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Neurogenic inflammation: with additional discussion of central and perceptual integration of nonneurogenic inflammation.

The Working Group on Neurogenic Inflammation proposed 11 testable hypotheses in the three domains of neurogenic inflammation, perceptual and central integration, and nonneurogenic inflammation. The working group selected the term people reporting chemical sensitivity (PRCS) to identify the primary subject group. In the domain of neurogenic inflammation, testable hypotheses included: PRCS have an increased density of c-fiber neurons in symptomatic tissues; PRCS produce greater quantities of neuropeptides and prostanoids than nonsensitive subjects in response to exposure to low-level capsaicin or irritant chemicals; PRCS have an increased and prolonged response to exogenously administered c-fiber activators such as capsaicin; PRCS demonstrate augmentation of central autonomic reflexes following exposure to agents that produce c-fiber stimulation; PRCS have decreased quantities of neutral endopeptidase in their mucosa; exogenous neuropeptide challenge reproduces symptoms of PRCS. In the domain of perceptual and central integration, testable hypotheses included: PRCS have alterations in adaptation, habituation, cortical representation, perception, cognition, and hedonics compared to controls; the qualitative and quantitative interactions between trigeminal and olfactory systems are altered in PRCS; higher integration of sensory inputs is altered in PRCS. In the domain of nonneurogenic inflammation, testable hypotheses included: increased inflammation is present in PRCS in symptomatic tissues and is associated with a heightened neurosensory response; PRCS show an augmented inflammatory response to chemical exposure. The working group recommended that studies be initiated in these areas.

Chemoreceptor Cells↗

Responses to controlled diesel vapor exposure among chemically sensitive Gulf War veterans.

OBJECTIVE: A significant proportion of Gulf War veterans (GWVs) report chemical sensitivity, fatigue, and unexplained symptoms resulting in ongoing disability. GWVs frequently recall an association between diesel and petrochemical fume exposure and symptoms during service. The purpose of the present study among GWVs was to evaluate the immediate health effects of acute exposure to chemicals (diesel vapors with acetaldehyde) with and without stress. METHODS: In a single, controlled exposure to 5 parts per million (ppm) diesel vapors, symptoms, odor ratings, neurobehavioral performance, and psychophysiologic responses of 12 ill GWVs (GWV-I) were compared with 19 age- and gender-matched healthy GWVs (GWV-H). RESULTS: Relative to baseline and to GWV-H, GWV-I reported significantly increased symptoms such as disorientation and dizziness and displayed significantly reduced end-tidal CO(2) just after the onset of exposure. As exposure increased over time, GWV-I relative to GWV-H reported significantly increased symptoms of respiratory discomfort and general malaise. GWV-I were also physiologically hyporeactive in response to behavioral tasks administered during but not before exposure. CONCLUSIONS: Current symptoms among GWV-I may be exacerbated by ongoing environmental chemical exposures reminiscent of the Gulf War. Both psychologic and physiologic mechanisms contribute to current symptomatic responses of GWV-I.

Adult↗

Representation of acute and persistent pain in the human CNS: potential implications for chemical intolerance.

The study of pain may be relevant to the study of chemical intolerance (CI) in many ways. Pain is often reported as a symptom of CI and it is defined as a subjective experience similar to many other symptoms of CI, making its objectification difficult. Furthermore, the CNS plastic changes that underlie the development of persistent pain states and abnormal pain responses may share some similarities with those involved in the sensitization to environmental chemicals. Functional brain imaging studies in humans demonstrate that acute pain evoked by nociceptive stimulation is accompanied by the activation of a widely distributed network of cerebral structures, including the thalamus and the somatosensory, insular, and anterior cingulate cortices. Abnormal activity within these regions has been associated with the experience of pain following damage to the peripheral or central nervous system (neuropathic pain) in a number of clinical populations. In normal individuals, activity within this network is correlated with subjective pain perception, is highly modifiable by cognitive interventions such as hypnosis and attention, and has been associated with emotions. Other cognitive mediators such as expectations can also produce robust changes in pain perception (e.g., in placebo analgesia). These effects likely depend on both higher-order cerebral structures and descending mechanisms modulating spinal nociceptive activity. These psychological processes can be solicited to reduce clinical pain and we speculate that they may further attenuate or promote central mechanisms involved in the transition from acute to persistent pain states. The investigation of central determinants of subjective experience is essential to assess the possibility that higher-order brain/psychological processes modulate and/or mediate the development of persistent pain states. These factors may contribute to the development of symptoms in CI.

Acute Disease↗

Environmental sensitivities: prevalence of major symptoms in a referral center: the Nova Scotia Environmental Sensitivities Research Center Study.

Although the phenomenon of environmental sensitivities (ES) has no clear etiology nor well-accepted pathophysiology, affected individuals experience symptoms that cause varying levels of dysfunction. Through a dedicated, government-funded research and treatment center, a detailed questionnaire covering 217 symptoms in 13 systems was mailed in 1997-1998 to 812 individuals referred to the center by physicians. A total of 385 (47%) questionnaires were returned, and data were analyzed on 351 individuals. Participants tended to be women (80%), middle-aged individuals (37% age 40-49 years), and those in higher educational groups (28% completed university), but there was wide variation in demographic variables. General symptoms such as difficulty concentrating, fatigue, forgetfulness, and irritability dominated the overall prevalence of symptoms since the start of their illness. Those related to irritation such as sneezing, itchy or burning eyes, and hoarseness or loss of voice were more common after exposure to environmental irritants. Ranking of symptoms using severity scores was consistent between men and women. Overall scores were higher in women, in participants who were separated or divorced, and in low-income groups. The type and consistency of symptoms experienced after exposure to triggering substances may not fit a purely psychogenic theory.

Adolescent↗

Salivary cortisol and self-reported stress among persons with environmental annoyance.

OBJECTIVES: Increased vulnerability to stress has been suggested as a possible mechanism behind medically unexplained conditions such as sensitivity to electricity and common smells. This study examined whether subjective environmental annoyance among the general population is associated with increased physiological reactivity or subjective stress scores. METHODS: Four groups were studied (N=141): an electrically annoyed (N=17), a smell-annoyed (N=29), and a generally annoyed group (N=39) and a reference group matched for age, gender, and socioeconomic status (N=56). Over 5 days, the participants collected saliva for cortisol determination at awakening, 30 minutes after awakening, 8 hours after awakening, and at 9 o'clock in the evening. On the evening preceding the fifth day, the participants ingested a 0.5-mg dexamethasone tablet so that possible differential suppression of the hypothalamic-pituitary-adrenal (HPA) axis could be assessed. Each day, the participants also rated their subjective stress and health complaints. RESULTS: No significant differences were found between the groups regarding cortisol secretion over 5 days. The dexamethasone suppression test showed inhibited cortisol secretion in all four groups. No associations were found between the cortisol concentrations and the self-reported stress scores or subjective health complaints. CONCLUSIONS: Although the environmentally annoyed groups showed no signs of increased HPA-axis activation, being annoyed by both electrical devices and smells seems to be related to increased psychological activation in terms of self-reported stress. Because the participants were otherwise healthy and recruited from the general population, the results imply that subtle psychological stress processes may be important in the early development of environmental annoyance.

Adult↗

Gulf War veterans' illnesses: a case study in causal inference.

The objective of this study was to determine from the published epidemiological literature whether there is evidence for a causal association between service in the Gulf War and illness in U.S. veterans. Eleven published studies were analyzed using standardized epidemiologic criteria for assessing causality. A consistent association was found between deployment to the Gulf and self-reports of symptoms. No consistency was seen in physical findings or laboratory results. Strength of association varied with different study designs. Dose-response information is limited, because of lack of quantitative data on exposures. Biological plausibility varies for different risk factors. Specificity of association is not seen. Frequency of self-reported symptoms is increased in U.S. Gulf War veterans compared to other veterans of the same era, but specific causes of illnesses cannot be ascertained. Major gaps in data that impeded this analysis include (1) lack of objective data on specific environmental exposures (2) lack of baseline health assessments, and (3) lack of objective measures of post-deployment health status. In future deployment of U.S. troops, accurate exposure and health data will be needed if the causes of subsequent illnesses are to be accurately assessed.

Environmental Exposure↗

Subacute toxicity of a mixture of nine chemicals in rats: detecting interactive effects with a fractionated two-level factorial design.

The present study was intended (1) to find out whether simultaneous administration of nine chemicals at a concentration equal to the "no-observed-adverse-effect level" (NOAEL) for each of them would result in a NOAEL for the combination and (2) to test the usefulness of fractionated factorial models to detect possible interactions between chemicals in the mixture. A 4-week oral/inhalatory study in male Wistar rats was performed in which the toxicity (clinical chemistry, hematology, biochemistry, and pathology) of combinations of the nine compounds was examined. The study comprised 20 groups, 4 groups in the main part (n = 8) and 16 groups in the satellite part (n = 5). In the main study, the rats were simultaneously exposed to mixtures of all nine chemicals [dichloromethane, formaldehyde, aspirin, di(2-ethylhexyl)phthalate, cadmium chloride, stannous chloride, butyl hydroxyanisol, loperamide, and spermine] at concentrations equal to the "minimum-observed-adverse-effect level" (MOAEL), NOAEL, or 1/3NOAEL. In the satellite study the rats were simultaneously exposed to combinations of maximally five compounds at their MOAEL. These combinations jointly comprise a two-level factorial design with nine factors (=9 chemicals) in 16 experimental groups (1/32 fraction of a complete study). In the main part many effects on hematology and clinical chemistry were encountered at the MOAEL. In addition, rats of the MOAEL group showed hyperplasia of the transitional epithelium and/or squamous metaplasia of the respiratory epithelium in the nose. Only very few adverse effects were encountered in the NOAEL group. For most of the end points chosen, the factorial analysis revealed main effects of the individual compounds and interactions (cases of nonadditivity) between the compounds. Despite all restrictions and pitfalls that are associated with the use of fractionated factorial designs, the present study shows the usefulness of this type of factorial design to study the joint adverse effects of defined chemical mixtures at effect levels. It was concluded that simultaneous exposure to these nine chemicals does not constitute an evidently increased hazard compared to exposure to each of the chemicals separately, provided the exposure level of each chemical in the mixture is at most similar to or lower than its own NOAEL.

Administration, Inhalation↗

[Chronic fatigue].

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Diagnosis, Differential↗

Perceived relation between odors and a negative event determines learning of symptoms in response to chemicals.

BACKGROUND: We investigated the effects of worrying information about chemical pollution on subjective symptoms in response to an odor that was previously associated with symptom episodes. METHODS: Ammonia and butyric acid in harmless concentrations were used as odor cues, and 10% CO2-enriched air was used to induce symptoms. One of two odors was consistently mixed with CO2-enriched air while the other odor was presented in room air during 80 s breathing trials (three trials of each). Next, information framing the experiment in the context of possible health-damaging effects of chemical pollution of our environment was presented to half the participants, whereas no information was given to the other half. Finally, both odor cues were presented with room air. Symptom scores were used as the dependent variable. RESULTS: Unexpectedly, participants reported more symptoms in response to the odor previously presented with air than to the odor previously presented with CO2-enriched air. Post-hoc analyses suggested a crucial role for perceived rather than actual contingencies between odor and symptom episodes. Information manipulation had no effect. CONCLUSIONS: Believing that a specific odor cue was associated with a symptom episode was more important than the actual association in order to provoke symptoms in response to harmless odor cues.

Adolescent↗

Diagnostic relevance of the determination of lymphocyte subpopulations in environmental medicine.

Earlier hopes that determination of lymphocyte subpopulations might become a strong diagnostic tool in environmental medicine have not been fulfilled in recent years. Analysis of the scientific literature rather shows that there are only few examples for environmental exposures causing reproducible shifts of lymphocyte subpopulations. Moreover, current knowledge suggests that "environmental diseases" are not associated with characteristic changes of subpopulation patterns. If lymphocyte subpopulations are analyzed, each diagnostic step, including indication, sample handling, analytic procedure and data-interpretation, should adhere to good quality criteria. Taking all together, the determination of lymphocyte subpopulations in the context of environmental medicine comes under category IV of the criteria of the Commission for Methods and Quality Assurance in Environmental Medicine of the German federal health authority (Robert Koch-Institute; RKI): "A procedure cannot be recommended because there is not sufficient information to justify it" (here: no solid trends in epidemiological examinations), "and because theoretical considerations speak against an application" (here: high physiological variability and missing exposure or substance specificity).

Antigens, CD↗

Subgrouping outpatients of an environmental medicine unit using SCL-90-R and cluster analysis.

Between 1999 and 2003 all consecutive outpatients of the environmental medicine unit of the Charité hospital in Berlin were invited to participate in a study on environmentally related disorders. One hundred and sixty-nine of the patients completed a psychosocial questionnaire which comprised SCL-90-R and 14 other tests. When compared with clinical controls, SCL-90-R mean scores of the environmental patients (EP) were found to lie in between those of inpatients of a psychosomatic clinic and melanoma aftercare patients; but they were, with exception of the somatisation dimension, much closer to the latter. Application of the TwoStep Cluster component of SPSS resulted in three subgroups with high, moderate and low scores which were significantly different (p<0.001) although separation was incomplete (87% correct identification; cross-validated discriminant analysis). With all subgroups, scores for somatisation, depression and obsessive compulsion were highest and those for phobic anxiety and psychoticism were lowest. SCL-90-R scores correlated well with results of the Freiburg Personality Inventory, Whiteley Index of hypochondriasis, the short form health questionnaire (SF-36), and the Composite International Diagnostic Interview (CIDI). Hierarchical grouping (average linkage between groups), performed with involvement of SCL-90-R data from literature, resulted in a dendrogram with three distinct groups and three outliers. EP with low SCL-90-R scores were assigned to a group which comprised also general populations (USA, Germany), allergy patients, and melanoma controls. Those with moderate SCL-90-R scores were placed in a group together with chronic pain patients, and 26 'environmentally ill' subjects. The third subgroup of EP formed a cluster with our psychosomatic controls, psychosomatic patients from another study, depressed people, and patients undergoing psychotherapy. The three outliers of the dendrogram, however, were SCL-90-R profiles obtained from persons with toxic waste exposure, neurotoxic workplace exposure or with solvent-induced chronic toxic encephalopathy.

Cluster Analysis↗

MMPI-2 validity, clinical and content scales, and the Fake Bad Scale for personal injury litigants claiming idiopathic environmental intolerance.

BACKGROUND: Idiopathic environmental intolerance (IEI) is a descriptor for nonspecific complaints that are attributed to environmental exposure. METHODS: The Minnesota Multiphasic Personality Inventory 2 (MMPI-2) was administered to 50 female and 20 male personal injury litigants alleging IEI. RESULTS: The validity scales indicated no overreporting of psychopathology. Half of the cases had elevated scores on validity scales suggesting defensiveness, and a large number had elevations on Fake Bad Scale (FBS) suggesting overreporting of unauthenticated symptoms. The average T-score profile for females was defined by the two-point code type 3-1 (Hysteria-Hypochondriasis), and the average T-score profile for males was defined by the three-point code type 3-1-2 (Hysteria, Hypochondriasis-Depression). On the content scales, Health Concerns (HEA) scale was significantly elevated. CONCLUSION: Idiopathic environmental intolerance litigants (a) are more defensive about expressing psychopathology, (b) express distress through somatization, (c) use a self-serving misrepresentation of exaggerated health concerns, and (d) may exaggerate unauthenticated symptoms suggesting malingering.

Adult↗