Multiple chemical sensitivities: A systematic review of provocation studies

Article Outline

• Abstract
• Methods
  • Search strategy
  • Review process
• Results
  • Search results
  • Studies using olfactory masking agents or nose clips
  • Studies not using olfactory masking agents
• Discussion
  • When is a “double-blind” study not truly double blind?
  • Strengths and weaknesses of this review
  • Future research and recommendations
• Acknowledgment
• Appendix. Supplementary data
• References
• Copyright

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.

Key words: Multiple chemical sensitivities, idiopathic environmental intolerance, MCS, IEI, cacosmia, provocation studies, functional somatic syndromes

Abbreviations used: MCS, Multiple chemical sensitivities, MTBE, Methyl terbutyl ether

Multiple chemical sensitivities (MCS) is a controversial diagnosis, first defined in the 1950s by a group describing themselves as clinical ecologists.¹ 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.² The reported symptoms span multiple organs and are poorly defined. Symptoms can include nausea, muscular pain, difficulties with memory, and fatigue.²

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.³ Conversely, other commentators have suggested that the mechanism underlying MCS is predominantly psychological, suggesting that somatic responses to chemicals might be learned responses.⁴ Others have argued that MCS is a sociocultural phenomenon related to fears of environmental pollution and concerns over industrialization.⁵

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?

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Methods 

Search strategy 

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.⁶

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:

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.² Neuropsychological outcomes were included because patients with MCS commonly complain of difficulties with memory and concentration.² Outcomes peripheral to the self-diagnosis of MCS, such as biomarkers, were excluded from this review.

Review process 

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).

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Results 

Search results 

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 dioxide⁷ and sodium lactate⁸ 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.⁹

Duplicate publications were included as one study.¹⁰, ¹¹, ¹², ¹³, ¹⁴ However, assessment of certain duplicate publications was not always clear-cut. For example, we have included 3 articles by Rea¹⁵, ¹⁶, ¹⁷ 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).¹⁸, ¹⁹ In the case of one unpublished study, no replies were received from the authors, and this was subsequently excluded.²⁰

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),²¹, ²², ²³, ²⁴, ²⁵, ²⁶ double-blind studies without masking (Table II),¹¹, ¹², ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁷, ²⁸, ²⁹, ³⁰, ³¹, ³² single-blind studies without masking (Table III),¹³, ¹⁴, ³³, ³⁴, ³⁵, ³⁶, ³⁷, ³⁸, ³⁹, ⁴⁰, ⁴¹, ⁴², ⁴³, ⁴⁴ and open-label studies or studies with unclear blinding (see Table E1 in the Online Repository at www.jacionline.org).¹⁰, ⁴⁵, ⁴⁶, ⁴⁷

Table I. Double- and single-blind provocation studies with olfactory masking

Reference	N	Exposure	Placebo	Mask	Route	Significant responses (P < .05 unless otherwise indicated)
Double blind
Smith and Sullivan21	36 CS	Specific to subject	Distilled water	Vanilla	Inh CC	No differences in neuropsychological testing
Staudenmayer et al22	20 CS	Specific to subject	Clean air	Peppermint, cinnamon, anise	Inh CC	No differences in number of symptoms, correct guesses, or objective signs to active and placebo exposures
Single blind
Georgellis et al23	14 CS/15 H	Acetone, VOCs ± FM	FM	FM	Inh	More 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 al24	10 CS/7 H	Glue, scented body wash, dryer sheet	Unscented shampoo, clean air	Wore nose clips; no olfactory mask	Inh	Changes 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 al25	11 CS	Perfume on damp compress	Saline on damp compress	Eye shields for Inh, nose clips for eye provocation; no olfactory mask	Inh/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 Lowhagen26	9 CS	Perfume on damp compress	Saline on damp compress	Nose clips; mask over mouth with or without carbon filter	Inh	Perfume 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 perfume

CS, Chemically sensitive subjects; Inh, inhaled; CC, chamber challenge; VOCs, volatile organic chemicals; FM, furfuryl mercaptan (coffee odor); H, healthy subjects; EMG, surface electromyography.

Table II. Double-blind provocation studies: no olfactory masking

CS, Chemically sensitive subjects; H, healthy subjects; VOCs, volatile organic chemicals; Inh, inhaled; CC, chamber challenge; EA, electrically annoyed subjects; N-BuAC, N-butyl acetate; MTBE, methyl tertiary butyl ether; 2-prop, 2-propanolol; PEA, phenyl ethyl alcohol; FC, forced choice method of discrimination; FOR, formaldehyde; NB, nonblind.

Table III. Single-blind provocation studies: no olfactory masking

CS, Chemically sensitive subjects; FC, forced-choice discrimination; Inh, inhaled; PEA, phenyl ethyl alcohol; H, healthy subjects; CC, chamber challenge; IA, isopropyl alcohol; FOR, formaldehyde; PYR, pyridine; PG, propylene glycol; MEK, methyl ethyl ketone; DB, double blind; SB, single blind.

Studies using olfactory masking agents or nose clips 

Three studies testing 70 chemically sensitive participants incorporated blinding and an olfactory mask and failed to show any significant effects on subjects with MCS after provocation with chemicals. One of these studies demonstrated that subjects with MCS were more likely to react adversely to placebo over active substances.²³ Three further studies incorporated the use of nose clips but no olfactory mask and tested 30 subjects with MCS, showing some significant effects, including changes to skin conductance, irritation, and dyspnea, after exposure with chemicals. These effects might have been mediated through the eyes (Table I).

Studies not using olfactory masking agents 

In a total of 8 of 13 studies described as double blind but not incorporating any olfactory masking agent, positive responses to provocations among subjects with MCS were reported (Table II). One of these studies used a forced-choice method of provocation and demonstrated that 20% of chemically sensitive participants showed positive responses whether provoked with active or sham substances.²⁹ One other study reported greater methyl terbutyl ether (MTBE) symptoms after 15% MTBE/gasoline provocations versus 11% MTBE/gasoline provocations.¹¹ However, the forced-choice stages of this trial failed to demonstrate that chemically sensitive individuals were better at differentiating between gasoline-only/gasoline-MTBE exposures with or without olfactory masking.¹¹

Fourteen studies incorporated single-blind methodology without olfactory masking agents (Table III). Five of these studies used forced-choice methods of discrimination, and all of these studies failed to demonstrate that chemically sensitive participants were better at detecting odors than healthy control subjects, whereas 1 of the forced-choice studies showed that participants with MCS were more likely to report negative responses to phenyl ethyl alcohol, usually described as a pleasant odor and commonly found in perfume.³³ One study testing 180 persons demonstrated that reporting of somatic symptoms and irritation from odors was related to bias conditions before exposure and was more likely in persons scoring highly on chemical odor intolerance indices.³⁴ Three of the single-blind studies, testing 46 individuals, failed to consistently reproduce symptoms after exposure. The majority of the single-blind studies confirmed that although active provocations did not affect neuropsychological functioning in healthy or chemically sensitive subjects (with the exception of one study⁴²), chemically sensitive subjects were more likely to report most odors as “unpleasant” compared with healthy subjects or report greater fatigue, somatic symptoms, or annoyance after active provocations.

There were 4 studies, testing 64 individuals under nonblind conditions (see Table E1 in the Online Repository at www.jacionline.org). Among these, all studies showed positive responses to provocations, with one study demonstrating violent “nocebo” responses to nebulized saline in the one single-blind exposure performed in the study.⁴⁵

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Discussion 

The findings demonstrate that chemical provocation studies that actively mask stimuli show that persons with MCS are unable to differentiate between active and control conditions, symptomatically or otherwise. Although subjects with MCS do react to masked provocations, this is at equal levels in both (active vs sham) conditions. However, under conditions in which participants are better able to discern differences between provocation stimuli because of insufficient masking of active and placebo conditions, individuals react more often to active over sham provocations. This pattern of response might be due to beliefs or expectations regarding the exposure.²³, ³⁴

The importance of prior expectations was reinforced in the study by Dalton.³⁴ Prior to exposure in this study, participants were informed that they were either to be exposed to “natural extracts with relaxing effects” (positive bias), industrial solvents (negative bias), or odorants “approved for olfactory research” (neutral). In this study participants were more likely to report irritation and characteristic symptoms when they believed they were being exposed to industrial solvents (harmful bias) over the positive or neutral-bias groups (P < .05). Using regression analysis, the author demonstrated that individuals rating high on “odor reactivity” scores were more likely to rate odors as irritating if given a negative bias condition than those rating lower on odor reactivity scores. Individuals with higher odor reactivity scores were also more likely to report somatic symptoms after exposures believed to be harmful.

When is a “double-blind” study not truly double blind? 

A difficulty with the analysis was the variable quality of many of the trials. Many studies did not use adequate masking agents and thus compromised study blindness because participants might have been able to tell to what they were exposed. For example, in some studies the placebo was relatively odorless and colorless, such as clean air or water, whereas the active agent included typically noxious/pungent substances, such as formaldehyde, volatile organic chemicals, or tobacco smoke. Most participants, whether reporting MCS or not, should be able to discern between such placebo and active substances. In one study described as double blind, the authors themselves noted that “the exposed subjects” were able to “smell the substances, as they obviously can.”²⁷ Although creating an adequate mask for test substances can be difficult, some investigators managed this by using olfactory maskers, such as coffee, peppermint, or vanilla.²¹, ²², ²³

It could be argued that adding an olfactory mask to provocations is simply adding a new chemical to which participants might also react. For example, in one study²³ participants were more likely to respond adversely to the coffee odor mask than to unmasked acetone or volatile organic chemicals, although the authors postulated that this could have been because the painters in this study were less accustomed to coffee odor placebo than acetone (which was present in their day-to-day environments) and therefore interpreted the coffee odor as threatening.

The problem of odorant masks was surmounted in one study by first exposing participants to clean air/olfactory mask–only provocations.²² Only participants not reacting to the initial olfactory mask exposures were eligible for entry into the actual double-blind study, which involved exposure to sham versus active provocations with olfactory masking agents.²² In other studies investigators exposed participants to chemicals at or below odor thresholds.¹⁰, ²⁹, ³², ⁴⁰, ⁴⁴ Most of these failed to demonstrate that subjects with MCS were better at detecting active provocations compared with healthy participants; however, they did tend to confirm increased states of autonomic arousal or MCS symptoms, independent of type of provocation, when compared with control subjects.

Others attempted to surmount the problem of blinding by making participants wear nose clips or face masks.²⁴, ²⁵, ²⁶ None of these studies used olfactory masking agents. Participants in these studies showed some response to active provocations, and the authors suggested that participants might have perceived provocations through the eyes. Such methods of blinding therefore appear less satisfactory than studies that use subolfactory threshold provocations or olfactory masking agents.

Strengths and weaknesses of this review 

The inclusion criteria for this review were kept broad to increase the number of studies that could be analyzed. However, this meant that included studies were heterogeneous. Some studies recruited their sample from the community by using questionnaires¹³ or included active workers with a history of exposure⁴⁴ rather than outpatients with MCS per se (A. Iregren, personal communication, June 2006). The characteristics of such a sample could differ significantly from self-professed subjects recruited from clinical ecology clinics. It could be argued that such studies should therefore be reviewed separately. Other studies introduced further subcategorizations of sensitivity (eg, “MTBE sensitive”¹¹ and “toxic encephalopathy types 2a/2b”⁴³). We still included these studies under the general rubric of chemical sensitivity if they met our inclusion criteria. This could be a potential disadvantage if there are distinctions between subgroups, which would be lost by combining all groups; however, MCS is a self-reported diagnosis that remains poorly defined, and in some respects grouping these studies together was therefore justifiable. Despite these shortcomings, the overall finding of this review, that the quality of blinding in provocation trials is of paramount importance in helping to establish possible mechanisms of response in participants, remains a valid and important one.

The heterogeneity of the reviewed studies limited the possibility of meta-analysis. Studies used a range of different concentrations, as well as types of exposure, over differing time periods. In a review of this type, location and publication biases are also important. Location bias was addressed by including databases set up by patient and user groups within our searches. We also ensured that articles that were not in English but appeared to relate to the aims of our study were retrieved and translated. Publication biases were reduced by contacting all main authors.

To our knowledge, this is the first systematic review of provocation trials in persons with MCS and builds on the findings of previous reviews.¹⁹, ⁴⁸, ⁴⁹, ⁵⁰ Unlike previous reviews,¹⁹, ⁴⁸, ⁴⁹, ⁵⁰ we endeavored to include all studies, whether conducted by groups associated with the clinical ecology movement or groups associated with psychology or medicine. Within this area, there are widely acknowledged polarities between groups,³, ⁵, ⁵¹ and we aimed to overcome this by contacting all persons involved in this field of research, irrespective of their background.

Future research and recommendations 

A striking finding was that the ability of participants with MCS to accurately detect or respond to active provocations was less likely when strict blinding was observed and when a mask of the experimental stimuli was incorporated. In addition, subjects with MCS did not show differences with respect to odor detection thresholds compared with healthy subjects nor, in general, were they better able to distinguish between active and control stimuli when exposed at levels that were subthreshold for odors. This therefore suggests that there could be salient psychological mechanisms operating that lead sufferers to respond, occasionally with marked physiologic responses, when they are aware of the exposure. Many of the responses recorded in the studies after unmasked provocations included outcomes consistent with autonomic arousal and anxiety. Therefore the findings suggest that a behavioral mechanism of action rather than a purely biologic or physiologic mechanism related to the characteristics of the substance might explain this condition. This is consistent with previous research that has suggested that behavioral conditioning could be an important mechanism in the pathogenesis of MCS. Participants with MCS exposed to carbon dioxide provocations can experience typical MCS symptoms similar to those experienced by patients with panic disorder.⁷, ⁸ Exposure to foul-smelling odors coupled with carbon dioxide can lead healthy participants to acquire typical somatic symptoms, including hyperventilation, chest tightness, and feelings of choking.⁵² Learned somatic symptoms can be re-elicited a week later after provocation with noxious odors alone and might generalize to new odors not used in initial provocations.⁵² Furthermore, symptom learning has also been shown to occur more readily in healthy participants given worrying a priori environmental information about exposures, and under such conditions, pleasant odors can become triggers for symptoms as well,⁵³ with participants' prior expectations rather than actual experimental conditions governing symptom learning.⁵⁴ Therefore the results of this study do not support recent policy initiatives to ban the use of fragrances in public places.⁵⁵ Our results suggest that imposing such measures could aggravate the problem further.

If behavioral conditioning is a mechanism of action, treatment for MCS might be possible by using cognitive behavioral therapy. This could be used in persons who do not necessarily have a comorbid psychiatric disorder.

Future work should focus on behavioral approaches in the treatment of MCS.

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We thank Gary Hahn for his assistance in the retrieval of many of the articles used in this review, as well as all of the authors who responded to queries sent to them. We also thank Toshiko Mori for help in translating Japanese articles.

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Appendix. Supplementary data 

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