Multiple chemical sensitivity (MCS) is an unexplained acquired medical condition that includes multiple, vague, recurrent, and non-specific symptoms in different organs. They are attributed to exposures to various and structurally unrelated environmental chemicals at concentration levels that are well tolerated by the majority of people and normally considered not to have toxic effects in humans [1–4]. MCS is included in the wider spectrum of idiopathic environmental intolerance (IEI), but it has also been described in the literature as chemical intolerance (CI), IEI, or toxicant-induced loss of tolerance (TILT) [5, 6].

The prevalence of this condition is difficult to estimate. Case rates differ when reported by medical staff in comparison with patients’ self-assessments [7]. The self-reported prevalence of MCS varies from 6.5% to 9% in the general population. In contrast, physician-diagnosed MCS was found in only 0.5% of the general population [8, 9].

When exposed to chemicals, people with MCS may experience symptoms that vary from one individual to another, but a typical triad of the most common symptoms, hyperosmia, asthenia, and dyspnea, is observed [1]. Other symptoms that are less frequent can also be present (Table 1).

The symptoms may arise immediately after a single first high-level chemical exposure, or they may gradually appear over time from recurrent low-level chemical exposures to substances that the person previously tolerated [10].

The Cullen criteria (1987) and the Nethercott criteria (1996), with or without the Lacour (2005) extension of the Nethercott criteria, are now the criteria most used to diagnose MCS [11–13]. The Environmental Exposure and Sensitivity Inventory (EESI); its short version, the Quick EESI (QEESI); or the Brief EESI (BREESI) can be used as evaluation forms to assess CIs [14–16].

Data sources and search strategy: The bibliographic research was done in February and July 2023, querying PubMed, ScienceDirect, ResearchGate, and UpToDate using the keywords “MCS”, “multiple chemical sensitivity syndrome”, “idiopathic environmental intolerance”, and “IEI”. The search was restricted to English-language papers and included grey literature.

Explanatory hypotheses have been explored and efforts have been made by scientific teams to understand the pathophysiology of MCS. Below we discuss the few proposed etiological hypotheses (Figure 1) [17, 18].

In a 1997 provocation test study, 15 patients with MCS symptoms underwent open challenges with products they deemed to cause distressing symptoms (nail polish remover, hair spray, disinfectant, perfume, bathtub sealant) and were observed clinically. Pre- and post-challenge pulmonary function tests were performed [pO₂, pCO₂, oxygen saturation (SaO₂)]. In the 11 patients who reproduced their typical symptoms upon challenge testing, hyperventilation was induced in every case, with a rapid fall in the pCO₂ in blood and no change or a rise in pO₂ or SaO₂, while pulmonary function remained unchanged. The authors concluded that hyperventilation is, at least in part, one of the mechanisms by which MCS patients develop their symptomatology [73].

Another placebo-controlled challenge (1996) with perfume in patients with asthma-like symptoms was performed. Nine patients known to have respiratory symptoms after being exposed to nonspecific irritating stimuli were provoked with perfume or a placebo (saline). The patients were tested in a special exposure chamber and a nasal clamp was used in order to avoid scent detection, so they breathed through the mouth during the provocations. The peak expiratory flow (PEF), pulse rate, SaO₂, respiratory rate, CO₂ in exhaled air, and symptom scores were measured before and after the exposure. Excepting one patient, all patients had a stronger reaction to perfume than to saline. Perfume can provoke symptoms suggesting hyperreactivity of the respiratory tract (dyspnea, coughing, hoarseness) without the presence of bronchial obstruction. When provoked with perfume with or without a carbon filter mask to evaluate if symptoms could be prevented in this manner, no differences in symptoms were noted. PEF values, pulse rate, SaO₂, respiratory rate, and CO₂ in the expired air were normal throughout the provocations with both saline and perfume. Since the patients had nasal clamps and could not smell during the provocation test, the authors concluded that the symptoms are not always transmitted via the olfactory nerve but might be induced by a trigeminal reflex through the respiratory tract or by the eyes [74].

Bornschein et al. [75] conducted a double-blind placebo-controlled study with an exemplary methodology. In a challenge “climate chamber” for chemical provocations, 20 subjects with MCS and 17 control subjects were exposed to a solvent mixture or a placebo (clean air) during six different exposure sessions. The solvent mixture consisted of 6 hydrocarbons (toluene, xylene, ethylacetate, heptan, decan, and undecan) of the 15 solvents that are the most common in houses. High-toxicity substances such as benzene and formaldehyde or strong-smelling compounds such as higher esters and monoterpenes were avoided in this study. The hypothesis that patients with MCS can distinguish reliably between solvents and placebo was not confirmed. There were no significant differences in neuropsychological parameters such as cognitive performance between the groups when exposed to an active agent vs. a placebo. The authors acknowledged as a study limitation the low recruitment rate of patients with MCS, as many of them refuse to participate in these studies due to fear of health risks [75].

In patients with MCS, near-infrared spectroscopy (NIRS) imaging revealed that odor processing was associated with increased regional cerebral blood flow (rCBF) in the pre-frontal area during olfactory stimulation. MCS patients were found to have an intensified perception of the intensity and unpleasantness of odors [76].

In 2006, Das-Munshi et al. [77] published a systematic review of provocation studies of individuals reporting MCS. In 37 studies conducted on 547 healthy controls and 784 individuals reporting MCS, blinding was inadequate in most studies, as odors of the chemical substances were apparent. In most controlled provocation studies no difference was found between MCS and control groups, suggesting that reactions to chemicals seem to be related to expectations and prior beliefs [77].

There are no generally accepted therapeutic principles. The social and emotional problems of these patients should be addressed in a compassionate manner [78]. If the patient has a genuine psychiatric disease, psychotherapeutic therapy is mandatory. As a means to express care for these patients, the Canadian Human Rights Commission has set a policy on environmental sensitivities in the workplace, highlighting the importance of reducing the use of chemicals and enforcing scent-free policies [79, 80].

The pathophysiology of MCS appears to be complex. Some interpretations of etiological mechanisms may be more objective than others.

To explain this large variety of symptoms, it could be hypothesized that the penetration of chemical substances through the nose and bronchi could induce a stimulation of the peripheral and CNS, bypassing the BBB and/or ionic channels like TRPs. This could explain the activation observed on SPECT and fMRI during acute exposure of MCS patients to chemical substances.

Moreover, an observed increase in cytokines might be involved in communication between the immune system and the CNS and further play a role in the onset and maintenance of depressive illness. However, this neurological and immunological hyperresponse is not always observed when performing challenge tests, since in some studies subjects with MCS did not show different results compared with healthy subjects with respect to odor detection thresholds or in distinguishing between active and control stimuli when exposed to subthreshold levels of odors. This suggests that behavioral conditioning could be an important mechanism in the pathogenesis of MCS.

Even if psychiatric conditions appear not to be the major cause of MCS, in the case of genuine psychiatric disease, psychotherapeutic therapy is mandatory.

Because of the complexity of the pathophysiology, there is no specific medication against MCS. However, CBT is encouraged, as it has a significant positive impact on the perception of illness.