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Patients with fibromyalgia (FM) have diffuse musculoskeletal pain; half report concomitant intolerance for low levels of environmental chemicals (CI). Previous investigators have hypothesized that the chronic pain and chemical intolerance reflect sensitization of different central nervous system limbic and/or mesolimbic reward pathways. We evaluated electroencephalographic (EEG) beta activity and blood glucose responses of FM patients with and without CI and normals during three repeated sucrose ingestion sessions and during a final, water-only session (testing for conditioning). The FM with CI exhibited oscillation (reversal in direction of change from session to session) at rest and then sensitization (progressive amplification) of EEG beta 1 over time across the 3 sucrose sessions versus controls. FM with CI showed sensitization of blood glucose over the 3 sucrose sessions, which, like the EEG findings, reverted toward baseline in the final water-only session. The data suggest that the subset of FM patients with CI have increased susceptibility to oscillation and physiological sensitization without conditioning, perhaps contributing to fluctuations in their chronic course.

Chemical intolerance (CI) is an individual difference trait in which persons report feeling ill in multiple physiological systems from low levels of a wide range of chemically unrelated environmental substances. This paper discusses the neural sensitization model for progressive host amplification of polysymptomatic responses elicited by chemical exposures following an initiating event. The sensitization model accommodates hypotheses for initiating and eliciting CI in human populations that involve both environmental chemicals and physical or psychological stressors. Recent studies in this laboratory have demonstrated sensitization in individuals with CI over repeated sessions for dependent variables such as electroencephalographic (EEG) activity and diastolic blood pressure. Psychological distress variables alone do not explain these findings. Individuals with CI and/or vulnerability to sensitization share specific characteristics, for example, female gender, certain genetic background (offspring of alcohol-preferring parents), and personal preference for high sugar/ carbohydrate intake. Overall, the data suggest that the 15-30% of the general population who report heightened CI are highly sensitizable. Sensitizability may serve an adaptive, sentinel function in threatening environments with poor signal-to-noise ratios. However, as sensitization gradually shifts operating set points of physiological systems out of the normal range in response to allostatic load, this process may contribute to the development of chronic, polysymptomatic health conditions such as multiple chemical sensitivity and/or fibromyalgia. Individual response specificity and stereotypy rather than toxicant properties may determine which types of central, autonomic, and/or peripheral nervous system dysfunctions manifest at subclinical and clinical levels.

The purpose of the present study was to investigate whether women with chemical sensitivity rated the intensity and pleasantness of three odorants [peppermint, vanilla, and propylene glycol (PG)] and odorless room air differently than women without chemical sensitivity. The ratings of the experimental group (women with self-reported chemical sensitivity and no history of sexual abuse) were compared to those of two control groups who did not report chemical sensitivity [sexually abused (SA) women and healthy women without sexual abuse history]. All subjects were exposed to odorants and odorless control stimuli once a week for 3 consecutive weeks. Our findings indicate that women with chemical sensitivity perceive odorants as neither more or less intense nor more or less pleasant than women without chemical sensitivity. Moreover, the control women without sexual abuse outperformed the women in the other two groups by correctly identifying the target bottle containing the odorant. These findings suggest that perception of odorants alone is unlikely to account for the symptoms associated with chemical sensitivity. These findings, along with those of Doty et al. (1988), support the notion that olfactory-sensory function does not differ between individuals with and without chemical sensitivity.

This paper summarizes theory and evidence for a neural sensitization model of hyperresponsivity to low-level chemical exposures in multiple chemical sensitivity (MCS). MCS is a chronic polysymptomatic condition in which patients report illness from low levels of many different, structurally unrelated environmental chemicals (chemical intolerance, CI). Neural sensitization is the progressive host amplification of a response over time from repeated, intermittent exposures to a stimulus. Drugs, chemicals, endogenous mediators, and exogenous stressors can all initiate sensitization and can exhibit cross-sensitization between different classes of stimuli. The properties of sensitization overlap much of the clinical phenomenology of MCS. Animal studies have demonstrated sensitization to toluene, formaldehyde, and certain pesticides, as well as cross-sensitization, e.g., formaldehyde and cocaine. Controlled human studies in persons with self-reported CI have shown heightened sensitizability in the laboratory to nonspecific experimental factors and to specific chemical exposures. Useful outcome measures include spectral electroencephalography, blood pressure, heart rate, and plasma beta-endorphin. Findings implicate, in part, dopaminergic mesolimbic pathways and limbic structures. A convergence of evidence suggests that persons with MCS or with low-level CI may share some characteristics with individuals genetically vulnerable to substance abuse: (a) elevated family histories of alcohol or drug problems; (b) heightened capacity for sensitization of autonomic variables in the laboratory; (c) increased amounts of electroencephalographic alpha activity at rest and under challenge conditions over time. Sensitization is compatible with other models for MCS as well. The neural sensitization model provides a direction for further systematic human and animal research on the physiological bases of MCS and CI.

This is a community-based study of odor sensitivity and respiratory complaints for persons reporting asthma (n = 14/141), hay fever (n = 72/140), and chemical odor intolerance (CI) (n = 41/181). CI, a symptom of multiple chemical sensitivity (MCS), was determined from self-ratings of feeling 'moderately' to 'severely' ill using the Chemical Odor Intolerance Index (CII). Index odors included perfume, pesticide, drying paint, new carpet odor, and car exhaust. Six additional odors [natural gas, disinfectants, chlorinated water, room deodorizers, and environmental tobacco smoke (ETS)] were also assessed in the health and environment survey. Asthmatics reported feeling 'frequently' to 'almost always' ill from the CII index odors of drying paint, new carpet odor, perfume, and cleaning agents compared to nonasthmatics. People with hay fever documented feeling 'frequently' to 'almost always' ill from pesticides, drying paint, and car exhaust compared to individuals without hay fever. The CI cited illness from air freshener, natural gas and chlorinated water, in addition to the index odors of perfume, paint, pesticides, new carpeting and auto exhaust. All three groups were significantly more likely to report feeling ill from ETS. People with asthma were significantly more likely to report lower lung complaints, such as wheeze and dyspnea. People with hay fever cited more chest tightness. The CI were significantly more likely to report upper and lower respiratory symptoms. Given this overlap in respiratory complaints, it could be that CI may serve to amplify these traditional immune-related disorders and/or suggest that having asthma or hay fever could make one more vulnerable to CI.

Previous studies indicate that low level chemical intolerance (CI) is a symptom of several different controversial conditions with neuropsychiatric features, e.g., chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and "Persian Gulf Syndrome". Prior studies suggest that limbic and/or mesolimbic sensitization may contribute to development of CI. The purpose of this report was to document the waking electroencephalographic (EEG) patterns of individuals with CI during chemical exposures presented over repeated sessions. Three groups of adult subjects who were recruited from the community participated in the study: self-reported CI who had made associated lifestyle changes due to their intolerance (CI/ LSC), self-reported CI who had not made such changes (CI), and normal controls without self-reported CI. Subjects underwent two sessions involving one-minute EEG recordings during exposures to low level chemical odors (a probe for limbic activation). The CI, but not the CI/ LSC, subjects had increased absolute delta power after the chemical exposures during the second, but not the first, session. The findings support the neural sensitization hypothesis for intolerance to low levels of environmental chemicals in vulnerable individuals. As in human studies of stimulant drug sensitization, those with the strongest past history with sensitizing agents may not show-term sensitization to low level exposures in the laboratory.

This cross-sectional telephone survey study assessed prevalence rates of current chemical sensitivity, frequency of chemical odor intolerance, and self-reported Persian Gulf chemical exposures among 41 randomly sampled Department of Veterans Affairs outpatients who were Persian Gulf War (PGW) and PGW-era veterans. The participants were drawn from an initial random list of 100 veterans, of whom 28 PGW and 20 era veterans had correct telephone data on file. Of those contacted, 86% of PGW veterans (24/28) and 85% of era veterans (17/20) agreed to participate. Significantly more PGW veterans with poorer global health after military service reported considering themselves now "especially sensitive to certain chemicals" (86%, 12/14) than did the PGW veterans or era veterans in stable health (both comparison groups 30%, 3/10). Among PGW veterans, the subset with worse health associated with marked increases in chemical odor intolerance since their military service had a significantly higher odds ratio for exposure to multiple chemicals, notably wartime pesticides and insect repellent, than did comparison groups. The high rate of chemical sensitivity of PGW veterans with deteriorated health is almost three times that in PGW-era veterans and in elderly primary care outpatient veterans at the same Department of Veterans Affairs medical center and in community-based civilian samples (i.e., 30%). These preliminary findings suggest the need for further study of chemical sensitivity, including tests for acquired increases in neural sensitizability to multiple low-level chemicals, in ill PGW veterans.

This study (ntotal = 35) compared early life stress ratings, parental relationships, and health status, notably orthostatic blood pressures, of middle-aged women with low-level chemical intolerance (CI group) and depression, depressives without CI (DEP group), and normals. Environmental chemical intolerance is a symptom of several controversial conditions in which women are overrepresented, that is, sick building syndrome, multiple chemical sensitivity, chronic fatigue syndrome, and fibromyalgia. Previous investigators have postulated that people with CI have variants of somatization disorder, depression, posttraumatic stress disorder (PTSD) initiated by childhood abuse or a toxic exposure event. One neurobehavioral model for CI, somatization disorder, recurrent depression, and PTSD is neural sensitization, that is, the progressive amplification of host responses (e.g., behavioral, neurochemical) to repeated intermittent stimuli (e.g., drugs, chemicals, endogenous mediators, stressors). Females are more vulnerable to sensitization than are males. Limbic and mesolimbic pathways mediate central nervous system sensitization. Although both CI and DEP groups had high levels of life stress and past abuse, the CI group had the most distant and weak paternal relationships and highest limbic somatic dysfunction subscale scores. Only the CI group showed sensitization of sitting blood pressures over sessions. Together with prior evidence, these data are consistent with a neural sensitization model for CI in certain women. The findings may have implications for poorer long-term medical as well as neuropsychiatric health outcomes of a subset of women with CI. Subsequent research should test this model in specific clinical diagnostic groups with CI.

Chemical intolerance, or reported illness from odors of common environmental chemicals (e.g., car exhaust, pesticides), is emerging as an important environmental and public health-care issue. Epidemiologic methods provide relevant heuristic devices for studies of complex disorders, such as chemical intolerance. The authors examined personal and reported parental cardiopulmonary disease prevalence rates in a community sample of chemically intolerant and control individuals. A county government (Tucson, Arizona) employee and kin subset (N = 181; 113 households) completed standard health questionnaires. Investigators determined chemical intolerance (n = 41/181) from self-reports of individuals who felt "moderately" to "severely" ill from exposure to at least three of five chemicals (i.e., car exhaust, pesticides, paint, new carpet, and perfume) on a Chemical Odor Intolerance Index. The authors chose the control group (n = 57/181) on the basis of self-reports of "never" feeling ill on the Chemical Odor Intolerance Index. The chemically intolerant group, which primarily comprised women (78% versus 51% of controls, p < .05), was significantly more likely to report-and to have sought--medical attention for heart problems, bronchitis, asthma, and pneumonia. Reports of heart problems in the chemically intolerant index cases and the occurrence of heart disease in both of their parents were significant (Fisher's p < .05). The chemically intolerant individuals were also significantly more likely to report maternal histories of chest problems (e.g., inhalant allergens, tuberculosis) than controls. The findings of the study suggested that the chemically intolerant individuals (a preponderance of whom were women [sex-related risk]) were more likely to have (a) reported cardiopulmonary problems (i.e., greater health risk); (b) actively sought medical care for these problems (i.e., increased medical utilization); and (c) reported more parental illnesses-particularly heart disease, asthma, and diabetes (i.e., genetic risk). Additional community-based studies of chemical intolerance are needed.

The symptom of intolerance to low levels of environmental chemicals (CI, chemical intolerance) is a feature of several controversial polysymptomatic conditions that overlap symptomatically with depression and somatization, i.e., chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and Persian Gulf syndrome. These syndromes can involve many somatic symptoms consistent with possible inflammation. Immunological or neurogenic triggering might account for such inflammation. Serum neopterin, which has an inverse relationship with l-tryptophan availability, may offer a marker of inflammation and macrophage/monocyte activation. This study compared middle-aged women with CI (who had high levels of affective distress; n = 14), depressives without CI (n = 10), and normals (n = 11). Groups did not differ in 4 p.m. resting levels of serum neopterin. However, the CI alone had strong positive correlations between neopterin and all of the scales measuring somatization. These preliminary findings suggest the need for additional research on biological correlates of 'unexplained' multiple somatic symptoms in subtypes of apparent somatizing disorders.

This paper summarizes the clinical phenomenology of multiple chemical sensitivity (MCS), outlines the concepts and evidence for the olfactory-limbic, neural sensitization model for MCS, and discusses experimental design implications of the model for exposure-related research. Neural sensitization is the progressive amplification of responsivity by the passage of time between repeated, intermittent exposures. Initiation of sensitization may require single toxic or multiple subtoxic exposures, but subsequent elicitation of sensitized responses can involve low or nontoxic levels. Thus, neural sensitization could account for the ability of low levels of environmental chemicals to elicit clinically severe, adverse reactions in MCS. Different forms of sensitization include limbic kindling of seizures (compare temporal lobe epilepsy and simple partial seizures) and time-dependent sensitization of behavioral, neurochemical, immunological, and endocrinological variables. Sensitized dysfunction of the limbic and mesolimbic systems could account in part for many of the cognitive, affective, and somatic symptoms in MCS. Derealization (an alteration in perception making familiar objects or people seem unfamiliar or unreal) is a common MCS symptom and has been linked with limbic dysfunction in clinical neuroscience research. Sensitization is distinct from, but interactive with, other neurobiological learning and memory processes such as conditioning and habituation (compare adaptation or tolerance). In previous studies, hypotheses for MCS involving sensitization, conditioning, and habituation (adaptation) have often been considered in isolation from one another. To design more appropriate chemical exposure studies, it may be important to integrate the various theoretical models and empirical approaches to MCS with the larger scientific literature on individual differences in these potentially interactive phenomena.

In this study, we tested the hypothesis that low-level chemical odor intolerance (i.e., "cacosmia") is a manifestation of heightened sensitizability to environmental stimuli. We examined supine heart rate and blood pressure of elderly individuals, who were classified as either having a higher degree of chemical odor intolerance (n = 12) or a lower degree of chemical odor intolerance (n = 13), upon awakening in a sleep research laboratory on 6 different days during an 8-wk protocol. During the 2 initial wk, they consumed a customary baseline diet (including ad lib milk and other dairy products), followed by 3 wk each of nondairy-containing and dairy-containing diets in randomly assigned, counterbalanced order. Measurements were made on 3 pairs of successive days, distributed over a 6-wk period, and on which different diets were consumed. The high-intolerance group had significantly higher mean supine systolic and diastolic blood pressures than did the low-intolerance group. Although subjects consumed milk products during both the initial baseline and subsequent dairy diet periods, the high-intolerance group had significantly higher heart rates and diastolic blood pressures later in the study than at baseline, especially when they were on the dairy diet. In contrast, the cardiovascular measures of the low-intolerance group lowered on average with time. The high-intolerance subjects had an increased mean diastolic blood pressure on the second days versus the first days in the laboratory (averaged across all diets). Collectively, the data suggest that elderly individuals with a high degree of chemical odor intolerance evidence (a) increased sympathetic tone in the cardiovascular system at rest over multiple measurements; and (b) greater sensitizability and/or lesser habituation of heart rate and diastolic blood pressure over time as a function, in part, of repeated environmental stressor exposures (i.e., a novel laboratory contextual setting and/or specific dietary constituents). Consistent with a sensitization model, the findings emphasize the need for two or more identical sessions at least 24 h apart in physiological studies of individuals with a high degree of intolerance for chemical odors versus normal individuals. The results of the blood pressure observations suggest that the possibility of abnormally labile autonomic function and cognitive sequelae in individuals with a high degree of intolerance for chemical odor increases with age.

This paper summarizes the key features of the olfactory-limbic, neural sensitization model for multiple chemical sensitivity (MCS) and presents relevant data on chemically intolerant human subjects from laboratory studies using quantitative electroencephalography, polysomnography, neuropsychological tests, cardiovascular measurements, and blood markers. MCS is a poorly understood chronic, polysymptomatic condition in which some prior controlled research studies have failed to find evidence to differentiate active from placebo tests. Closer examination of past MCS research, however, reveals that studies have failed to incorporate the design and methodological approaches necessary to test for nonimmunological sensitization. Time-dependent sensitization (TDS) is a well-documented phenomenon in the pharmacology literature involving the progressive increase in a given response by the passage of time between the initial and subsequent exposures to a substance or a stressor. As in MCS, multiple, chemically unrelated agents can trigger TDS. Females time-sensitize more readily than do males. Pharmacological and nonpharmacological (stress) stimuli can cross-sensitize. Dopaminergic pathways in the brain and the hypothalamic-pituitary-adrenal axis are likely involved in TDS. Data on the symptomatology of MCS point to central nervous system involvement, including limbic regions that receive input from both olfactory (odor) and trigeminal (irritant) pathways. Limbic and mesolimbic brain regions are among the most sensitizable to repeated, intermittent environmental stimuli. Sensitizable individuals can show no difference or lesser responses to a test substance on initial exposure, but later exhibit much greater increases in responsivity on the next exposure after a period of days. For future research, it is essential to distinguish chemical intolerance symptoms such as derealization, sudden mood changes, musculoskeletal pain, menstrual dysfunction, and uncontrollable sleepiness from chemical phobia and avoidance behaviors. This model permits hypothesis-driven research on MCS and has major implications for interpretation of apparently positive and negative tests for "true" as opposed to "perceived" sensitivity to low levels of environmental chemicals.

This paper addresses the evidence for the face, construct, and criterion-related validity of the olfactory-limbic/neural sensitization model for multiple chemical sensitivity (MCS). MCS is a poorly-understood, controversial condition in which low levels of environmental chemicals are reported to trigger disabling levels of illness in certain individuals. Neural sensitization processes could generate an endogenous amplification of responsivity to exogenous substances, thereby providing a plausible explanation for the apparent lack of a classical toxicological dose-response relationship in MCS. Convergent data from both survey and psychophysiological studies of MCS patients and of persons from the community without MCS, but who report elevated frequency of illness from chemical odors (cacosmics), support the involvement of the limbic system and the sensitizability of cacosmics, as predicted by the model. Recent studies show that cacosmics do sensitize their heart rate, blood pressure, and plasma beta-endorphin responses to repeated exposures to a novel laboratory procedure involving dietary manipulations over time. Cacosmia may represent a pathological form of neural plasticity. Taken together, the model and the available evidence suggest the need for more intensive investigation of MCS from the standpoint of possible neurobiological mechanisms affecting cognitive, emotional, and somatic functions.

Subjective sleep complaints and food intolerances, especially to milk products, are frequent symptoms of individuals who also report intolerance for low-level odors of various environmental chemicals. The purpose of the present study was to evaluate the objective nature of nocturnal sleep patterns during different diets, using polysomnography in community older adults with self-reported illness from chemical odors. Those high in chemical odor intolerance (n = 15) exhibited significantly lower sleep efficiency (p = .005) and lower rapid-eye-movement (REM) sleep percent (p = .04), with a trend toward longer latency to REM sleep (p = .07), than did those low in chemical intolerance (n = 15), especially on dairy-containing as compared with nondairy (soy) diets. The arousal pattern of the chemical odor intolerant group differed from the polysomnographic features of major depression, classical organophosphate toxicity, and subjective insomnia without objective findings. The findings suggest that community elderly with moderate chemical odor intolerance and minimal sleep complaints exhibit objectively poorer sleep than do their normal peers. Individual differences in underlying brain function may help generate these observations. The data support the need for similar studies in clinical populations with chemical odor intolerance, such as multiple chemical sensitivity patients and perhaps certain veterans with "Persian Gulf Syndrome."

This study examined plasma beta-endorphin as a marker of the physiological stress response in community elderly who were either high (n = 15) or low (n = 15) in self-rated frequency of illness from environmental chemical odors. Individuals who report nonatopic multiple sensitivities to or intolerances for low levels of environmental chemicals also claim high rates of comorbid food sensitivities or intolerances. Subjects gave 9 AM blood samples for plasma beta-endorphin 90 min after ingesting either 1% fat cow's milk or a soy-based nondairy drink, on six different mornings in the laboratory after all-night sleep recordings. The six sessions-were divided into three sets of two successive days each, with each set [involving baseline (ad lib milk), nondairy (soy-based), and dairy diets] separated from the next by 3 weeks. In the chemically tolerant subjects, stably lower beta-endorphin levels suggested that milk may have been a physiologically less stressful beverage than was the soy drink. In contrast, the chemical odor intolerant group exhibited a) increased levels of plasma beta-endorphin averaged over the 6 days (p = .02); and b) marked fluctuations in endorphin from one laboratory day to the next (Group x Diet x Day interaction, p = .005). The findings were consistent with time-dependent, context-dependent sensitization of beta-endorphin in the chemical odor intolerant individuals.

The psychological, neuropsychiatric, and somatic characteristics of young adults who have different degrees of cacosmia (i.e., feeling "ill" from the odor of xenobiotic chemicals) and who have self-described "chemical sensitivity" were examined. A total of 800 college students completed the following: a self-rating scale for frequency of odor intolerance for 10 common substances, Simon Environmental Illness Symptom Survey, the SCL-90-R, Barsky Amplification Scale, Pearlin-Schooler Mastery Scale, Cheek-Buss and Kagan Shyness scales, Marlowe-Crowne Social Desirability Scale, and a health-symptom and physician-diagnosed checklist. Two pairs of groups were compared: (1) subjects in the top 16% (i.e., cacosmics) and bottom 15% (noncacosmics) of the sample with respect to odor intolerance scale scores; and (2) subjects from the entire sample who did (28%) or did not (72%) consider themselves to be "especially sensitive to certain chemicals.¿ Cacosmics and the chemically sensitive subjects scored significantly higher on measures of psychological distress and amplification of somatic symptoms, but there was little evidence of lifestyle change, as assessed by the Simon Survey. Compared with their respective comparison groups, cacosmic and chemically sensitive groups had significantly higher incidences of illnesses associated with chemicals, alcohol intake, opiate drug use, and caffeine use, even after controlling for the psychological measures and histories of atopic allergy. Subjects with and without neuropsychiatric symptoms were differentiated with respect to chemical odor intolerance, but subjects with and without atopic allergies and possible autoimmune diseases were differentiated with respect to chemical sensitivity. Females were more cacosmic than males. Cacosmia is defined by a population subset, with or without occupational xenobiotic exposures or disability, that has distress and symptom amplification and neuropsychiatric and somatic symptoms, none of which are explained fully by psychological measures. Prospective clinical studies are possible with such individuals. The data are also consistent with a time-dependent sensitization model for illness from low-level chemical exposures.

We previously hypothesized that individual differences in (a) limbic system reactivity and (b) central nervous system sensitizability underlie vulnerability to environmental stimuli, not only in the controversial clinical condition multiple chemical sensitivity (MCS), but also in the general population. Earlier research has shown overlaps in the characteristics of persons who report noise and air pollutant sensitivities. This study assessed questionnaire responses of 897 young adult college students who reported high versus low frequency of illness from several environmental chemical odors and concomitantly high versus low sensitivity to environmental noise. Subjects who reported increased rates of illness from chemical odors with or without noise sensitivity scored significantly higher (P < 0.0001) on a measure of limbic system symptomatology derived from ictal sensory, somatic, mnemonic, and behavioral manifestations of temporal lobe epilepsy. The group rating high both for illness from chemicals and for noise sensitivity had characteristics predictive of heightened sensitizability from the animal research on time-dependent sensitization (progressive response amplification to repeated, intermittent stimuli over time): i.e., higher female to male ratio (gender risk factor), increased rates of drug abuse problems in blood relatives (genetic risk factor), trait shyness (hyperreactivity to novelty), and increased carbohydrate craving. Despite the increased family histories of drug abuse and levels of personal anxiety and depression, the chemical- and noise-sensitive group reported the lowest rates of current smoking or personal drug abuse problems and the highest frequency of illness from drinking a small amount of alcohol. Taken together, the findings suggest that limbic system dysfunction associates more with chemical than with noise sensitivity; that individuals with both chemical and noise sensitivity may be the most sensitizable subset of the population for prospective studies, and that, in their substance use patterns, young adults with both chemical and noise sensitivity are more similar to MCS patients than are their peers with chemical or noise sensitivity alone.

Background: Cacosmia, which is a predictor of cognitive deficits in industrial samples, is a core symptom of several controversial syndromes. Previous studies of cacosmic populations have considered only psychiatric but not medical or family histories of identified patients., Method: This questionnaire survey study examined subjective characteristics of illness from chemical odors, sensitivity to chemicals, psychological and stress profiles, and medical, psychiatric, and family health histories of 28 middle-aged women with cacosmia in self-reported poor health attributed to chemicals (MCS), 17 controls with cacosmia in good health, and 20 normal controls without cacosmia in good health., Results: Those with MCS rated themselves in significantly poorer overall health with higher Pennebaker symptom scores, a larger number of chemical triggers, and greater frequency of illness from chemicals than the other two groups, even after controlling for variables on which the groups differed (i.e., education, Symptom Checklist-90 [revised] somatization, obsessive-compulsiveness, depression, anxiety, phobic anxiety, psychoticism, Barsky Somatic Symptom Amplification, and Cheek-Buss shyness). Despite increased levels of affective distress, those with MCS reported the greatest intolerance for alcohol and the lowest alcohol consumption., Conclusion: The data suggest that women with MCS report increased disability, multiple medical diagnoses including inflammatory and gynecologic dysfunctions, and psychological distress. The data are consistent descriptively with the phenomenology of somatization disorder. However, the persisting significance of group health rating differences after controlling for psychological variables, the lack of differences in life stress ratings between those with MCS and healthy cacosmics, the later age at onset (60% after age 30 years), and the lack of excess family psychiatric histories in this sample of women with MCS suggest a potential role for an organic factor in the evolution of poor health in certain cacosmics.

The present paper summarizes the proposed time-dependent sensitization (TDS) and partial limbic kindling model for illness from low-level chemicals; reviews and critiques prior studies on CNS aspects of multiple chemical sensitivity (MCS); and outlines possible experimental approaches to future studies. TDS is the progressive and persistent amplification of behavioral, neurochemical, endocrine, and/or immunological responses to repeated intermittent stimuli over time. Partial limbic kindling is a progressive and persistent lowering of the threshold for eliciting electrical afterdischarges, but not motor seizures, in certain brain structures such as amygdala and hippocampus; behavioral consequences include increased avoidant behaviors. The focus of the paper is the controversial claim of altered sense of smell and illness from low levels of environmental chemicals (i.e., "cacosmia"), levels that should not have any biologically harmful effects by the rules of classical neurotoxicology. A major perspective of this paper is that the phenomenology of MCS is similar to that of time-dependent sensitization (reverse tolerance) and tolerance as studied in the substance abuse literature. The TDS model for MCS proposes that neurobiological amplification underlies the symptoms and phenomenology of these patients, including their behavioral features of heightened affective and somatic distress. It is hypothesized that MCS patients, who are mostly women, may be individuals who sensitize to substances rapidly and to the extreme, to the point of aversive symptomatology with less complete capacity for development of tolerance. Possible parallels between MCS and TDS include: (a) initiation by single or multiple intermittent stimuli; (b) lasting changes in subsequent reactivity to low levels of chemically unrelated substances; (c) cross-sensitization between the stressors and pharmacological agents; (d) greater vulnerability of individuals who are female, who have certain genetic characteristics, and/or who may be hyperreactive to novelty (cf. trait shyness); (e) lack of obvious differences between sensitized and unsensitized individuals at baseline without eliciting exposures; (f) bidirectionality (bipolarity) of sensitized responses; (g) both context-dependent (conditioned) and context-independent (unconditioned) amplification of responses. To minimize variability between studies, research in this area needs (a) consensus on a working case definition of MCS or at least of cacosmia as a specific symptom in a subset of well-defined medical and psychiatric disorders; and (b) proper design of chemical challenge studies in MCS, controlling for individual differences in sensitizability and for the properties of sensitization (e.g., repeated intermittent exposure tests) and tolerance (e.g., removal from customary ambient air exposures prior to testing).