problems driving an automobile, grocery shopping, wearing certain types of clothing, or staying away from office buildings or other workplaces.
The physical examination often is normal in patients with MCS, but particular attention should be paid to examination of the respiratory tract, skin, and nervous system.
Diagnostic Tests
Although routine laboratory evaluations usually do not reveal any consistent diagnostic abnormalities, it is essential to rule out other nonoccupational diseases through a comprehensive history, review of previous records, and appropriate diagnostic studies. The presence of asthma and/ or allergic disorders should be considered carefully and an appropriate workup undertaken. A few patients may have increased airway responsiveness and develop symptoms of chest tightness or shortness of breath on exposure to low-level environmental contaminants. Pulmonary function testing with nonspecific airway challenge testing may be indicated depending on history and symptoms. As suggested by the clinical history, confirmatory serologic and/or skin testing for common aeroallergens may be useful. If contact dermatitis is suspected, diagnostic level IV patch testing should be performed.
If a focal neurologic defect is suggested by history or physical examination, additional neurodiagnostic testing may be indicated. One patient with symptoms of altered odor sensitivity was found to have papilledema and a visual-field defect and was determined to have a treatable occipital lobe meningioma. Single-photon-emission computed tomographic or positron-emission tomographic studies of brain perfusion, computerized electroencephalographic analysis, or visual-evoked response and brain stem auditory-evoked response have not revealed consistent neurotoxic or neuroimmunologic brain changes in patients with MCS and should be used primarily to confirm clinical findings.
Additional psychological evaluation should be considered if the history suggests the presence of significant psychiatric disorder. Psychiatric consultation and/or treatment may be advised regardless of the etiology of MCS because many patients may have significant psychiatric morbidity with this disorder. Caution is advised in the interpretation of neuropsychological test results because these techniques are very sensitive but not specific. Abnormal test results could be a result of a neurologic, medical, or neuropsychiatric disorder. Neuropsychological studies have not shown significant differences between MCS patients and controls on tests of verbal learning, memory functioning, and psychomotor performance.
The capsaicin inhalation test has been used to assess sensory hyperreactivity in patients with MCS, but this test is not widely available for routine use, and its correlation with symptoms and response to treatment is not reliable for diagnosing MCS. The capsaicin concentration causing five coughs or more (C5) can be used to verify presence of lower airway symptoms related to odorous chemicals.
There is no convincing evidence that MCS is caused by a disturbance of heme synthesis, and tests for porphyrin metabolism in blood, urine, or stool specimens have not been correlated with clinical symptoms.
Several controversial techniques have been employed for the diagnosis of MCS, including provocation-neutralization testing, chemical and food challenges, inhalant challenges, serologic testing for Epstein-Barr virus antibodies and various autoantibodies, blood testing for organic hydrocarbon and pesticides, and hair testing for heavy metals. Many of these tests have no diagnostic utility. There is no evidence linking MCS to past infection with the Epstein-Barr virus. There is no association between MCS and levels of organic hydrocarbons or pesticides in blood or fatty tissue, and knowledge of minute residues of these chemicals may serve only to mislead and alarm the patient. Unless specific exposures are suspected, the use of biomarkers (eg, detailed profiles in serum of lipid-soluble toxins and their metabolites or heavy metals in the hair matrix) have little role in the diagnosis of patients with MCS. These tests have not been correlated with any pathologic consequences in MCS or control groups.
Blinded provocation testing has been employed in research studies but has not been evaluated rigorously as a useful diagnostic technique for individual patients. In a double blind placebo controlled trial, patients with MCS and controls underwent exposure sessions (solvent mixture and clean air in random order, double-blind) in a challenge chamber. There were no differences between the groups with regard to sensitivity, specificity, and accuracy were found. Cognitive performance was not influenced by solvent exposure, and did not differ between the groups. Likewise, immunologic testing has not been shown to be diagnostic for specific chemical exposure or associated illness.
In the absence of other concurrent medical conditions suggested by history, physical examination, or routine laboratory testing, the diagnosis of MCS relies on the patient’s history of multiple symptoms triggered by low-level chemical exposures.
Treatment
Patients with MCS should be advised that, as with a chronic illness, treatment is not directed at a “cure” but rather at accommodation. Care should emphasize relief of symptoms and a return to active work and home life. These treatment strategies entail a treatment alliance between patient and clinician without judgment regarding the etiology of MCS. Ethnographic studies have shown that many MCS patients manage their symptoms through a combination of prevention/avoidance, detoxification, and emotional self-care. In addition to symptoms and the ongoing difficulty in living with this condition, social relationships and daily life may be affected greatly. For some individuals, education regarding general principles of toxicology (eg, routes of exposure of toxic chemicals and routes of elimination) may be reassuring if they are concerned about long-term storage of chemicals in the body and the fear of ongoing damage. Elimination of exposures at home, workplace, or school through a variety of strategies (including room air filters) often is implemented by patients. In one case series of MCS patients from an occupational health practice, improvement in symptoms was associated with self-reported avoidance of specific substances or materials. Two of the three most highly rated treatments as reported by a large series of MCS patients were creating a chemical-free living space and chemical avoidance. While many patients report empirical improvement of symptoms, avoidance of low-level irritants has not been tested in controlled scientific studies. In some patients, avoidance may reinforce the notion of disability and lead to further isolation, powerlessness, and discouragement.
Although it is not clear whether psychological symptoms are the cause of MCS or simply accompany the diagnosis, specific cognitive and behavioral interventions may be most useful in the treatment of MCS. A biopsychosocial model of illness conceptualizes a close correlation between physical and psychological diseases. MCS may be a heterogeneous disorder with more than one causal mechanism. Significant psychophysiologic symptoms may occur after exposure to low-level volatile compounds in persons with and without coexisting or preexisting psychiatric illness. Similar to techniques used in other functional syndromes, behavioral strategies such as response prevention, systemic desensitization, graduated exercise regimens, and progressive relaxation may help patients to regain normal activities, minimize role impairment, and curtail sick behaviors.
Improving the patient’s understanding of the role of stress on illness and enhancing coping mechanisms for the impact on daily life may be helpful. Biofeedback-assisted relaxation training and cognitive restructuring have been reported with some success in MCS patients. Adults with MCS who completed an 8-week mindfulness-based cognitive therapy program (MBCT) generally reported benefiting in terms of improved coping strategies and sleep quality. Treatments with demonstrated efficacy in panic disorder also may be of benefit in MCS, and conversely, treatments that reinforce anticipatory anxiety and avoidance behavior may be detrimental.
Pharmacologic treatment for specific symptoms suggestive of depression or anxiety, in conjunction with other behavioral techniques, may offer some relief as part of an overall treatment program. In addition, antidepressants sometimes alleviate somatic symptoms (particularly pain and insomnia) and may improve the functional status of some MCS patients. One case report demonstrated dramatic improvement in a patient with MCS who received a selective serotonin reuptake inhibitor.
Patients in whom panic responses may be at least a contributing factor to symptoms might be responsive to intervention with psychotherapy to enable their desensitization or deconditioning of responses to odors or other triggers. These patients also may be helped by anxiolytic medications, relaxation training, and counseling for stress management.
A number of controversial methods have been used for the treatment of MCS, including elimination or rotary diversified diets, vitamins or nutritional supplements, oxygen, antifungal and antiviral agents, thyroid hormone supplement, supplemental estrogen or testosterone, transfer factor, chemical detoxification through exercise and sauna treatment, intravenous gamma-globulin, and intracutaneous or subcutaneous neutralization. A specially designed chemical-free environmental control unit has been used as a method to decrease blood pesticide levels and improve symptoms as well as intellectual and cognitive function. Controversial treatment methods offer hope of improvement to many individuals with MCS, and some patients do report symptom improvement over time. Many of these treatment methods are expensive and rarely are covered by health insurance. These treatment methods have not been validated through carefully designed, controlled trials, may have unwanted side effects, and may serve to reinforce counterproductive behaviors. Patients should be advised that such treatments are controversial, have not been subject to controlled clinical trials, and are not recommended by most medical professional organizations.
Follow-up studies indicate that up to half of MCS patients may improve over a period of years, but the majority continue to remain symptomatic with a major impact on career, marriage or family and other common daily activities.
REFERENCES
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SELF-ASSESSMENT QUESTIONS
Select the one correct answer to each question.
Question 1: Symptoms of multiple chemical sensitivity (MCS)
a. typically follow pesticide exposure
b. are helpful in the diagnosis of chronic fatigue syndrome
c. are invariably due to occupational or environmental chemical exposures
d. resemble those of sick-building syndrome
Question 2: Idiopathic environmental intolerance (IEI)
a. is a term favored over multiple chemical sensitivity by NIOSH
b. connotes an allergic cause
c. denotes that the link between symptoms and exposure is not caused by classic allergy
d. is a term that has been adopted universally
Question 3: The Quick Environmental Exposure and Sensitivity Inventory (QEESI)
a. can be used to assess chemical intolerance
b. finds that most respondents meet criteria for chemical intolerance
c. identifies individuals with low rates of comorbid allergies
d. misses somatization disorders