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Multiple chemical sensitivities: A systematic review of provocation studies

2006; Elsevier BV; Volume: 118; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2006.07.046

1097-6825

Jayati Das‐Munshi, George Rubin, Simon Wessely,

Fibromyalgia and Chronic Fatigue Syndrome Research

A systematic review of provocation studies of persons reporting multiple chemical sensitivities (MCS) was conducted from databases searched from inception to May 2006. Thirty-seven studies were identified, testing 784 persons reporting MCS, 547 control subjects, and 180 individuals of whom a subset were chemically sensitive. Blinding was inadequate in most studies. In 21 studies odors of chemicals were probably apparent; 19 of these reported positive responses to provocations among chemically sensitive individuals, and 1 study demonstrated that negative expectations were significantly associated with increased symptom reporting after provocations. Seven studies used chemicals at or below odor thresholds, and 6 failed to show consistent responses among sensitive individuals after active provocation. Six studies used forced-choice discrimination and demonstrated that chemically sensitive individuals were not better at detecting odor thresholds than nonsensitive participants. Three studies tested individuals by using nose clips/face masks and confirmed response, possibly mediated through eye exposure. Three studies used olfactory masking agents to conceal stimuli, and none of these found associations between provocations and response. We conclude that persons with MCS do react to chemical challenges; however, these responses occur when they can discern differences between active and sham substances, suggesting that the mechanism of action is not specific to the chemical itself and might be related to expectations and prior beliefs. A systematic review of provocation studies of persons reporting multiple chemical sensitivities (MCS) was conducted from databases searched from inception to May 2006. Thirty-seven studies were identified, testing 784 persons reporting MCS, 547 control subjects, and 180 individuals of whom a subset were chemically sensitive. Blinding was inadequate in most studies. In 21 studies odors of chemicals were probably apparent; 19 of these reported positive responses to provocations among chemically sensitive individuals, and 1 study demonstrated that negative expectations were significantly associated with increased symptom reporting after provocations. Seven studies used chemicals at or below odor thresholds, and 6 failed to show consistent responses among sensitive individuals after active provocation. Six studies used forced-choice discrimination and demonstrated that chemically sensitive individuals were not better at detecting odor thresholds than nonsensitive participants. Three studies tested individuals by using nose clips/face masks and confirmed response, possibly mediated through eye exposure. Three studies used olfactory masking agents to conceal stimuli, and none of these found associations between provocations and response. We conclude that persons with MCS do react to chemical challenges; however, these responses occur when they can discern differences between active and sham substances, suggesting that the mechanism of action is not specific to the chemical itself and might be related to expectations and prior beliefs. Multiple chemical sensitivities (MCS) is a controversial diagnosis, first defined in the 1950s by a group describing themselves as clinical ecologists.1Randolph T.G. Human ecology and susceptibility to the chemical environment. Charles Thomas, Springfield (IL)1962Google Scholar Subjects with the condition have a range of subjective symptoms after exposure to low levels of chemicals. Such chemicals can be as diverse as petrol or diesel, perfume, pesticides, or newspaper print.2Cullen M.R. The worker with multiple chemical sensitivities: an overview.in: Cullen M. Occupational medicine: state of the art reviews. Vol. 2. Hanley and Belfus, Philadelphia1987Google Scholar The reported symptoms span multiple organs and are poorly defined. Symptoms can include nausea, muscular pain, difficulties with memory, and fatigue.2Cullen M.R. The worker with multiple chemical sensitivities: an overview.in: Cullen M. Occupational medicine: state of the art reviews. Vol. 2. Hanley and Belfus, Philadelphia1987Google Scholar The underlying cause of MCS remains disputed. On the one hand, there are suggestions that MCS is a biologic response to low-level chemicals, having an effect on a variety of organ systems, including the immune, nervous, endocrine, or respiratory systems, with a mechanism distinct from accepted immunologic hypersensitivity mechanisms.3Rea W.J. Mitchel M.J. Chemical sensitivity and the environment.Immunol Allergy Pract. 1982; 4: 21-31Google Scholar Conversely, other commentators have suggested that the mechanism underlying MCS is predominantly psychological, suggesting that somatic responses to chemicals might be learned responses.4Van den Bergh O. Winters W. Devriese S. Van Diest I. Learning subjective health complaints.Scand J Psychol. 2002; 43: 147-152Crossref PubMed Scopus (73) Google Scholar Others have argued that MCS is a sociocultural phenomenon related to fears of environmental pollution and concerns over industrialization.5Shorter E. Multiple chemical sensitivity: pseudodisease in historical perspective.Scand J Work Environ Health. 1997; 23: 35-42PubMed Google Scholar One way of addressing competing models is through experimental trials incorporating systematic exposure to stimuli claimed to trigger symptoms in subjects with MCS. There have been many such trials, both by those identifying themselves with the clinical ecology movement, as well as by those who suggest psychological mechanisms. To date, however, there have not been any systematic reviews of such trials. The present review aims to examine all such trials. Two key questions were tested: (1) Are subjects with MCS able to identify sham or active stimuli under double-blind provocation conditions in which an adequate placebo is also used? (2) Does the adequacy of blinding in trials have an effect on outcomes? A systematic search of databases was conducted from inception to May 2006. Databases included Allied and Complementary Medicine Database (AMED), Applied Social Sciences Index and Abstracts (ASSIA), Cinahl, Cochrane Collaboration Library, Embase, Index to Theses, Web of Science, Medline, and Psychinfo. Further references were obtained from databases set up by user groups available through the Worldwide Web.6Larson C.A. Coping with multiple chemical sensitivity: Internet resources.Health Care Internet. 1998; 2: 57-73Crossref Google Scholar Search terms used included MeSH term headings or free-text key words relating to MCS, such as “idiopathic environmental intolerance,” “chemical intolerance,” and “multiple chemical sensitivities.” Studies were included in the review if they met all of the following conditions:1.Participants had a previous history of characteristic MCS symptoms2Cullen M.R. The worker with multiple chemical sensitivities: an overview.in: Cullen M. Occupational medicine: state of the art reviews. Vol. 2. Hanley and Belfus, Philadelphia1987Google Scholar after exposure to typical provocations that could include synthetic or natural chemicals.2Cullen M.R. The worker with multiple chemical sensitivities: an overview.in: Cullen M. Occupational medicine: state of the art reviews. Vol. 2. Hanley and Belfus, Philadelphia1987Google Scholar2.The study included provocation with a suitable active stimulus either identified by the subject as usually provoking a response consistent with the reported symptoms of MCS or a stimulus considered as characteristic of those leading to a response in these subjects.2Cullen M.R. The worker with multiple chemical sensitivities: an overview.in: Cullen M. Occupational medicine: state of the art reviews. Vol. 2. Hanley and Belfus, Philadelphia1987Google Scholar3.The study included a control arm consisting of either a placebo provocation or an unexposed resting state.4.Provocations were conducted within standardized settings. Trials performed in the participant's home or workplace, rather than in a laboratory, were excluded.5.The trial was double blind, single blind, or nonblind.6.Single case reports were excluded. Outcomes analyzed included the ability of subjects with MCS to correctly identify provocative stimuli under test conditions, as well as subjective reports or observer-measured outcomes of discomfort/irritation in keeping with classic MCS complaints after exposure to chemicals.2Cullen M.R. The worker with multiple chemical sensitivities: an overview.in: Cullen M. Occupational medicine: state of the art reviews. Vol. 2. Hanley and Belfus, Philadelphia1987Google Scholar Neuropsychological outcomes were included because patients with MCS commonly complain of difficulties with memory and concentration.2Cullen M.R. The worker with multiple chemical sensitivities: an overview.in: Cullen M. Occupational medicine: state of the art reviews. Vol. 2. Hanley and Belfus, Philadelphia1987Google Scholar Outcomes peripheral to the self-diagnosis of MCS, such as biomarkers, were excluded from this review. The literature search, assessment of inclusion, and data extraction were conducted by using a structured table (JD). All main authors were contacted and asked if they had any unpublished data to reduce publication biases (JD). Accuracy of data extraction was cross-checked by a second reviewer (GJR). Differences were resolved by discussion among all 3 authors (JD, GJR, and SW). Using the MeSH terms and key words described above, approximately 10,000 titles or abstracts were identified, from which 165 were obtained for examination in full because they appeared relevant to the review. Of the 165 obtained studies, 113 were excluded because they were not relevant to our review. In addition, 15 studies were excluded because they did not meet all of the entry criteria for our review. This included studies using carbon dioxide7Poonai N. Antony M.M. Binkley K.E. Stenn P. Swinson R.P. Corey P. et al.Carbon dioxide inhalation challenges in idiopathic environmental intolerance.J Allergy Clin Immunol. 2000; 105: 358-363Abstract Full Text Full Text PDF PubMed Google Scholar and sodium lactate8Binkley K.E. Kutcher S. Panic response to sodium lactate infusion in patients with multiple chemical sensitivity syndrome.J Allergy Clin Immunol. 1997; 99: 570-574Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar and studies using the chemical found in chili, capsaicin, as a provocation. We excluded these because they are not classic stimuli described by subjects with MCS. Several other studies were excluded because they used outcome measures peripheral to the self-diagnosis of MCS. One further study was excluded because the authors were explicit in stating that the initial sample did not include persons with a prior reported hypersensitivity or intolerance to chemicals.9Dalton P.H. Dilks D.D. Banton M.I. Evaluation of odor and sensory irritation thresholds for methyl isobutyl ketone in humans.AIHA J (Fairfax, Va). 2000; 61: 340-350Google Scholar Duplicate publications were included as one study.10Van Thriel C. Haumann K. Kiesswetter E. Blaszkewicz M. Seeber A. Time courses of sensory irritations due to 2-butanone and ethyl benzene exposure: influences of self-reported multiple chemical sensitivity (sMCS).Int J Hyg Environ Health. 2002; 204: 367-369Crossref PubMed Scopus (20) Google Scholar, 11Fiedler N. Kelly-McNeil K. Mohr S. Lehrer P. Opiekun R.E. Lee C. et al.Controlled human exposure to methyl tertiary butyl ether in gasoline symptoms: psychophysiologic and neurobehavioral responses of self reported sensitive persons.Environ Health Perspect. 2000; 108: 753-763Crossref PubMed Scopus (45) Google Scholar, 12Molhave L. Bach B. Pedersen O.F. Human reactions to low concentrations of volatile organic compounds.Environ Int. 1986; 12: 167-175Crossref Scopus (300) Google Scholar, 13Bell I.R. Kline J.P. Schwartz G.E. Peterson J.M. Quantitative EEG patterns during nose versus mouth inhalation of filtered room air in young adults with and without self-reported chemical odor intolerances.Int J Psychophysiol. 1998; 28: 23-35Crossref PubMed Scopus (9) Google Scholar, 14Camp JE, Morgan MS. Upper respiratory irritation from carbonless copy paper exposure. In: Swedish Council for Building Research. 3rd International Conference on Indoor Air Quality and Climate. Vol. 3. Stockholm: Swedish Council for Building Research; 1984. p. 393-6.Google Scholar However, assessment of certain duplicate publications was not always clear-cut. For example, we have included 3 articles by Rea15Rea W.J. Environmentally triggered small vessel vasculitis.Clin Ecol. 1977; 38: 245-251Google Scholar, 16Rea W.J. Environmentally triggered cardiac disease.Clin Ecol. 1978; 40: 243-251Google Scholar, 17Rea W.J. Environmentally triggered thrombophlebitis.Clin Ecol. 1976; 37: 101-109Google Scholar as separate studies, given that they appeared to report slightly different results. However, because the samples included in each article reported almost identical sets of highly idiosyncratic sensitivities, we remain uncertain as to what the true relationship was between the articles. Several authors confirmed further unpublished studies but were unable to supply these (K. Osterberg, personal communication, May 2006; N. Fiedler, L. Molhave, and M. R. Joffres, personal communication, September 2005). One author reported having done more than 15,000 individual double-blind challenges but had stopped publishing findings (W. Rea, personal communication, September 2005). Abstracts for 2 unpublished studies were also included, and further details were obtained by contacting the authors (S. Bornschein, personal communication, May 2006; T. Hummel, personal communication, June 2006).18Bornschein S. Hausteiner C. Roemmelt H. Forstl H. Nowak D. Zilker T. Double-blind chemical exposure in patients with MCS.J Toxicol Clin Toxicol. 2005; 43 ([abstract]): 436Google Scholar, 19Vieregge S. Hummel T. Roscher S. Jaumann M.P. Kobal G. Intranasal chemoreception in patients with multiple chemical sensitivities and healthy controls.Chemical Senses. 2000; 25: 801Google Scholar In the case of one unpublished study, no replies were received from the authors, and this was subsequently excluded.20Kurtz D. White T. Belknap E. Perceived odor intensity and hedonics in subjects with multiple chemical sensitivity.Chem Senses. 1993; 18: 584Google Scholar Studies were categorized by the quality of blinding used: double- or single-blind studies that also included an odorous masking agent to prevent identification of the stimuli (Table I),21Smith S. Sullivan K. 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Lee C. et al.Controlled human exposure to methyl tertiary butyl ether in gasoline symptoms: psychophysiologic and neurobehavioral responses of self reported sensitive persons.Environ Health Perspect. 2000; 108: 753-763Crossref PubMed Scopus (45) Google Scholar, 12Molhave L. Bach B. Pedersen O.F. Human reactions to low concentrations of volatile organic compounds.Environ Int. 1986; 12: 167-175Crossref Scopus (300) Google Scholar, 15Rea W.J. Environmentally triggered small vessel vasculitis.Clin Ecol. 1977; 38: 245-251Google Scholar, 16Rea W.J. Environmentally triggered cardiac disease.Clin Ecol. 1978; 40: 243-251Google Scholar, 17Rea W.J. Environmentally triggered thrombophlebitis.Clin Ecol. 1976; 37: 101-109Google Scholar, 18Bornschein S. Hausteiner C. Roemmelt H. Forstl H. Nowak D. Zilker T. Double-blind chemical exposure in patients with MCS.J Toxicol Clin Toxicol. 2005; 43 ([abstract]): 436Google Scholar, 19Vieregge S. Hummel T. Roscher S. Jaumann M.P. Kobal G. 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Lioy P. et al.Responses to diesel vapor exposure among chemically sensitive Gulf War veterans.Psychosom Med. 2004; 66: 588-598Crossref PubMed Scopus (27) Google Scholar, 47Kimata H. Effect of exposure to volatile organic compounds on plasma levels of neuropeptides, nerve growth factor, and histamine in patients with self-reported multiple chemical sensitivity.Int J Hyg Environ Health. 2004; 207: 159-163Crossref PubMed Scopus (33) Google ScholarTable IDouble- and single-blind provocation studies with olfactory maskingReferenceNExposurePlaceboMaskRouteSignificant responses (P < .05 unless otherwise indicated)Double blind Smith and Sullivan21Smith S. Sullivan K. Examining the influence of biological and psychological factors on cognitive performance in chronic fatigue syndrome: a randomized, double-blind, placebo-controlled, crossover study.Int J Behav Med. 2003; 10: 162-173Crossref PubMed Scopus (22) Google Scholar36 CSSpecific to subjectDistilled waterVanillaInh CCNo differences in neuropsychological testing Staudenmayer et al22Staudenmayer H. Selner J.C. Buhr M.P. Double-blind provocation chamber challenges in 20 patients presenting with “multiple chemical sensitivity.”.Regul Toxicol Pharmacol. 1993; 18: 44-53Crossref PubMed Scopus (88) Google Scholar20 CSSpecific to subjectClean airPeppermint, cinnamon, aniseInh CCNo differences in number of symptoms, correct guesses, or objective signs to active and placebo exposuresSingle blind Georgellis et al23Georgellis A. Lindelof B. Lundin A. Arnetz B. Hillert L. Multiple chemical sensitivity in male painters: a controlled provocation study.Int J Hyg Environ Health. 2003; 206: 531-538Crossref PubMed Scopus (15) Google Scholar14 CS/15 HAcetone, VOCs ± FMFMFMInhMore irritation from placebo (coffee odor) vs active agent in CS; no differences in eye redness or nasal cavity changes after exposure between CS and H Joffres et al24Joffres M.R. Sampalli T. Fox R.A. Physiologic and symptomatic responses to low-level substances in individuals with and without chemical sensitivities: a randomized controlled blinded pilot booth study.Environ Health Perspect. 2005; 113: 1178-1183Crossref PubMed Scopus (22) Google Scholar10 CS/7 HGlue, scented body wash, dryer sheetUnscented shampoo, clean airWore nose clips; no olfactory maskInhChanges to skin conductance in CS compared with after placebo noted; however, no differences in EMG, pulse, respiration, temperature, and cognition between active and control groups Millqvist et al25Millqvist E. Bengtsson U. Lowhagen O. Provocations with perfume in the eyes induce airway symptoms in patients with sensory hyperreactivity.Allergy. 1999; 54: 495-499Crossref PubMed Scopus (53) Google Scholar11 CSPerfume on damp compressSaline on damp compressEye shields for Inh, nose clips for eye provocation; no olfactory maskInh/eye(1) Airway exposure: greater dyspnea (P < .05) after perfume provocations compared with placebo. (2) After eye exposure: significant dyspnea (P < .01), cough (P < .05), and eye irritation (P < .05), compared with placebo. Millqvist and Lowhagen26Millqvist E. Lowhagen O. Placebo-controlled challenges with perfume in patients with asthma-like symptoms.Allergy. 1996; 51: 434-439PubMed Google Scholar9 CSPerfume on damp compressSaline on damp compressNose clips; mask over mouth with or without carbon filterInhPerfume provoked a stronger response in CS (P < .01); no significant reduction of symptoms with face masks; eye symptoms (P < .05) and dyspnea (P < .05) to perfumeCS, Chemically sensitive subjects; Inh, inhaled; CC, chamber challenge; VOCs, volatile organic chemicals; FM, furfuryl mercaptan (coffee odor); H, healthy subjects; EMG, surface electromyography. Open table in a new tab Table IIDouble-blind provocation studies: no olfactory maskingReferenceNExposurePlaceboRouteSignificant responses (P < .05 unless otherwise indicated)Bornschein et al18Bornschein S. Hausteiner C. Roemmelt H. Forstl H. Nowak D. Zilker T. Double-blind chemical exposure in patients with MCS.J Toxicol Clin Toxicol. 2005; 43 ([abstract]): 436Google Scholar20 CS, 20 HVOCs less than odor threshold (800 μg/m3)Clean airInh, CCNo difference in proportion of correct ratings between CS and H (true-positive and true-negative ratings/total number of ratings: 46.9% H vs 55.1% CS)Osterberg et al28Osterberg K. Persson R. Karlson B. Orbaek P. Annoyance and performance of three environmentally intolerant groups during experiment challenge with chemical odors.Scand J Work Environ Health. 2004; 30: 486-496Crossref PubMed Scopus (23) Google Scholar29CS, 16EA, 39CS/EA, 54 HN-BuAc (0.37, 1.5, 6 ppm)Base line stateInh CCNo differences between groups in smell intensity; CS/EA group showed increased annoyance, sustained fatigue, and membrane irritation compared with HFiedler et al11Fiedler N. Kelly-McNeil K. Mohr S. Lehrer P. Opiekun R.E. Lee C. et al.Controlled human exposure to methyl tertiary butyl ether in gasoline symptoms: psychophysiologic and neurobehavioral responses of self reported sensitive persons.Environ Health Perspect. 2000; 108: 753-763Crossref PubMed Scopus (45) Google Scholar12CS/19 HGasoline, gasoline + 11% MTBE, and gasoline + 15% MTBEClean airInh CCCorrected for multiple comparisons; no differences between CS and H on any symptom subscale, except greater MTBE symptoms after 15% MTBE/gasoline vs 11% MTBE/gasoline provocationVieregge et al19Vieregge S. Hummel T. Roscher S. Jaumann M.P. Kobal G. Intranasal chemoreception in patients with multiple chemical sensitivities and healthy controls.Chemical Senses. 2000; 25: 801Google Scholar∗Chemically sensitive subjects were the same individuals in these experiments.23CS/23 H2-propRoom airInhCS not better at odor identification and discrimination vs HHummel et al29Hummel T. Roscher S. Jaumann M.P. Kobal G. Intranasal chemoreception in patients with multiple chemical sensitivities: a double-blind investigation.Regul Toxicol Pharmacol. 1996; 24: s79-s86Crossref PubMed Scopus (74) Google Scholar∗Chemically sensitive subjects were the same individuals in these experiments.23 CS2-prop, PEARoom airInh FC20% of CS showed symptoms regardless of challenge; no effect on PEA detection with FCKjaergard et al27Kjaergaard S.K. Molhave L. Pedersen O.F. Human reactions to a mixture of organic compounds.Atmos Environ. 1991; 25A: 1417-1426Crossref Scopus (84) Google Scholar14 CS/21 H22 VOCsClean airInh CCCS “more likely” to report irritation, tiredness, worse expiratory flow rate, and impaired digit symbol test results compared with H; no statisticsRea et al30Rea W.J. Ross G.H. Johnson A.R. Smiley R.E. Fenyes E.J. Chemical sensitivity in physicians.Bol Asoc Med P R. 1991; 83: 383-388PubMed Google Scholar19 CSVariety (eg, FOR, pesticides)SalineInh, oralOral: 14/19 responded with usual symptoms; Inh: 10/10 responded to at least one with usual symptoms; no statisticsRea et al31Rea W.J. Ross G.H. Johhnson A.R. Smiley R. Sprague D.E. Fenyves E.J. et al.Confirmation of chemical sensitivity by means of double blind inhalant challenge of toxic volatile chemicals.Clin Ecol. 1989; VI: 389-393Google Scholar50 CSVOCs; pilot light (NB)Saline, waterInh50% reacted to ≥1 active substances; 10 CS: increased pulse (P < .001)Pan et al32Pan Y, Rea WJ, Johnson AR, Fenyves EJ. Formaldehyde sensitivity. Clin Ecol 1989;VI:79-84.Google Scholar49 CS/14 H0.74% FORSpring waterInh31/49 (63.3%) CS positive, 1 (2.0%)