Rev Environ Health 2015; 30(4): 251–271

Dominique Belpomme, Christine Campagnac and Philippe Irigaray*

Reliable disease biomarkers characterizing andidentifying electrohypersensitivity and multiple
chemical sensitivity as two etiopathogenic
aspects of a unique pathological disorder
DOI 10.1515/reveh-2015-0027
Received September 11, 2015; accepted November 2, 2015

Abstract: Much of the controversy over the causes of electrohypersensitivity (EHS) and multiple chemical sensitivity(MCS) lies in the absence of both recognized clinical criteria and objective biomarkers for widely accepted diagnosis.
Since 2009, we have prospectively investigated, clinicallyand biologically, 1216 consecutive EHS and/or MCS-self
reporting cases, in an attempt to answer both questions. We
report here our preliminary data, based on 727 evaluable of839 enrolled cases: 521 (71.6%) were diagnosed with EHS, 52(7.2%) with MCS, and 154 (21.2%) with both EHS and MCS.
Two out of three patients with EHS and/or MCS were female;mean age (years) was 47. As inflammation appears to be a
key process resulting from electromagnetic field (EMF) and/or chemical effects on tissues, and histamine release ispotentially a major mediator of inflammation, we systematically measured histamine in the blood of patients. Near
40% had a increase in histaminemia (especially when bothconditions were present), indicating a chronic inflammatory
response can be detected in these patients. Oxidative stressis part of inflammation and is a key contributor to damage
and response. Nitrotyrosin, a marker of both peroxynitrite(ONOO°-) production and opening of the blood-brain barrier (BBB), was increased in 28% the cases. Protein S100B,
another marker of BBB opening was increased in 15%.
­Circulating autoantibodies against O-myelin were detected*Corresponding author: Philippe Irigaray, PhD, ARTAC, 57-59 rue dela convention, 75015 Paris, Phone: +33 (0)1 45 78 53 54,
Fax: +33 (0)1 45 78 53 50, E-mail: philippei.artac@gmail.com;
Association for Research and Treatments Against Cancer (ARTAC),
F-75015 Paris, France; and European Cancer and Environment
Research Institute (ECERI), Brussels, Belgium
Dominique Belpomme: Paris V University Hospital, France; andEuropean Cancer and Environment Research Institute (ECERI),
Brussels, Belgium
Christine Campagnac: Hospital Director, seconded from Assistance
Publique-Hôpitaux de Paris (AP-HP), Paris, France; and European
Cancer and Environment Research Institute (ECERI), Brussels, Belgium

in 23%, indicating EHS and MCS may be associated with
autoimmune response. Confirming animal experiments
showing the increase of Hsp27 and/or Hsp70 chaperone
proteins under the influence of EMF, we found increased
Hsp27 and/or Hsp70 in 33% of the patients. As most patients
reported chronic insomnia and fatigue, we determined the
24 h urine 6-hydroxymelatonin sulfate (6-OHMS)/creatinin
ratio and found it was decreased ( < 0.8) in all investigatedcases. Finally, considering the self-reported symptoms of
EHS and MCS, we serially measured the brain blood flow(BBF) in the temporal lobes of each case with pulsed cerebral ultrasound computed tomosphygmography. Bothdisorders were associated with hypoperfusion in the capsulothalamic area, suggesting that the inflammatory process involve the limbic system and the thalamus. Our datastrongly suggest that EHS and MCS can be objectively
characterized and routinely diagnosed by commerciallyavailable simple tests. Both disorders appear to involve
inflammation-related hyper-histaminemia, oxidative stress,
autoimmune response, capsulothalamic hypoperfusion and
BBB opening, and a deficit in melatonin metabolic availability; suggesting a risk of chronic neurodegenerative disease.
Finally the common co-occurrence of EHS and MCS strongly
suggests a common pathological mechanism.
Keywords: biomarkers; cerebral hypoperfusion; electro­
hypersensitivity; limbic system; multiple chemicalsensitivity.

Introduction
In 1962, Randolph first described clinically (1) what is today
commonly called multiple chemical sensitivity (MCS) (2); ahuman pathological disorder that has been identified anddefined in 1999 during an international consensus meetingon the basis of the six following criteria: “1. The symptoms
are reproducible with [repeated chemical] exposure; 2. The
condition is chronic; 3. Low levels of exposure [lower thanpreviously or commonly tolerated] result in manifestations

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252

Belpomme et al.: EHS and MCS as a unique pathological disorderof the syndrome; 4. The symptoms improve or resolve when
the inciting agents are removed; 5. Responses occur to multiple chemically unrelated substances; 6. [Added in 1999]:
Symptoms involve multiple organ systems” (3). Although
the precise worldwide prevalence of MCS remains unclear,
it is expected that due to the vastly increased number ofthe various chemical products that have been put on themarket during the last few decades, MCS is becoming an
increasing prevalent pathological disorder (4).
The recent rise of wireless telecommunication worldwide also confronts scientists with the question of whether
anthropogenic electromagnetic fields (EMFs) such as
emitted by cell phones, wireless internet, and high voltage
power lines, can cause adverse health effects as it is the casefor chemicals. In 1991 Rea first described what he called
electromagnetic field sensitivity (5). Six years later, Bergqvist
et al., in a report prepared by a European group of experts for
the European Commission coined the term electrohypersensitivity (EHS) to encompass in a unique concept the clinicalconditions in which EHS self-reporting patients complain ofsymptoms they attribute to EMF exposure (6). Since 1998,
Santini et al. in France, reported symptoms experienced byusers of digital cellular phones and the health risk of people
living near cellular phone base stations (7, 8).
In 2004, because of the increasing worldwide prevalence of EHS, the World Health Organization (WHO)organized an international scientific workshop in Prague(Czech Republic) in order to define and characterize EHS.
Although not acknowledging EHS as being caused by
EMF exposure, the Prague working group defined EHS
as “a phenomenon where individuals experience adverse
health effects while using or being in the vicinity of devices
emanating electric, magnetic, or electromagnetic fields …
whatever its cause, EHS is a real and sometimes a debilitating problem for the affected persons” (9). However, following this meeting, WHO proposed to use the alternative
term “idiopathic environmental intolerance (IEI) attributed to electromagnetic fields” (IEI – EMF), indicating
there is no proven causality between the occurrence of IEI– EMF (formerly EHS) and EMF exposure (9).
In view of the poor knowledge of pathogenesis andetiology of EHS and MCS, most mainstream medical,
sanitary and societal bodies maintain there is not sufficient scientific proof to support the concept that clinicalsymptoms experienced by EHS and/or MCS self-reporting
patients are really caused by EMF and/or chemical exposure, respectively. This is particularly the case for EHS
patients, for whom in comparison to sham controls, thereproduction of clinical symptoms in the presence of
EMFs have globally failed to demonstrate a causal link, inblind or double-blind studies (10).

Moreover, the lack of recognized disease biomarkers
objectively characterizing EHS and MCS has resulted inclinical symptoms being dismissed as psychogenic; and/or EHS and MCS are conflated with psychosomatic or
psychiatric diseases, and not recognized as true organic
disorders caused by the environment (11–16). This is particularly the case for radiofrequency EMF, for which somescientists believe that EHS is an uncertain and confusing
concept (17); whereas some others, on the basis of theirown clinical experience agree that excessive exposure
may cause EHS (5, 18, 19).
Here, we present our own experiences based on the
preliminary analysis of a series of 1216 consecutive investigated cases of self-claimed EHS and/or MCS, in the framework of an ongoing prospective clinical study aiming at
identifying and characterizing EHS and MCS both clinically and biologically; through the use of biomarkers
detected and measured in the peripheral blood and theurine of patients. Our data clearly shows that EHS andMCS should be recognized as genuine somatic pathological entities; that patients with EHS and/or MCS are nonpsychosomatic nor psychiatric patients; and probablythat EHS and MCS are two etiopathogenic aspects of asingle pathological disorder.

Search for reliable diseasebiomarkers
The identification and measurement of reliable biomarkers is a crucial step for identifying and characterizing diseases. This is a fortiori the case for any new pathologicalentity or clinical syndrome such as MCS, EHS or otherenvironmental intolerance syndrome. However, to ourknowledge, such an approach has proven inconclusive for
MCS (20) and EHS (21).
We thus searched for characteristic biomarkers andselected a battery of biological tests which could be routinely used clinically in environmental medicine practicefor taking care of EHS and/or MCS self-reporting patients.
In addition, due to the reported clinical symptoms,
we systematically measured the brain blood flow (BBF) in
both cerebral hemispheres of these patients by using echodoppler of the middle cerebral artery (22) and measured
centimeter by centimeter brain pulsatility by using pulsed
ultrasound-based cerebral computerized tomosphygmography, which allows centimetric resolution pulsed ultrasound recording of cerebral pulsatility (23–25), to localize
more precisely the BBF in the different areas of the two
temporal lobes. Our working hypothesis was that under

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Belpomme et al.: EHS and MCS as a unique pathological disorderthe influence of environmental factors such as EMFs and/or chemicals, some neuro-inflammation and oxidative
stress might occur in the brain, with blood-brain barrier(BBB) disruption as a consequence.
We thus routinely measured the inflammation-associated high-sensitivity C reactive protein (hs-CRP) in the
peripheral blood; and levels of vitamin D2-D3, as it has
been suggested that low levels of its metabolite, the secosteroid 25 hydroxy-vitamin D (25-D) could be a consequencerather than a cause of inflammatory and/or autoimmune
processes (26), and that vitamin D deficiency is associatedwith abnormal development and functioning of the central
nervous system (CNS) (27, 28). Since it has been shown thatupon brain injury, degeneration or infection, the inflammatory response may trigger degranulation of mast cells,
leading to a massive release of histamine in the blood (29),
we systematically measured the levels of histamine in the
peripheral blood. In addition, as the best known mastcell degranulation mechanism involve crosslinking of thehigh affinity surface IgE receptor (30), we also measured
total IgE levels in the peripheral blood. It is well known
that histamine is a potent mediator of inflammation and isable to increase BBB permeability through oxidative and/or nitrosative stress (31, 32). So we looked for possible oxidative and/or nitrosative stress-related biomarkers of BBB
disruption; and identified nitrotyrosine (NTT), because
it results from the toxic effects of peroxynitrite (ONOO°-)
on proteins (33–36). Such a BBB opening marker has also
been shown for the calcium-binding protein S100B, produced and released predominantly by peri-vascular astrocytes (37–40). During the inflammatory process, it is wellknown that cells produce excessive amount of superoxide(O2°) and nitric oxide (NO°), and that although NO° is aweak free radical resulting from the action of nitric oxide
synthase, its excessive intracellular production is associated with cytotoxic properties because of the formation of
extremely reactive nitrogen species such as peroxynitrite.
The biochemical reaction in the form of O2°+NO° = > ONOO°may thus explain why NTT (which results from oxidativeand nitrosative stresses) is associated with BBB disruption(32, 41). Dosage of free NTT and protein-combined NTT as
well as protein S100B in the peripheral blood of EHS and/or MCS patients was thus an important element of thebattery of biological tests we used.
We also considered that non thermal radiofrequency
often is a repetitive stress leading inter alia to continuous
heat shock protein (HSP) over-expression and release in
exposed tissues, particularly in the brain (42–46). HSPs
are a family of highly conserved proteins with chaperone
functions acting to maintain the structural conformationof cellular proteins. Their over-expression under stress253

conditions which promotes an inflammatory response iswell known (47–49). We thus speculated that the major
inducible stress protein HSP70, which has been shown tooppose to neuronal apoptosis (50, 51) and to BBB disruption (51, 52), so eliciting some neuroprotection could be
involved as it could be also the case for HSP27 (53, 54).
However, under chronic EMF exposure it was reported
that, as compared to controls, intracellular HSP70 levels
may decline (55). We thus systematically measured HSP70
and HSP27 levels in the peripheral blood of EHS and/or
MCS patients in order to try to determine whether thesechaperone proteins are a marker of EMF and/or chemicals
chronic exposure; as it has been shown for non-thermal
EMF exposure in experimental studies (42–46).
Moreover, during oxidative and nitrosative stressproteins may be extensively modified and denatured andso acquire new epitopes which can explain their loss of
specificity and biological activity, hence the synthesis of
autoantibodies (56, 57). This is the case for EMF exposure which has been shown to alter DNA replication andmitosis and form abnormal proteins (42, 58, 59) and soto produce electro-oxidation-related IgE ­autoantibodies(60). We consequently hypothesized that under the influence of environmental EMFs and/or chemicals, CNS proteins such as O-myelin may be so denatured that theyacquire autoantigenic properties. Consequently we thus
systematically searched for and measured autoantibodies
against O-myelin in the blood of patients.
Finally, since some effects of EMF exposure havebeen reported to be mediated by the pineal hormone,
melatonin (61), and given the fact that in our series
many patients had sleep disturbance, we also systematically measured melatonin metabolism in these patients.
However, as measurement of endogenous melatonin in
urine is not useful because of its low unmetabolized levels(62), we measured levels of its metabolite 6-hydroxymelatonin sulfate (6-OHMS) and creatinine in 24 h urine, todetermine the 6-OHMS/creatinine ratio. Note that sincecreatinine is excreted in a relatively constant amount ineach patients, we used this ratio to reduce the variabilityof 6-OHMS measurement attributed to urine dilution.
The test battery for identifying and characterizing EHS
and MCS is summarized in Table 1. Technical information
about the methods we used for carrying out all biologicaltests and the BBF analysis are summarized as follows:
For the biomarker study, all patients were investigated by using commercially available biochemical tests
and values for each patient were compared to the normalreference values obtained from the commercial companies. Sensitivity, specificity and reproducibility of thesetests were thus those defined by these companies. Each

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Belpomme et al.: EHS and MCS as a unique pathological disorder

Table 1: Disease biomarkers investigated in self-reporting EHS
and/or MCS patients with their normal values.
Biomarker

Normal range

High-sensitivity C reactive protein (hs-CRP)
Vitamin D2-D3
Histamine
IgE
Protein S100B
Nitrotyrosine (NTT)Heat shock protein 70 (HSP70)
Heat shock protein 27 (HSP27)
Anti-O-myelin autoantibodies
Hydroxy-melatonin sulfate (6-OHMS)
6-OHMS/creatinine≤ 3 mg/L≥ 30 ng/mL≤ 10 nmol/L≤ 100 UI/mL≤ 0.105 μg/L
≥0.6 μg/L and ≤ 0.9 μg/mL≤ 5 ng/mL≤ 5 ng/mL
Negative≥ 5 ng/L and ≤ 40 ng/L
≥ 0.8 and ≤ 8

assay was performed according to the manufacturer’s
method. Hs-CRP and 25-OH vitamin D were measured
by using an automated immunoassay [Architect Ci 4100
(Abbott Laboratories, Abbott Park, Chicago, IL, USA)];for Histamine measurement we used an ELISA specifictest; for protein S100B, a quantitative automated chemiluminescent immunoassays [Liason S100 (DiaSorin
Deutschland GmbH, Dietzenbach, Germany)]; for NTT, a
competitive ELISA test (Cell Biolabs Inc., San Diego, CA,USA); for anti-O-myelin antibody detection, a Western
Blot qualitative analysis (IMMCO Diagnostics, Buffalo,
NY, USA); for HSP 27 and HSP 70, specific high sensitivity enzymatic immunoassays (Stressgen Biotechnologies
Corporation, San Diego, CA, USA); and for 5-hydroxymelatonin-sulfate, a urine ELISA test (IBL InternationalGmbH, Hamburg, Germany).
In addition, to these biochemical tests we used a noninvasive ultrasonic cerebral tomosphygmography methodthat we specifically set-up to investigate the blood flowin the patient temporal lobes and determined for eachpatient a pulsometric index (PI) that we measured centimeter by centimeter from the cortex to the diencephalicmedial area (see Figure 1). This index varies between the
territories studied. In this study, Pi determination for eachcerebral territory in 727 EHS and/or MCS patients wascompared to a retrospective series of 141 normal subjects
which allowed to establish the normal median reference
values of PI (see Figure 2). Finally since our study is stillongoing we did not reported any statistical analysis. This
will follow in specific further papers.

Search for clinical diagnosis criteria
In 2009, at the time we initiated this prospective cohort
study, we were aware there was no available recognized

Probe

Skin
Bone
CortexSub-Cortex
Superficial MCA
Deep MCA
Capsulothalamic area
Vertebrobasilar

Figure 1: Pulsometric index (PI) obtained by a computerized ultrasonic cerebral tomosphygmography (UCTS) in the different area of
temporal lobes.
Data are expressed as mean pulsometric index (PI). PI varies
between territories studied: 3+4 correspond to cortico sub-corticalarea; 3+4+5, to the superficial area of the middle cerebal artery(MCA); 5+6+7, to the deep area of the MCA; 7, to the capsulothalamic area; 3+4+5+6+7, to the complete area depending of the MCA;
8+9, to the vertebrobasilar area; 3+4+5+6+7+8+9, to the complete
temporal lobe.

biological markers for defining objectively EHS and MCS;
this led us to use clinical criteria as inclusion criteria. For
MCS, as already above mentioned, we used the six criteriathat had been reported in the 1999 international workshop(3) and for EHS, we used similar criteria. However, as in an
unpublished feasibility study we showed that many EHS
patients when they are in the vicinity of chemicals may
present with olfactory abnormalities consisting in subjective odor disruption; we systematically added a seventhclinical criteria to the six ones already defined during
the 1999 consensus meeting on MCS, in order to further
characterize clinically MCS and distinguish it from EHS.
Accordingly patients with MCS, unlike EHS patients, werecharacterized not only by the simple odor intolerance,
but more specifically by symptoms of mucous inflammation in the nose, the oropharynx and/or the laryngotracheo-bronchus tract; manifesting clinically as rhinitis,
oropharyngeal dysesthesia or laryngitis and/or bronchospasms, respectively.
To further avoid any confounding pathology, allpatients of the present prospective series have been

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Belpomme et al.: EHS and MCS as a unique pathological disorder

A

B

Standard deviation of adult normality

Right

Left

UCTS

T
o
t
a
l

T
o
t
a
l

M
C
A

M
C
A

R
i
g
h
t
T

R
i
g
h
t

CORT.

SUP.
MCA

DEEP
MCA

CAPS.
THAL.

VERT.
BAS.

VERT.
BAS.

Standard deviation of adult normality

CAPS.
THAL.

DEEP
MCA

SUP.
MCA

CORT.

Right

Left

UCTS

T
o
t
a
l

T
o
t
a
l

M
C
A
R
i
g
h
t

M
C
A

CORT.

SUP.
MCA

DEEP
MCA

CAPS.
THAL.

VERT.
BAS.

VERT.
BAS.

CAPS.
THAL.

DEEP
MCA

SUP.
MCA

CORT.

R
i
g
h
t

Zonal perfusion capacities

Zonal perfusion capacities

Figure 2: Example of diagrams obtained by using UCTS exploring the global centimetric ultrasound pulsatility in the two temporal lobes ofa normal subject (A) and in a EHS self-reporting patient (B).
Measurements are expressed in Pulsometric index (PI). Note that in A and B mean values of PI in each explored area recorded is from thecortex to the internal part of each temporal lobe; so on the left part of the two diagrams A and B for the right lobe from the left to the right;
and on the right part of these diagrams for the left lobe from the right to the left. Note also that in A (normal subject) all values are over thenormal median values whereas in B (EHS-self reporting patients) values in the capsulothalamic areas (the fifth and the second column for
the right and left temporal lobe, respectively) are under the normal median values.

interviewed face to face at length during their medical consultation and questioned systematically about their past
medical history and the type and conditions of occurrenceof their clinical symptoms, thanks to the use of a validated
pre-established questionnaire. In addition, all patients
have been carefully physically examined. Also, before
inclusion, all patients were systematically investigatedby usual routine blood tests and medical imaging including Brain MRI and/or scanner and carotid echodoppler inorder to eliminate any known unrelated CNS pathology.
Finally, based on the above clinical finding for both
EHS and MCS patients we used the following inclusion
criteria:
1. Absence of known pathology accounting for theobserved clinical symptoms;
2. Reproducibility of symptom occurrence under the
influence of EMFs and/or multiple chemicals whatever their incriminated source;
3. Regression or disappearance of symptoms in the caseof EMF and/or multiple chemical avoidance;
4. Chronic evolution;
5. Symptoms such as headache, superficial and/or deep
sensibility abnormalities, skin lesions, sympatheticnerve dysfunction, reduced cognitive ability including loss of immediate memory and attention and/or
concentration deficiencies, insomnia, chronic fatigue
and depressive tendency, all main clinical symptoms
reported as non-specific symptoms in the scientific
literature (13, 19), but which when grouped together

6.

7.

may evoke clinically the diagnosis of EHS (data notshown);
No serious pre-existing pathology such as atherosclerosis, diabetes, cancer; and/or neurodegenerative or psychiatric diseases which have been associated with EHS
and/or MCS in the past or at the inclusion time but would
render difficult the interpretation of clinical symptoms
and biomarker data (see Section “EHS/MCS as a possible sentinel pathological disorder”); and finally
For each patient written informed consent.
Study of this large cohort of patients was not a casecontrol study neither a randomized study so there wasno specific control group.

As depicted in Table 2, on a total of 1216 investigated consecutive cases, 839 are presently analyzed of whom 727 areevaluable, 521 with EHS (71.7%), 52 with MCS (7.1%) and154 with both EHS and MCS (21.2%), regardless of whether
MCS occurred before or after EHS. Only 29 patients, i.e. 3%
claimed to suffer from EHS and/or MCS but did not meetthe inclusion criteria. In fact most of these patients claimed
to be electrohypersensitive. Although many of them wereassociated with a putative neurologic or psychiatric disorder, EHS could not be clearly established. Also excluded
were patients with EHS and/or MCS who were in addition,
diagnosed as suffering from heavy pathology evidenced
after inclusion, or who were lost to follow-up, or for whom
results of the biological investigation were not available atthe time of analysis.

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Belpomme et al.: EHS and MCS as a unique pathological disorder

Table 2: Summary of the present ongoing prospective clinic-biological study of EHS and/or MCS-self reporting patients.
Patients groups
Total investigatedTotal presently analyzed
Neither EHS nor MCS
Not evaluable
Evaluable
Sex ratio
Mean ageMedian age [range]a

Total

EHS

MCS

EHS/MCS

1216
839
29
83
727
495 W/232 M
68%/32%47.9±12.4
47 [16–83]

521
344 W/177 M
66%/34%48.2±12.9
48 [16–83]

52
34 W/18 M
65%/35%48.5±10.3
47 [31–70]

154
117 W/37 M
76%/24%46.7±11.2
46 [22–76]

The range of values is indicated in square brackets, e.g. [minimum-maximum].

a

Demographic panorama

In this series, median age is about 47 years and does
not differ according to EHS, MCS and EHS/MCS diagnosis.
As indicated in Figure 3, all age categories are represented
and mainly include young and old adults, but it appears
that adolescents may be also associated with EHS. Thismay be due to their excessive use of wireless technology(essentially mobile phones and other devices) at this age.
In fact, outside of the present series, we have observedthat infants and children could also be suffering from EHS.

This large cohort of investigated patients originated frommany different European countries, and from other countries worldwide such as the US, Canada, Australia, Russia,
China, Middle East and Africa. This allows some estimation the demographic picture of so called EHS and/or MCS
patients. The demographic data are depicted in Table 2
and Figure 3.
A noteworthy finding which was observed in many
countries is that women appear to be much more susceptible to EHS and/or MCS than men, since in our series two
thirds are female, with no difference between EHS andMCS rates. Note however, that the female predominanceappears to be more pronounced for patients with both
EHS and MCS, where three out of four are female (Table 2).

A

10

30

40

C

10

50

60

70

80

90

30

40

50

10

EHS

20

30

D

MCS

20

Biomarker results are indicated in Tables 3–5 and in
Figure 4.

B

Total

20

Analysis of biochemical markers

60

70

80

90

10

40

50

60

70

80

90

70

80

90

EHS/MCS

20

30

40

50

60

Figure 3: Age categories according to the total number of evaluable patients (A) and to the three EHS (B), MCS (C) and EHS/MCS (D) analyzed groups of patients.

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257

Table 3: High-sensitivity C reactive protein (hs-CRP), immunoglobulin E (IgE), vitamin D2-D3 and histamine in the peripheral blood of EHS
and/or MCS self-reporting patients.
Patients groupsnhs-CRP> 3 mg/L
Vitamine D< 10 ng/mL
Vitamine D≥ 10 ng/mL and < 30 ng/mL
Histamine> 10 nmol/L
IgE> 100 UI/mL

EHS

MCS

EHS/MCS

521
78 (14.97%)[3.27–51.91]
33 (6.33%)[4.81–9.70]
300 (57.58%)[10.40–29.70]
182/491 (37%)[10.08–360.00]
115 (22.07%)[101–1387.60]

52
3 (13.46%)[3.5–10]5 (9.62%)[4.80–8.00]
25 (48.07%)[10.70–27.90]
18/44 (36.7%)[10.80–90.00]
8 (15.38%)[131.10–294.87]

154
22 (14.28%)[3.27–21.61]
16 (10.39%)[7.10–9.90]
92 (59.74%)[15.00–28.60]
59/142 (41.5%)[10.10–1797.50]
38 (24.68%)[103.30–1200.00]

Note that for each biomarker the range of values is indicated in square brackets, e.g. [minimum-maximum].

Table 4: Protein S100B and nitrotyrosin (NTT) in the peripheral blood of EHS and/or MCS self-reporting patients.
Patients groupsn
S100B> 0.105 μg/L
NTT
> 0.9 μg/mL
Increased S100B and/or NTT
Increased histamine, S100B and/or NTT

EHS

MCS

EHS/MCS521
73/495 (14.7%)[0.105–2.090]
77/259 (29.7%)[0.92–8.20]
133/250 (53.2%)
220/327 (71.8%)

52
6/51 (19.7%)[0.110–0.500]
6/29 (26%)[1.10–3.10]
12/22 (54.5%)
27/36 (75%)

154
28/142 (10.7%)[0.110–0.470]
22/76 (28.9%)[0.91–3.10]
46/73 (63%)
91/125 (79.1%)

Note that for each marker the range of values is indicated in square brackets, e.g. [minimum-maximum].

Table 5: HSP70 and HSP27 chaperone proteins and anti-O-myelin autoantibodies in the peripheral blood of EHS and/or MCS self-reporting
patients.
Patients groupsn
Hsp 70> 5 ng/mL
Hsp 27> 5 ng/mL
Hsp70 and/or Hsp27
Anti-O-myelin autoantibodies

EHS

MCS

EHS/MCS

521
91/486 (18.7%)[5.90–11.20]
123/476 (25.8%)[5.20–11.20]
162/487 (33.3%)
109/477 (28.8%)52
4/52 (7.7%)[7.10–7.70]
6/52 (11.5%)[5.90–9.20]
9/52 (25%)
8/47 (17%)

154
36/142 (7.6%)[5.20–32.20]
42/132 (11.5%)[5.10–25.00]
56/142 (39.4%)
33/140 (23.4%)

Note that for each marker the range of values is indicated in square brackets, e.g. [minimum–maximum].

High-sensitivity C reactive protein (hs-CRP)
An increase in hs-CRP levels was found globally in 107
patients (14.7% of the cases), and more precisely in 78
patients (15%), seven patients (13.5%) and 22 patients(14.3%), respectively in the three EHS, MCS, EHS/MCS
individualized groups (Table 3); suggesting that in suchcases, patients were associated with some type of systemic inflammation. We thus systematically looked for

unrelated causes of inflammation and/or infection in thesepatients, but with the exception of three cases, we did not
found any. Furthermore, since hs-CRP is considered as abiomarker of age-related cognitive decline or dementia,
and more particularly of Alzheimer’s disease (63, 64), we
systematically searched for Alzheimer’s disease in thesepatients. In two cases, Alzheimer’s disease was discovered after inclusion and considered as possibly the resultsof excessive past EMF exposure (see Section “EHS/MCS as

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Belpomme et al.: EHS and MCS as a unique pathological disorder

Lower limit of normal

EHS (n=300)

Mean

EHS/MCS (n=89)

MCS (n=21)

0.9

0.9

0.9

0.8

0.8

0.8

0.7

0.7

0.7

0.6

0.6

0.6

0.5

0.5

0.5

0.4

0.4

0.4

0.3

0.3

0.3

0.2

0.2

0.2

0.1

0.1

0.1
0

0

0
0.042±0.003[0.002–0.625]

0.041±0.016[0.005–0.344]

0.048±0.006[0.001–0.343]

Figure 4: 24 H urine 6-OHMS/creatinine ratio in EHS and/or MCS self-reporting patients.

a possible sentinel pathological disorder”). But, because
chronologically, Alzheimer’s disease appeared to follow
the initial occurrence of EHS, we considered that for thesetwo patients, Alzheimer’s disease might have been theconsequence of EHS rather than simply associated with
it. Nevertheless, these two cases were categorized as nonevaluable cases in the present analysis.

Vitamin D2–D3
As indicated in Table 3, a profound decrease in the levelsof the secosteroid 25-D is found globally in 184 patients(25.3% of the cases), and in 121 patients (23.2%), 12 patients(23.1%) and 51 patients (33.1%) in the three groups, respectively. As already discussed (see Section “Search for reliable disease biomarkers”), these data agree with theconcept that decrease in vitamin D2–D3 levels appear to bea consequence rather than a cause of inflammation and soneed to be therapeutically normalized.

Histamine
An important finding in our study is the discovery that
histamine in the peripheral blood is increased in nearly
40% of the patients and that this increase does not differ
between the three groups investigated (Table 3). Thisfinding suggests that histamine is not only a natural clinical biomarker of EHS and MCS, but also may play a crucialrole in the pathogenesis of both clinical entities, since it
has been shown to be not only a neurotransmitter produced and released by the CNS, but also an inflammatory
mediator produced and released by mast cells in many
inflammatory processes including neuro-inflammation(see Section “Pathophysiological relevance”).

IgE
Levels of circulating IgE were found to be increased in
22%, 15.4% and 24.7% of the three EHS, MCS and MCS/EHS
groups, respectively. Since histamine release from mast
cells involve the high affinity IgE mast cell surface receptor and IgE (30, 65), we searched for a correlation between
histamine and IgE levels in the peripheral blood of thepatients. As it will be further discussed, it seemed not tobe the case (see Section “Pathophysiological relevance”).

Protein S100B
Levels of circulating protein S100B have been found to be
globally increased in 107 patients (15.5%), with no differences between the three groups (Table 4). As we will discussed (see Section “Some insight into etiopathogeny”)
this finding confirms previously reported data showing
the glia-derived S100B protein is a biomarker of hypoperfusion-associated brain damage or dysfunction (39, 40,
66–68), and more particularly of neurodegenerative diseases such as Alzheimer’s disease (69) and amyotrophic
lateral sclerosis (70); but differs from the negative results
obtained in non EHS healthy subjects for whom protein
S100B levels has been shown to be normal within the 2 hfollowing GSM mobile phone use (71–73).

Nitrotyrosin
Likewise, increased NTT blood levels have been detected
globally in 105 patients (29%), with no difference between
the three groups. Moreover, as indicated in Table 4, itappears that increased levels of protein S100B and/or NTT
can be detected in approximately 55%–60% of the cases.

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Belpomme et al.: EHS and MCS as a unique pathological disorder

Since, as previously indicated, protein S100B and NTT
could be potential markers of BBB disruption, we consider
that such disruption could be evidenced clinically in over
50% of the patients, whatever their EHS and/or MCS clinical presentation.

HSP70 and HSP27
As indicated in Table 5, depending of the group considered, increased levels of the HSP70 and HSP27 chaperone
proteins were detected in the peripheral blood in about
7%–19% and about 11%–26% of patients, respectively.
Collectively, 25%–40% of the patients were found to be
associated with increased levels of HSP70 and/or HSP27,
without difference between the 3 so far individualizedgroups, meaning that HSP70 and HSP27 are circulating
biomarkers not only of EMF chronic exposure as it is thecase in animal experimental studies (42–46) but also ofchemical chronic exposure. HSP70 and HSP27 seem to be
more frequent in EHS patients than in MCS patients.

Autoantibodies against O-myelin
As indicated in Table 5, autoantibodies against O-myelin
have been detected globally in 17% to nearly 29% of thepatients studied with no difference between the threegroups, suggesting that in these patients EHS and/or MCS
were associated with some type of autoimmune response.
Here too, it is more frequent in EHS than in MCS.

Melatonin
6-OHMS and creatinine were measured in the 24 h urineof a number of patients. As indicated in Figure 4, all investigated patients had a decrease in the 6-OHMS/creatinine
ratio; suggesting that these patients have decreased antioxidant defenses (74, 75), and so may be at risk of chronic
diseases (see Sections “Pathophysiological relevance” and“EHS/MCS as a possible sentinel pathological ­disorder”).
Moreover, this decrease might explain why such patients
present sleep disturbance.

Clinical forms of EHS and/or MCS without
detectable biomarkers
Increase in hs-CRP and vitamin D2–D3 blood levels are
non-specific biological parameters. On the other hand,259

although none of our biomarkers are per se specific(see Section “Some insight into etiopathogeny”) the
increased serum level of histamine, protein S100B and
NTT in the peripheral blood seems more characteristicof EHS and MCS, because of their pathophysiologicalrelevance. However, as indicated in Table 4, increased
levels of histamine, protein S100B and/or NTT were
found in only 70%–80% of the patients, meaning that in
20%–30% of the cases in our series, EHS and MCS could
not be objectively characterized by these biomarkers.
However, in such patients in addition, to the clinicalpicture the objective diagnosis of EHS and/or MCS could
still be made based on the abnormal recording of brain
pulsed ultrasound computed tomosphygmography.

Pathophysiological relevanceIn our study we have shown that EHS and MCS both areassociated with the same biological abnormalities. Thisstrongly suggests that both pathological entities share aunique common pathophysiological mechanism.
Since histamine was found to be increased in the
peripheral blood of nearly 40% of the patients, this molecule appears to be a key pathogenic mediator, whatever theenvironmental stressors. Indeed, the fact that histaminelevels were not found to be increased in all patients doesn’tmean that patients for whom there is no histamine bloodlevel increase have no local histamine production andrelease in their tissues or at other times. Moreover, we will
outline below that histamine is not just a neuro-inflammation mediator. Histamine plays a critical pathophysiological role as a neurotransmitter in the brain. For example
neuronal histamine has been shown to be involved in thesleep cycle, motor activity, synaptic plasticity and memory(76–79): all types of neurologic and/or psychologic alteredfunctions or symptoms that we have observed clinicallyin EHS and/or MCS bearing patients (data not shown). In
addition, histamine release from sympathetic nerves canbe experimentally induced by nerve stimulation (80) andit has been shown that H1 receptor may play a major rolein the regulation of sympathetic nerve activity (81). This
may explain why EHS and/or MCS patients may present
clinically with some transitory sympathetic-related symptoms such as tachycardia, tachyarrhythmia and/or arterialpressure instability (data not shown) when exposed to
EMF and/or chemical stressors (82). Moreover, following
ischemic-hypoxic damage, histamine release from nerve
endings has been found to be enhanced, possibly contributing to some ­neuroprotection (83).

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Belpomme et al.: EHS and MCS as a unique pathological disorder

However, histamine is also a unique molecule which
fulfils all criteria that have been historically established
for defining an inflammatory mediator (84). Histamine ismainly produced and stored in perivascular tissue resident mast cells and circulating basophils, and released
in inflammatory tissues through established mechanisms
predominantly involving cell surface receptors. Regarding
histamine release from skin mast cells, the best known
degranulation mechanism involves IgE and the high affinity IgE cell surface receptor (30).
In our study, we found elevated levels of circulating
IgE in about 20% of the patients, whatever the EHS and/or
MCS group considered. However, in such cases, we didn’t
find any positive correlation between the levels of circulating histamine and the levels of circulating IgE nor thepresence of skin lesions. This suggests that skin lesions
and circulating histamine level increase in EHS and/or
MCS patients are not related to an allergic process.
Also it has been shown that advanced glycation end
products (AGEs) can activate mast cells through RAGE,
the receptor of AGEs, and may contribute to initiating a
vicious circle involving increased AGE formation and ROS
production, hence increased low-grade chronic inflammation (85). Similar biological effects may also be obtainedwith protein S100B which has been shown to engage RAGE
in macrophage/microglia and endothelial cells; and so
depending of its extracellular concentration, to contribute
either to chronic inflammation via NFκB activation or toanti-apoptotic effects and trophic protection in the courseof pathological conditions such as brain insult or diabetes(86). Since AGEs have been shown to be involved in diabetes mellitus (87) although all included patients had no diabetes type II at inclusion time, we systematically search fora possible occurrence of diabetes type II in EHS and/or MCS
patients during the follow up of this study, but with the
exception of two cases, all patients were free from diabetes.
Predominantly found at host/environment interfaces
such as skin, respiratory and gastrointestinal tracts (88)and closely associated with blood vessels, mast cells playa crucial sentinel role in host defense (89). Consequently,
more precise investigations remain to be done in EHS and/or MCS patients to determine what mast cell-associatedtissue histamine release come from.
However, since brain mast cells have been shown tobe critical regulators of the pathogenesis of CNS diseases
including stroke, traumatic injury and neurodegenerative
diseases (83, 90) (see also Section “EHS/MCS as a possible
sentinel pathological disorder”) we systematically looked
for brain pathologic alterations in EHS and /or MCS patients.
Routine cerebral MRI and/or scanner as well as carotid
echography were critically considered to be normal in all

evaluable cases. We thus measured the BBF-related pulsatility in the patient hemispheres by using echodoppler of the
middle cerebral artery, and found that resistance index andsystolic and diastolic velocity indexes were associated withcerebral hypoperfusion in one or the two hemisphere in
50.5% of the cases, whatever the patient group considered(data not shown). More precisely, by using pulsed ultrasound computed tomosphygmography, we found that incomparison to normal subjects, cerebral pulsatility in EHS
and /or MCS patients was decreased or even completely
abolished in one or the two temporal lobes (Figure 2), suggesting that BBF might be specifically decreased or abolished in this brain area. We found that this abnormality,
although being not specific, was so frequently observed inthese patients that it may represent a typical brain alteration
similar to that found in Alzheimer’s disease and other neurodegenerative diseases (see Section “EHS/MCS as a possible sentinel pathological disorder”). This finding therefore,
strongly suggests that brain could be the main target ofenvironmental EMFs and/or chemicals in EHS and/or MCS
patients, and that both cerebral hypoperfusion and subsequent histamine release whatever its neuronal or mast cellorigin could be main contributing factors to BBB disruption.
Furthermore, we found that cerebral blood pulsatility was
quasi-constantly decreased in the capsulothalamic area ofthe temporal lobes, which includes the limbic system andthe thalamus, and so correspond to particularly vulnerable
areas to environmental stressors in the brain.
Confirming this capsulothalamic hypothesis, it has
been shown that experimentally-induced brain ischemiahypoxia can increase BBB permeability (91–94) and thathippocampal pathology arising after chronic hypoperfusion can give rise to cognitive impairment and moreparticularly memory deficit (95), a pathophysiologicalmechanism that supports both the key role of cerebral
hypoperfusion/hypoxia in neurodegenerative diseases
such as Alzheimer’s disease (96) and our clinical observation of frequent cognitive defects in EHS and/or MCS
patients. How cerebral hypoperfusion/hypoxia may arise
from the neuro-inflammation process remains however,unclear. Cerebral blood flow restriction and consequently
impaired oxygen supply may occur due to local oedematous swelling, artery and/or capillary vasoconstriction
and/or increased BBB permeability induced by histamineor other neuro-inflammation mediators (97, 98). While
hypoxia itself rather than ischemia can induce histamine
release (99). In addition, less efficient oxygen utilization due to mitochondrial uncoupling may be associatedwith impaired oxygen supply (100). As a consequence ofhypoxia and impairment of mitochondrial functioning,
reduced sensorial excitability, hence transitory loss of

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Belpomme et al.: EHS and MCS as a unique pathological disordermotor, sensory and cognitive function may occur during
EHS and/or MCS processes; but this loss of function may
progress to permanence and universality in the case ofchronic neurodegenerative diseases (97, 101).
Under the influence of environmental stressors, notonly mast cells (102, 103), but also microglia cells andastrocytes (31, 104–106) play a crucial role in BBB disruption. Indeed the resident CNS tissue macrophages glial
cells such as microglia cells and astrocytes, and the resident CNS mast cells are probably the first cells to respondto any neuro-inflammatory stimuli. In addition, it has
been shown that tachykinin peptides such as substance P,
can trigger microglial activation and subsequent releaseof proinflammatory molecules, thereby contributing in
addition, to mast cells to the development of microgliamediated inflammation and BBB break down (107–109). It
is indeed well known that under the influence of neuroinflammatory stressors, such as EMF and particularly
during mobile device (GSM) prolonged exposure, microglia cells can migrate to the site of injury, proliferate andrecruit astrocytes (110), what is commonly called gliosis –a first cellular neuro-inflammation response which produces and releases NO°, ROS and inflammatory mediators(105, 111). Moreover, astrocytes express histamine receptors (112) which after activation can trigger release ofcytokines, which are themselves able to induce histamine release through mast cell degranulation in positive
feedback loop (113). Finally, our finding of both cerebral
hypoperfusion and histamine release, supports previous
data according to which BBB disruption is obtained more
efficiently when these two factors are combined (91).
At a molecular level it has been evidenced that histamine and other neuro-inflammation mediators induce
oxidative and nitrosative stress and so change the molecular composition and functional state of the BBB endothelial tight junctions, hence increasing permeability of the
BBB (32, 104, 114, 115). As a consequence of this process
circulating inflammatory cells may thus transmigrate into
the CNS and so amplify the neuro-inflammation response(116, 117). Note that such oxidative/nitrosative stressinduced BBB disruption has not only been evidenced as aconsequence of chronic cerebral hypoperfusion (118) but
also proved to occur under the influence of EMF exposure
at non thermal as well as thermal levels in several animalstudies (104, 119–122).
Melatonin suppression as a consequence of EMF exposure has been experimentally evidenced both in animals
and humans (123–125). We found that 6-OHMS 24 h-urine
excretion was decreased in all the investigated cases,
whatever the EHS and/or MCS patient group considered.
Although this finding suggests that melatonin production

261

might have been decreased in these patients, EMF exposure have been reported to be incapable of altering melatonin synthesis and secretion (126). So an alternativeplausible explanation is that decrease in 6-OHMS excretion may reflect decreased melatonin metabolic availability, due to an increased uptake and utilization of melatonin
as a free radical scavenger (127, 128). Such reduction inmelatonin bioavailability may thus contribute to decrease
host defence mechanisms and may account for the factthat patients submitted to prolonged and intensive EMF
exposure may be at risk of neurodegenerative diseases andcancer (129), particularly of breast cancer (130) (see Section“EHS/MCS as a possible sentinel pathological disorder”).
The development of the oxidative/nitrosative stressrelated autoimmune response may also contribute to
weaken the protective effect of the chaperone proteins
HSP70 and HSP27 (131) as has been evidenced for example
in stroke patients (132). Indeed the role of histamine inmodulating the immune system (133), the disturbanceof the immune system by EMFs (134) and the progressive increase in oxidative and nitrosative stress as long as
chronic exposure to EMFs and/or chemicals persists may
explain why the physiological defence mechanisms ofthese patients may finally collapse.
On the basis of our data we therefore, propose the following pathophysiological model of co-MCS/EHS exposure:1) Under the influence of EMFs and/or chemicals a cerebral hypoperfusion/hypoxia-related neuro-­inflammation
may occur; 2) Due to the release of histamine and othermediators BBB disruption and permeability increase may
be induced through resulting oxidative and/or nitrosative
stress; 3) Circulating inflammatory cells could then enter
the brain to initiate a vicious circle which may considerably
amplify the neuro-inflammation process; and finally 4)
Because of oxidative and nitrosative stress and subsequent
decreased melatonin bioavailability and autoimmune
response, physiological defence mechanisms are weakened making EHS and/or MCS patients potentially at risk ofchronic neurodegenerative diseases and cancer.
Part of this model has been proposed separately for
histamine release from mast cells in EHS (135) and for the
NO/NOOH- nitrosative stress cycle in MCS (136). Our proposed EHS/MCS common pathogenic model is summarized in Figure 5.

Some insight into etiopathogeny
Certainly this study does not prove a causal link between
EMFs and EHS, or between chemicals and MCS, but it
does strengthen the evidence for such a possibility. To our

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262

Belpomme et al.: EHS and MCS as a unique pathological disorder

Environmental stressors

Resident microglia cells
Astrocytes andmastocytes
Cerebralhypoperfusion/hypoxia

Primary local
inflammatory
response

Histamine
And other mediators

Oxidative and nitrative
stressBBB disruption

Inflammation
amplification

Transmigration of
circulating inflammatory
cells

Capsulothalamic neuroinflammation
Mainly involving the limbic system andthe thalamus

Figure 5: Proposed hypothetic EHS/MCS common pathogenic
model based on EHS/MCS induced-neuroinflammation, cerebral
hypoperfusion, histamine release, oxidative/nitrosative stress and
BBB disruption.

knowledge this is the first time that EHS and/or MCS havebeen objectively characterized by the use of several different types of biomarkers and in a large prospective series ofpatients. This finding should avoid the frequent erroneousinterpretation that EHS and/or MCS patients are psychosomatic patients (11–14, 17, 137) and so strongly suggeststhat EHS and MCS are genuine somatic pathological entities. Furthermore, our study revealed that with the exception of the two cases of Alzheimer’s disease which weredetected soon after inclusion, and several other cases ofneurodegenerative diseases which were diagnosed during
the follow-up (these cases have been considered as nonevaluable cases) (see Section “EHS/MCS as a possible sentinel pathological disorder”), all EHS and/or MCS patients
had no detectable psychiatric disease.
As previously mentioned we should however, notethat none of the biomarkers so far identified in our study
are specific of EHS and/or MCS. This is the case for histamine which is known to be increased in the serum ofpatients with typical migraine (138–140) and/or allergy(30) and for HSP70 and HSP27 which has been shown to be
increased in several neurodegenerative diseases (141, 142);
and for protein S100B which acts normally as a physiological intracellular regulator and extracellular signal and so

has been shown to be expressed and released not only bydamaged CNS cells such as glial cells and neurons, butalso by different non CNS cells such as chondrocytes, adipocytes, melanocytes, myofibers and other non CNS cells(67, 86, 143). This explains why the detection of increased
levels of protein S100B in the serum of patients does notmean they are necessarily EHS and/or MCS patients.
Other pathological disorders such as neurodegenerative
diseases, psychiatric diseases such as bipolar disorder orcancer (70, 144, 145) may be indeed also concerned by such
S100B protein levels. Likewise NTT is not only a generalmarker of inflammation but also more particularly amarker of atherosclerosis (146). Increased levels of NTT arethus also non-specific. As already indicated (see Section“Search for reliable disease biomarkers”) we therefore,
paid attention for excluding from our series all cases associated with neuropsychiatric diseases and/or other serious
pathologies such as atherosclerosis and type 2 diabetes inorder to eliminate any confounding factors.
Unlike the reported negative result of histamine
increase in MCS patients (147), we found increased histamine levels globally in about 40% of MCS, EHS or MCS/EHS patients. Since it has been shown that increased histamine levels may in fact appear only when MCS patientsare submitted to environmental stressors such as volatileorganic compounds (VOC) (147), we thus wonder whether
the 60% of patients in our series who were not associatedwith detectable increased histamine levels may in fact bepatients who were not exposed to environmental EMF and/or chemical stressors just before histamine measurement.
Such interpretation may also involve the fact that in ourseries we detected increased S100B protein levels in only
15% of the patients, since the increased levels of protein
S100B following brain injury are fleeting (39, 40, 66–68).
However, since EHS and MCS share similar biologicalabnormalities and so may share a common pathophysiological mechanism (see Section “Analysis of biochemicalmarkers”), these two so far clinically individualized entities may represent two etiopathogenic aspects of a uniquecommon pathological disorder. Arguments in support are
the following: 1. EHS and MCS are associated with a similar
symptomatic clinical picture; 2. Both entities share identical biological abnormalities including histamine release,oxidative and nitrosative stress, and BBB opening; 3. Bothentities are characterized by a similar BBF decrease, andthis cerebral hypoperfusion take place in the majority ofcases predominantly in the same areas, i.e. mostly in thetemporal lobes, more precisely in the capsulothalamicarea; 4. either EHS or MCS occur first; 5. Using the same
therapeutic protocol, similar positive clinical results canbe obtained in both cases (data not shown).

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Belpomme et al.: EHS and MCS as a unique pathological disorder

Because EHS and MCS were historically identified
clinically and distinguished from each other on the basisof individual potentially environmental stressors, some
confusion has emerged. That is, unlike EHS and/or MCS
which are still considered as subjective entities becauseof a lack of etiological substratum, many other internationally recognized diseases were medically characterized
before discovery of their etiopathological mechanisms. In
fact, the acknowledgment of EHS and MCS as resulting
from environmental causes oppose to powerful socioeconomic interests and may explain why they are still not recognized as genuine pathological disorders by national orinternational bodies and health institutions (137).
Moreover, it is well known that diseases are multifactorial and this may explain why current research failed toattribute a causal origin to EHS and/or MCS. Case-control
epidemiologic studies and provocation studies, globally
have failed to demonstrate a causal link between EMF andEHS (13, 137), as it may also be the case for chemicals andMCS. These negative results however, do not exclude thepossibility of a causal link, as observational studies are difficult to conduct and objective inclusion/exclusion criteria
and endpoint evaluation criteria were not clearly defined
because of a lack of objective reliable biomarkers. Moreover,
if we accept the concept that EHS and/or MCS are part of acommon multifactorial disease, clearly those findings may
also have been biased by multiple related or unrelated confounding exposure factors and so may have been associatedwith a reduction of signal-to-noise ratio, thereby obscuring
evidence of a possible causal link. Moreover, black box epidemiology and provocation studies focus on risk factors
without satisfactory understanding pathogenesis.
There are in fact several arguments for a causal roleof EMFs and/or multiple chemicals in the genesis of
the so far individualized EHS/MCS pathological disorder: 1. Self-reporting occurrence of clinical symptoms
depending on electromagnetic and/or chemical sources,
2. ­Efficient removing or lessening of clinical symptoms in
EHS patients and/or MCS patients in case of avoidance of
EMFs and/or chemicals, respectively (19); 3. Appearanceof biological abnormalities (positive detection of biomarkers) when patients are exposed to electromagnetic and/or chemical sources, and regression or disappearance of
these biological abnormalities (normalization of biomarkers) when patients are withdrawn from electromagnetic
and/or chemical sources, a finding that confirm objectively self-reporting patient symptoms (data not shown);
4. a possible common underlying pathophysiologicalmechanism involving oxidative and/or nitrosative stressassociated neuro-inflammation and BBB opening (seeSections “Demographic panorama” and “Analysis of263

biochemical markers”); and finally 5. Identical or similar
biological abnormalities detected in humans as comparedto those evidenced experimentally in animals submitted
to EMF and/or chemicals exposure. Although our dataaccount for clinical symptoms and biological abnormalities associated with an intolerance syndrome andhighlight its pathogenesis, they do not account for susceptibility and more particularly, hypersensitivity whichin addition, to intolerance both characterize EHS andMCS. Virtually all diseases result from the interaction ofgenes and the environment, hence the concept of genetic
susceptibility via constitutive genes which can further thepathogenic role of environmental stressors (148). Theoretically such susceptibility could explain why some subjects
are particularly suffering from EHS and/or MCS and notothers. A genetic predisposition including gene variantsof drug-metabolizing enzymes has been reported for MCS(149–151) but this has not been confirmed (152, 153), suggesting that to define MCS biologically, redox state andcytokine profiling should be considered instead (153).
Our data reveal that women are more susceptible thanmen to EHS or MCS and this susceptibility concerns both
EHS and MCS (see Section “Search for clinical diagnosis criteria”). This suggests some still undetermined sexrelated genetic susceptibility. To our knowledge there is noreported study on genetic predisposition in EHS patients.
As magnetosomes are detectable in the human brain andmeninges (pia mater and dura mater) (154), and becausesome EMF-related biological effects are achieved throughmagneto-reception (155), we speculated that some type of
innate genetic predisposition to EHS might result from thepresence of a high number of magnetosomes in the brain
and meninges of susceptible patients. This may reveal to betrue particularly for non-thermal EMFs (156). Other hypothesis may include acquired susceptibility through epigenetic
mechanisms related to EHS and/or MCS prolonged exposure and some biological synergistic potential between
EMF exposure and low dose organic or inorganic chemical
contamination (157, 158). This may be particularly the casefor heavy metals which, as for EMF, have been shown torelease proinflammatory cytokines (159, 160).
It is worthy of note that metallic dental alloys areassociated with release of heavy metals such as mercury,lead and cadmium into oral cavity (161, 162) and so may
contribute to EHS (158). It has been shown that EMFs
such as GSM frequencies emitted from mobile phone
may induce or accelerate the mercury vapor release fromdental amalgam (163) and consequently may contributenot only to EHS but also to MCS (164).
An intriguing unknown pathophysiological mechanism referred to as sensitivity-related illness (SRI) (4) or

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264

Belpomme et al.: EHS and MCS as a unique pathological disorderas toxicant-induced loss of tolerance (TILT) (165) has been
put forward in order to account for the fact that patientswith EHS and/or MCS cannot tolerate weak intensity of
EMFs and/or low concentration of chemicals. We define
acquisition of such a hypersensitivity state with two criteria: 1. Decrease in the tolerance threshold for EMFs orchemicals; and 2. Extension of this decreased tolerance
threshold to the whole electromagnetic spectrum or tomultiple structurally unrelated chemicals, as disease progress. Although our data may suggest a role of the limbic
system and the thalamus, to our knowledge no clear
pathophysiological explanation of this intriguing brainrelated hypersensitivity condition has yet been given.

EHS/MCS as a possible sentinel
pathological disorder
The BBB protects the brain against potentially harmful
toxic chemicals which may have contaminated the bloodand thereby is currently regarded as a physiological structure that plays a crucial role in maintaining brain homeostasis (166–169). However, the BBB cannot protect thebrain against EMFs (170). This may explain why EMFs areprobably a major stressor associated with BBB disruption
and brain inflammation, and why oxidative stress andmore particularly oxidative/nitrosative stress-induced BBB
breakdown may be causally involved in neurodegenerative diseases (171, 172), such as Alzheimer’s disease (AD)(173–176), Parkinson’s disease (PD) (177), multiple sclerosis(MS) (178), Huntington’s disease and amyotrophic lateralsclerosis (70) and even possibly psychiatric diseases suchas schizophrenia, autism and bipolar disorder (179–182).
Since the first reports on EMF exposure-related BBB
disruption (119, 183) conflicting data have emerged (122)leading to search for new tests for evidencing BBB disruption in EHS and/or MCS patients. BBB permeability
imaging (184) in addition, to search of peripheral biomarkers could be helpful. Using protein S100B and NTT as
biomarkers our data tend to show that BBB opening could
be detected in 55%–60% of patients; but this result does
not mean the remaining cases could not have been associated with BBB opening we were unable to detect.
There is indeed compelling evidence that chronic
neuro-inflammation is a long lasting and potentially selfperpetuating process including an initially long-standing
release of inflammatory mediators, leading to increasedoxidative and nitrosative stress. This process may thus
persist long after the initial environmental trigger and consequently can contribute to neurodegeneration throughfree radical attack on neural cells (185). This is particularly
the case in AD and PD for which toxicity of free radicals
have been demonstrated to contribute to protein and DNA
injury, inflammation, tissue damage and subsequent neuronal degeneration and apoptosis (175, 176, 183, 185–187).
We have shown that patients with EHS and/or MCS
often have cerebral hypoperfusion and histamine release,two factors that in addition, to the production of autoantibodies have been evidenced to occur in AD (173, 174) andPD (188–192); hence contributing to neuro-inflammation
and BBB dysfunction. Moreover, several studies have shownthat prolonged occupational exposures to low or extremely
low frequency EMFs are associated with AD (193–196) andsuch a link has recently been confirmed in a meta-analysis
based on more than twenty epidemiological studies (197).
Although it has been shown in a single study that longterm high frequency EMF exposure could protect against
and even reverse cognitive impairment in mice bearing a socalled animal equivalent of AD (198), there is currently no
scientific reason to believe that in humans prolonged radiofrequency EMF exposure as it is the case with excessive cell
phone and/or mobile phone use will be not also causally
related to AD occurrence (199). Moreover, it has been shownthat neurodegenerative diseases are in fact multifactorial
and that, as it has been hypothesized, ferrimagnetic metals
in food chain may contribute to initiate these neurodegenerative diseases under the influence of EMF exposure (200).
Typically AD starts with mild memory deficits, primarily affecting short term memory and gradually progresses to loss of retrospective memory and dementia. An
important finding in our still ongoing study is that most of
EHS and/or MCS patients had decreased cognitive ability
manifested by loss of immediate memory and attention
and concentration deficiency (see Sections “Search forreliable disease biomarkers” and “Analysis of biochemicalmarkers”). Since EHS and/or MCS pathogenesis appears tobe associated with brain pathophysiological abnormalities
similar to that occurring in neurodegenerative disorders,a question is whether EHS and/or MCS are either a preneurodegenerative state or an unrelated pathological disorder whose environmental causal origin might however,be similar to that of neurodegenerative diseases. Nevertheless, whichever these two possible etiopathologic alternatives, EHS and/or MCS might be considered as some type ofenvironmental sentinel pathological disorder.
It is worthy of note that in our series, in addition, to thetwo cases of AD, which were diagnosed a few months after
inclusion, another case of AD and two cases of PD were discovered in association with EHS during the patient follow
up. Moreover, at inclusion time we excluded two casesof AD, two cases of PD, three cases of multiple sclerosis,

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Belpomme et al.: EHS and MCS as a unique pathological disorderand one case of Huntington disease, which were found tobe associated with EHS. In addition, we excluded seven
EHS or EHS/MCS cases because they were associated withprevious or simultaneous carcinoma: breast carcinoma (3cases), brain tumor (2 cases) and lymphoma (1 case). We
also excluded three MCS cases because they were associated with lymphoma (1 case) and thyroid endocrinopathy(2 cases).
Certainly long term longitudinal analysis and replication of this ongoing prospective study will be necessary
to establish whether EHS and/or MCS could be related toneurodegenerative disease and/or cancer, and thus may
announce or reflect occurrence of these pathologies.

The growing worldwide healthproblem
Whatever the causal origin of EHS and/or MCS, there iscompelling evidence that EHS and/or MCS self-reporting
patients constitute an unsolved, large and growing healthproblem worldwide.
As far as EHS is concerned, about 1%–10% of theinvestigated population, e.g. 5% in Switzerland (13), 5%
in Ireland, 9% in Sweden, 9% in Germany and 11% inEngland are presently estimated to be EHS self-reporting
persons (201). Given the seven billion persons worldwide
using cordless and/or mobile phone it is expected thesepercentages may increase in the 50 next years. However,
because at the time these estimations were made there wasno objective criteria for identifying EHS (21), these datarequire confirmation by more objective investigations.
By using the battery of biomarkers we have investigated in this study it now seems possible to objectively
characterize and identify EHS and MCS. Although termed“idiopathic”, IEI has been defined as abnormal responses
possibly triggered by exposure to organic chemicals and/or metals. It is believed that in addition, to MCS several
pathological disorders such as fibromyalgia and chronic
fatigue syndrome, because they may share a similar environment-related intolerance condition, could be part of
IEI. We have shown multiple lines of evidence that EHS
and MCS share a similar pathogenesis and so might be thesame pathological disorder whatever their putative causal
stressors. This strongly reinforces the concept that both
EHS and MCS must be part of the so called IEI syndrome.
Since the WHO publication in 1993 on EMFs (202), muchprogress have been made in the identification and understanding of EMF effects on the organism, while EHS has still
not been clearly characterized and acknowledged by WHO.

265

Present research vainly focus on the causal role of
EMFs and chemicals as possible triggers of EHS and MCS,
respectively and not enough on the actually unmet healthcare needs at a socioeconomic and public health setting
for persons with environmental sensitivity (203), as it isparticularly the case for EHS and/or MCS persons.
We therefore, strongly propose that whatever their
proofs for their causal origins, EHS and MCS should
clearly be added to the next version of the WHO international classification of diseases (ICD) on the basis on theirclinical and pathological description; as has been the casefor many other diseases.
Acknowledgments: This work was supported by a specific
grant from the ARTAC provided by patient’s donations andnon-profit grants from Foundation Lea Nature-France,
Foundation Pour une Terre Humaine-France and Foundation Un Monde par Tous-France. The authors acknowledge
Dr. Natalio Awaida from “Labo XV-Paris” for the high qualityof the blood analysis, Tony Tweedale from R.I.S.K. (Rebutting Industry Science with Knowledge) (Brussels, Belgium)for his review and valuable comments on early draft. The
authors thank also Ms Meris Michaels (an ARTAC member
from Switzerland) for her specific financial support.
Conflicts of interest statement: All the authors declare no
financial conflict of interests.

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