9
Use of Biologic Markers In Controversial Areas Of Environmental Health

In recent years a number of concerns have been voiced about the effects of chemical contaminants of the air, water, and food supply on human health. Clinical syndromes or disease entities have been described in which there is an alleged susceptibility to these chemicals at concentrations generally present in the environment and tolerated by most of the population. Terms such as sick-building syndrome (SBS), multiple-chemical-sensitivity (MCS) syndrome, and environmental illness (EI) have come into use to describe illness in groups of patients whose reactions to environmental toxicants are either induced by or exacerbated by exposure to the so-called chemical environment. A related syndrome, reactive-airways-dysfunction syndrome, also has been described. Some authors have claimed an immune pathogenesis for chemical sensitivities; others have dismissed the entire area as a somatization disorder or mass hysteria.

The controversies in this area could not be resolved by the Subcommittee on Immunotoxicology. Members of the group believe that there is insufficient evidence that MCS is an immunologic problem and that this report is not the proper place to provide a definitive discussion of these issues. Nonetheless, the group's members decided to devote a chapter to these issues, because it will be necessary to use immune-system biologic markers to determine whether the immune system is involved with these disorders; this is an area of increasing national concern, with significant but uncounted patient populations suffering morbidity and disability, no matter what the cause; and the work of this subcommittee can be a stepping stone to a more definitive discussion by another group. The emphasis in this chapter is on health effects of exposure to airborne chemicals. This chapter addresses six questions:

  • Does the alleged chemical environment exist as a measurable entity?

  • What is known about the exposure of the population to the substances that have been alleged to produce symptoms in susceptible people?

  • What are the potential health effects of these compounds?

  • What evidence is there that some individuals are susceptible to toxicants at levels present in the ambient air that are tolerated by most of the population?

  • What is the nature of SBS and MCS, and what case definitions have been given?

  • What steps should be taken to resolve



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Biologic Markers in Immunotoxicology 9 Use of Biologic Markers In Controversial Areas Of Environmental Health In recent years a number of concerns have been voiced about the effects of chemical contaminants of the air, water, and food supply on human health. Clinical syndromes or disease entities have been described in which there is an alleged susceptibility to these chemicals at concentrations generally present in the environment and tolerated by most of the population. Terms such as sick-building syndrome (SBS), multiple-chemical-sensitivity (MCS) syndrome, and environmental illness (EI) have come into use to describe illness in groups of patients whose reactions to environmental toxicants are either induced by or exacerbated by exposure to the so-called chemical environment. A related syndrome, reactive-airways-dysfunction syndrome, also has been described. Some authors have claimed an immune pathogenesis for chemical sensitivities; others have dismissed the entire area as a somatization disorder or mass hysteria. The controversies in this area could not be resolved by the Subcommittee on Immunotoxicology. Members of the group believe that there is insufficient evidence that MCS is an immunologic problem and that this report is not the proper place to provide a definitive discussion of these issues. Nonetheless, the group's members decided to devote a chapter to these issues, because it will be necessary to use immune-system biologic markers to determine whether the immune system is involved with these disorders; this is an area of increasing national concern, with significant but uncounted patient populations suffering morbidity and disability, no matter what the cause; and the work of this subcommittee can be a stepping stone to a more definitive discussion by another group. The emphasis in this chapter is on health effects of exposure to airborne chemicals. This chapter addresses six questions: Does the alleged chemical environment exist as a measurable entity? What is known about the exposure of the population to the substances that have been alleged to produce symptoms in susceptible people? What are the potential health effects of these compounds? What evidence is there that some individuals are susceptible to toxicants at levels present in the ambient air that are tolerated by most of the population? What is the nature of SBS and MCS, and what case definitions have been given? What steps should be taken to resolve

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Biologic Markers in Immunotoxicology problems in definition of such disease states and the frequency of diseases or syndromes related to xenobiotic exposure and the mechanisms underlying these syndromes? EVIDENCE OF EXPOSURE TO ORGANIC CHEMICALS The toxicants implicated in chemical-sensitivity syndromes are predominantly low-molecular-weight hydrocarbons that often have additional atoms of nitrogen, oxygen, and the halogens. Some of these organic compounds occur naturally—they are found in edible and toxic plants. Some are synthetics used as pesticides, pharmaceutical agents, perfumes, disinfectants, and food additives. Others, including the volatile organic compounds (VOCs), are products of combustion, including vehicle exhaust, tobacco smoke, and emissions from heating units. Outgassing from synthetic materials also can contribute to the presence of VOCs in the air. Table 9-1 lists some of the sources of compounds that allegedly cause problems for sensitive individuals (Randolph, 1962). The Total Exposure Assessment Methodology (TEAM) study was designed to measure VOCs in drinking water, indoor air, and outdoor air and to quantify the demographics of a group of people in Elizabeth and Bayonne, New Jersey. Eleven of 19 compounds studied (chloroform, 1,1,1-trichloroethane, benzene, styrene, o-xylene, carbon tetrachloride, m/p-xylene, m/p-dichlorobenzene, ethylbenzene, trichloroethylene, and tetrachloroethylene) were consistently present in personal air samples taken in the breathing zone of the subjects and in exhaled air at higher concentrations than found in the outdoor air of the two cities (Wallace et al., 1985). The correlation between personal air samples and exhaled air measurements was better than that between outdoor air and exhaled air concentrations. It was concluded that these toxicants are found more frequently indoors and that the population gets a stronger dose from indoor sources than from outdoor sources. The early phases of the TEAM study compared personal air in homes to outdoor air. Later work was extended to include public buildings (Sheldon et al., 1988a,b). Eight compounds were found at greater concentrations in the indoor air of new buildings than in outdoor air. Concentrations were greater in the indoor air by factors of as much as 100. The TEAM study is an important contribution to environmental medicine. It verifies the existence of the ''chemical environment," points out that indoor air quality is a major determinant of body burden of VOCs, and provides a list of such chemicals that must be assessed for chronic toxicity and for eliciting hypersensitivity responses in susceptible persons. Other studies of indoor air have focused on radon, asbestos and other fibers, tobacco smoke, formaldehyde, indoor combustion, moisture, and microorganisms and allergens from biologic sources (NRC, 1981). The microorganisms and biologically derived allergens may play an important part in indoor air pollution, but are not within the scope of this project. HEALTH EFFECTS OF INDOOR AIR CONTAMINANTS In discussing the health effects caused by exposure to VOCs, it is helpful to distinguish two classes of health effects that have been described. Class A syndromes have one distinct, quantifiable clinical response, such as bronchospasm, depression, or cardiac arrythmia, resulting from an exposure to a single well-defined airborne chemical. A number of studies ranging from scientifically conducted double-blind studies to case reports and anecdotal data have discussed class A syndromes, and it is accepted that airborne chemicals can cause a variety of clinical responses in susceptible individuals at doses tolerated by most of the population. The responses range from occupational

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Biologic Markers in Immunotoxicology TABLE 9-1 Agents Reported to Cause Symptoms in Chemically Sensitive Individuals Indoor air contaminants Utility gas Combustion products of gas, oil, or coal Coal smoke Fumes from fresh paint, turpentine, mineral spirits, detergents Fragrances from toiletries and perfumes Cleaning products, such as bleach, ammonia, disinfectants Insect sprays and repellents Odorous synthetic carpets, pads, adhesives, and building materials Outdoor air contaminants Automobile and diesel exhaust Industrial air pollutants, especially from refineries and storage tanks Paint-manufacturing and sulfur-processing fumes Fumes from roof tar and roads Chemical additives and contaminants of food and water Insecticide and fumigant residues Some chemical preservatives Sulfur residues Chemical flavoring and sweetening agents Plastic containers and lined tins Chlorine in water Synthetic drugs, cosmetics, and miscellaneous chemicals Medications, including aspirin, sulfonamides, synthetic vitamins Allergic extracts or other biologic materials that contain phenol Cosmetics Synthetic textiles Bed linens washed with detergents, dried in gas driers, or impregnated with synthetic starch or sizing   Source: Randolph (1962). asthma caused by toluene diisocyantate (TDI) (Chapter 3) to a lupus-like syndrome caused by laboratory exposure to hydrazine (Chapter 4). Class B syndromes are those in which there is a variety of symptoms, sometimes highly subjective and difficult to quantitate, that result from exposure to several odorous chemicals. SBS and MCS fall into this category. These illnesses are highly controversial, and some researchers consider them to be hysterical in origin or a form of somatization (Terr, 1986); others consider them important, distinct clinical syndromes worthy of case definitions and serious study (Cullen, 1987). It is important to distinguish the two classes. Although there are solid scientific

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Biologic Markers in Immunotoxicology data to support the existence of class A syndromes, complaints of chemical susceptibility are sometimes dismissed as hysterical, even when there is a well-defined, quantifiable clinical response that is amenable to scientific study. Furthermore, there could be a relationship between emotional state and physiologic response. For example, a patient with occupational asthma who has had severe reactions to chemicals, such as TDI, might develop hysterical symptoms from exposure to other noxious odors. There have been several reports of chemical exposures that cause well-characterized class A illnesses in patients at dose levels normally tolerated by the population at large. It is well documented that low-molecular-weight organic compounds can cause allergic and autoimmune diseases, as in the case of a laboratory worker who developed a disease similar to systemic lupus erythematosus after exposure to hydrazine in the workplace (Reidenberg et al., 1983). The disease went into remission when the patient avoided contact, and then resumed—with symptoms of rash, fatigue, and arthralgias—within 2 days of the patient's resuming work with the material. Peripheral-blood lymphocytes from the patient and her twin sister, but not from three normal control subjects, showed a dose-dependent inhibition of the mitogenic response to concanavalin A after in vitro exposure to hydrazine. Pokeweed-mitogen-stimulated IgG production decreased in the patient and her twin sister after daily in vivo exposures to hydrazine. Provocative challenges have been used to document that inhalants, such as tobacco smoke and perfumes, can induce bronchospasm in some patients with asthma (Shim and Williams, 1986). Bronchoconstriction occurred after exposure to perfumes and colognes in four patients, with forced expiratory volume in 1 second declining 58% in the most severely affected. Shim and Williams's survey of 60 asthma patients found that more than half were sensitive to tobacco smoke, perfumes, or other inhalants; these patients made lifestyle changes to avoid contact with these substances. Substantial declines in pulmonary function after provocative challenges also have been documented in asthma patients with a history of sensitivity to tobacco smoke (Stankus et al., 1988). The onset of asthma in previously healthy individuals following a single high-level exposure to an irritating vapor, fume, or smoke has been termed reactive-airways-dysfunction syndrome (RADS) (Brooks et al., 1985a,b). Symptoms develop from minutes to hours after exposure, which is most often associated with an industrial accident. Respiratory symptoms and bronchial hyperreactivity persist for months to years, and chronic airways disease that is difficult to treat can result. An increasing incidence of depression in the United States has been documented (for a review, see Klerman and Weissman, 1989). In this tragic epidemic, the role of environmental chemicals or the stress imposed by our more complicated lifestyle has not been clarified. Psychiatric disorders that arise from exposure to specific organic compounds at levels tolerated by most persons are best documented for pharmaceutical agents. Depression and psychiatric disorders are associated with use of tricyclic antidepressants, scopolamine, amphetamines, phenylcyclidine, phenylpropanolamine, and other pharmaceuticals (Ellenhorn and Barceloux, 1988). Case reports of depression caused by the inhalation of home furnace fumes have been reported (Randolph, 1955). Cases of psychosis resulting from exposure to air contaminants at concentrations tolerated by the normal population have been described (Randolph, 1962). Toxic psychosis can occur from exposure to a number of chemicals, including organophosphate pesticides (Gershon and Shaw, 1961). Nasal disorders have been associated with exposure to some chemical toxicants. Vasomotor rhinitis, a condition of nasal congestion, and chronic rhinosinusitis, which is well recognized by allergists and otolaryngologists, can be exacerbated by exposure to

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Biologic Markers in Immunotoxicology fumes from solvents, newsprint, and vehicle exhaust at levels tolerated by the general population. A vasomotor lability is postulated for these intractable disorders, and patients report various degrees of relief to be achieved by avoiding contact with the irritants. In addition, some persons who have vasomotor rhinitis are sensitive to temperature changes, and some have symptoms that are exacerbated by drinking alcoholic beverages. Some workers with documented occupational exposure to various solvents are known to develop aversion reactions to odorous chemicals at levels tolerated by most people. Cacosmia has been defined as "nausea, headaches, and subjective distress in individuals exposed to neutral odors" (Ryan et al., 1988). Citing the "rich neural interconnections between the olfactory system and the temporal regions of the brain," Emmett (1976) hypothesized that complaints of cacosmia could correlate with decreased performance on neurobehavioral tests that are sensitive to dysfunction of the temporal lobe. Workers exposed to solvents, a group known to suffer from cacosmia, were targeted. Relative to a 17-member control group, solvent-exposed workers performed considerably worse on tests of learning and memory, spatial skills, attention and mental flexibility, and psychomotor speed and manual dexterity. There were no differences in tests of general intelligence, picture completion, or similarities subtests. Complaints of cacosmia correlated with poor performance on oral learning and immediate visual reproduction tests. Other investigators have documented complaints of fatigue, tension, irritability, mood changes, and difficulty with concentration and memory in solvent-exposed workers relative to controls (Husman, 1980; Juntunen et al., 1980; Struwe and Wennberg, 1983). Both cacosmia and neurobehavioral abnormalities in solvent-exposed workers can persist for long periods after the exposure ends. A study of 12 patients with nonarterio-sclerotic cardiac arrhythmias or chest pain had their arrhythmias reproduced by challenge with low airborne concentrations of chemicals that they inhaled (Rea, 1978). The objective measurement was cardiac rhythm. The exposures were double-blinded, but odor masking was not reported. Such cardiac reactions to challenges have been described (Harkavy, 1963; Taylor and Harris, 1970) and could represent cardiac anaphylaxis (Booth and Patterson, 1970; Levi, 1972). LaMarte et al. (1988) evaluated two patients who claimed that occupational exposure to carbonless copy paper caused hoarseness, cough, rash, and flushing. These patients also met the criteria for a scientifically verifiable chemical sensitivity. Patch testing was used to identify the causative chemical as alkylphenol novolac resin. A patient exposed in a blind study developed laryngeal edema that was verified by direct examination of the vocal cords by video endoscopy of the larynx. Plasma histamine was measured before and after challenge, and it rose by a factor of 6. Class B syndromes are much more difficult to understand conceptually and are more difficult to study scientifically than are class A syndromes, because of methodologic difficulties. SBS occurs when there is an outbreak of well-defined symptoms in occupants of a building (World Health Organization, 1983). Several outbreaks, with the most common symptoms being irritation of the eyes and mucous membranes of the respiratory system, headache, fatigue, and mental confusion, have been reported in association with tightly sealed, energy-efficient buildings. Questionnaires administered by physicians documented significantly greater numbers of complaints of headache, lethargy, dry skin, irritation of eyes, running noses, and dry throats in air-conditioned buildings than were found in naturally ventilated buildings (Finnegan et al., 1984). Differences in globe temperature, dry-buld temperature, relative humidity, moisture content, and air velocity, as well as concentrations of positive and negative ions, carbon monoxide, ozone, and

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Biologic Markers in Immunotoxicology formaldehyde have been eliminated in a comparative study as the cause of SBS (Robertson et al., 1985). Although complex factors could play a role in the syndrome, attention has focused on the presence of VOCs in poorly ventilated air; concentrations of VOCs inside office buildings greatly exceed outdoor levels (Hollowell and Miksch, 1981). Some authorities suggest that SBS is of psychologic origin or that it represents an anxiety state, mass hysteria, or a conditioned reflex. Investigators at the Karolinska Institute in Sweden have demonstrated, however, that blinded passers-by exposed to a mobile breathing chamber linked to the air supply of a "sick building" experienced the same reactions to building air as had the building's inhabitants (Berglund et al., 1984). Chemically related syndromes are distinct from syndromes associated with airborne microbiologic antigens associated with IgE-mediated outbreaks of respiratory illness in buildings (Solomon, 1990). A relationship between SBS and MCS was postulated by Hirzy and Morison (1991), after some workers exposed to new carpeting at the Environmental Protection Agency's Waterside Mall office in Washington, D.C., exhibited induction of MCS. After analyzing the data on temporal and geographic concentrations of 4-phenylcyclohexene in the mall, Hirzy and Morison (1991) suggested that this compound can produce symptoms characteristic of SBS and induce MCS. Controlled studies of humans exposed to mixtures of VOCs found in new homes are being undertaken and show promise in resolving controversy in this area. A Swedish study exposed chemically sensitive individuals to a representative mixture of VOCs and found subjective reactions of discomfort and reduced digit span, a measure of concentration (Molhave et al., 1986) Volunteers with no history of chemical sensitivity complained of increased headache, general discomfort, and unpleasant odor, but not cognitive dysfunction, when exposed to a similar mixture (Otto et al., 1990). Nasallavage data have been presented that suggest that polymorphonuclear cells migrate into the upper airway of humans 18 hours after a 4-hour exposure to VOCs (Koren et al., 1990). The concept of the chemical environment as an entity that causes disease was extensively discussed by allergist Theron Randolph in a series of papers culminating in his 1962 book Human Ecology and Susceptibility to the Chemical Environment (Randolph, 1962, and references therein). Randolph described a group of patients who had adverse reactions that resulted from apparent individual susceptibility to chemical compounds inhaled at doses far below normally toxic levels. Symptoms were different from those of allergic reactions and included chronic illnesses that he reported would go into remission when the subjects avoided the compounds that caused the difficulty. Table 9-1 is a list of the chemicals that Randolph reported to cause reactions in his patients. Table 9-2 lists the characteristics of the illness discussed by Randolph. The symptoms he described include a variety of physical complaints (headache, arthralgia, myalgia, palpitation, bronchospasm, and seizure) and mental complaints (loss of concentration, confusion, depression, irritability, inappropriate anger, hallucinations, and manic states). His work has been highly criticized, primarily by the academic community of allergists, who cite problems with his methods and with the lack of scientific evidence of the existence of the specific adaptation syndrome (Executive Committee of the American Academy of Allergy and Immunology, 1986). CASE DEFINITIONS OF MULTIPLE-CHEMICAL-SENSITIVITY SYNDROME On the basis of patients he and others had seen at occupational-medicine clinics

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Biologic Markers in Immunotoxicology TABLE 9-2 Randolph's Characterization of MCS An acquired disorder, often following an exposure to unusually high levels of an organic chemical. Symptoms related to chemical exposures both psychiatric (depression, mania, hallucinations, anxiety) and physical (arthritis, bronchospasm, rhinitis). Stimulatory syndromes triggered by acute exposures (for example, mania) followed by withdrawal symptoms hours to days after removal from an exposure (for example, headache, depression). Adaptative phenomena: chemically sensitive individuals do not have acute reactions to chemical exposures while living in the chemical environment; during this phase, chronically ill. Spreading phenomena: the illness progressive, with the patient becoming susceptible to larger numbers of chemicals and having more serious symptoms as the illness progresses. Avoidance: by avoiding the chemical environment, the chemically sensitive individual has resolution of symptoms and remains well. around the country, Cullen (1987) formulated a case definition of MCS. It has seven diagnostic features, which are listed in Table 9-3. Cullen's definition is highly restrictive and does not apply to many groups of patients with chemical sensitivities, such as asthma patients who react to odors; persons with SBS who complain only of headaches, mucous-membrane irritation, and lethargy; and individuals with xenobiotic-induced autoimmunity. Cullen proposed his definition to distinguish a specific population of patients from the many who claim chemical sensitivities, and although a population that fits this definition exists, further refinements will probably be made as academic physicians become more involved with research in this area. An operational definition has been proposed by Ashford and Miller (1989): The patient with multiple chemical sensitivities can be discovered by removal from the suspected offending agents and by re-challenge, after an appropriate interval, under strictly controlled environmental conditions. Causality is inferred by the clearing of symptoms with removal from the offending environment and recurrence of symptoms with specific challenge. A study that found objective abnormalities in a group of patients who claimed to have MCS was performed at the University of Pennsylvania's Smell and Taste Center. Eighteen subjects with a history of MCS were studied for abnormalities in olfactory threshold (Doty et al., 1988). Although the olfactory thresholds to phenyl ethyl alcohol and methyl ethyl ketone were found not to be elevated relative to a control group, nasal airway resistance measured with a rhinomanometer was higher both before and after challenges in the chemically sensitive group. Under some conditions, nasal airway resistance was increased by exposure to the chemicals. Before testing, patients in the control group and in the chemically sensitive group completed a survey to determine depression (the Beck depression inventory). Members of the group with MCS were scored as more depressed than were members

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Biologic Markers in Immunotoxicology TABLE 9-3 Cullen's MCS Case Definition The disorder is acquired as a result of some environmental exposure, insult, or illness that can be documented. Symptoms involve more than one organ system. Symptoms recur and abate in response to predictable stimuli. Symptoms are elicited by exposures to chemicals of diverse structural classes and toxicologic modes of action. Symptoms are elicited by demonstrable exposures. This criterion is to exclude delusional patients. Exposures that elicit symptoms must be very low—many standard deviations below the "average" exposures known to cause adverse human responses. No single widely available test of organ-system function can explain the symptoms. of the control group. This study—which could not be blinded, because one of its objectives was to measure olfactory threshold—illustrates that there are circumstances in which odor masking or blinding is not feasible or desirable. This study did not rely on patient assessment or symptom scores. Another study used structured diagnostic interviews and self-reported measures of somatization and psychopathology to determine that a group of MCS patients had a greater incidence of anxiety and depression than did a control group (Simon et al., 1990). The patients in the report of Simon et al. were workers from one plant. While many workers had complaints, only those with lingering problems were in the patient group. Psychiatric illness has been reported in chemically sensitive patients since the original description (Randolph, 1962), and many feel that chemical exposures lead to psychiatric illnesses. Others believe that psychiatric illness is causative, that is, chemically sensitive patients have a primary psychiatric illness that leads to an inappropriate aversion to odorous chemicals. Clinical research should be able to resolve this controversy. It will be interesting to see whether the techniques of Simon and collaborators can be used to establish or disprove this connection. IMMUNE-SYSTEM DYSFUNCTION IN MCS PATIENTS Three studies of immune-system markers in patients alleged to have MCS have offered conflicting results. Decreased absolute suppressor-cell counts and increased CD4:CD8 ratios relative to controls were found in one study (Rea et al., 1982), a decreased CD4:CD8 ratio was found in another (Levin and Byers, 1987), and no consistent abnormality was detected in a third (Terr, 1986). The study by Rea and his collaborators evaluated seven patients with rheumatoid arthritis, 70 patients with "vascular dysfunction," and 27 asthma patients. Chemical sensitivity was established by "inhaled challenge under rigid environmentally controlled conditions in a glass and steel testing booth. Challenges were double-blinded with three placebos acting as controls." Vascular dysfunction results in such symptoms as headache and mental

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Biologic Markers in Immunotoxicology confusion attributed to environmentally induced vasospasm. The study by Rea and co-workers (1982) grouped patients by diagnosis, and the abnormal values could result from the underlying disorder, rather than chemical sensitivity. Rheumatoid arthritis or other specific conditions are induced by or exacerbated by exposure to xenobiotic substances according to these authors. A different study of 43 patients with rheumatoid arthritis undergoing water fasting in a controlled environment reported statistically significant improvement of seven indicators of arthritis (Kroker et al., 1984). A long-term study to see whether interventions of this nature can modify chronic diseases seems warranted, given the inadequacy of current therapies for severe progressive rheumatoid arthritis. Rea et al. (1982) proposed that chemical exposure can induce vascular dysfunction that leads to symptoms that involve several organ systems. This could prove to be a unifying concept in explaining how symptoms can arise in more than one organ system. Further work in this area by other investigators is necessary to substantiate the hypothesis. Certainly, if odors or chemical inhalants were to induce localized vascular spasm in susceptible individuals, perhaps through an olfactory-limbic-autonomic link, a large number of clinical manifestations, from headache to myalgia, could result. The fact that the "vascular dysfunction" group of Rea et al. had a variety of unspecified T-cell abnormalities could be significant and warrants confirmation by independent groups. Levin and Byers (1987) have presented an elaborate theory of intolerance to the chemical environment that results from immune dysregulation. The evidence of this hypothesis involves a generalization supported by data from patients in Woburn, Massachusetts, exposed to trichloroethylene; individuals in rural Wisconsin exposed to a variety of industrial solvents, dyes, and pesticides; New Mexico workers exposed to industrial chemicals in a computer-chip factory; and residents of Catachee, South Carolina, exposed to polychlorinated biphenyls. These patients allegedly developed chemical sensitivities and had decreased CD4:CD8 ratios, which is opposite to the increased CD4:CD8 ratios found by Rea et al. Levin and Byers do not give scientific support or documentation that these patients are indeed chemically sensitive. Terr (1986) evaluated 50 patients with a diagnosis of EI for the California Worker's Compensation Appeals Board and found no evidence of immune-system dysfunction. He saw a group of patients with alleged chemical sensitivities who had histories of other disorders (such as asthma or depression). He compiled results of immunologic tests found in the medical records of these patients and performed by different physicians or laboratories, and he found no evidence of immune dysfunction. He concluded that the presence of other disease and the lack of evidence of immune dysfunction suggested that these patients did not have EI. His patients had a variety of complaints and diagnoses, and laboratory data were not standardized. He described no challenge procedures or other methods to determine whether the patients had exacerbations of their illnesses from exposure to the chemicals, even though the population included patients with such diagnoses as asthma and dermatitis, which clearly can result from occupational exposure. Terr's method for determining that there was no chemical associated with complaints was to argue that, because he could give other diagnoses to the patients' illnesses, they could not be diagnosed as having EI. This argument is inadequate for patients who are given other diagnoses that can be caused by or exacerbated by environmental exposures. Terr's conclusions are a poorly supported opinion expressed by one who has evaluated patients on behalf of a workers' compensation appeals board. The study of markers of effect on the immune system would have served as a more reliable basis for such evaluations. One group has studied antibodies to low-molecular-weight hydrocarbons complexed

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Biologic Markers in Immunotoxicology with albumin in chemically sensitive individuals (Thrasher et al., 1988). In a preliminary study, six patients with multiple subjective health complaints historically related to chronic formaldehyde exposure had antibodies to formaldehyde-human serum albumin (f-HSA) as follows: IgE (two patients), IgM (three of four tested patients), and IgG (five patients). All six patients had elevated levels of antigen memory cells (Ta-1). A flulike illness developed in these patients after exposure to formaldehyde. In a study of 67 patients with common complaints that included a lingering flulike illness, sensitivity to airborne chemicals, symptoms of emotional and cognitive distress, and upper and lower airway disease, 65 had antibodies to f-HSA (Broughton and Thrasher, 1988). The low titers in most cases (1:4 was the most prevalent) and inadequate data on titers in unaffected populations make these observations meaningless. In contrast, R. Patterson and collaborators (1989) have analyzed IgG antibody against f-HSA in 35 patients who either had symptoms attributed to formaldehyde exposure or had a history of intravenous exposure to formaldehyde from formaldehyde-sterilized renal-dialysis membranes. In no case was there a correlation between serum antibody titers to formaldehyde and disease. Only one of 16 patients with symptoms attributed to formaldehyde exhibited antibody, and the dialysis patients with high levels of specific IgG against formaldehyde had no sensitivity to airborne exposures. None of the studies discussed here can be considered conclusive. The hypothesis that there is something called "environmental illness" characterized by immune dysregulation and hypersensitivity to chemicals has not been rigorously supported. However, there is strong evidence that groups of patients with specific immunopathologic diseases can have their illnesses exacerbated by or even caused by xenobiotic exposure. Well-established examples include xenobiotic-induced lupus and asthma induced after exposure to airborne chemicals. A crucial step in resolving the intense controversy in the area of chemical sensitivities will be the development of refined terminology. To this end, members of the subcommittee believe that whenever possible the term "multiple chemical sensitivity" should be replaced with a specific diagnosis to avoid the confusion between diagnosis and etiology that is inherent in the term. The application of a specific diagnosis should not exclude the possibility that the illness could be related to chemical exposures. If a patient has emphysema secondary to cigarette smoking, it is clear that the diagnosis is emphysema, and the etiology of the disease is cigarette smoking. The MCS label implies that chemical exposures make the person ill, but many different clinicopathologic entities can arise from adverse reactions to chemicals. Hence, MCS has been used by various observers to describe a broad range of problems, ranging from cardiac arrythmia or vasculitis reproducible by challenge to somatization disorders with reactions to sham challenges. An analogous case applied to a patient with asthma who is allergic to pollens, molds, danders, house dust, and mites would be to give a diagnosis of multiple aeroallergen sensitivity. In this case, the diagnosis of extrinsic asthma is one appreciated by all physicians and patients. BIOLOGIC MARKERS OF SENSITIVITY TO CHEMICALS Provocative Challenge Provocative challenge, in which individuals with alleged hypersensitivity are exposed to incriminated chemicals in a blinded fashion, is the standard in the field of human immunotoxicology. Ashford and Miller (1989) found agreement on this point in their interviews of allergists and clinical ecologists. However, provocative challenge is a research tool only, and it must be refined. One problem involves odor masking for testing individuals who might suffer from cacosmia,

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Biologic Markers in Immunotoxicology that is, who could react nonspecifically to any strong odor. Skin Tests Skin testing with automobile exhaust, formaldehyde, and synthetic alcohol, for example, has been used as a diagnostic test for chemical hypersensitivity. For skin tests to be accepted, several large, independent studies of patients must demonstrate that persons with verified MCS have positive skin tests, and that an equal number of individuals without MCS have negative skin tests to these substances. Until these studies are done, skin tests must be considered experimental and a research tool. ANTIBODIES TO FORMALDEHYDE-HUMAN SERUM ALBUMIN ADDUCTS One group has advocated using the presence in serum of f-HSA antibodies as a biologic marker for MCS. For these tests to be accepted, it must be demonstrated in several large series of patients by independent investigators that persons with verified chemical susceptibilities have positive tests and that an equal number of individuals without unique problems associated with chemical exposure have negative titers to these antibodies. Until these studies are done, these tests must be considered experimental and a research tool. Avoidance Regimens Isolation from the chemical environment, with resolution of chronic symptoms, has been advocated as a diagnostic tool for MCS. The ubiquitous presence of VOCs and the claim that patients can acclimate—not react acutely to chemical exposures, but have chronic symptoms while continuously exposed to low levels—make this an attractive method for diagnosis. This approach is applied by clinicians of all persuasions in diagnosing drug intolerance and should be a valuable research and clinical tool, whether the chemical exposure associated with the problem is airborne or dietary. T-cell Helper-to-Suppressor Ratios Ratios of CD4 to CD8 cells, measured by fluorescence-activated cell sorters or other instruments, have been proposed as biologic markers of chemical sensitivity. Rea et al. (1982) suggest that this ratio is elevated for patients with some, but not all, diagnoses. Because there is considerable overlap between normal and affected subjects, this test is of no use in the clinical evaluation of individual patients. Levin and Byers (1987), on the other hand, claim a decrease in this ratio; Terr (1986) finds no abnormality of the ratio. However, the exposure in the workplaces may not be equivalent. The CD4:CD8 ratio cannot be recommended as a biologic marker for chemical sensitivity, although it could have some use in comparing groups of patients in clinical research settings. CONCLUSIONS There are several distinct clinicopathologic entities that in selected cases are either caused by or exacerbated by exposure to xenobiotic substances, particularly low-molecular-weight organic chemicals. These include asthma and rhinitis, cacosmia as defined by Ryan et al. (1988), autoimmune diseases (including systemic lupus erythematosus), laryngeal edema, depression, psychosis, and other neurobehavioral disorders. Although the associations between these disorders and xenobiotics have best been demonstrated for pharmaceuticals, the extent to which inadvertent exposure to environmental toxins, particularly the VOCs found in indoor air and the natural and additive

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Biologic Markers in Immunotoxicology chemicals found in foods, can induce or exacerbate physical disorders remains an important public-health question. The sick-building syndrome is a real phenomenon, in which susceptible occupants of closed buildings have symptoms of headache, eye and nasal irritation, mucous-membrane irritation, lethargy, and difficulty with concentration. A role for VOCs in the etiology of this syndrome is suggested, and the hypothesis that this syndrome is solely of psychologic origin is not consistent with existing data. The reported evidence is inadequate to define a distinct clinicopathologic entity, MCS syndrome, that is different from the associations between the chemicals and illnesses discussed above. However, there is a significant patient population—poorly enumerated, but growing—that claims dysfunction and disability due to an intolerance to xenobiotics (mostly VOCs) at levels commonly encountered in industrialized societies and apparently tolerated by most people. There is insufficient evidence to ascribe an immune etiology to this disorder. The medical profession has not developed consistent or adequate approaches to the evaluation, treatment, and reimbursement of such patients. Social agencies, insurance companies, and other societal groups cannot deal effectively with this patient population until the medical questions are resolved. Even with a concerted effort, it will be some time before this can happen, and humane and uniform interim measures must be instituted to help affected persons. The use of anecdotal reports without standardized case definitions and attention to alternative explanations will not resolve the current controversies surrounding this issue. A series of well-designed studies, including studies in controlled-exposure facilities and multiple epidemiologic and psychosocial studies, is required to address this problem. RECOMMENDATIONS Because sick-building syndrome appears to be a real phenomenon caused by contamination of indoor air with VOCs that cause discomfort to a substantial number of persons, programs should be developed to establish indoor air pollution standards for homes, schools, and workplaces. These standards should restrict VOCs or other chemicals involved in indoor air pollution to levels below those at which significant numbers of occupants suffer headaches, mucous-membrane irritation, eye and nose irritation, lethargy, and difficulty with concentration. Well-designed clinical and epidemiologic studies that use appropriate immune-system biologic markers should be performed to investigate the relationship between environmental chemicals and specific syndromes of uncertain origin, namely MCS. A workshop was convened with experts from environmental and occupational medicine, allergy and clinical immunology, epidemiology, public health, immunology, psychiatry, and other disciplines to advise the Subcommittee on Immunotoxicology on the MCS syndrome. The proceedings of this workshop will be published later. The recommendations of this workshop were: A case-comparison study of patients seen in occupational and environmental medicine should enroll patients who claim to respond to low levels of environmental chemicals. The information from this multi-center study should be used to study the prevalence of MCS in the general population. Populations with well-defined exposures, such as victims of a toxic spill or workers with uniform occupational exposure, could be studied longitudinally for the development of chemical sensitivities. Patients with multiple chemical sensitivity will be selected because of symptoms or signs related to chemical exposures at levels tolerated by the population at large. The chemicals in

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Biologic Markers in Immunotoxicology question are different from the well-recognized allergens, such as dust, molds, pollens, and danders. Symptoms must wax and wane with chemical exposures and may occur in one or more organ systems. Although many patients describe the onset of this syndrome with an acute toxic chemical exposure, such an initiating exposure is not required for inclusion. Patients with pre-existent or concurrent diseases such as asthma, arthritis, and psychiatric illnesses are not to be excluded from study, because many believe that chemical exposures play a role in inducing or exacerbating these conditions. Research units or environmental control units in which MCS patients will be housed in a chemical-free environment are needed. Challenges will then be conducted in a double-blinded fashion with attention to adaptation and de-adaptation phenomena. Responses of patients to controlled exposure should be monitored with immunologic, neurologic, endocrinologic, psychologic, and social markers and measures. Dose-response relationships should be studied.

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