Inflammatory Mediator Profiling of n-butanol Exposed Upper Airways in Individuals with Multiple Chemical Sensitivity.

BACKGROUND: Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by reports of recurrent symptoms in response to low level exposure to various chemical substances. Recent findings suggests that dysregulation of the immune system may play a role in MCS pathophysiology. OBJECTIVES: The aim of this study was to examine baseline and low dose n-butanol-induced upper airway inflammatory response profiles in MCS subjects versus healthy controls. METHOD: Eighteen participants with MCS and 18 age- and sex-matched healthy controls were enrolled in the study. Epithelial lining fluid was collected from the nasal cavity at three time points: baseline, within 15 minutes after being exposed to 3.7 ppm n-butanol in an exposure chamber and four hours after exposure termination. A total of 19 cytokines and chemokines were quantified. Furthermore, at baseline and during the exposure session, participants rated the perceived intensity, valence and levels of symptoms and autonomic recordings were obtained. RESULTS: The physiological and psychophysical measurements during the n-butanol exposure session verified a specific response in MCS individuals only. However, MCS subjects and healthy controls displayed similar upper airway inflammatory mediator profiles (P>0.05) at baseline. Likewise, direct comparison of mediator levels in the MCS group and controls after n-butanol exposure revealed no significant group differences. CONCLUSION: We demonstrate no abnormal upper airway inflammatory mediator levels in MCS subjects before or after a symptom-eliciting exposure to low dose n-butanol, implying that upper airways of MCS subjects are functionally intact at the level of cytokine and chemokine production and secretory capacity. This suggests that previous findings of increased cytokine plasma levels in MCS are unlikely to be caused by systemic priming via excessive upper airway inflammatory processes.

Management of polysensitized patient: from molecular diagnostics to biomolecular immunotherapy.

A panel of Italian allergists gathered to discuss the issue concerning the management of polysensitized patients. The main conclusions were as follows: polysensitization is a relevant clinical characteristic as it affects about 70-80% of the global allergic population; the diagnostic pathway needs the use of an adequate and thorough methodology, based on the demonstration of consistency between history and documented sensitization; polysensitization and polyallergy are not synonymous: true allergy should always be demonstrated; polysensitization does not constitute a limitation to allergen immunotherapy prescription, as 1-2 allergen extracts could be effective in polysensitized patients; the allergen immunotherapy product characteristics should include the following: high efficacy and optimal safety profile, standardized production, and documented presence and titration of the major allergen.

[Pathophysiology of multiple chemical sensitivity]. / Physiopathologie du syndrome d'hypersensibilité chimique multiple.

INTRODUCTION AND BACKGROUND: Multiple chemical sensitivity (MCS) is a complex clinical entity that includes a large number of non-specific symptoms, associated in a univocal manner in each patient and triggered by exposure to various chemicals at low concentrations, well below those known to cause toxic effects. However, no objective test exists currently to diagnose this syndrome. One of the main reasons is that the pathophysiology is poorly understood. However, many explanatory hypotheses have been proposed. VIEWPOINTS AND CONCLUSIONS: Patients with symptoms of MCS are often encountered by pulmonologists. Their suffering is undeniable but, unfortunately, the lack of understanding of the pathophysiological mechanisms makes treatment difficult and empirical.

[Peculiarities of immune disorders in workers of activated carbon production].

One of priority approaches in occupational medicine and health risk evaluation is study of immune system features in individuals exposed to occupational chemical hazards. The studies revealed reliable changes in immune parameters (positive annexin tag, disorders of cytokine profile)-- that proves retarded apoptosis precesses in workers engaged into activated carbon and coagulants production. Marked disorders of cellular regulation in machinery operators of activated carbon and coagulants production are seen with observed normal content of phenol in the air of workplace.

Capsaicin-induced neurogenic inflammation in the skin in patients with symptoms induced by odorous chemicals.

BACKGROUND: Intradermal injection of capsaicin induces the axonal release of neuropeptides, vasodilatation and flare, e.g. neurogenic inflammation. The spatial profile of neurogenic inflammation in the skin has been studied in various experimental models. Polarization spectroscopy imaging introduced recently may be used for the quantitative assessment of the temporal profile of neurogenic inflammation expressed as erythema intensity. PURPOSE: In the present study, we aimed to compare capsaicin-induced erythema intensity with the flare area in patients with symptoms induced by odorous chemicals, thereby comparing the temporal and spatial profiles of neurogenic inflammation. METHODS: Sixteen patients fulfilling Cullen's criteria for multiple chemical sensitivity (MCS) and 15 eczema (EC) patients with airway symptoms elicited by odorous chemicals were compared with 29 age-matched, healthy controls. Participants were administered two intradermal injections of capsaicin 3.3 and 33µM. Erythema intensity was measured by polarization spectroscopy imaging and flare response was quantified by visual inspection. RESULTS: Erythema intensity and flare area did not differ between patients and controls, and they were not correlated. Erythema intensity and flare area showed a dose-dependent increase (P<0.05). Erythema intensity increased with age at 3.3µM but not at 33µM capsaicin, whereas the flare area increased with age at both concentrations (P<0.05). CONCLUSION: Capsaicin-induced erythema intensity and visual flare were normal in patients with MCS and EC patients with airway symptoms from odorous chemicals. Polarized light spectroscopy was a useful method for the measurement of the rapid temporal changes in erythema of experimental reactions.

Chemical allergens--what are the issues?

Chemical allergy describes the adverse health effects that may result when exposure to a chemical elicits an immune response. Allergy develops in two phases. In the first phase, exposure of an inherently susceptible subject results in stimulation of an immune response or immunological priming. If the then sensitised subject is exposed on a subsequent occasion to the same chemical then an accelerated and more aggressive secondary immune response will be provoked resulting in inflammation and the signs and symptoms of a clinically discernible allergic reaction. The two forms of chemical allergy of greatest relevance for occupational toxicology are skin sensitisation resulting in allergic contact dermatitis, and sensitisation of the respiratory tract associated with occupational rhinitis and asthma. In this brief survey we identify what we believe currently represent the key issues and key challenges in these areas.

Sites of dermatitis in a patch test population: hand dermatitis is associated with polysensitization.

BACKGROUND: Sites of dermatitis in larger series of contact allergic patients are rarely reported. Increased risk of polysensitization has been linked only to stasis dermatitis and leg ulcers. However, a large proportion of polysensitized individuals may have dermatitis in other skin areas. OBJECTIVES: To examine the site of dermatitis at time of first appearance in contact allergic individuals with special focus on the distribution of dermatitis in polysensitized individuals and to examine if widespread dermatitis is more frequent in polysensitized than in single/double-sensitized patients. METHODS: A matched case-control study was carried out including 394 polysensitized and 726 single/double-sensitized patients who responded to a postal questionnaire. All subjects were recruited from a hospital patch test population. RESULTS: The hands were the most frequent and the anogenital region was the least frequent skin area affected with dermatitis. Dermatitis on the hands/wrists [odds ratio (OR) 1.58], in the armpits (OR 1.56) and on the back (OR 1.91) was positively associated with polysensitization. The hands were the only skin area with dermatitis which maintained the association to polysensitization in two subpopulations consisting of, respectively, individuals with and without atopic eczema. Dermatitis on the scalp was negatively associated with polysensitization (OR 0.66) primarily for individuals without atopic eczema. The dermatitis did not seem to be more widespread in polysensitized compared with single/double-sensitized patients. CONCLUSIONS: Special awareness in patients with hand dermatitis seems justified either to prevent development of multiple contact allergies or to document polysensitization as an aetiological factor.

Detection of low-level environmental chemical allergy by a long-term sensitization method.

Multiple chemical sensitivity (MCS) is characterized by various signs, including neurological disorders and allergy. Exposure may occur through a major event, such as a chemical spill, or from long-term contact with chemicals at low levels. We are interested in the allergenicity of MCS and the detection of low-level chemical-related hypersensitivity. We used long-term sensitization followed by low-dose challenge to evaluate sensitization by well-known Th2 type sensitizers (trimellitic anhydride (TMA) and toluene diisocyanate (TDI)) and a Th1 type sensitizer (2,4-dinitrochlorobenzene (DNCB)). After topically sensitizing BALB/c mice (9 times in 3 weeks) and challenging them with TMA, TDI or DNCB, we assayed their auricular lymph nodes (LNs) for number of lymphocytes, surface antigen expression of B cells, and local cytokine production, and measured antigen-specific serum IgE levels. TMA and TDI induced marked increases in levels of antigen-specific serum IgE and of Th2 cytokines (IL-4, IL-5, IL-10, and IL-13) produced by ex vivo restimulated lymph node cells. DNCB induced a marked increase in Th1 cytokine (IL-2, IFN-gamma, and TNF-alpha) levels, but antigen-specific serum IgE levels were not elevated. All chemicals induced significant increases in number of lymphocytes and surface antigen expression of B cells. Our mouse model enabled the identification and characterization of chemical-related allergic reactions at low levels. This long-term sensitization method would be useful for detecting environmental chemical-related hypersensitivity.

Coagulation cascade and fibrinolysis in patients with multiple-drug allergy syndrome.

BACKGROUND: Previous studies have shown that patients with multiple-drug allergy syndrome (MDAS) frequently have positive autologous serum skin test results, similar to patients with chronic urticaria (CU). Recent investigations have found that patients with CU show signs of thrombin generation and activation of the tissue factor pathway of the coagulation cascade. OBJECTIVE: To study thrombin generation and fibrinolysis in patients with MDAS. METHODS: Nine patients with MDAS underwent autologous plasma skin testing (APST) and measurement of plasma prothrombin fragment F(1 + 2) and D-dimer levels. Furthermore, the basophil histamine-releasing activity of plasma from patients with MDAS was evaluated. Plasma samples from 74 healthy control subjects and 13 patients with CU were used as negative and positive controls, respectively. RESULTS: All 9 patients with MDAS had positive APST results, and 7 showed elevated plasma levels of fragment F(1 + 2). In patients with MDAS, the median F(1 + 2) level (339 pmol/L; interquartile range [IQR], 250-401 pmol/L) significantly exceeded that in healthy controls (159 pmol/L; IQR, 123-196 pmol/L) (P = .001) but did not significantly differ from that in controls with CU (292 pmol/L; IQR, 182-564 pmol/L; P = .38). Plasma D-dimer levels were normal in all the patients with MDAS and were significantly lower than in controls with CU (P = .009). Finally, the histamine-releasing activity of plasma from patients with MDAS was significantly increased and correlated with F(1+ 2) levels (r = 0.68; P = .04). CONCLUSION: Positive APST results and thrombin generation indicate a common physiopathologic background in MDAS and CU. The lower D-dimer levels suggest that fibrinolysis occurs less intensely in MDAS than in CU.

Human monocytoid THP-1 cell line versus monocyte-derived human immature dendritic cells as in vitro models for predicting the sensitising potential of chemicals.

Immature dendritic cells (DCs) modulate differentiation markers following in vitro exposure to chemicals generating contact allergies. THP-1 is a monocytoid cell line maintaining some differentiating plasticity. In this study, human DCs and THP-1 cells were compared as in vitro models to predict contact sensitisation of chemicals with different sensitising potential. Expression of CD80 and CD86 was assessed by flow cytometry after exposure to subtoxic concentrations of potent (2,4-dinitrochlorobenzene, DNCB and p-phenylendiamine, PPD), strong (thimerosal, TMS), moderate (sodium tetrachloroplatinate, Na2PtCl4) sensitising compounds as well as of non-sensitising, irritating sodium dodecyl sulphate (SDS) as compared to a vehicle of sensitising substances (dimethyl sulphoxide, DMSO). Up-regulation of CD86 following in vitro incubation of DCs and THP-1 cells with DNCB, PPD, TMS and Na2PtCl4, but not with SDS, was observed. The CD80 membrane marker was up-regulated on DCs following in vitro incubation with DNCB and PPD, but not with TMS, Na2PtCl4. and SDS. On THP-1 cells, only DNCB up-regulated CD80 expression. In conclusion, both the cell line THP-1 and DCs are promising in vitro models for assays aiming at predicting the sensitisation potential of chemicals. THP-1 cell line is by far easier to handle and offers relevant advantages from the practical point of view.

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).

Multiple chemical sensitivities following intolerance to azo dye in sweets in a 5-year-old girl.

BACKGROUND: Cases of multiple chemical sensitivities (MCS) have been reported predominantly in adult patients, but pediatric cases have rarely been reported. METHODS: We present a 5-year-old girl who suffered from recurrent reactions accompanied by urticaria, angioedema, headaches, dyspnea, loss of consciousness, and abdominal pain that were not eradicated, but were instead exacerbated, by various treatments with antihistamines and intravenous corticosteroids. Her diet diary revealed that symptoms occurred after ingestion of colorful sweets such as candies and jellybeans. Open challenge tests with food additives and nonsteroidal anti-inflammatory drugs (NSAIDs) were performed after elimination of these items. Skin prick tests using additives and NSAIDs, which were dissolved in saline, and prick- prick tests using candies and jellybeans, were carried out. RESULTS: Open challenge tests with Tartrazine, aspirin and acetaminophen were positive, whereas skin prick tests using additives and NSAIDs and prick-prick tests using candies and jellybeans were all negative. Consequently, intolerance to azo dyes and NSAIDs such as aspirin was diagnosed. However, she appeared to react to multiple chemical odors such as those of cigarette smoke, disinfectant, detergent, cleaning compounds, perfume, and hairdressing, all while avoiding additives and NSAIDs. On the basis of her history and the neuro-ophthalmological abnormalities, a diagnosis of severe MCS was made and she was prescribed multiple vitamins and glutathione. CONCLUSIONS: The present results suggest that in pediatric MCS, food and drug additives containing azo dyes might play important roles as elicitors.

[Clinical aspects of patients with MCS - from the standpoint of allergy].

BACKGROUND: "Sick House Syndrome" is thought to be an illness caused by indoor environments such as allergens, bacteria and chemical compounds. But it is not yet an established clinical entity. "Sick House Syndrome" overlaps in part with Multiple Chemical Sensitivity (MCS) whose symptoms are induced by very small amount of volatile chemical compounds. METHODS: We selected possible cases of MCS from patients who visited our specially built facility for"Sick House Syndrome" by tentative criteria as follow: (1)histories of chemical compounds exposure, (2)multi-organ symptoms, (3)exclusion of other disease(s) which may be responsible for symptoms, (4)chronic symptoms. Clinical aspects of the possible cases were examined. RESULTS: Fifty out of about 130 patients were the possible cases of MCS, 38 females and 12 males, aged 15 to 71 years old. Forty two out of 50 patients (84%) had a history and/or a complication of allergic diseases. This rate is much higher than the rate of prevalence of allergic diseases in Japanese population. Allergic rhinitis was the most popular allergic disease in the possible cases. Total IgE values were relatively low, 32 patients (64%) showed the IgE value below 200 IU/ml. No patients showed anti-formaldehyde IgE antibody. Decreased reactivity and decreased sensitivity of histamine release from peripheral blood were observed after challenge tests with chemical compounds. CONCLUSION: Allergic reactions can not be the causative mechanism(s) of the MCS, which is induced by multiple and different chemical compounds. Our results, however, suggest that patients having allergic diseases may be easily suffered from MCS or MCS may strengthen symptoms of allergic diseases.

Mucosal symptoms elicited by fragrance products in a population-based sample in relation to atopy and bronchial hyper-reactivity.

BACKGROUND: Exposure to perfume and fragrance products may, in some individuals, cause symptoms from the eyes and airways. The localization, character and risk factors of such symptoms in the general population are unknown. OBJECTIVE: To investigate both the localization and character of symptoms from the eyes and airways elicited by fragrance products, and the associations between such symptoms and skin prick test reactivity (atopy), methacholine bronchial hyper-reactivity (BHR), allergic rhinitis and asthma. METHODS: A questionnaire on mucosal symptoms elicited by fragrance products was posted to 1189 persons who had participated in a Danish population-based study of allergic diseases in 1997/1998. The study included measurement of BHR, atopy, forced expiratory volume in 1 s (FEV1), and serum eosinophilic cationic protein (serum ECP). RESULTS: The response rate was 79.6%. Symptoms from the eyes or airways elicited by fragrance products were reported by 42%. BHR (adjusted odds ratio 2.3, 95% confidence interval 1.5-3.5) was independently associated with symptoms from the eyes and airways elicited by fragrance products. There were no significant associations between these symptoms and atopy, FEV1 or serum ECP. CONCLUSIONS: Mucosal symptoms from the eyes and airways were common in this population. BHR was a significant and independent predictor of these symptoms. The lack of association with atopy suggested that IgE-mediated allergic mechanisms do not play a major role in the development of these symptoms.

Approaches to testing for food and chemical sensitivities.

Testing for food and chemical sensitivities usually becomes necessary as part of the evaluation of otolaryngology patients who have chronic illness. The more complex the patient, and the more recalcitrant the problem is to treatment, the more likely it is that allergies, and especially food or chemical sensitivities, are involved in the pathogenesis of the illness. Failure to consider all major allergen contacts, including foods and chemicals, can lead to inadequate therapy. Similarly, failure to understand total allergic and oxidant load and the effects of chemical toxicity can lead to inappropriate or ineffective treatment. Clinically, food allergies occur in two different types: immediate, anaphylactic, fixed reactions and delayed, chronic, cyclic reactions. Different test methods have been developed for the two types. Fixed food allergies can be safely and efficiently detected by in vitro specific IgE or histamine release tests. Cyclic food allergies are best detected by either oral food challenges or by the IPDFT test. Choosing the best test for a particular patient requires a clear understanding of the two food allergy types and how their clinical presentations differ. Other tests for food allergies are compared and contrasted with these primary tests. Chemical sensitivity also occurs in two different clinical types: allergic, and toxic. True allergy to chemical haptens, either type I, IgE-mediated, or type IV, delayed hypersensitivity, occurs with significant frequency but is often unsuspected. Chemical toxicity can be caused by the aftereffects of an acute exposure or as a result of chronic, low-level exposure, but is even more frequently unsuspected and will not be diagnosed without a high index of suspicion. Both types of chemical sensitivity need to be addressed in any patients who have either a high allergen or chemical exposure load [105]. Either in vitro or in vivo tests can be used for chemical allergy detection; the advantages of each are outlined. Chemical toxicity screening tests are available and useful but do not detect all possible toxicants. Definitive toxic chemical tests usually require specialized laboratory facilities and expert consultation, for which possible sources are specified. The most important point in testing for food or chemical sensitivity is to be aware that food or chemical sensitivity can be contributing to a specific patient's clinical problems. Only then can appropriate investigations be undertaken to understand and then, perhaps, to intervene successfully in that illness.

Toxicant-induced loss of tolerance.

Drug addiction and multiple chemical intolerance (abdiction) appear to be polar opposites--the former characterized by craving and dependency, the latter by aversion. However, when the two are viewed in juxtaposition similarities emerge, revealing a common underlying dynamic, one which appears to be a new paradigm of disease. TILT, or toxicant-induced loss of tolerance, bridges the gap between addiction and abduction and has the potential to explain a variety of illnesses, including certain cases of asthma, migraine headaches and depression, as well as chronic fatigue syndrome, fibromyalgia and "Gulf War syndrome". This paper argues that both addiction and chemical intolerance involve a fundamental breakdown in innate tolerance, resulting in an amplification of various biological effects, particularly withdrawal symptoms. While addicts seek further exposures so as to avoid unpleasant withdrawal symptoms, chemically intolerant individuals shun their problem exposures, but for the same reason--to avoid unpleasant withdrawal symptoms. These observations raise critical questions: do addictive drugs and environmental pollutants initiate an identical disease process? Once this process begins, can both addictants and pollutants trigger symptoms and cravings? TILT opens a new window between the fields of addiction and environmental medicine, one that has the potential to transform neighboring realms of medicine, psychology, psychiatry and toxicology.

Mediators of inflammation and their interaction with sleep: relevance for chronic fatigue syndrome and related conditions.

In humans, activation of the primary host defense system leads to increased or decreased NREM sleep quality, depending on the degree of early immune activation. Modest elevations of certain inflammatory cytokines are found during experimental sleep loss in humans and, in addition, relatively small elevations of cytokines are seen following commencement of pharmacological treatments with clozapine, a CNS active antipsychotic agent, known to have immunomodulatory properties. Cytokines such as TNF-alpha, its soluble receptors, and IL-6, present in the periphery and the CNS, comprise a link between peripheral immune stimulation and CNS-mediated behaviors and experiences such as sleep, sleepiness, and fatigue. The debilitating fatigue experienced in chronic fatigue syndrome and related diseases may also be related to altered cytokine profiles.