Multiple Chemical Sensitivity: Potential Role For Neural Sensitization

Program in Neuroscience, Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 991646520

* Address all correspondence to: Barbara A. Sorg, Ph.D., Program in Neuroscience, Department of VCAPP, Washington State University, Pullman, WA 991646520; Phone, 5093354709; Fax: 5093354650; email: barbsorg@vetmed.wsu.edu

ABSTRACT: An emerging issue in environmental health is the phenomenon of multiple chemical sensitivity (MCS). Multiple chemical sensitivity is a controversial disorder characterized by multiorgan symptoms in response to lowlevel chemical exposures that are considered safe for the general population. The onset of MCS is often attributed to prior repeated chemical exposures in the home and/or workplace, and, once initiated, symptoms are triggered by extremely low levels of many chemicals/foods. No single case definition exists for MCS due to several issues that call into question its validity as a distinct illness induced by prior chemical exposure. Hypotheses regarding the etiological basis for MCS range from direct toxicological effects of chemicals to the notion that MCS is purely a psychological "belief system". One leading hypothesis suggests that MCS represents a neural sensitization phenomenon, wherein susceptible individuals demonstrate extreme sensitivity to chemicals and odor intolerance due to central nervous system (CNS) sensitization processes. The recent development of an animal model for MCS provides some support for the sensitization hypothesis and may offer evidence for behavioral changes observed in at least a subset of those reporting MCS.

KEY WORDS: chemical intolerance, multiple chemical sensitivity, sensitization, mesolimbic dopamine, conditioned fear, avoidance, Gulf War Syndrome.

Multiple chemical sensitivity (MCS) is a phenomenon whereby individuals report an increased sensitivity to chemicals in the environment and attribute their sensitivities to prior exposure to the same or often structurally unrelated chemicals. Multiple chemical sensitivity has been reported in several groups of individuals, including a subset of those exposed to "sick buildings", pesticides, solvents involving volatile organic compounds (VOCs), and those serving in the Persian Gulf War (Gulf War Syndrome).Among the most common symptoms reported in MCS are extreme fatigue, headache, gastrointestinal problems, muscle and joint pain, depression, memory and concentration difficulties, irritability, dizziness, anxiety, and upper airway irritation 1-4 Several additional symptoms have been reported after exposure to a wide range of chemicals and are shown in Table 1. Multin.system complaints are common, and a widely used definition of MCS described.by Cullen 5 includes the involvement of multiple organ systems as one of its defining features.

ACTH, adrenocorticotropic hormone; CGRP, calcitonin generelated peptide; CI, chemical intolerance; CRH, corticotropinreleasing hormone; HPA, hypothalamicpituitary adrenal; IL1, interleukin1; MCS, multiple chemical sensitivity;NKA, neurokinin A; SubP, substance P; VTA, ventral tegmental area; VOC, volatile organic compound.

The development of MCS has been described as a dualphase process. 1,6,7 The initiation phase is thought to be the stage during which either repeated exposure to chemicals, a highlevel chemical exposure (such as that occurring during a chemical spill), or other stressful life events initiate the process of later sensitivity to chemicals. Thus, the initiation of MCS appears to set the individual on a course during which very low levels of subsequent chemical exposure elicit the symptoms described above. The experience of symptoms is described as the elicitation phase; it is during this phase that individuals report extreme sensitivity to odors and feelings of illness from chemical exposures encountered at the home and workplace. Another term used for the elicitation phase is triggering.1It is emphasized that while MCS is typically thought to be initiated by extremely lowlevel, repeated exposures, this conception may be inaccurate. The initiation of MCS may well be caused by low or moderate exposures (as in a remodeling event or pesticide spraying), or even highlevel exposure (as in a chemical spill), while the elicitation of symptoms after a subsequent encounter with chemicals appears to occur at much lower levels. Fiedler et al.8 have reported that less than 40%of MCS patients in their study could not identify an initiating event. Further, other events, such as previous life stressors, should be considered as possible initiators of MCS.9-11 Another distinction between the two phases of MCS is that the number of chemicals that appears to initiate MCS, while diverse, is not as widely varied as the number of chemicals that triggers symptoms in chemically sensitive individuals.1

There are likely varying degrees of disabling symptoms in individuals reporting MCS, but some reports indicate that the prevalence of severe MCS in the U.S. is approximately 4%, 10,12with a greatly reduced quality of life for the patient.13However, additional studies need to be conducted to ascertain the proportion of the population reporting the most severe symptoms. Less severe problems with chemical exposures have been reported in approximately 15 to 30% of the population. 10,14,15

Respiratory
Dyspnea, cough, chest pain and tightness, shortness of breath, rhinorrhea, nasal and eye burning, pharyngeal irritation

A recent review of several studies revealed a highly consistent ratio of women to men of approximately 4:1, with an average age of onset in the fourth decade.16 There exists increasing political, social, and economic pressures to find a case definition for MCS. MCS patients visit their health care provider an average of 23 times per year.2 The costs to society are also incurred through lost productivity and disability payments.

Despite the prevalence of MCS reports in the U.S. population, the etiology and very existence of MCS is intensely debated for several reasons. Many of these are briefly mentioned here but are outlined in greater detail below. First, myriad symptoms resulting from chemical exposures have been reported (see Table 1), and a single case definition has not been agreed on to date. Second, objective physical signs underlying the many symptoms have not been consistently found. Third, extremely low levels of chemicals have been reported to elicit symptoms. Fourth, doubleblind chemical challenge studies are difficult to conduct due to odors associated with the chemical, and a causeeffect relationship thus has been difficult to rigorously establish. Finally, strong overlaps exist with symptoms of other disorders, including somatoform disorder, chronic fatigue syndrome, fibromyalgia, panic disorder, and posttraumatic stress disorder.

Patients with MCS generally experience a reproducible constellation of symptoms, but each patient may have a different set of symptoms to the same chemical. Thus, there is often a specificity within each patient, although some have reported a change in symptoms from a particular chemical over time.1 Another common feature in MCS is intolerance to various foods. Rea17 reported that 80% of those with MCS have food intolerance. In addition, individuals reporting MCS are intolerant to the effects of alcohol and other drugs, including medications, making the feasibility of conventional pharmacotherapies questionable at present.

The reason for the growing number of individuals with MCS in the population is unknown. The increase may be attributed to an everincreasing popularization of the belief that environmental chemicals can produce MCS. Alternatively, there may be a proportion of the population that is sensitive to repeated exposures to some of the approximately 70,000 chemicals currently on the market; notably, relatively few of these chemicals have been tested for behavioral effects. 18,19

Typically, those with MCScomplain of ill effects from chemicals that are present in very low concentrations in the environment (the elicitation phase), suggesting that an amplification has occurred in either the direct effects of chemicals or the perception of illness from chemicals. Bell et al.7 have described a mechanism by which this amplification may occur. They have noted that MCS has many parallels with the phenomenon of neural sensitization in rodents observed after repeated exposure to drugs of abuse as well as environmental stressors. Neural sensitization is defined as the progressive and enduring enhancement in behavioral and neurochemical measures after repeated, intermittent exposure to a variety of stimuli, the most common of which are psychostimulants and environmental stressors.20,21 Bell and coworkers7 have postulated that limbic regions of the central nervous system (CNS) become sensitized by repeated chemical or life stressors and produce heightened responsiveness to later presentation of chemicals.

Another potential model of MCS first proposed by Bell et al7 is that of limbic kindling. Kindling is a form of sensitization in which repeatedly presented electrical stimuli to the brain (usually the amygdala) that initially do not produce seizures can, with the passage of time, produce fullblown seizures in response to the same level of stimulus.22

The majority of this review presents findings from studies that provide a general description of MCS as well as the controversial issues surrounding this phenomenon, and also explores a variety of hypotheses regarding the etiology of MCS. The last part focuses on the development of animal models for MCS, with a primary emphasis on the neural sensitization hypothesis. A model based on this hypothesis has been developed recently in this laboratory, and the findings provide some evidence to support a role for CNS sensitization after repeated chemical exposure.

A few points about terminology used throughout this review should be noted. First, the use of the phrases "MCS patients" or "individuals with MCS" refers to those individuals with a constellation of symptoms that do not describe any other single illness and best fit the phenomenon currently called MCS (as often defined by the Cullen criteria; see below). Use of this term is not intended to imply a known origin of chemical exposures in producing the state of MCS. It is the intent of this review to explore various hypotheses, including chemical exposures, to explain the onset/maintenance of MCS. Second, unless otherwise specified, throughout this review use of the word "chemical" refers to chemicals entering the body via inhalation, dermal contact, or ingestion (as with foods).

Vague descriptions of an MCSlike phenomenon date back to over 100 years. Charles Beard23 described a disorder called "neurasthenia", in which individuals experienced mental and physical fatigue, inability to concentrate, loss of memory, irritability, poor sleep, food intolerances, and other symptoms similar to MCS.24 A term originally proposed by Cullen,5 MCS was described as follows: "MCS is an acquired disorder characterized by recurrent symptoms, referable to demonstrable exposure to many chemically unrelated compounds at doses far below those established in the general population to cause harmful effects. No single widely accepted test of physiologic function can be shown to correlate with symptoms". A more recent survey of physicians suggests the following criteria be used: (1) affected individuals report symptoms following exposures at very low levels to multiple, structurally unrelated chemical substances; (2) the responses are reproducible; (3) the symptoms resolve or improve when the incitants are removed; and (4) the condition is chronic.25

Several different names have been proposed that are synonymous with MCS, including allergic toxemia, cerebral allergy, chemical AIDS, ecological illness, environmental illness, idiopathic environmental intolerances, immune dysregulation syndrome, multiorgan dysesthesia, systemic candidiasis, total allergy syndrome, 20th century disease, yeast disease, and odor aversion.26-30

Recently, the term "Chemical Intolerance " (CI) has been used to describe a feeling of illness from low levels of environmental chemicals and is sometimes used interchangeably with MCS, although it encompasses a broader range of individuals who have been diagnosed with other conditions and (often illdefined) illnesses. For example, new onset food and chemical intolerance is reported in 80% of Gulf War Veterans who have become chronically ill with Gulf War Syndrome,31 60% of solventexposed workers,32 approximately 30% of chronic fatigue syndrome and 25 to 50% of fibrornyalgia patients.2 Chemical intolerance in these populations suggests some potential overlaps with these phenomena (see Overlaps with Psychiatric Illness and Other Disorders below). Like MCS, up to 70 to 80% of those reporting CI are women.8,33

Another issue closely related to the MCS phenomenon is Sick Building Syndrome (SBS). Sick building syndrome is a syndrome in which the symptoms are similar to MCS,34 but are generally experienced only while the individual is located in the "Sick Building". Poor air quality, temperature, workplace stress, volatile toxic chemicals, infectious agents, and mass hysteria (currently termed mass psychogenic illness) have all been implicated in SBS.34-40

Miller4l has introduced the term "toxicantinduced loss of tolerance" or "TILT" as a mechanism for MCS. The phrase "loss of tolerance" is intended to avoid confusion with "sensitivity" and "sensitization", terms used by allergists to describe welldefined immune responses. Loss of tolerance is described as a loss of natural tolerance to low levels of environmental chemicals.' Miller postulates that chemical exposures produce a broad range of diseases involving single organ systems (as in migraine or asthma) or multiple organ systems (as in MCS or Gulf War Syndrome). This theory suggests that chemical sensitivity is a sentinel symptom for the TILT family of illnesses, as fever is for infectious diseases. The authors hypothesize that the intolerance to chemicals represents a class of disorders, similar to multiple types of cancer, which can be brought about by different mechanisms.

Finally, MCS is believed by some to be a "fashionable illness";42 in other words, simply another name for illnesses throughout history for which no conventional cause has been found, such as hysteria, neurasthenia, fibromyalgia, Da Costa's syndrome, soldier's heart, and reactive hypoglycemia, among others.43,44

Several arguments have been made for and against the existence of MCS as a disorder caused by prior exposure to chemicals. At the heart of the debate is whether exposure to chemicals is capable of initiating a longlasting sensitivity (MCS symptomatology) to subsequent presentation of lowlevel chemicals in the environment. There exist several reasons that clinicians/investigators have questioned the validity of MCS as a disorder produced by chemical exposures. These are each addressed below.

Nearly all reports of exposure are retrospective, excepting rare cases in which possible causative exposures are known, such as extensive remodeling in the workplace.' Some MCS patients indicate that there is no identifiable exposure that initiated a progressive sensitivity to environmental chemicals/foods, but the relative percentage that cannot identify an initiating event has not been studied in depth. Therefore, MCS can be physician or selfdiagnosed, but is often based on the patient establishing the causal relationship between exposure and symptoms, and selfreporting of symptoms can be unreliable.45 On the other hand, the argument can be made that most psychiatric illnesses are based on selfreporting, and no diagnostic tests are currently available for these disorders, yet many are treatable.

Table 1 lists some of the most common symptoms reported in MCS. The wide variety of symptoms in several organ systems has hindered development of any clear diagnostic criteria for MCS.

Most clinicians report no changes in measures of physiological function that could explain multisystem complaints in MCS 42,46 -55 Some MCS symptoms appear similar to those reported after organic solvent exposure. There are overlaps between MCS and solventexposed individuals, but there are also some apparent differences, including average length of exposure and chronicity of symptoms.54 It is not known if there may be similar mechanisms in producing overlapping symptoms between individuals with MCS and those with higherdose solvent exposures; thus, some of the main findings from solvent exposures will be mentioned briefly. Several studies have documented complaints such as fatigue, irritability, mood changes, loss of concentration and memory in solventexposed workers56,58 and after pesticide exposure.4,59,60 In solventexposed workers, a delay of the P300 latency of the auditory evoked potential, a measure of attentional performance, was decreased.61 Workers exposed to solvents have demonstrated decreased performance on learning and memory, attention, and mental flexibility62 and complaints of cacosmia, a feeling of illness from chemicals,63 have been associated with poor performance.62 Intolerance to chemicals has been reported in 60% of solventexposed workers,32 and intolerance was the best predictor of cognitive deficits rather than cumulative exposure to the chemical.63

In patients with MCS and those reporting Cl, some deficits in cognitive function have been found on verbal54 and visual memory tests.8 Slower reaction times in a divided attention task have been demonstrated in a community elderly group with intolerance to chemicals.64 Bell et al.64 suggest that the cognitive deficits may be due to sleep disturbances in this population.65 A decrease in cognitive function, especially in tasks that demand high attention, may be explained by an increased resting EEG alpha activity in the right frontal region.66

Neuroimaging studies have demonstrated regions of hypoperfusion after chemical exposures.67,68 However, Mayberg69 has pointed out that caution is warranted in these studies due primarily to the variety of behavioral states of the patient during brain scans.

A number of medical and psychiatric diagnoses have been made in those who consider themselves intolerant to chemicals or describe themselves as "chemically sensitive".70 Among the symptoms in collegeage students are nasal allergies, hives, breast cysts, premenstrual disorder, and childhood hyperactivity.14Among communitybased middleaged individuals, rhinitis, migraine, irritable bowel, ovarian cysts, menstrual dysfunction, depression, anxiety, and panic disorder are found.70 Community elderly also rate higher for a number of these physician-diagnosed symptoms.10

One of the difficulties in acceptance of MCS as a diagnosis is that a wide variety of chemical structures found in pesticides, carpets, and organic solvents, among thousands of other chemicals, are reported to produce similar biological responses. Table 2 presents a list of some of the chemicals commonly reported by MCS patients to either initiate and/or trigger MCS. The multiple substances to which individuals are sensitive are often chemically unrelated. These observations are in contrast to food/drug allergy, in which immunologic specificity is demonstrated objectively by inflammation. In addition, allergic reactions are welldefined responses, such as rhinitis or asthma. Interestingly, several of the classes of compounds listed as problematic in Table 2 have been shown to induce apoptosis.71-78 Although speculative, an apparent nonspecificity of responses may be due to sensitivity of certain transduction pathways in various cell types to chemicalinduced apoptosis.

There does not appear to be a doseresponse curve in symptom provocation (elicitation phase).79,80 For all toxicants, there is a limiting dose below which no response occurs. However, in MCS, symptoms are reported at levels that are far below the no observed adverse effect levels (NOAELs). It should be stressed, however, that elicitation of MCS symptoms by apparently very low exposures should be considered separate from initiating exposures, which may be much higher in at least a subset of individuals (see Overview of MCS). Toxicologists maintain that elicitation of symptoms in MCS patients does not follow standard doseresponse relationships, although the threshold of response is difficult to determine due to the nature of the doseresponse curve at very low levels.81 Low threshold limit values (TLVs) are determined by different criteria for different chemicals (i.e., based on odor, irritation, systemic effects on organs).81 A commonly accepted line distinguishing normal from abnormal responses is the 95% level; values lying outside this are regarded as deviant.

One of the difficulties in acceptance of MCS as a distinct disorder is the widespread overlap with other illnesses and disorders, some of which are illdefined themselves. Buchwald and Garrity2 have examined patients diagnosed with chronic fatigue syndrome, fibromyalgia, and MCS. Approximately 50 to 70% of those with chronic fatigue syndrome and fibromyalgia reported sensitivity to solvents, perfumes, and other odors that MCS patients report as triggering symptoms. The authors suggested that these three illnesses may in fact be identical. Slotkoff et al.82 has also recently shown that approximately half of fibromyalgia patients report nonmusculoskeletal symptoms suggestive of MCS and sensitivity to several chemicals. In addition to chronic fatigue syndrome8,33,83 and fibromyalgia,2,8,33 MCS symptoms appear to overlap with other illnesses, such as somatization or hysteria,42,51,52,84 depression,8,85 anxiety (especially panic disorder),42,49,51,86,87 and personality disorders.88

Although doubleblind challenges are particularly difficult where odors are concerned, some studies have been reported in the literature. Rea and coworkers89-92 demonstrated that a subset of MCS patients responded to relatively low levels of doubly blinded chemical challenges at a significantly higher rate than placebo presentation. Patients were housed in a chemically lesspolluted environment and were fasted for 3 to 4 days prior to challenge. However, it is difficult to determine whether the study design was truly blinded, because the patients may have detected the chemicals via olfaction.92 Other studies reported no significant differences between responses to chemicals and to placebo.93-95 These studies have been criticized because they were conducted in the deadapted state (i.e., no previous removal of the individual from ambient air in the home and workplace), or highlevel chemical challenges were "masked" by copresentation of other odors such as peppermint, so that the selfreported problem chemicals would not be detected. Another argument that has been made for the equivocal results by challenge studies is that not all patients will react within minutes; some MCS patients report symptoms hours after a chemical exposure .92 Difficulties in interpretation of challenge studies occur when negative results are found, including the criticisms that the challenge period is too short or the challenge dose is not high enough.96

Ashford and Miller1 strongly advocate the use of an "environmental medical unit" (EMU) to isolate individuals from background exposures to chemicals prior to challenge studies. They suggest that an ideal window for removal from daily exposures to an EMU and challenge exposure is 4 to 7 days. The deadapted state (not in a state of tolerance) has been emphasized heavily for immunologic testing for food and other sensitivities.96,97 Some of the major criticisms expressed by Ashford and Miller1 are that (1) subjects are most often not in a deadapted state prior to challenge, (2) open challenges should be performed prior to blind challenge (or masking challenge) to ensure that subjects are not reactive to placebo, and (3) care must be taken regarding the time since the last exposure so that the individual is not still reacting to the last exposure. These criticisms have arisen due to reports that patients become acclimated to chemicals and experience chronic symptoms as long as they are exposed to incitants, but will not react acutely to chemical exposures unless removed from the problem chemicals for several days prior to challenge.

Few studies have employed a design that incorporates similarly exposed individuals who do not develop MCS symptoms. This issue seems critical, given the confusing picture thus far presented by the MCS phenomenon. Several parameters (physiological, neuropsychological, psychiatric) need to be compared between the two groups and followed longitudinally to identify changes relevant to MCS, as has been suggested previously.98 Notably, Bolla 99 performed neuropsychological testing in 35 individuals who were chemically exposed and healthy controls. Half of the chemically exposed met the Cullen criteria for MCS. Tests of verbal learning and memory, executive function, and psychomotor function were performed. While the MCS group performed below the nonexposed controls, they were no different from the nonMCS, chemically exposed group. While the argument could be made that only basal states were tested (i.e., in the absence of a chemical challenge), the results from this study suggest that the changes in performance may only be indicative that chemical exposure has occurred. Thus, the pattern of neuropsychological and/or physiological responses is just as likely to be compensatory that brings the system back to homeostasis, but is unrelated to MCS.

Recently, longitudinal studies have been carried out in PTSD (My insert: Post-Traumatic Stress Disorder) patients to determine biochemical differences between those who do and those who do not develop PTSD after traumatic stimuli. Cortisol levels measured immediately after trauma were lower in those who later developed PTSD.100 PTSD is often described as a sensitization disorder, and, based on the longitudinal studies above, it has been suggested that certain individuals may be predisposed to become sensitized to traumatic stressors.100 If there are similarities between MCS and PTSD (see Psychogenic Origin below), MCS may also be an endpoint reached by those predisposed to sensitization to environmental stimuli in the form of chemicals/foods. Therefore, identification of pathological changes that may contribute to or predict the onset of MCS will be a critical step toward understanding this phenomena. The question remains whether MCS represents the extreme on a continuum of sensitivity to chemicals in the environment or whether it is a qualitatively different pathological state.

Patients with MCS often seek the help of a clinical ecologist. The clinical ecologist, Theron Randolph, as well as others, proposed that exposure to small amounts of environmental substances, including food and environmental chemicals, could contribute to psychological and somatic illnesses.101,102 The primary tenets of clinical ecology rest on Selye's general adaptation syndrome, in which adaptation to stressors occurs, and at some point adaptation is compromised.103 Similarly, clinical ecology posits the "total load" theory of chemicals and environmental stressors: at a particular level of total load, the individual loses adaptability and illness results.

The fundamental elements of the adaptation hypothesis are (1) there exists a biphasic pattern of response to the incitant. An increased biological response followed by a withdrawal period occurs. As individuals are exposed to a multitude of substances daily, they may be in stimulatory and withdrawal states for different substances at any given time. It is postulated that these stages overlap and thus have a high likelihood of interfering with attempts to observe causeandeffect relationships between chemical/food challenge and symptoms.

The treatment procedures have largely been criticized by the medical establishment due to unorthodox testing and treatment procedures. 104-106 Briefly, treatment by a clinical ecologist consists of three key phases. First, systematic avoidance of the offending agent is made, including strict dietary restrictions and living within an environmental chamber that isolates the individual from exposure to chemicals. Second, provocation with the offending agent is made to establish which chemicals/foods produce symptoms. Neutralization is the third process, whereby a lower dose of the offending agent is delivered, often sublingually or subcutaneously. This neutralization procedure has been used in asthma and food allergy.107,108

In a review of 50 cases of patients diagnosed with MCS, 60% developed one or more new symptoms during the therapy provided by clinical ecologists.47 Although there is no similar report of patients who were not involved with therapy from clinical ecologists for comparison, the findings indicate that, in this group of patients, these therapeutic strategies do not alleviate symptoms in the majority of MCS patients. In contrast, another study of 42 patients indicated statistically significant improvement on the MMPI and Weschler Adult Intelligence ScaleRevised (WAISR), including "alienated depression, ineffectiveness, effortful processing, vigilance and effective energy", although the study was conducted over a 1 month period only.l09

Of primary concern is that, in perhaps a substantial subset of MCS patients, reinforcement by clinical ecologists to avoid what are believed to be harmful chemicals may strengthen any phobic anxiety and avoidance, further producing social, dietary, and occupational restrictions that are potentially harmful.

Numerous investigators/clinicians have considered possible cause(s) of MCS and have largely become aligned with one of two views: the origin of MCS is either "psychogenic" or "biogenic" (i.e., toxogenic) in nature. Psychogenic explanations posit that MCS patients have a traditional psychiatric disorder, and that the symptoms of MCS have been misattributed to environmental chemicals/foods. Biogenic explanations, often made by clinical ecologists, argue that environmental agents are the primary cause of physiologic as well as psychologic symptoms. Some physicians/investigators believe that both environmental and psychologic factors are key elements.110

At this point, it is worth addressing what is meant by the term "psychogenic" or "psychologic". A tremendous lack of understanding neurochemical events underlying physiological/behavioral responses forces consideration of these terms to describe the origin of and/or contribution to the maintenance of MCS, as well as other illness states (see below). Some argue that the distinction between psychological and physiological is artificial and therefore this division should be abandoned. However, Gots 111 reasons that a distinction between psychogenic and biogenic explanations for MCS is necessary when treatment issues are considered. For example, he points out that dizziness due to ear infection is treated with antibiotics, while dizziness caused by stage fright is treated with behavior modification and anxiolytics, and argues that medical practice must be based on current knowledge. Use of the term psychogenic in this review is an acknowledgment that specific neurochemical processes guiding physiological/behavioral events are not well understood. Therefore, at least for the present, terms such as psychogenic or psychological may be most practical for the purposes of designing current treatment strategies. However, their acceptance and use should not preclude continuous reevaluation of more accurate terminology to describe neurochemical events that drive physiological/behavioral responses.

The absence of objective physiological changes to explain symptoms reported in MCS (see above) combined with the high incidence of psychiatric illness have pointed to the possibility that there is a strong psychological component in the presentation of MCS. Psychological exacerbation of several disease states has been documented for years, among them are cancer, 112 heart disease,113 chronic pain,114 asthma,115 and headache.116-118 Therefore, it is reasonable to expect that psychological processes may influence the development and/or course of MCS.

Psychiatric evaluations of MCS patients indicate a higher rate of depression,8,51,85,88 anxiety,42,49,86,87 somatization disorder,51,86 and personality disorders.88 Patient history indicates that psychological and sometimes physical symptoms existed prior to the reported chemical exposure 42,48 Clinical ecologists submit that symptoms, including psychological, can be explained by immune dysfunction, or that psychological symptoms are a result of chronic illness. A second school of thought maintained by some psychiatrists is that MCS represents a psychiatric disorder in which primary or secondary gains are sought.119 Staudenmayer and Selner119,120 have suggested that MCS is an "irrational belief system" that chemicals produce symptoms, and suggest that at least half of MCS patients could be deprogrammed of their beliefs, while the remaining have true sensitivities to chemicals. Investigators also suggest that among the MCS population, there is a subset that has true sensitivities to chemicals, but fail to further address the latter topic and thus to some extent reinforce the view that the majority of MCS patients can be relieved of symptoms via behavioral modification.95

Some of the studies implicating a psychological component in MCS have been criticized due to methodologic problems ranging from bias in sample selection (i.e., patients involved in litigation), measurement, and study design problems.110 These authors reviewed 10 studies considered to support a psychogenic origin for MCS. Some of their primary conclusions were that the reporting of multisystem complaints in the absence of physical findings is not sufficient evidence to propose a psychogenic origin, especially when MCS has not been subjected to rigorous scientific studies. In addition, it is important to bear in mind that a substantial proportion do not have pre or comorbid psychiatric illness. 8,51,70,85,110

Recently, it has been proposed that symptoms such as impaired cognition, dizziness, headache, tremor, abdominal pain, parasthesia, and breathlessness reported by individuals with food hypersensitivities are similar to those symptoms elicited by hyperventilation.121,122 Some investigators have also proposed that the symptoms reported by MCS patients are a result of anxietyinduced acute or chronic hyperventilation. 121 Recent studies have supported the idea that at least some symptoms of MCS may result from hyperventilation in response to odor presentation. In one study, of 25 patients who met the Cullen criteria for MCS (with exception of an identifiable exposure), 19 had symptoms suggestive of hyperventilation syndrome and were openly challenged with their selfidentified triggers.123 Signs of hyperventilation as well as blood gases were monitored. In 11 out of 15 patients, challenge with the chemical reproduced the symptoms selfreported as being characteristic of their condition, while four patients demonstrated no symptoms after challenge. Thus, the authors concluded that hyperventilation is a mechanism by which at least some MCS patients may respond to chemical challenges.

It has been hypothesized that hyperventilation provides a "training period" during which learning takes place, and somatic symptoms may be attended to more strongly by certain individuals. Hypervigilance in perception of symptoms and a negativistic interpretative bias have been offered as mechanisms for hyperventilation in at least some MCS symptoms.124-126 Van den Bergh and coworkers127-129 have found that odors with negative valence can be paired with C02 to induce hyperventilation symptoms in the presence of odor alone (see Conditioning to Odors below).

The wide variety of trigger compounds in MCS strongly argue for an anxietyassociated mechanism, and in some cases could be described as panic disorder or agoraphobia. 130,131 More recently, selfidentified MCS patients received peripheral sodium lactate infusion, which commonly triggers panic attacks in DSMIVdiagnosed panic disorder patients. 132 In five out of five patients, lactate infusion administered in a singleblind fashion produced a paniclike state with reproduction of their MCS symptoms, while no patients reacted to placebo. 133 Although the presence of paniclike states in MCS patients does not rule out a chemical-induced origin, these preliminary findings support the idea that CNS pathways involved in anxiety are altered in individuals reporting MCS.

Guglielmi et a1.,134 and Schottenfeld and Cullen130,131 have suggested that traumatic neurotoxic exposure may produce development of an atypical PTSD in susceptible individuals. Posttraumatic stress disorder is characterized by intrusive recollections of the event in thoughts, words, or dreams and is accompanied by an increased arousal and avoidance of the stimuli associated with the traumatic event(s). Thus, occupational exposure in some individuals may present as an atypical form of PTSD in which the individual reports recurrent somatic symptoms. 130,131 This idea is consistent with Morrow et al.,135who found that solventexposed persons closely resemble those diagnosed with PTSD on the MMPI profile. Similar to individuals with MCS, PTSD victims are prone to a wide variety of health problems.136

Schottenfeld9 reports that early childhood stress/ trauma is present in a high percentage of individuals with MCS. Bell et al.10 have found some support for early life stress in selfreported chemical intolerance. Staudenmayer et al.11 have also reported increased rates of childhood abuse in individuals presenting with MCS. Those systems involved in homeostasis after stressful stimuli are the same as those hypothesized as being dysregulated in MCS, such as the immune system, limbic brain circuitry, and autonomic responses.137

The coexistence of psychiatric symptomatology in MCS may be useful in determining subtypes of MCS. In a study by Fiedler et al.,8 MCS patients without an identifiable chemical exposure (as the initiator of chronic MCS symptoms) had higher rates of psychiatric illness compared with those who reported a clear chemical exposure that was believed to initiate MCS. Others have discussed the possibility that MCS patients comprise an heterogenous population9,138 (see Evidence for MCS Subpopulations below). Lehrer139 points out that addressing psychological components of MCS does not necessarily imply that MCS is not organic in origin. In several other disease/disorders, such as migraine headaches 140 irritable bowel syndrome, 141,142 and hypertension, 143 a psychological component as part of the treatment procedure is effective.

In summary, psychiatric diagnosis does not exclude chemicalinduced etiology, and repeatable responses to triggers does not necessarily imply that there is no psychological component in MCS. Doubleblind, placebocontrolled studies can help elucidate a role for psychologic factors in response to triggers.

Many of the compounds that have been identified as initiators or triggers of MCS produce deficits in CNS function in the general population when these chemicals are present in higher concentrations. 144,145 Genetic polymorphisms in metabolic enzyme activity may produce increased susceptibility to toxic effects of chemicals.146 Some neurotoxicologists have suggested that risk assessment based on toxicity testing in animals may be substantially underestimating the true situation in humans due to the wide genetic diversity of the human population.146,147 Cancer studies have determined that enhanced risk due to genetic predisposition occurs at lowlevel exposures to certain chemicals, but that no difference in genetic susceptibility occurs at higher dose exposures. 148,149 These studies may be relevant for the MCS population, especially where lowerdose exposures are suspected.

There is an intrinsic appeal in the notion that extreme sensitivity to chemicals in the environment may be explained by wide variations, either inherited or acquired, in the ability to metabolize/ excrete chemicals. Although there are a few reports of detoxification enzyme measurements in patients with MCS, thus far the findings have not been suggestive of any major changes.150-153

Individuals with allergic diseases develop inflammation of the mucosa and IgEdependent responses to specific allergens. Classic allergy is primarily limited to the skin and respiratory tract and is mediated by IgE antibodies. The resulting symptoms are bronchial and nasal hyperirratibility.154,155 Symptoms in these individuals are generally confined to coughing, wheezing, hoarseness, and irritation of the upper airway after exposure to household products, cigarette smoke, and other irritants.156 The limited symptoms in these atopic individuals are in contrast to those with MCS in which multiple sites are affected. Studies so far suggest that classic allergy does not occur at a higher rate in individuals reporting MCS.16,51 However, as pointed out by others,1 allergy as defined by IgEmediated responses does not explain a range of hypersensitivities experienced by patients.

The findings of immune system changes in individuals with MCS have been mixed. Some studies have found decreases in T4/T8 ratios (helper: suppressor ratios),157 while others report an increase in T4/T8 ratios.158 Still others have found no changes in Bcell, Tcell counts, immunoglobulins, or natural' killer cells 49,51,55,159 However, patient selection is variable, ranging from selfreported chemically sensitive individuals in worker's compensation appeals47 to others with diagnosed vasculitis, asthma, or rheumatoid arthritis who report sensitivity to certain chemicals.158 In addition, most studies do not give a chemical challenge, examining parameters only under "baseline" conditions.

Another approach has been to measure antibody levels to particular organic compounds after exposure to those chemicals. The results of these studies are also in conflict, with reports of increased antibodies160 and no correlation between physiological complaints from exposure and specific antibody production.161

Both increases and decreases in immune system measures have been demonstrated in occupationally exposed workers, suggesting that immune suppression or autoimmunity may develop.162 However, interpretation of altered immune system parameters should be made with caution.163 In summary, no profound changes in the classic immune system parameters measured so far appear to be present in individuals reporting MCS.

Evolutionarily, the trigeminal system located in the eyes and upper respiratory tract is believed to be a critical system for detection of noxious airborn chemicals. 164 Trigeminal nerves in the nose are activated by many chemicals.165 Stimulation of nonmyelinated Cfibers occurs after irritant chemical exposure. 164,166 Neurogenic inflammation is the process by which neuronal stimulation produces inflammatory responses independent from antigeninduced immunemediated inflammation. 167 Tachykinin peptides, such as substance P (subP) and neurokinin A (NKA), as well as other peptides, are released in the airway in response to irritant chemicals, and can produce several responses involving inflammatory cells.168 SubP causes increased vasodilation and vascular permeability and is potent in its ability to release histamine and other mediators of tissue inflammation from mast cells.169-172

Most chemical exposures believed to initiate/ trigger MCS are airborn, and thus the first site of direct interaction occurs in the upper respiratory mucosa. Investigators have found a high prevalence of chronic inflammation in the upper airway of individuals with MCS85,173 and in those with reactive upper airways syndrome, an asthmalike condition that develops and persists after chemical exposures. 174 Meggs172 has proposed a "neurogenic switching" phenomenon to explain shifting of inflammatory sites from the upper airway to other organ systems. This hypothesis suggests that histamine release at one site, for example, could stimulate sensory nerves and thus produce afferent signals to the CNS. Multiple chemical sensitivity may be initiated by chemical exposures in sensitive individuals as a result of abnormalities in physiological cascades following the inflammatory response in the upper airway (neurogenic inflammation), 164,167,175 and recently Dietert and Hedge176,177 have argued for a neuralimmune system approach to the investigation of MCS. Irritant chemicals therefore may provide a chemical "stress" in susceptible individuals and potentially initiate the process of MCS. Individuals considered most susceptible to irritants may have alterations in excitability of sensory neurons, synthesis, receptors, or metabolism of neuropeptides.168,178

However, neurogenic inflammation alone may not account for the wide range of symptoms reported after chemical exposure. Inflammation and infection activate a series of events known collectively as the acute phase response. 179 The consequences of the inflammatory response are increases in inflammatory cytokines in nasal tissue,180 In addition, increases occur in interleukin1b (IL-1b) in specific brain areas, HPA axis activation, brain monoamine release, increased slowwave sleep and decreased social interaction, among other responses. 181-185 Activation of the HPA axis appears to be mediated via IL1binduced increases in corticotropinreleasing hormone (CRH) and is activated by both peripheral or central IL1 administration. 186,187 Conventional stress effects mimic many of the acute phase response events, including increased IL1b mRNA and 1L1b activity,188,189 and stressinduced responses such as increases in adrenocorticotropic hormone (ACTH) and hypothalamic monoamines are reduced by the competitive IL1 antagonist IL1Ra.189

Repeated activation of stress pathways may lead to altered functioning of the stress response that is found in fibromyalgia and chronic fatigue syndrome, two disorders with considerable overlap with MCS.190,191 Clauw and Chrousos190 hypothesize that fibromyalgia and chronic fatigue syndrome are a result of dysregulation of the HPA axis. Bell and Amend192 have reported a greater dexamethasoneinduced suppression of cortisol levels in individuals with CI. Similar results have been reported in fibromyalgia and chronic fatigue syndrome as well as PTSD patients.100,190,193 These findings may offer some support for dysregulation of the HPA axis in MCS. Although highly speculative, inflammatory responses to chemical irritants in susceptible individuals may be a link in repeatedly activating the HPA axis. This may ultimately result in the ability of several classes of compounds to trigger altered HPA axis functioning.

Odors can provide an indicator of air quality.194 Doty et al.85 have asked the question of whether MCS patients possess a lower threshold for odors. Very low levels of rose oil (phenyl ethyl alcohol) or a solvent (methyl ethyl ketone) were presented to 18 MCS patients and 18 controls. No differences in threshold between the groups were found, but nasal resistance and respiratory rate were significantly higher in the MCS group. The increased nasal resistance is consistent with the findings of chronic inflammation in the upper airways of MCS patients.85,173 In concordance with the absence of odor threshold differences in the study mentioned above, Fiedler et al.8 also reported no changes between MCS patients and controls in the ability to identify several

different odors. Kobal and coworkers195 have examined the chemosensory eventrelated potentials in MCS patients to determine the intensity of an olfactory and/or trigeminal stimulus. While no controls have yet been examined for comparison, this method may provide important information regarding higherlevel processing of olfactory/ trigeminal information after chemical challenge.

Odors have been shown to worsen asthmatic symptoms in a high percentage of asthma patients.196 Odors commonly identified and avoided are insecticide, perfume, household cleaners, cigarette smoke, and paint, among others. In the few patients tested in this study, blocking the odor via occlusion of the nostrils did not alter the response in 3/4 patients, and reports of odorinduced asthma also occurs in anosmics, suggesting that odor may not be a necessary component in the onset of symptoms. These findings are consistent with EEG studies, in which food odor and food imagery in the absence of food odors produced similar EEG changes in normal individuals, suggesting a cognitive component may play a large role in the response to Stimuli.197

Chester198 have postulated that fatigue states reported by individuals with sick building syndrome are a result of a reflex that occurs after irritant stimulation of the trigeminal nerve. In animals, trigeminal stimulation produces decreases in locomotor activity and thus discourages activity, and he suggests that this is a defense mechanism against predation. Furthermore, he proposes that similar stimulation of trigeminal nerves in humans is perceived as fatigue.198

Several investigators have proposed that odors act as conditioned stimuli in triggering symptoms in MCS patients. 130,134,199-203 Guglielmi et al.134 propose a twofactor model, in which classic conditioning underlies the development of conditioned physiological reactions, and operant conditioning is responsible for the maintenance of the avoidance of chemicals. Some evidence exists that conditioning (to odors) may play only a partial role in symptom onset. Shim and Williams196 report that anosmic patients still report symptoms to chemical exposures, and other studies have demonstrated that odors at levels too low to be detected induce changes in EEG alpha activity and alter behavioral responses on a visual search task.204 Thus, neural alterations occur after chemical exposure in the absence of conscious awareness of odors. On the other hand, odor may not always serve as the conditioning cue, and other environmental cues may elevate anxiety/stress levels to induce and/or exacerbate existing sensitivities.205,206

However, odors can serve as strong conditioning cues in normal subjects, and therefore may play a role in triggering symptoms in a subset of MCS patients. Recent studies by Van den Bergh and coworkers have given some insight into basic learning processes regarding odors with positive and negative valence. In a study of nonMCS, psychosomatic patients reporting hyperventilation complaints128 and in a separate study of normal subjects,127 individuals were conditioned to odors of either positive valence (niaouli, a mixture of oils containing mainly eucalyptus oil) or negative valence (dilute ammonia) paired with C02enriched air as the unconditioned stimulus to trigger hyperventilation. Both odors were present in concentrations that, given by themselves, did not alter breathing patterns. Several physiological measures indicative of hyperventilation as well as subjective somatic complaints were monitored. The results from both studies indicate an elevated level of somatic complaints after the negatively valencedodor, but not the positively valenced odor, paired with C02. In addition, stronger conditioning effects on typical hyperventilation complaints occurred in psychosomatic patients when compared with normal controls from a previous study. 127 An additional recent study conducted by this group in normal subjects found that butyric acid, a pure odor stimulant (nonirritant) that was rated equal to ammonia regarding negative valence, also produced conditioned hyperventilation, suggesting that an inherent learning process may occur when negatively valenced odors are paired with a negative event, and that odor alone is sufficient for this pairing to occur. 129 Moreover, fearrelevant images, but not neutral images, also produce conditioned hyperventilation.206 Consistent with the effects of positive or negative valence of odors on behavior, the acoustic startle reflex in humans has been shown to increase during presentation of hydrogen sulfide odor when compared with presentation of vanillin, even though both stimuli were rated equally intense, and no difference in heart rate or electrodermal activity was found between the two odor conditions.207 These studies collectively suggest that odors with negative valence can influence affective responses to the environment.

Some evidence for the possible existence of a conditioned response in MCS individuals is provided by Arnetz et al.,208 who applied what they considered to be a "neutral" treatment, that of acupuncture, to patients with environmental illness, or MCS. Such treatment improved patients' wellbeing, including skin symptoms, use of analgesics, and memory impairments. The authors speculated that positive treatment results may have been at least partly due to a weakening of the conditioned response that patients had learned between bodily symptoms and environmental agents.

Finally, it should be pointed out that conditioning is learning. Although not wellunderstood, external and internal cues drive psychophysiological learning processes. The ability of external and/or internal cues to produce psychophysiological changes is perhaps most remarkably demonstrated by reports of contrasts occurring within the same individual with multiple personality disorder. Differences in dominant handedness, allergic sensitivities, responses to medication, and visual function have been found across alter personality states in multiple personality disorder.209-211

Sparks et al.202 have reviewed four potential hypotheses regarding the origin of MCS, including (1) MCS is a biological reaction to chemical exposures, (2) psychological stress may initiate MCS and symptoms are elicited by lowlevel chemical exposures, (3) MCS represents psychiatric illness states, such as anxiety or depression, and (4) MCS is an illness behavior (a belief system). Consistent with these observations, Schottenfeld9 has suggested that MCS patients are comprised of an heterogenous group of individuals who report symptoms for different reasons. Five different groups have been proposed and include the following: (1) those with unusual sensitivities that are not understood from an immunological basis, (2) those who amplify normal bodily sensations and misattribute them to chemical exposures, (3) those who amplify mild reactions to environmental substances and become ill, (4) those who have a primary psychiatric disorder, and (5) those individuals whose psychiatric disorders may be secondary to MCS, resulting in a further disability.

There is evidence to support that MCS patients may be divided into at least two major groups, those presenting with or without psychiatric symptoms. In a doubleblind study of patients reporting food hypersensitivity, 4 of 23 patients demonstrated clear symptoms associated with atopic syndrome after provocation testing, while hypersensitivity could not be confirmed in 19 of the patients after provocation. Psychiatric evaluation revealed no psychiatric illness in the 4 whose hypersensitivity was objectively observed, but in all but one of the 19, psychological symptom scores were indicative of psychiatric illness, most notably neurotic depression.212 In addition, as mentioned above, Fiedler et al.8 found that MCS patients without an identifiable chemical exposure (as the initiator of chronic MCS symptoms) had higher rates of lifetime psychiatric illness compared with those who reported a clear chemical exposure that was believed to initiate MCS.

The vast literature on behavioral neurotoxicity studies in animals will not be reviewed; however, neurobehavioral toxicology studies in animals may be expected to offer insights into possible mechanisms of onset/maintenance of MCS in humans, especially where repeated lowlevel, longterm effects of chemicals are explored. However, relatively few studies to date have specifically attempted to develop animals models for MCS.

One model currently being explored utilizes the Flinders Sensitive Line (FSL) and Flinders Resistant Line (FRL) of rats213 These rats were selectively bred for sensitivity to acute presentation of an organophosphate and have been used extensively as a model for depression.214 These rats may also model several aspects of MCS, in that they demonstrate greater sensitivity to several compounds, including nicotinic, muscarinic, dopaminergic, GABAergic, and serotonergic receptor stimulation.213 In addition, FSL rats show other features, such as decreased locomotor activity and increased REM sleep, similar to human depressives, and thus this model may offer insights for the subpopulation of individuals with MCS that are depressed (see Psychogenic Origin above). The applicability of these animals for MCS should be made with caution, however, because selective breeding may produce alterations in several neurotransmitter systems that are not necessarily associated with the organism's greater sensitivity to organophosphorus compounds.

Rogers et al215have begun to examine cognitive performance on a complex operant task in rats after repeated, lowlevel toluene exposure. Preliminary analyses of the data indicate that the greatest effects on performance decrements occur after repeated toluene vs. acute, highlevel exposure. This same lowlevel toluene exposure has been reported previously to alter spatial memory in rats.216

Another model that may be useful to examine is based on the phenomenon of limbic kindling. Kindling is a form of sensitization in which repeatedly presented electrical stimuli to the brain (usually the amygdala) that initially do not produce seizures can, with the passage of time, produce fullblown seizures in response to the same level of stimulus.22 Studies in animals have demonstrated that many chemicals implicated in inducing MCS symptoms, including pesticides and organic solvents, promote seizures and/or kindling in limbic structures.217-220 Although it is not believed that full kindling mimics events in MCS,221 partial kindling may produce alterations in behavior222,223 and thus have relevance for modeling certain aspects of MCS.

Most studies implicate changes occurring within the CNS in the majority of MCS patients.4,16,85 Regardless of whether the origin of MCS is "biogenic" or "psychogenic", CNS circuitry is likely to be altered in MCS. Many of the chemicals that have been attributed to triggering symptoms in MCS patients are solvents and pesticides, whose primary effects are on the CNS, and are neurotoxicants when present in higher concentrations. Therefore, it may be useful to concentrate on the most commonly reported symptoms: those that involve the CNS.

Bell and coworkers7,224,225 have put forth a leading hypothesis that chemical sensitivities may be akin to sensitization observed in rodents after repeated psychostimulants. They hypothesize that amplification of responses in chemically sensitive individuals develops via a CNS sensitization process, with particular emphasis on limbic circuitry due to its relatively high sensitivity to various perturbations (such as electrical and chemical kindling), and widespread involvement in cognitive and affective dysfunctions, as observed in individuals with chemical sensitivity. 1,226,227

Neural sensitization is defined as an increased neuronal responsiveness to a stimulus after repeated prior exposure to the same or different stimulus. The term neural sensitization as defined here will be referred to simply as "sensitization" and excludes reference to immune system sensitization. Sensitization is a type of learning and typically is studied in laboratory animals. The repeated stimuli used to induced sensitization commonly include drugs of abuse, especially psychostimulants such as cocaine and amphetamine.21,228 In addition, application of repeated stressors, such as footshock, tail pinch, or restraint stress, also produce sensitized behavioral responding to psychostimulants given at a later time.20,229-232 In addition to repeated exposure to stimuli, single exposures combined with the passage of time have also been shown to produce sensitized behavioral and neurochemical responses.233 This form of sensitization has been termed "timedependent sensitization".

The phenomenon of sensitization is believed to model certain aspects of drug abuse, such as increased craving after repeated drug use,234 and the development of paranoid psychosis.235,236 Relevant to stressinduced sensitization, disorders such as panic disorder and PTSD are modeled by the CNS sensitization paradigm in rodents.235,237 These sensitization models are based on several similar characteristics with regard to the amplification and persistence of responses to outside stimuli, exacerbation by stressors, and the ability to condition to stimuli, among others.238

Several features of sensitization appear parallel to those of chemical sensitivity, as previously discussed. 1,7,239,240 The similarities include the progressive increase in sensitivity to drugs/chemicals; 6, 235,241 the apparent permanence of sensitivity; 1,21 the lack of symptoms/sensitization in the absence of chemical/drug and the onset of symptoms/sensitization upon chemical challenge; 1,3,21 the greater sensitivity of females vs. males;3,242 the spreading of sensitization in response to stimuli other than the initial stimulus used to induce sensitization (as with crosssensitization between psychostimulants and stress, and between different classes of drugs of abuse); 3,20,228 and the apparent timedependent nature of sensitization, wherein responses increase with the passage of time.7,233,243-245

An additional similarity is the distinct separation of sensitization and MCS into two phases. In sensitization studies, these phases are termed initiationand expression. (see Reference 228 for review). Initiation refers to the collection of cellular/molecular events that is necessary to produce a sensitized state after subsequent elicitation by drug. Initiation events are thought to take place within the midbrain dopaminergic neurons in the ventral tegmental area (VTA), as several drugs administered locally within this site produce sensitized behavioral responding to psychostimulants and morphine.228 The expression phase of sensitization refers to the longlasting/permanent changes that have been induced earlier by prior drug/stress exposure and are those changes that mediate sensitized responding to drugs. Similarly, MCS has been divided into two phases parallel to those used to describe sensitization in the rodent. Initiation refers to the event (s) associated with low, moderate, or highdose exposures; these often occur repeatedly, but MCS symptoms also have been reported after single dose exposures (e.g., during a chemical spill or pesticide spraying). Subsequent elicitation of symptoms by very low doses of chemicals parallels the expression phase of sensitization.

A final, potentially important, similarity is the conditioned stimulus control over sensitization in rodents and possibly in humans with MCS (see Conditioning to Odors). Conditioned stimulus control over psychostimulantinduced sensitization of locomotor responses has been described. 246,247 Recent findings have demonstrated that the control of conditioned cues during psychostimulantinduced sensitization occurs to a remarkable degree.248,249 In one study,248 all cues for administration of amphetamine were removed (e.g., removal of rats from the home cage, handling, needle jab), and drug injections were given i.v. in the home cages and thus were completely unsignaled. The results demonstrated that the acute amphetamineinduced locomotor response was greatly attenuated, and no sensitization developed. Identical studies with cocaine showed no effect of environmental cues on the acute cocaineinduced locomotor response, and sensitization after repeated cocaine administration developed only after the highest dose was administered.249 The results together suggest an extraordinary ability of environmental cues to control druginduced effects in rats. In addition to sensitization, environmentalspecific tolerance has also been shown.247,250

There appear to be similarities between the phases of exposure described by clinical ecologists and those described for drug abuse. First, adaptation or tolerance after repeated drug exposure is well known in substance abuse.251 Although the withdrawal symptoms are described by Randolph as "addiction", the current term that best fits this description is physical dependence, a state that develops as a result of tolerance produced by resetting of homeostatic mechanisms in response to repeated drug use. The state of physical dependence can only be determined by the presence of withdrawal symptoms. In MCS patients, low "neutralizing" doses of the problem chemical may attain the same effect as some current drug abuse treatment strategies, which utilize slowonset and offset agonist occupancy to avoid withdrawal and craving symptoms.252 It should be noted that the term neutralization implies a reversal of biological systems toward the original state. It remains untested, however, if this occurs after neutralization therapy by clinical ecologists. Whether neutralization therapy in MCS is a useful strategy for longterm treatment is controversial; such treatment would appear to oppose the basic tenet of clinical ecologists that exposure to even lowlevel chemicals may ultimately produce a worsening of the MCS condition.

The role of CNS sensitization in altered behavior of a rat model for MCS will be discussed at length below. Sensitization of the CNS in the context of pain pathways may also be highly relevant to MCS, as many of the complaints are based on pain (see Table 1), and thus nociceptive pathways will be mentioned briefly here. Persistent pain can be produced by tissue or nerve injury. An enhanced pain response to noxious stimuli is referred to as hyperalgesia and an enhanced response to nonnoxious stimuli is called allodynia. Some of these changes are produced by Nmethylnaspartate (NMDA) receptor activation,253 cytokines,254 and neuropeptides, including subP, calcitonin generelated peptide (CGRP), and dynorphin.255 Central sensitization is an increase in the excitability of spinal cord neurons to stimuli. This sensitization is at least partially due to a phenotypic switch within Afibers to subPproducing fibers,256 decreases in descending inhibition via diminished sensitivity of GABA and glycine receptors,257 and altered second messengers,258 resulting in increased excitability of the postsynaptic targets in the spinal cord. Ursin259 has incorporated sensitization of the PNS and CNS as explanatory mechanisms for muscle pain in somatization disorder. Affective responses to pain, which recently have been explored in normal individuals using positron emission tomography (PET scan), involve a role for the anterior cingulate cortex.260 These studies may have important applications for MCS patients to determine if they exhibit any differences in affective responses to nociceptive stimuli.

Sensitization of behavioral and neurochemical responses to drugs of abuse and stress in rodents provides a potential framework for understanding how environmental chemicals may amplify a variety of biological/psychological responses after repeated, intermittent exposure. Based on this information and the sensitization hypothesis of chemical sensitivity, recently this laboratory has attempted to develop an animal model for MCS by focusing on CNS sensitization after repeated chemical exposure. These studies have begun to examine behavioral changes akin to those observed in individuals with MCS, such as greater sensitivity to chemical manifest as exaggerated avoidance and increased anxiety after chemical exposure. Formaldehyde was the chemical used for these studies because it is among the most ubiquitous volatile organic compounds found in indoor air, present in hundreds of common products such as paper, insulation, wood products, and resins, and appears to produce illness in many humans with sensitivity to chemicals.1 Below are described some strategies recently explored in this laboratory to gain insight regarding amplification of CNS responses after repeated chemical exposure.

An initial and simple test of the hypothesis put forth by Bell et al.7is that repeated chemical exposure crosssensitizes to the locomotor activating effects of a subsequent psychostimulant administration, much as repeated stress or psychostimulant exposure produces sensitized responding to these drugs at a later time (see above). If repeated inhalation of a chemical such as formaldehyde produces sensitization of the CNS in the rat, this effect should be elicited by a psychostimulant such as cocaine.

Figure 1 shows that repeated formaldehyde inhalation at high levels (11 ppm) administered for 1 hr/day x 7 days produced crosssensitization to cocaineinduced horizontal activity 2 days after withdrawal and a trend for augmented vertical activity approximately 3 to 4 weeks after withdrawal.261 No differences in the response to saline challenge were found between control and daily formaldehyde pretreated rats at either withdrawal time (not shown).

Figure 1 also shows the results of lowerlevel (approximately 1 ppm) formaldehyde inhalation given daily for 1 hr/day x 7 days.262No difference in cocaineinduced locomotor activity was found between groups for either horizontal or vertical activity at early or late withdrawal.

Similarly, saline injection did not alter horizontal or vertical activity at the early withdrawal time (data not shown).

FIGURE 1. Cocaineinduced horizontal and vertical activity after 7 days or 20 days of Air or Formaldehyde (Form) pretreatment at early (2 days) and late (3 to 6 weeks) withdrawal periods after daily treatment. Values are mean ± sem of photocell counts obtained over a 2hr period for horizontal or vertical activity in rats. *P < 0.05, compared with control condition at the same time point using a twotailed ttest.261,262

In contrast to the 7day inhalation, formaldehyde inhalation given at approximately 1 ppm for 20 days (1 hr/day x 5 days x 4 weeks) produced crosssensitization of vertical activity at both early and late withdrawal periods (Figure 1). No crosssensitization was observed for horizontal activity. Saline injection did not alter horizontal or vertical activity differentially between the two groups (data not shown).

Reports of an augmentation in vertical (rearing) but not horizontal activity in cocaine or stresssensitized rats has been observed previously,232,263 and the blockade of vertical but not horizontal activity by the NMDA receptor antagonist MK801 has been reported.264 Moreover, the blockade of opioid receptors by naltrexone prevented the vertical but not horizontal response to acute and repeated amphetamine.265 It remains unclear if specific circuitry within the mesolimbic pathway is altered to produce enhanced vertical when compared with horizontal activity, but the differences may also be a function of the relative degree of sensitization.266 Peripheral cocaine263 and amphetamine267 injections have been shown to produce a dosedependent increase in horizontal activity, while vertical activity in the same animals demonstrates an inverted Ushaped curve, indicating that animals given higher doses of these drugs maintain horizontal activity, while reducing their rearing behavior.

The crosssensitization to cocaine in daily formaldehyde pretreated rats provides evidence suggesting that enhanced dopamine transmission within the mesolimbic system (VTA to nucleus accumbens projection) may occur after repeated exposure to formaldehyde. These results are in agreement with previous studies in animals and a recent study in humans that has linked repeated volatile organic compound exposure with altered dopaminergic function.216,268-270 The effects of repeated exposure to volatile organic solvents has largely been examined with toluene in the neostriatal region of rats as well as in whole animal behavioral responses to apomorphine. The findings from shorterterm studies (3day exposure, 6 hr/day) suggest a decrease in affinity of the D2 dopamine receptor with a decrease in sensitivity of presynaptic D2 receptors but an increase in apomorphineinduced locomotor activity at apomorphine doses considered to activate postsynaptic dopamine receptors.269 These effects appear to be dosedependent and shortacting when only a 3day exposure is given. With longerterm treatment (4 weeks), a persistent elevation (17day withdrawal) of apomorphineinduced locomotor activity has been observed.216 A significant increase in the Bmax values for a D2 agonist has also been found in the latter study. Thus, it appears that striatal dopaminergic systems are affected by these treatments, and animals demonstrate an enhanced responsiveness of dopamine agonistinduced locomotor output. However, these studies have focused on changes in dopamine receptors occurring within the striatum rather than the nucleus accumbens, and therefore it is unknown if similar changes occur within the latter region, which more importantly modulates apomorphineinduced locomotion. The present results are also in agreement with a previous study demonstrating enhanced physiological and behavioral sensitivity in mice after repeated exposure to formaldehyde.271,272 Although formaldehyde does not enter the brain, alterations in electroencephalographic activity in cortical and limbic structures have been described after formaldehyde and other chemical exposures.217 An increased concentration of cocaine in the brain due to formaldehydeinduced changes in the pharmacokinetics of cocaine has not been ruled out in the present studies, and ongoing experiments are addressing this issue.

One possibility for the observation that longterm formaldehyde exposure crosssensitizes to cocaine's effects is that the repeated inescapable formaldehyde exposure may provide a stressful stimulus due to its irritant properties on the upper airway. Irritant levels in humans are reported to occur at approximately 0.1 to 1.0 ppm.271 Typical occupational and home exposure levels are less than 0.2 ppm, but can reach 1 to 2 ppm.271,273,274 Formaldehyde does not penetrate into the brain due to its high reactivity, and thus sensitization between the stress of repeated daily formaldehyde exposure and psychostimulants may be occurring.20,231,275 It remains to be tested if formaldehydeinduced effects are acting via those pathways utilized by stressinduced sensitization, or are
producing effects either independently or in concert with stress. Whether the effects of formaldehyde exposure occur through stressinduced (i.e., via activation of the HPA axis) vs. other chemicalinduced pathways may have implications for prevention and/or treatment strategies in chemically sensitive individuals.

The behavioral changes observed after repeated formaldehyde exposure may provide a link with some of the symptomatology in individuals with MCS. It is possible that chemical effects occur to a greater extent if the situation is perceived as inescapable or if an elevated stress level is present at the time of exposure to chemical. For example, inescapable footshock stress administered with the pesticide, dieldrin, produces greater impairment of performance when compared with when escapable footshock stress is administered.276

Several investigators41,138,277,278 have proposed that MCS may be diametrically opposite to drug addiction in that the former represents movement away from chemicals, while drug addiction represents movement toward chemicals (drugs of abuse). Miller41 has used the word "abdiction" to describe an aversion to chemicals vs. "addiction" to chemicals/drugs. The notion that MCS and drug abuse may have clinical features that oppose each other yet share genetic predisposition is supported by reports of significantly greater family history of drug abuse in individuals who considered themselves intolerant to chemicals.279 Significant increases in the rate of alcoholism in the blood relatives of MCS patients has also been reported recently by Black (personal communication).

Those with MCS and Gulf War Syndrome report high alcohol intolerance (such as intoxication and severe hangover after lowlevel consumption).3,4,280 Several studies indicate a low rate of substance abuse in MCS patients and/or those who report increased sensitivity to chemicals,4,14,70,279 although some reports indicate that MCS individuals have intense food cravings (especially carbohydrates).3,31These findings are opposite to studies indicating a higher rate of alcohol/substance abuse in conditions of psychological distress .281,282

Schottenfeld9 has pointed out the possibility that those who seek out solvent intoxication when compared with those who become aversive to solvent odors may be due to differences in sensitivity of the individual. For example, an anxiety response may be initiated in the MCS patient, while inhalant abusers may not activate these systems. In addition, Schottenfeld9 and Ross138 consider the differences between these two groups in expectation (i.e., pleasurable vs. anxious) regarding the outcome of exposure to solvents. For example, a commonly abused solvent, trichloroethylene, produces many of the same symptoms as MCS, such as headache, fatigue, irritability, depression, and alcohol intolerance, but individuals who abuse this inhalant nevertheless find the intoxicating effects pleasurable.

Because the hallmark of MCS in humans is the avoidance of chemicals, exploration of alterations in CNS circuitry guiding attention toward or away from stimuli may be fundamental for modeling MCS. A key issue may be understanding what guides avoidance and anxiety to aversive stimuli. Limbic system components are critically involved in the conditioned response to stimuli. Most central to the formation of conditioned associations with aversive stimuli is the amygdaloid nuclear complex. The amygdala contributes significantly to autonomic, neuroendocrine, and behavioral responses to incoming stress.283-285 The VTA is a critical site for sensitization to psychostimulants (see Reference 228 for review), and may also be important for sensitization to repeated stress and/or formaldehyde. There are extensive interconnections between the brain regions to which VTA dopamine neurons project and the sites involved in conditioned fear and extinction of fear responses. The amygdala, lateral septal area, hippocampus, and prefrontal cortex are sites believed to be heavily involved in the extinction process and all receive dopamine afferents from the VTA.286,287 Dopamine neurons project from the VTA to the central, basolateral, and intercalated nuclei of the amygdala.286 In turn, the central amygdala sends projections to dopamine neurons in the VTA. The basolateral nucleus projects to the nucleus accumbens, prefrontal cortex, and hippocampus.288

Among other regions such as the amygdala, the mesolimbic dopamine system is important for avoidance responding. Depletion of dopamine in the nucleus accumbens or dopamine antagonist administration impairs avoidance responding to an aversive stimulus (footshock).289-291 These treatments have been shown to be specific for the avoidance response rather than due to deficits in associative learning or the ability to locomote.290 Therefore, hypersensitivity of mesolimbic circuitry may in part determine the motivation to approach or avoid stimuli, depending on previous experience.

Development of an animal model for MCS in this laboratory recently has focused on avoidance responding to formaldehyde as an aversive odor/ irritant.292 The behavioral endpoint measured was the avoidance response to formaldehyde after repeated treatment with two known sensitizers of mesolimbic circuitry, cocaine and footshock stress. Hypersensitivity of mesolimbic circuitry may in part determine the motivation to approach or avoid stimuli, depending on previous experience. Our results are consistent with the idea that prior repeated experience with a reinforcing stimulus (cocaine) increases approach behavior to a novel aversive stimulus (18% formaldehyde), while prior repeated experience with an aversive stimulus (footshock) produces an increased trend toward avoidance behavior to formaldehyde (Figure 2). Direct involvement of the nucleus accumbens in the increased approach behavior after daily cocaine is supported by our observations that microinjection of the dopamine antagonist fluphenazine into the nucleus accumbens just prior to the approach/avoidance test attenuated the increased approach behavior in daily cocainepretreated rats, with no alteration in daily saline controls (unpublished results). Therefore, it is possible that sensitization of mesolimbic circuitry increases the salience of the stimulus (formaldehyde presentation in the approach/avoidance box), and thus the degree to which the organism approaches or avoids that particular stimulus. The notion that mesolimbic and mesocortical dopamine is involved in attention to stimuli has been addressed recently.293

Additional studies in this laboratory have begun to focus on the role of gonadal hormones in producing approach/avoidance behavior. Such studies may have important implications for the predominance of MCS reported in females (approximately 80%), and an average age of onset of 35 to 40 years, when gonadal hormones may begin to decline and/or become dysregulated. The potential influence of hormonal changes may be related to premenstrual disorder and menstrual dysfunction in college age and middleaged individuals who consider themselves intolerant to chemicals,14,70 as well as increased aversion to odors in pregnancy.294

c. Conditioned Fear, Extinction, and Avoidance Responses After Repeated Formaldehyde Exposure

Other ongoing experiments involve examination of a conditioned response to an odor paired with footshock in airexposed controls and rats previously given repeated formaldehyde inhalation. These studies were done to determine if repeated chemical exposure may enhance the ability to remember an odor paired with an aversive event and/or fear responses associated with that odor. Results from the conditioned fear studies are suggestive that rats receiving formaldehyde exposure have a greater difficulty in extinguishing the fear response to a conditioned odor stimulus.292 Given that there is increased airway irritation in individuals with MCS and possibly in rats exposed to repeated daily formaldehyde, it is reasonable to speculate that neural pathways that must mediate attention to stimuli may necessarily be amplified in order to guide the organism to avoid further irritating stimuli. Additional experiments will need to be done to confirm this finding, and to determine whether the response is specific to odor as the conditioned cue. Previous studies have shown that tail shock given 1 day before a fearconditioning paradigm will enhance fear conditioning.295 In contrast, repeated cocaine treatment diminishes fear conditioning.296 Thus, our results using repeated formaldehyde treatments are more in line with the notion that formaldehyde acts as a stressor. Animal studies that examine the brain areas responsible for the pairing of two stimuli, such as odor with irritation/ aversion, may be helpful in determining specific sites involved in conditioning. Such studies have been conducted using cFoslike immunoreactivity to determine where in the brain conditioned taste aversion develops.297

FIGURE 2. Effect of daily cocaine or footshock stress on approach/avoidance behavior to 18% Formaldehyde (Form) placed on one side of the approach/avoidance box. Values are expressed as the mean ± sem of percent time spent on Form side. *P < 0.05, compared with saline pretreatment group using a twotailed ttest. (Reprinted from Toxicology and Industrial Health, 1999, Volume 15 (3/4), by permission of Stockton Press292)

Figure 3 shows a hypothetical relationship between those who acquire dependence on drugs of abuse and individuals who acquire MCS based on previous speculation41,138,277,278 and the findings in animals presented here. The left panel indicates that there is a wide diversity in the approach/avoidance responses toward chemicals (including drugs of abuse). Only a percentage of the population becomes dependent on drugs of abuse. Likewise, a proportion of the population reports MCS symptoms. These two subpopulations may represent the extremes of responses to drugs/ chemicals in their approach or avoidance to these agents and perhaps the associated altered states. The right panel represents the inverse of the curve shown in the left panel. This hypothesized relationship suggests that individuals who are most susceptible to sensitization (i.e., learning) in certain CNS circuitry are those who develop MCS after repeated chemical exposure and those who develop drug dependence after repeated exposure to drugs of abuse. Although highly speculative at this point, hypersensitivities via neurologicimmunologic pathways are proposed to produce sensitivity to certain chemicals. This group of individuals may be those who consider themselves especially sensitive to some chemicals. In the absence of sensitization within the CNS, hypersensitivities may remain specific for a particular chemical. In contrast, sensitization within the CNS may produce the MCS condition, in which multiple chemical hypersensitivies are manifest. This type of learning may be considered similar to the sensitization of the CNS thought to occur in drugdependent individuals.234 Repeated perturbation by drugs of abuse are known to alter several indices in the brain. In a similar fashion, repeated perturbation by environmental chemicals in sensitive individuals may also produce sensitization, but it is accompanied by an amplified avoidance of chemicals.

Several questions remain regarding the utility of CNS sensitization studies as a model for MCS in humans. Among the most critical is whether this model will have predictive validity for MCS, and therefore whether effective treatments can be developed. Alterations in behavioral function, either basally and/or those elicited with appropriate stimuli (e.g., dopamine agonists, aversive experiences) reflect changes in integration of several CNS processes,298 and these behavioral responses may provide clues as to specific neural circuitry involved. Any changes in behavior after repeated chemical exposure in animal models suggest that similar alterations may occur in humans manifest as altered responses to subsequent chemical stimuli. Such findings in animals would merit rigorous investigation in humans with MCS.

Additional approaches to developing animal models for MCS include utilization of various genetic strains and selective breeding of rodents. These strategies are likely to provide important clues regarding individual susceptibility to environmental perturbations. In addition to the Flinders rats mentioned earlier, a second type of model employing selective breeding that may be particularly interesting to explore employsrodents selected for alcohol preference. Some of these are Long Sleep and Short Sleep mice, which have been bred for sensitivity to alcoholinduced disruption of the righting reflex; Withdrawal SeizureProne or WithdrawalSeizureResistant mice; HOT and COLD mice, referring to the hypothermic effects of alcohol; alcohol Preferring and Nonpreferring rats: and High AlcoholDrinking and Low AlcoholDrinking rats.299,300 While these animals have not been examined in the context of MCS, they may serve as useful models, especially given the nonspecificity of alcohol and organic solvent effects in the brain, and the possible link between MCS and drug/alcohol use in blood relatives of MCS patients (see Approach/Avoidance above).

FIGURE 3. Hypothetical relationship between MCS and drugdependent states. The left panel shows a subpopulation susceptible to acquire MCS, in which individuals manifest an extreme in avoidance behavior, and those susceptible to develop drug dependence and thus an extreme in approach behavior toward drugs of abuse. The right panel shows the inverse relationship and hypothesized susceptibility to sensitization of CNS circuitry after repeated exposure to environmental chemicals in MCS patients and drugs of abuse in those who becomes drug dependent. Genetic and psychosocial factors are each likely to substantially contribute to acquisition of these extreme states.

Another potentially useful strategy that has not been exploited is the use of different inbred rodent strains. Some examples are the Lewis and Fischer rat strains. Current studies in these and other strains have sought to find patterns of neurochemical/molecular changes in mesolimbic brain areas responsible for drugseeking/drugtaking behaviors as well as sensitization to drugs of abuse and stress,301-303 and these studies are based on several findings from investigations of single rodent strains.301,304-310 More recently, transgenic and knockout mice have allowed for examination of the role of single proteins in regulating the behaviors mentioned above.304,305,311-314 If overlapping neural substrates mediate the effects of drugs of abuse and environmental chemicals, these approaches may be highly useful for understanding individual susceptibility issues in MCS.

The existence of MCS as an illness is highly controversial and the etiology of symptoms reported by those diagnosed with MCS remains unknown. The many and varied symptoms (which most often involve the CNS) as well as the absence of any major physiological changes to support reported symptoms have produced doubt about the role of chemical exposures in producing MCS, and several investigators/clinicians have proposed a psychogenic origin for this disorder. In addition, skepticism regarding the existence of MCS stems from accounts that very lowlevel chemical exposures promote the onset of symptoms. In this regard, however, the apparent temporal aspects of MCS reports are not always appreciated. Initiation of MCS may occur after low, moderate, or highdose exposures. The extremely high sensitivity to chemical exposures, which typifies descriptions of MCS, is believed to occur a period of time after the initiating event(s) has taken place (weeks or months) and is referred to as the elicitation, or triggering, phase. Some studies have suggested that previous life stressors may also initiate MCS, and thus one common element with chemical exposures may be activation of the stress (HPA axis) pathway via inflammatory responses in the respiratory system and/or perceived toxicity of chemicals in the home/workplace. Altered function of this axis may occur after repeated stimuli and/or the passage of time, producing abnormal functioning of the HPA axis in response to a wide range of stimuli, including different classes of chemical compounds. Ultimately, feedback pathways from an altered HPA axis may modify CNS function.

The present lack of understanding a biological basis for lowlevel chemicals as causative factors in triggering the symptoms of MCS patients should provide impetus to initiate rigorous, doubleblind, placebocontrolled studies that would help verify or refute reports by MCS patients that chemicalexposures initiate/trigger their illness. In addition;the findings that odors themselves alter neural functioning and behavior in control human subjects suggests a potentially critical link with symptom provocation in MCS patients and deserves careful investigation. Continued exploration of animal models that mimic aspects of MCS should focus on neural plasticity within the CNS and its interaction with the immune system.

The author is grateful to Debra L. Davidson, Tressa Hochstatter, James L. Willis, Thomas C. Nowatka, Neesha Wendling, Dr. Hal H. Westberg, Dr. Ronald E. See, and Dr. Catherine Ulibarri for assistance with some of the work described here. The research involving these studies was supported by the Wallace Research Foundation and PHS Grants DA 08212 and ES 09135 (BAS).

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