We have also specified the type of imaging analysis, as they have a different resolution power.
Studies where the chemical stimulation is represented exclusively by carbon dioxide in concentrations of between 5% and 35%48 and by capsaicin49,50 are not included in this classification.
The observed studies present different substance exposure modes: aerosols with facemask or by dynamic olfactometer,21,22,32,36,42,43 chemical room at controlled temperature and humidity14,23–25,33,37,40,41,44–46 or smelled through bottle,28,31 and soaked paper discs or even through sticks.26,27,29,30,43 Substances may be harmless as the smells of banana, coconut, chocolate, vanilla, cedar, and lavender oil.21,22,26,27,29–31 Some are toxic such as volatile organic compounds (VOCs), alcohols, and solvents in general,14,23–46 but their concentrations are always below the legal limits. Many authors agree that stress is an important risk factor and some speculate a psychosomatic origin of the syndrome.14,30–32,37,40 Other researchers tend to rule out this theory in favor of a neurogenic inflammatory origin and hyper-reactivity to stimuli of the limbic system21,22,25,46 associated with frontal and prefrontal cortex hypo-activity in MCS cases with respect to controls as detected by positron emission tomography (PET), single photon emission computerized tomography (SPECT), or magnetic resonance imaging (MRI) analysis.
The analysis of the articles has led us to deduce the following schematization (Table 1 ) based on the derivative conclusions dividing them into three large groups:
A = toxicological theory; B = psychological theory; C = no conclusion.
These studies did not lead to homogeneous result probably due to differences in type of exposure, substances used, the different selection criteria adopted in dividing the suspect MCS (sMCS), from the controls also with regard to the severity of the symptoms, and possibly to the different power resolution in the Imaging techniques used.
In addition, the number of tests and the sample are often limited. On the basis of these considerations, we highlight some studies,21,22 in which, following olfactory stimulation, a hyperactivation of the amygdala and the olfactory cortex is detected in sMCS, not counterbalanced by the activation of frontal and prefrontal areas as otherwise evidenced by the controls. These metabolic differences would be the basis of the different responses to olfactory stimuli between sMCS and controls and would suggest authors toxicological theory of hyperreactivity and limbic sensitization with neuronal inflammation. To the same conclusion also comes Orriols et al,25 although the results are different from those noted by the authors mentioned above, but anyway indicative of brain dysfunctions in the processing of the stimulus. Diametrically opposite is the opinion of the authors Azuma et al30 and Hillert et al.31 According to them, the reiteration of olfactory stimulation would cause emotional responses30 and the reduction of the activation of the olfactory regions in the MCS, according to top-down regulations.31
Regarding our bibliographic research, we highlight that only in three studies,34,35,46 the authors substantially propose the toxicological hypothesis of neuronal sensitization, while in several others,14,26,32,37,40,41,42,45 the authors speculate a psychological response in sMCS, compared with controls, or anyway anxiety as a risk factor to the development of syndrome. According to these authors, both the changes in some physiological parameters such as heart rate, pressure, and respiration between sMCS and controls, rather than the exact opposite, that is, the lack of modifications of some other parameters (eg, cortisol level), following the stimulation, would be a proof of emotional nature of the problem.
As outlined in the table, several other studies show controversial results, inducing the authors to come to no conclusion.23,24,27–29,33,39,43
The previous considerations for the Imaging Analysis regarding the importance of a greater standardization are also valid for Nonimaging studies.
Observational and Longitudinal Epidemiological Studies
In the current review, we analyzed about
- 24 cross-sectional studies of prevalence;
- 22 cohort and case–control studies.
Analysis of Inclusion Criteria
In most of the epidemiological studies, people are recruited following interviews and through the compilation of different kinds of questionnaires51–60 or standardized questionnaire as the EESI or QEESI,61–74 CGES,75 Huppe,76 Environmental medicine questionnaire (EMQ), or chemical sensitivity scale for sensory hyper-reactivity (CSS-SHR),50,77 Chemical Odor Intolerance Index (CII).78,79 Sometimes, the syndrome has been diagnosed by doctors without pointing out the diagnostic procedure.80,81 The inclusion criteria described by Cullen with or without Lacour revision were also cited in some articles.
Analysis of Exclusion Criteria
Exclusion criteria were not standardized but decided by individual authors, depending on the study model, so that we have both: studies in which these criteria are made explicit66–69,72,75,79 and others where they are not specified.57–59,61,64,82,83
Emergency Department and Hospital Admissions
Normally, there is no specific information regarding the prevalence of attendances at ED or hospital admissions, although sometimes the subjects were recruited from the Hospital/clinic waiting rooms or from specific Research Centre for this syndrome.61,64–68,76,82,83
Analysis of Risk Factors
Beside specific questions about exposure to chemicals and related symptoms,51–92 some studies51–53,58,59,62–65,68,71,75–77,79,80,82,83,86,88,90,92 have carried out questionnaires to assess the psychological condition (DSM-IV, SCL 90, NEO, CIDI, etc). Sociodemographic surveys have also been performed and surveys on the simultaneous presence of other diseases such as asthma, allergies, cardiorespiratory problems, autoimmune diseases, cancer, etc.51,52,54,57,58,61–66,68,70,72,74,76,78,82–87,89 These information are useful to get a feedback on the prevalence of symptoms and to characterize the individual social, psychological, and physical conditions of the observed persons. It was found that women are more affected than men,57,89 and that the socioeconomic and cultural level is medium up to high. Due to the diagnostic difficulty, the lack of standardized criteria for case definition, and the different prominence given to the syndrome in different countries, the estimated prevalence is variable from a minimum of 1% to more than 15%.53,57,64,87,88
According to psychiatric and psychological test results, some authors have detected a frequent association between levels of anxiety, depression, psychotic disorders, and MCS,50,58,59,64,71,75–77,80,82,83,86,88 results that led some of them to suppose that both stress50,58,59,75,77 and/or female gender50 may represent risk factors. An increase in the prevalence of other diseases in cases versus controls was also detected: asthma, allergies, atopic dermatitis, autoimmune, neurological, gynecological, cardiopulmonary diseases, etc.51,54,61,68,78,85
Some researchers are trying to determine whether this syndrome causes an inflammatory condition without concurrent infections, with the release of the related chemical mediators and dysregulation of the immune system. In the study by Dantoft et al,68 the levels of 14 interleukins (ILs) and inflammatory factors in blood samples of Danish individuals were analyzed. IL-1β, IL2–4–6, the IL4/IL13, and the alpha factor of tumorous necrosis are increased in comparison to controls. Nevertheless, in a challenge study,24 the same authors found no differences in the concentrations of inflammatory mediators detected in nasal fluids in MCS cases versus controls.
Changes in cytokine levels may be indicative of an inflammatory process that is not generated from the nose after olfactory stimulations. In this scenario, the sensitivity to substances may also be caused by different polymorphisms involved in the detoxification of xenobiotics, which could lead to an accumulation of oxidizing substances and subsequent damage. In some studies,69,72,74 various polymorphisms of Cyp 450 (Cyp 2C9, Cyp 2C19, Cyp 2D6, etc) were analyzed, also including glutathione transferase and peroxidase (glutathion S-Transferase M1, glutathion S-Transferase T, glutathion S-transferase P), aldehyde dehydrogenase, superoxide dismutase (SOD2), and paraoxonase (PON1).69,73,74 The SOD2 polymorphism69 and a specific variant of NOS3 67 seem to be associated with the syndrome and increased levels of oxidative stress. Glutathione both reduced and oxidized are decreased in the MCS cases and there is also an altered pattern of cytokines,74 different from that observed in the study of Dantoft et al.68 Controversial results, positive72 and negative,74 were observed for some frequencies of Cyp isoforms. Caccamo et al72 have studied the prevalence of some haplotypes of the Cyp 450 family (cyp 2C9*2 and Cyp 2C9*3; Cyp 2C19*2 and CYP 2D6 ht) in MCS cases, suspected cases, or patients with fibromyalgia and chronic fatigue and in controls. They have discovered a higher frequency of the haplotypes mentioned above in MCS patients that could be evaluated, together with others, as possible risk factor of MCS.
The recent study by the team of Gugliandolo et al66 noted a decrease in the levels of oxidized/reduced glutathione and Coenzyme Q10 and a greater damage in lymphocytes in MCS patients than controls. These findings led to conclude that there is an increase in oxidative stress due to the decreased activity of detoxifying enzymes. An increased concentration of free radicals and peroxynitrite can be detected, with subsequent release of cytokines.
Among epidemiological papers of particular importance are cohort and case–control studies of workers exposed to various chemicals60,69–71,73,90–93 joined in some cases with chemical provocation essays.25,38–40 It should be noted that in these kinds of studies, mainly male workers were involved, due mostly to the type of occupation. There is a small occurrence of MCS diagnoses.90 It could be caused by the “healthy worker” effect, which can be explained by selective or self-selective processes both for the access to the employment phase and for the continuation of the activity. The bias of the healthy worker effect is a known factor in the field of occupational medicine and is involved in underestimates of morbidity and mortality if the follow-up of the worker is not conducted in a comprehensive manner.70,94
Particularly relevant among cohort studies is the one conducted by the team of Davidoff et al.60 They took into account a cohort of workers employed in the excavation of a tunnel under the service area of a disused petrol pump. In some well documented cases, workers were exposed to gasoline vapors over the allowed limits. During working hours, some workers developed symptoms similar to those reported to MCS. Considering the sociocultural and psychological characteristics of the sample, the authors do not consider likely easy suggestibility with associated psychosomatic symptoms. Furthermore, the same authors in a subsequent study92 believe that psychological questionnaires such as the Minnesota Multiphasic Personality Inventory (MMPI-2) may be misleading because it might be the State of chronic disease, not accurately diagnosed, to lead to a gradual isolation of patients whether within family or in social and working life, helping to aggravate the psychological state of anxiety and frustration. In another study,89 seven patients with previous occupational exposure to neurotoxic undergo PET with F18 radioactive tracer of deoxyglucose (FDG). Compared with controls, there is a hypometabolism in cortical and hypermetabolism in limbic areas. The authors consider this involvement of the CNS as the possible cause of symptoms similar to panic attacks.
Although over the years, the researchers have made several steps toward a better definition of this syndrome, it is still not possible to diagnose MCS with absolute certainty, as the many and diverse symptoms that patients complain following ”low-dose” exposures to chemicals, not well defined in most cases, are common to various pathologies, both physical and psychic. It is still lacking an adequate agreement about the definition of “case” and about proper inclusion and exclusion criteria of patients in the studies.
As to the personal risk factors, experts basically agree on the predominance of the female than male gender and on the association with medium-high social and cultural categories. On the contrary, some epidemiological researches have tried to analyze the importance of certain genetic polymorphisms involved in the detoxification process, in order to highlight differences that might be involved in the variability of the response and then the increased vulnerability to chemical insults. The results, however, still limited in number, are currently conflicting for the part concerning the importance of genetic variability component rather than epigenetic mutation. Even the profession does not seem to always play a major role, though some risk categories have been identified.
In recent years, several experimental studies were performed with exposure of susceptible individuals to chemicals both toxic and harmless, aimed to analyze both the psycho-physiological changes such as heart and respiration rate,14,23,31,45 concentration and memorization ability, and changes in brain activity in different areas.21–23,25,31,36
The conclusions are still uncertain and controversial, although a greater involvement of the activity of the limbic system and of the autonomic nervous system at the expense of cortical areas is broadly confirmed.
The versatility of the methods used in the existing studies and the lack of standardized protocols in toxicology, especially for human trials, makes evaluating the efficiency of the test and the accuracy of the conclusions even more complicated.
DISCUSSION AND OUTLOOK
From the analysis of the results observed in the current review, it is difficult to assess the weight of the self-induced psychological component compared with the physiological one, considering that exposition to high doses of specified substances has straight effects on the CNS, mimicking a psychiatric syndrome.95–97 Lacking clarifications on the etiology, diagnosis, and excursus of the syndrome, patients may feel unfairly labeled as mentally ill, with high disrepute and impacts on their lives.92 It is a major importance from an ethical–professional and legal point of view to take into account this aspect before reaching to conclusions.
In the hypothesis that both factors can also coexist, studies should focus more on the bio-toxicological and physiological parameters changes, as a result of exposure to toxic substances below the TLV, as already thoroughly expressed in previous opinion both by the working group coordinate by the Italian National Institute of Health19 and by Italian “National Institute for occupational accident insurance” (INAIL).20
It could also be considered that some solvents can cause sensitization of the myocardium to endogenous catecholamines, with possible arrhythmias up to atrial fibrillation and cardiac arrest.97 Such an eventuality, even though still not detected in any epidemiological study so far, could lead to an increased risk of cardiopulmonary disease78 or death in patients with MCS, as a result of even reduced environmental and professional exposure, a fortiori ratione in case of a clinical trial. For these reasons, sensitization trials on human could be hazardous because of the possible damage and stress possibly inflicted to the individual. However, to properly evaluate this syndrome, subjects should be exposed to subtoxic doses at concentrations to be evaluated with accuracy and for an appropriate period of time, in order to detect cases of bioaccumulation with detoxification difficulty. Another issue is the need to re-evaluate whether to make increasingly stringent exclusion criteria. Considering that MCS is a syndrome that progresses to increasingly serious stages, with the gradual onset of multiple pathologies, the multi-pathology criterion for exclusion from the sample7 may be acceptable as a precautionary measure to avoid further risk to the patients. On the contrary, this criterion could become counterproductive if is adopted to deny the presence of MCS as it may have been the MCS itself the determinant of the onset of other diseases (autoimmunity, heart disease, respiratory, neuropsychiatric, etc).1,7
Moreover, the absence of stronger evidence in MCS diagnosis protocols, based on specific measures of exposure to chemicals and their biological and physiological effects, could lead to an erroneous estimation of the impact of MCS on the population health status. This is a major problem especially in the field of prevention, particularly for groups at greater risk. We should at least draw up validated and harmonized guidelines for this type of essays, which involves serious ethical issues, and have an appropriate number of repeatable tests just like it does for the toxicological evaluation of chemical substance in the in vivo experiments on animals.
As evidenced, this syndrome, along with other occupational disease, such as toxic-organic solvent psycho-syndrome or chronic toxic encephalopathy,95,96 can play an important role in the appreciation of suitability to the task, with all the repercussions that this can cause, up to the request of disability. From the statistical and epidemiological point of view, it would be appropriate to detect temporary or permanent unfitness to chemical risk, or even the reasons for sudden changes in position that could occur in different working environments.
A careful analysis of case studies occurring in the workplace20 may highlight cases of MCS without the need to perform ad hoc experiments. Executing appropriate and consistent environmental controls for chemical risk is an important factor to prevent both accidents and occupational diseases in workplaces with exposures above the limits and to prevent workers to stay in contaminated places.70 These considerations are particularly relevant in the light of the development of portable electronic devices (ie, eNose) that could highly facilitate the task.
Personal electronic tools, adequately set on defined exposure limits and equipped with audible warning on thresholds exceeding, would be appropriate. The fact that these instruments are wearable by the worker is important to monitor exposure in real time, as with evaporation, substances disperse in the environment. When a suspicion of intoxication, albeit at low doses, arises, it is important to check the biomarkers such as, for example, the presence of the substance or its metabolites in body fluids (blood, urine) as well as the physiological and neurophysiological parameters, also in order to rule out exposures to higher than accepted doses. A careful analysis of both medical and working records could highlight the factors characterizing the phenomenon for the MCS.
As the syndrome might, at a low dosage, mimic a more or less strong poisoning, it is possible, in our opinion, that MCS patients arrive at ED with symptoms similar to those of an intoxication, in which the nervous and cardiovascular system are primarily involved.97
As highlighted in the above indicated studies, the analysis of the patient at anamnestic and etiological level is of great importance. In particular, it should be inquired about the differences in timing and mode of manifestation between endogenous psychiatric syndromes and those caused by chemicals in order not to err on the diagnosis, as symptoms can overlap.
In this regard, more information gathering would be useful in order to perform longitudinal epidemiological studies.
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