Multiple chemical sensitivity is described as an acquired multi-organ condition, where recurring symptoms are muscular weakness and fatigue, confusion and memory loss, minor and major depression, general anxiety, panic disorders and post-traumatic distress, respiratory distress, chronic bronchitis and asthma, ear-nose-throat disturbances, autoimmune disorders, gastrointestinal and genitourinary tract malfunction, and migratory joint pains [23,33]. Prevalence studies are complicated by the uncertain diagnostic criteria, nevertheless epidemiological studies have estimated up to 15% of the USA population in the scholar and working age to be affected with chemical sensitivity at varying severity degrees [34]. Events of exposure to trace concentrations of common odorous substances, including volatile organic compounds (VOCs), perfumes, fresh paint, cleaning chemicals, print and toners, carpeting, and numerous other products, are self-reported as connected to the onset and perpetuating of symptoms by MCS patients, although it is widely stated that adverse reaction is provoked as well by inodorous incitants, primarily selected drug categories and water or food additives and contaminants [35]. A relevant role is also attributed to airborne or food microbial load, especially mould contamination, heavily called into play also for sick building/house syndromes, a frequent comorbidity in MCS [36].

The diagnosis is set on the basis of anamnestic criteria and thorough enquiry on possible trigger exposure, through the medically assisted compilation of validated questionnaires [8,37]. Due to the prevalence of neurologic symptoms, and to the persisting lack of recognized molecular markers for MCS, clinicians incline to classify it among the somatoform disorders, on the basis of several studies demonstrating unsatisfactory results of provocation studies, thoroughly reviewed by Das-Munshi et al. [38]. The rather numerous and diverse leading pathogenetic hypotheses postulated for this syndrome take into consideration both organic and psychiatric/psychological factors. Among the possible somatic mechanisms, the more developed approaches include immunological dysregulation, neurogenic inflammation, limbic kindling and neural sensitisation, toxicant-induced loss of tolerance, altered xenobiotic metabolism, altered nitric oxide/peroxynitrite cycle, behavioural conditioning, psychological/psychiatric factors (for recent extensive review, see [20]).

A relevant part of the clinical and experimental data addressing organic/molecular causes accounts for an impairment of the chemical defensive system as a suitable mechanism underlying the MCS condition. Indeed, adaptation to the chronic non-physiological load of conventional compounds, such as cosmetics, detergents, preserving agents and eccipients, pharmaceutical drugs, as well as to brand new molecules, like slow degrading nanomaterials for medicinal use [39] characterizing the rapidly changing environment, requires an extraordinary metabolic effort. The concerted action of constitutive and inducible, strictly regulated, protective pathways, featuring this metabolic chemical-defensive network, has presumably evolved very early in primitive eucariots, far before immune system development, in order to detoxify low-molecular-weight organic and inorganic compounds, including heavy metals, as well as endogenous non-protein signaling molecules, mediators of inflammation, degradation products, and toxic by-product of cellular metabolism [40]. Human complex detoxification system is a common target of inherited or acquired genetic defects and epigenetic factors. Subjects with gene single nucleotide mutations (snips) or deletions display incomplete detoxification of exogenous/endogenous toxins or/and excessive generation of toxic by-products, whilst hyper-functional genes (duplicated or multiplicated) determine higher-than-normal rates of metabolization [41]. Notably, evidences on the possible role of malfunctioning phase I metabolizing enzymes in the susceptibility to non-tumor environment-associated pathologies are still limited and contradictory.

The scant experimental evidence gathered so far in controlled clinical/laboratory studies on MCS patients still poorly support the whole body of medical hypotheses. In particular, available clinical data prove, though only indirectly, that functional or/and genetic defects of endogenous enzymes detoxifying hydrogen-/lipid-peroxides or stable toxic products of lipid peroxidation, may cause chronic oxidative stress and consequent metabolic and immunologic alterations characteristic for the patients with environmental SRI. Our group has recently demonstrated [17] relevant alterations vs. healthy controls of erythrocyte catalase, glutathione peroxidase (Gpx), glutathione transferase (GST) activities, and of decreased levels of glutathione and polyunsaturated fatty acids, in association with specific alteration patterns of pro-inflammatory cytokines, significantly correlated with clinical manifestations in a representative group of MCS Italian patients, has registered some progress towards the identification of reliable markers of disease onset and progression. These and other possible validated markers may also be useful for a correct and evidence-based evaluation of treatment outcomes and follow-up, to-date unfortunately still unaccomplished.

Gulf War veterans syndrome is a paradigmatic as well as a paradoxical example for all professional and civil intoxication-borne multi-organ and multi-symptom syndromes. Following the Gulf War of 1991, a series of studies on veterans have documented severe health adverse outcomes, mostly chronic in nature, with a wide variety of clinical signs. Most frequent manifestations included sleep disorders, chronic fatigue syndrome, headaches, gastrointestinal disorders, fibromyalgia, multiple chemical sensitivity, anxiety and depression, sexual disability, post-traumatic syndrome, and more, resulting in a degree of disability not found in military personnel not deployed to the Gulf War [23,42]. Relevant studies, thoroughly reviewed by Thomas et al., [43] have linked these conditions to exceptionally severe and prolonged intoxicating events, most notably multiple vaccinations, exposure to depleted uranium and powerful chemical toxicants present in war theatres. Other conditions connected to this polymorphic disorder are the post-traumatic stress disorder [44] and the burn-out syndrome [21], displaying similar impairment of the immunologic and neuro-endocrine patterns, and overlapping symptoms.

Fibromyalgia is a chronic pain syndrome, often leading to working and social inhability. It is characterized by widespread inflammatory rheumatic disease with non-articular musculoskeletal pain, acute febrile illness, paresthesia, fatigue, primary sleep disorders, memory and concentration impairment [45], major depressive disorder, migraine, and irritable bowel syndrome [46], as stated by consensus diagnostic guidelines [45]. The unavailability of specific anatomic, histological, or molecular disease markers complicates the diagnosis. Environmental factors, including certain foods and chemicals, may trigger the development of the chronic pain disorders in individuals with a genetic predisposition [47] FM is often co-morbid with Chronic Fatigue Syndrome, which is diagnosed on the basis of unexplained disabling fatigue lasting for at least six months and not healing with rest, along with several non-specific accompanying symptoms, including disordered sleep physiology and non-restorative sleep syndrome, diffuse myalgia, cognitive and behavioural impairement [48]. The still unclear patho-physiological mechanism bases upon immunological findings, related to altered cytokines profiles, decreased function of natural killer cells, presence of autoantibodies, reduced response of T cells to mitogen and other specific antigens [49]. The activation of peripheral and central inflammatory and oxidative stress pathways has been recently called into play [50].

Chronic intoxication with inorganic mercury due to amalgam fillings is claimed as a major trigger and incitant in MCS [51] and CFS [52]. Amalgam disease is as yet a controversial disabling condition, occurring in allegedly metal-sensitive subjects who carry dental fillings, which contain almost 50% mercury amalgam, with tin-copper-silver and zinc. This material, used since almost two centuries in dental care and thus considered safely bio-compatible, release Hg vapors contaminating saliva, though in daily doses far lower than those known to induce neurological symptoms [53]. Indeed, tissue contamination through dental root and jaw bone transmission has also been proven [54,55]. Mercury vapor is biologically oxidized to Hg bivalent cation, the toxic form of mercury deriving from cellular metabolic oxidation, a far more damaging species than lead and cadmium bivalent ions, because of its higher affinity with thiols, causing irreversible inhibition of cystein containing proteins. Inorganic Hg contained in dental amalgam is transformed into organic methyl-mercury by residential microorganisms in the mouth and in the gastrointestinal tract [56,57].

Chronic Hg intoxication has been connected with a wide variety of symptoms, ranging from cutaneous and oral mucosa signs [58] with increased infection susceptibility, to persistent fatigue with joint and muscle pain, neurological symptoms [59] and vegetative disorders, headache, migraine, lack of concentration, low memory capacity, depression, sleeping disorders. Clinical reports have linked dental amalgam implants with prevailing skin and mucosa manifestations of autoimmune diseases [60–62]. Few rigorous evidences have also linked dental amalgam to increased risk of multiple sclerosis, the association with Alzheimer’s or Parkinson’s disease also being investigated [63,64]. Studies on the dentist category have generally documented neither abnormal death and disease rates, nor any disability susceptible of association with Hg vapors, based on the assumption that their urinary or blood Hg levels were not significantly elevated. In particular, no consistent associations have ever been found between urinary Hg concentration, or the chronic index of Hg exposure, and any category of neurological or psychogenic symptoms [65]. It must be noted though, that Hg concentration in body tissues was proven to be independent of urinary, blood, saliva and hair concentrations [66]. Mercury disposition occurs in fact mainly through stools, in a ratio of 12 to 1 to urine excretion, this latter probably reflecting only kidney, and not total-body burden [67,68]. In support, urine levels of Hg below 5 μg/L (the No Observed Adverse Effect Level—NOAEL—for mercury) have been reported in cases of occupational intoxication [69]. Moreover, data assessing a very long-term persistence of elevated Hg tissue levels after chronic or acute professional intoxications are available [70]. Up-to-date, the invalidating complex of symptoms labeled as amalgam disease stays almost unrecognized by both clinical community and legal agencies. Methodological flaws of published studies and possible conflict of interest of dentist professional associations in official position papers have been recently thoroughly reviewed by Mutter et al. [71].

Electro-magnetic hypersensitivity is a condition perceived to be consequent to the exposure to environmental electro-magnetic stressors, followed by recovery through the complete isolation from triggers [72,73]. Electro-magnetic fields represent indeed one of the major indoor pollutants in the western world. Subjects complain functional symptoms of the nervous system, i.e., dizziness, fatigue, headache, difficulties in concentration, memory problems, anxiety, depression, respiratory, gastrointestinal, eye and vision manifestations, palpitations, chronic fatigue, fibromyalgia, skin inflammatory and allergic reactions of face, hands and forearms. These and other disorders are generally self-reported by patients, in the absence of somatic pathological signs supporting a specific case definition, with the main exception of skin manifestations. Pioneering reports from Scandinavia deal in fact with dermatological symptoms, subjective-itching, burning- and objective-redness, dryness-appearing during work with video display units [74,75]. This syndrome is subjectively attributed to the exposure to frequencies in the radio, microwave, kilohertz, and extremely low-frequency ranges of EMF or radiofrequencies, including the “dirty electricity” due to poor isolation of electric wires and telephonic lines, wireless devices, wi-fi, etc., though no conclusive demonstration of causal relationship has been drawn so far. Physical parameters characterizing these EMF sources vary considerably, therefore irradiation levels are difficult to classify and standardize for provocation studies purposes [76]. Again, in most cases, exposure levels called into play are far below those known to cause physiological changes in animal models [77], or adverse health consequences in industrial settings. Electric pollution has been connected, in limited studies encouraging deeper investigation, to increased risk of chronic and degenerating diseases, including asthma, diabetes, and multiple sclerosis [78].

As in the case of Hg intoxication, compelling evidences are available only on acute and chronic health disorders deriving from professional exposures to high intensity fields, in electric power plants, whilst meager data are available on chronic sub-acute exposures below recommended reference levels, occurring in the civil life. No entirely convincing hypothesis on mode of action has been proposed and proven so far, while provocation studies have provided uncertain results. Data about specific heavy metal blood concentrations of cadmium, mercury and lead in EHS subjects [79] appear relevant, especially in the frame of the considerable overlapping of symptoms with amalgam disease, as related to chronic fatigue, headaches, general malaise and insomnia, although intoxication levels reported are below toxic concentrations. Also in this case, methodological doubts concerning biological samples analyzed, not necessarily representative of effective tissue and organ loads [80], raise the alarm that even negligible metal concentrations may be actively mobilized from tissue under EMF exposure, and exert immuno-toxic effects, with inflammatory cytokine hyper-production and release.

Irritable bowel syndrome (IBS) is a rather common gastrointestinal functional disorder characterized by recurrent abdominal pain or malaise due to enteric and central nervous system modified functions, with stool abnormal frequency or consistency, microbial flora abnormalities with altered host-microbiota interactions and immune activation [81], and consequent disturbed defecation, once again in the absence of structural abnormalities and reliable biomarkers of disease. This condition, estimated to have 5–25% prevalence in the world population, again more frequently reported for the female gender, is not presently clarified in terms of patho-physiological mechanism, and is diagnosed exclusively according to symptom classification-based guidelines and exclusion of other known causes of organic pathologies, such as celiac or colon cancer diseases [82]. IBS is a heterogeneous condition presenting very frequent co-morbidity with other disturbances, mainly migraine headache, fibromyalgia and chronic pelvic pain, anxiety and depression, somatization, stress sensitivity, with consequent low quality-of-life scores bearing relevant socioeconomic impact [83]. As in the case of other SRI, investigations about genetic predisposition have led up-to-now to no definite results, in spite of the wide array of candidate genes proposed [84].

At present, specific diagnostic tools are extremely limited and generally not validated, and the whole clinical process suffers from the lack of case definition in the majority of these conditions, except fibromyalgia, diagnosed on the basis of consensus guidelines [85,86]. It is also generally recognized that the identification of all possible agents leading to xenobiotic intolerance in SRI is difficult, due to the wide variety of potential environmental and nutritional triggers and incitants, often very different between the first precipitating event and the following crises [1]. MCS diagnosis is based on the compliance to Cullen’s inclusion anamnestic criteria coupled with exclusion of any other known organic cause [8], and on the scoring resulting from the Environmental Exposure and Sensitivity Inventory (EESI), a standardized instrument for measuring self-reported chemical sensitivities based on a multistep questionnaire [87], or its locally modified forms [88,89].

The search for reliable, sensitive, and specific organic biomarkers of disease, possibly measurable by non-invasive techniques, remains today the primary unmet urgent goal for SRI diagnosis, and in particular for MCS. The wide variety of proposed etio-pathogenic mechanisms, calling into play neuro-endocrine, immunologic, genetic or metabolic factors, has generated a disparate array of laboratory tests of claimed diagnostic value and specificity, ranging from the determination of a complete array of toxins, organic and inorganic contaminants in different biological samples, immunologic monitoring, genetic tests, oxidative stress markers, etc. Neurologic imaging approaches to prove functional brain impairment have also been taken into consideration, due to the prevalence of CNS symptoms. None of the main directions in MCS diagnostics has found till today acceptable levels of consensus within the bio-medical community and the sanitary regulatory organs. We will here limit the discussion to the approaches that are presently most developed.

In the field of physical diagnostics, functional brain imaging has gained some clinical consensus, due to the heavy involvement of neurological symptoms in response to the exposure to low quality outside and indoor air quality, bearing sub-toxicological levels of VOCs and other environmental chemicals able to trigger sick building(home) syndrome and MCS abnormal reactions [17,20]. Early neuro-physiological studies in the nineties have raised the hope to detect a specific abnormal functional brain reaction to low dose airborne chemicals or a neurotoxic damage in the brain of MCS patients by position emission tomography (PET) [137] or single photon emission computer tomography (SPECT) [138], thereafter often applied in the clinical practise to MCS patients for selective diagnosis and legal compensation purposes. Various neurological investigations on limited numbers of MCS or CFS subjects with both PET and SPECT have shown limited significant functional limbic or cortical alterations, in response to challenge with volatile chemicals. Nevertheless, overall results have failed so far proving with sufficient specificity the occurrence of neurotoxic or neuro-immunologic changes vs. control subjects [139,140]. Possible detection of specific brain function alterations of significant relevance though imaging techniques should be better confirmed in larger standardised provocation studies with low-dose exposure, comparing chemically sensitive subjects versus normal subjects having a previous experience of chemical exposure without adverse effects in order to assess unequivocally relevance of results and to exclude confounding psychological factors.