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Chemical Intolerance

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Current Rheumatology Reviews, 2015, 11, 167-184 167

Chemical Intolerance

Thomas M. Dantoft1,2*, Linus Andersson3, Steven Nordin4 and Sine Skovbjerg5

1
Danish Research Centre for Chemical Sensitivities, Copenhagen University Hospital, Gentofte, Den-
mark; 2Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark;
3
Department of Occupational and Public Health Sciences, University of Gävle, Umeå, Sweden;
4
Department of Psychology, Umeå University, Umeå Sweden; 5Research Centre for Prevention and
Health, Capital Region, Copenhagen, Denmark

Abstract: Chemical intolerance (CI) is a term used to describe a condition in which the sufferer expe-
riences a complex array of recurrent unspecific symptoms attributed to low-level chemical exposure
that most people regard as unproblematic. Severe CI constitutes the distinguishing feature of multiple
chemical sensitivity (MCS). The symptoms reported by CI subjects are manifold, involving symptoms
from multiple organs systems. In severe cases of CI, the condition can cause considerable life-style limitations with severe
social, occupational and economic consequences. As no diagnostic tools for CI are available, the presence of the condition
can only be established in accordance to criteria definitions. Numerous modes of action have been suggested to explain
CI, with the most commonly discussed theories involving the immune system, central nervous system, olfactory and respi-
ratory systems as well as altered metabolic capacity, behavioral conditioning and emotional regulation. However, in spite
of more than 50 years of research, there is still a great deal of uncertainties regarding the event(s) and underlying mecha-
nism(s) behind symptom elicitation. As a result, patients are often misdiagnosed or offered health care solutions with lim-
ited or no effect, and they experience being met with mistrust and doubt by health care professionals, the social care sys-
tem and by friends and relatives. Evidence-based treatment options are currently unavailable, however, a person-centered
care model based on a multidisciplinary treatment approach and individualized care plans have shown promising results.
With this in mind, further research studies and health care solutions should be based on a multifactorial and interdiscipli-
nary approach.
Keywords: Chemical intolerance, coping, management strategies, multiple chemical sensitivity, pathophysiology, review, risk
factors, sensitization.

INTRODUCTION Further, and unlike many known toxicological effects, there

Chemical intolerance (CI) is an encompassing term for
the subjective experience of symptoms attributed to chemical
exposures that most people regard as unproblematic [1-3].
Individuals with CI often, but not always, react to exposure
that has an odor, such as perfume, strongly scented flowers
or fabric softeners [4]. The phenomenon is thus often re-
ferred to as smell sensitivity or similar labels, which may be
a misnomer as the problem does not necessarily have to do
with the sense of smell. CI symptoms include slight annoy-
ance from a certain exposure, to the debilitating, multi-organ
reactions found in severe clinical cases [4]. Severe CI consti-
tutes the distinguishing feature of multiple chemical sensitiv-
ity (MCS). The pathophysiology of CI is still poorly under-
stood and the symptoms cannot be explained by traditional
toxicological dose-response relationships which state that
chemicals only affect an organism if above a certain concen-
tration, i.e. its threshold dose. The exposures to which suf-
ferers attribute CI symptoms are generally below this dose,
in some cases even below sensory detection thresholds [5].
*Address correspondence to this author at the Danish Research Centre for
Chemical Sensitivities, Copenhagen University Hospital, Gentofte,
Denmark; Tel: +45-26163397; Fax: +45-39978458;
E-mail: thomas.meinertz.dantoft@regionh.dk
is no clear relationship between the triggering exposure and
the symptoms. With these challenges in mind, the objective
of the review was to critically examine the scientific litera-
ture on CI with emphasis on syndrome characteristics,
pathophysiological mechanisms, risk factors, treatment mo-
dalities and coping strategies
Symptoms and Symptom Triggers
The exposure agents associated with CI symptoms in
susceptible persons are numerous and chemically diverse.
Being exposed to Eau de Cologne may cause dizziness and
nausea for one person, difficulty breathing and eye irritation
for another [4, 6]. It is thus not possible to tie one chemical
exposure to a certain set of symptoms or to symptom sever-
ity. A common feature in people reporting CI is that the
number of symptom-eliciting exposures increase over time,
which is known as “spreading” [7]. At an initial stage, peo-
ple with CI often report a few problematic exposures,
whereas more severe cases may report symptoms following
exposure from a large number of structurally unrelated
chemicals. Table 1 provides an overview of frequently self-
reported symptom-eliciting exposure substances in CI [8].
The list is by far not complete, and there are multiple other
examples of exposures that may elicit symptoms.

17-/15 $58.00+.00 © 2015 Bentham Science Publishers

168 Current Rheumatology Reviews, 2015, Vol. 11, No. 2
Table 1. Percentage of individuals with clinical CI responding affirmatively to the question of ever having experienced unpleasant
reactions elicited by inhalation of odors or chemicals [8];
Symptom Trigger
Car exhausts
Other persons wearing of perfume, aftershave or deodorant
Cleaning agents
Freshly printed papers or magazines
Smoke from wood burner
Nail polish remover, glue, or markers
Cooking fumes
Tar or wet asphalt
New furniture
Soft plastic or rubber
New electronic equipment
The nature and number of symptoms experienced by per-
sons with CI are equally diverse, and commonly described as
a complex range of symptoms from multiple organ systems.
It is common to categorize these symptoms into different
domains depending on where in the body they are expressed.
Andersson and et al. developed a questionnaire for assessing
the most prevalent CI symptoms. Out of 82 possible symp-
toms, 27 were reported by at least 20% of the participants
(average of test and re-test) and were included in the ques-
tionnaire under five different categories [9]. These symptoms
are given in Table 2 with some additional data from other
studies illustrating the complexity of the symptomatic expe-
rience by persons troubled by CI.
Case Definitions
As no diagnostic tool is available, CI is established in
accordance to criteria definitions [10]. A number of dif-
ferent definitions are given in Table 3. The term MCS was
first coined by Randolph in the 1950s, who argued that
chemical substances in modern society represented a po-
tential threat to public health. Later on, several case defi-
nitions have been suggested, and in 1996 the term idio-
pathic environmental intolerance (IEI) was introduced as
a replacement of MCS [11, 12]. The main argument for
using the label IEI is that MCS implicates that chemical
substances are the cause of symptoms. As no study has
found a causal connection between exposure and illness,
this criterion has been removed from the IEI definition
[11, 12]. The suggested name change has not gained un-
divided support. In the scientific literature, MCS and IEI
are therefore often used interchangeably when referring to
this severe form of CI. CI can be considered as an um-
brella term covering both milder and severe forms of reac-
tions to chemicals where a direct toxicological effect can-
not be found. CI will be used throughout this review to
describe the condition without reference to any assump-
tions about the underlying etiology.
Dantoft et al.
%
73.8
68.8
60.3
53.9
50.4
39.7
36.2
34.8
28.4
24.8
14.9
The definitions in Table 3 contain several uncertainties
that has been discussed previously (e.g. by McKeown-
Eyssen et al. [13]). For instance, how low is a ‘low level
exposure’? Do extremely low exposures, e.g. those barely
detectable by current instruments, still count? How quickly
must symptoms appear following exposure or disappear
after withdrawal in order to be linked with exposure?
Miller has suggested that symptoms can be delayed by sev-
eral days after exposure [14]. Must the symptoms occur
only after exposure, and is it necessary that they disappear
altogether when the source of the chemical is no longer
present? Does ‘multiple organ systems’ refer to anatomical
areas or physiological systems and functions? For how long
should symptoms have been occurring to consider them as
chronic? What is the definition of ‘chemically unrelated
substances’?
Lacour et al. have suggested a clarification of the 1999
consensus criteria [15, 16]. They propose that ‘chronic con-
dition’ should be interpreted as an illness that has been pre-
sent for at least six months, and which causes significant
life-style or functional impairments. In addition, symptoms
from the central nervous system (CNS) such as headache,
fatigue and cognitive deficits should be present, and ’mul-
tiple organ systems’ should be interpreted as at least one
CNS symptom and one which originates in another organ
system. The authors also suggest that syndromes that over-
lap with CI, such as chronic fatigue syndrome and fi-
bromyalgia should constitute exclusion criteria for MCS,
unless they emerge after the development of MCS symp-
toms [16].
Despite attempts to specify criteria for severe CI, major
limitations still exist regarding sensitivity and specificity.
This limitation is not confined solely to CI, but is present in
all forms of definitions based on subjective symptom reports
[17]. Nevertheless, the absence of widely accepted case cri-
teria for establishing the presence and degree of CI chal-
lenges progress in this field.
Chemical Intolerance Current Rheumatology Reviews, 2015, Vol. 11, No. 2 169

Table 2. Prevalence in percentage of 27 symptoms reported by CI subjects from four investigations. Listed symptoms were re-
ported by at least 20% of CI individuals on a list of 82 possible symptoms [9].

Symptoms %1 %2 %3 %4

Head-related

Headache 66 88 58 33

Head fullness/pressure 32

Airway, mucosae and skin

Eye irritation/burning 65 77 12

Nasal congestation/discharge 64

Coughing 60

Sneezing 58

Throat irritation/hoarseness 52 11

Shortness of breath 47

Skin irritation/redness 30 19

Asthma or wheezing 29 59

Excessive mucus production 27

Postnasal drip 22

Cognitive and affective

Feeling tired/lethargic 51 46 27

Feeling irritable/edgy 44

Concentration difficulties 39 32 37

Sleep disturbance 26 51 20

Feeling depressed 24

Feeling tense/nervous 23 45 13

Memory difficulties 22 29

Absent-minded 21

Feeling worried 21 17

Gastrointestinal

Abdominal swelling/bloating 26 30 15

Abdominal gas 25

Cardiac, nausea and dizziness symptoms

Nausea 30 55 14 12

Chest discomfort 23

Dizziness/lightheadedness 22 46 22 19

Heart pounding 21 27
1
General CI [9].
2
General CI [48] .
3
General CI [23].
4
Diagnosed MCS [178].
170 Current Rheumatology Reviews, 2015, Vol. 11, No. 2 Dantoft et al.

Table 3. Some definitions of chemical intolerance.

Source Term Definition

Cullen [10] MCS1 ’Multiple chemical sensitivities (MCS) is an acquired disorder characterized by recurrent symptoms, referable
to multiple organ systems, occurring in response to demonstrable exposure to many chemically unrelated com-
pounds at doses far below those established in the general population to cause harmful effects. No single widely
accepted physiological function can be shown to correlate with symptoms’

National Research Coun- MCS1 1. Sensitivity to chemicals […] at levels tolerated by the population at large that is distinct from such well rec-
cil [179] ognized hypersensitivity phenomena as IgE-mediated immediate hypersensitivity reactions […]
2. Sensitivity may be expressed as symptoms and signs in one or more organ systems.
3. Symptoms and signs wax and wane with exposures. It is not necessary to identify a chemical exposure asso-
ciated with the onset of the condition. Preexistent or concurrent conditions, e.g. asthma, arthritis, somatization
disorder or depression, should not exclude patients from consideration.

Nethercott et al. with
additions by the 1999
Consensus [15, 180]
MCS1 1. The symptoms are reproducible with [repeated chemical] exposure.
2. The condition is chronic.
3. Low levels of exposure [lower than previously or commonly tolerated] result in manifestations of the syn-
drome.
4. The symptoms improve or resolve when the incitants are removed.
5. Responses occur to multiple chemically unrelated substances.
6. [Added in 1999]: Symptoms involve multiple organ systems3.

Ashford and Miller [181] MCS1 ‘The patient with multiple chemical sensitivities can be discovered by removal from the suspected offending
agent and by rechallenge, after an appropriate interval, under strictly controlled environmental conditions. Cau-
sality is inferred by the clearing of symptoms with removal from the offending environment and recurrence of
symptoms with specific challenge.’

International Programme IEI2 1. An acquired disorder with multiple recurrent symptoms.

on Chemical Safety [12] 2. Associated with diverse environmental factors tolerated by the majority of people.
3. Not explained by any known medical or psychiatric/psychologic disorder.
1
= Multiple chemical sensitivity (MCS). 2= Idiopathic environmental intolerance (IEI). 3 = The criteria specifying “that symptoms have to be present in multiple organ systems” was
added to the Nethercott er al. MCS criteria in accordance with the recommendation provided by the 1999 consensus group.

EPIDEMIOLOGY AND ASSESSMENT
CI can be considered a general term that includes condi-
tions ranging from relatively mild cases to cases with con-
siderably compromised quality of life. When the criterion
has been set to include mild cases of CI, using questions
such as “Do chemical odors make you sick?” the prevalence
has been as high as 25-33% in US, Australian and Scandina-
vian adult populations [8, 18-20]. When, instead, the ques-
tion refers to being more intolerant than what is considered
as normal, or when immediate body reactions are requested,
the prevalence rate falls to 9-16% in US, German and Swed-
ish populations [20-24].
Several valid and reliable questionnaire instruments are
available for assessment of various aspects of the epidemi-
ology of CI, in some cases with cutoff scores and norma-
tive data. In the mid-1990s Kipen et al. provided a scale
based on ratings of subjective reactions to 122 odorous
substances [25]. Partly due to its extensive time consump-
tion, five of the 122 substances (pesticide, paint, perfume,
car exhaust and new carpeting) were extracted to constitute
the Chemical Odor Intolerance Index. For each substance,
the respondent rates on a 5-point scale the frequency of
feeling ill from the odor [26]. Miller and Prihoda developed
the Quick Environmental Exposure Sensitivity Inventory
(QEESI) [27, 28], which originates from the Environment
Exposure and Sensitivity Inventory [29]. The QEESI is a
screening instrument for CI, and consists of five scales: the
Symptom Severity scale, the Chemical Intolerances scale
(extent to which certain odors or exposures make one sick),
the Other Intolerances scale (extent to which a variety of
other exposures make one sick), the Life Impact scale, and
the Masking Index (“hidden” exposures from routinely
used products). The first four QEESI scales consist of 10
items to respond to on an 11-point scale, and the Masking
Index consists of ten dichotomous items. The original ver-
sion of the QEESI is in English, but versions are also avail-
able in Japanese [30, 31], Spanish [32], Swedish [33] and
Danish [34].
The University of Toronto Health Survey (UTHS) as-
sesses fulfilled case definitions of MCS. In addition, the
UTHS asks about general health, demographic characteris-
tics of relevance for CI, which of 171 symptoms the respon-
dent has had in the previous 12 months, which symptoms
have been linked to exposures, and which of a list of expo-
sures have provoked symptoms [35].
The 21-item Chemical Sensitivity Scale (CSS) [36] was
developed to be analogous to the Noise Sensitivity Scale
[37]. Using Likert scales, the CSS quantifies degree of nega-
tive affective reactions to and behavioral disruptions caused
by odorous and pungent environmental substances. From the
Chemical Intolerance
21-item CSS, an 11-item version was formed referred to as
the Chemical Sensitivity Scale for Sensory Hyperreactivity
[38, 39]. Another instrument, the Chemical Odor Sensitivity
Scale (COSS) is an 11-item screening scale that assesses
strong responses to the odor of common environmental
chemicals [40]. The COSS was derived from the 67-item
Questionnaire of Chemical and General Environmental Sen-
sitivity [41, 42], referring to strong responses to a variety of
environmental stimuli.
More recently, questionnaire instruments have been de-
veloped and metrically evaluated to assess CI-related symp-
tom prevalence and attribution of symptoms to specific envi-
ronmental exposures and sources. In one study the 27 most
commonly reported symptoms in CI were selected and
grouped into five symptom categories, constituting the Idio-
pathic Environmental Intolerance Symptom Inventory [9].
The Environmental Hypersensitivity Symptom Inventory
was subsequently developed for broader assessment that, in
addition to CI, covers symptoms commonly reported also in
nonspecific building-related symptom, sound intolerance and
IEI to electromagnetic fields [43]. This inventory includes 40
symptoms covering five symptom categories. Finally, the
40-item Environmental Symptom-Attribution Scale (ESAS)
is available that, with a 7-point category scale, quantifies
degree to which health symptoms are attributed to specific
environmental exposures and sources. The ESAS consists of
the Odorous/Pungent, Building-Related, Sound, and Elec-
tromagnetic Field Subscales, and has a Global Scale as well
[44]. The questionnaire instruments described above can be
most useful in epidemiological research on CI, although few
of them so far have been used in population-based studies.
Concerning consequences of odor exposure, other than
symptoms, prevalence rates of 17-19% have been found in
Scandinavian adult populations regarding annoy-
ance/affective reactions and adjustment of behavior [8, 20,
45]. The prevalence of CI appears to be somewhat lower
among younger populations. Thus, in a population-based
study of Swedish teenagers, 16% reported being bothered by
strong odors, and 3.7% were high on affective reactions and
behavioral disruptions [46]. This latter percentage for teen-
agers can be compared with a prevalence rate of 18.7% in
adults [20].
Concerning more specific consequences of odor expo-
sure, 3.3-4.5% of US and Danish adult populations report
that their symptoms influences their choice of stores when
shopping and 0.8-1.8% report having lost their employment
[8, 21, 47, 48]. Using combined cut-off scores for the
Chemical Intolerance and Life Impact Scales of the QEESI
have provided a prevalence rate for CI of 8.2% in a Danish
population sample [34] and 7.5% in a Japanese population
sample [49].
Turning to clinical criteria for CI, IEI attributed to
chemicals and MCS are of particular relevance. Although IEI
is a fairy commonly studied condition of CI, there is sparse
documentation of its prevalence. However, 6.7% of a Swed-
ish adult population-based sample [24] fulfilled criteria for
IEI [12]. Considerable more documentation is available re-
garding MCS. Prevalence rates for reporting having received
a diagnosis of MCS by a physician were 0.5% in a German
[23], 1.0% in a Japanese [49], 0.9-2.9% in two Australian
Current Rheumatology Reviews, 2015, Vol. 11, No. 2 171
[19, 50], 2.4% in a Canadian [51], 3.3% in a Swedish [24],
and 2.5-3.9% in two US [22] population-based samples. In
another study in the US the prevalence was 6.3% when in-
cluding both MCS and environmental illness [21]. In a
Swedish sample, 3.6% [24] were found to fulfil criteria for
MCS.
PATHOPHYSIOLOGY
The underlying pathophysiological mechanisms in CI
still remain disputed. A reasonable assumption would be that
a characteristic feature of CI sufferers is a particularly acute
sense of smell, but this does not seem to be the case [52-55].
Perhaps even more perplexing, several studies suggest that
CI is not characterized by higher ratings of perceptual prop-
erties, such as the intensity of an exposure [54, 56, 57].
There are, however, examples where individuals with CI rate
olfactory chemical exposure as more intense, unpleasant and
symptom eliciting, compared with controls [58]. There are
some evidence that suggest altered trigeminal reactivity,
measured by lower trigeminal detection thresholds [59], and
higher ratings of pungent intensity [52, 56, 59, 60], whereas
others have found no such effect [54, 60]. The ambiguous
sensory and perceptual deviations suggest that the commonly
used term “smell sensitivity” may not be a good descriptive
term of CI, as many sufferers seem to react to exposure that
they do not necessarily perceive as strong. It has also led
researchers to search for explanations of CI symptoms that
do not rely on assumptions of sensory deviations. Other
pathophysiological theories include the immune system,
CNS, olfactory and respiratory systems as well as altered
metabolic capacity, behavioral conditioning and psychiatric
disorders. Considering the controversy regarding the nature
of CI, the following pathophysiological review should not be
considered exhaustive but seen as an attempt to cover the
major topics presented in the literature.
Theory and Empirical Findings of Central Sensitization
Amplification of nociceptive stimuli within the CNS cir-
cuitry as a model for understanding the heightened respon-
siveness to low levels of structurally unrelated chemicals in
CI has been suggested by several experts [61, 62]. Disturbed
central pain mechanisms, which may manifest as pain hyper-
sensitivity, is a probable contributing factor in persistent
pain, and in generalized pain disorders such as fibromyalgia
[63]. Pain is also part of CI symptomatology, which together
with the symptomatic overlap with fibromyalgia, inspired
Rainville and et al. to propose pain as a relevant model for
studying CI [61]. The concept of central sensitization, which
has been defined by the International Association for the
Study of Pain as an “increased responsiveness of nociceptive
neurons in the CNS to their normal or subthreshold afferent
input”, is common in pain research and in the understanding
of the mechanisms underlying generalized pain disorders
[63]. A broad range of methods, collectively referred to as
quantitative sensory testing (QST), has been developed to
study human pain pathways, including central sensitization
[64]. The basic principle of QST is the application of soma-
tosensory stimuli that generate signals in peripheral nerve
fibers (first-order neuron), and central pathways from the
dorsal horn of the spinal cord (second-order neuron) to
172 Current Rheumatology Reviews, 2015, Vol. 11, No. 2
thalamus (third-order neuron) and further to cortical struc-
tures in the brain [65].
To the best of our knowledge, only two studies have
evaluated the functioning of central pain regulatory path-
ways in CI using QST methods. To experimentally induce
central sensitization in persons with CI, Holst et al. applied
intradermal capsaicin injection [66]. Capsaicin activates the
endings of afferent nociceptive c-fibers leading to measur-
able sensory changes such as primary and secondary hyper-
algesia, neurogenic inflammation (flare) and allodynia [67].
Their main findings were an increased area of secondary
punctate hyperalgesia in persons with CI compared to a
healthy control group, suggesting altered central pain proc-
essing in CI [66]. Tran et al. aimed to reproduce the finding
by Holst et al. and to further characterize pain processing in
CI [68]. These authors also reported findings of an enlarged
area of capsaicin-induced secondary punctate hyperalgesia in
the CI group, and increased pain sensitivity to cold pressor
pain (immersion of the hand in ice-water for 5 minutes). Ex-
amining the within-subject variability of capsaicin-induced
secondary punctate hyperalgesia in the same CI group 1 year
after the initial study, Tran et al. found smaller variability in
the CI group compared to the control group (Tran MTD et
al. Submitted manuscript). Altogether these results suggest
that the functioning of some aspects of central pain regula-
tory mechanisms is altered in CI, and that these alterations
are sustained after 1 year.
Theory of Neural Sensitization
One of the most cited models of CI is the so-called neural
sensitization theory [6, 69, 70]. Bell et al. suggest that CI
symptoms are the effect of an acquired hyper-responsiveness
that is manifested in several body systems, but with special
focus on nerves in the limbic system of the brain. The hyper-
responsiveness is assumed to go through two phases. In the
initiation phase, the organism is in a state where repeated
low or medium level or a few strong exposures cause persis-
tent changes in the function of the (nervous) system [69]. In
the elicitation phase, the hyper-responsiveness is provoked
by even very weak exposure. The sensitization is described
as non-specific – exposures that elicit symptoms do not nec-
essarily need to be the same as the initial triggering stimulus.
The suggested underlying mechanism of this spreading is
referred to as cross sensitization [6].
The neural sensitization theory defines sensitization in
several different ways. On the inferential level, Bell has sug-
gested that sensitization in CI is an expression of a patho-
logical plasticity in many functional and organ systems [71].
That is, sensitization can be observed in central structures
such as the limbic system, as well as peripherally in, e.g.
receptor cells or in the form of endocrine disruptions. Used
on this level, sensitization refers to a general disposition of
an individual, rather than an isolated, measurable process.
The model does, however, also describe sensitization in the
form of “limbic kindling”. Kindling is a form of sensitiza-
tion, and has mostly been studied in animal models where
electrical shocks to the amygdala, which initially do not
cause severe reactions, lead to full-blown seizures after re-
peated stimulations [72]. In the neural sensitization model,
kindling is defined as “permanent increases in limbic neu-
Dantoft et al.
ronal excitability and associated behaviors via repeated sub-
threshold stimulation” [70].
The neural sensitization theory is rather eclectic. It does
not require that the exposure that elicits sensitization by ne-
cessity must be chemical, or even external in nature. Both
initiating and eliciting stimuli may be endogenous – that is,
the perception of an exposure (even without an actual physi-
cal stimulus) may result in the proposed sensitization [2, 3].
Similar to the central sensitization theory, the neural sensiti-
zation model is assumed to be a valid model for other condi-
tions such as post-traumatic stress disorder, fibromyalgia and
chronic fatigue syndrome [2, 3].
Neurogenic Inflammation Theory
The theory of neurogenic inflammation has a slightly
different focus than the neural sensitization theory, as it
mainly deals with peripheral reactions and afferent nerves
[73-75]. Neurogenic inflammation is described as a patho-
logical change in peripheral C-fibers. The change is not
specified, but may involve, e.g. neuropeptide content, recep-
tor alterations, or the density of nerve fibers. When the C-
fibers are stimulated, they release neuropeptides such as sub-
stance P, calcitonin gene-related peptide and neurokinin A at
the nerve endings. Peripheral axon reflexes propagates the
inflammatory response to other peripheral sites. Signals also
reach the brain, where the inflammation is carried to yet
other parts of the body through the sympathetic and para-
sympathetic nervous system. Importantly, the neurogenic
inflammation hypothesis comes in two forms – one that ne-
cessitates an initial chemical injury, and one that does not
[73]. A working group on neurogenic inflammation has pro-
posed several testable hypotheses [73]. CI sufferers would
for instance, have increased density of c-fiber neurons in
sensitized tissues, produce greater amounts of neuropeptides
and prostaglandins, have increased and prolonged responses
to exogenous C-fiber activators such as capsaicin or CO2 and
lower trigeminal detection thresholds compared with non-ill
controls (for the complete list of hypotheses, see Bascom et
al. [73]).
Psychophysiological Studies
Studies regarding altered reactions in the CNS have
revealed that CI sufferers deviate from controls in terms of
electrophysiological outcome measures such as electroen-
cephalography [71, 76] and event-related potentials [57],
whereas other studies have found no such effects [54, 77,
78]. Using positron emission tomography (PET), Hillert et
al. revealed that individuals with CI had higher regional
cerebral blood flow (a secondary measure of neural activa-
tion) compared with controls in the anterior cingulate cor-
tex, but lower in olfactory regions [56]. Hillert et al. also
reported that women with CI had reduced serotonin 5-HT1A
receptor binding potential in the amygdala and anterior
cingulate cortex, compared with controls [79]. Another
study, using functional magnetic resonance imaging, re-
vealed that persons with CI had a higher blood-oxygen-
level-dependent signal in the thalamus and parietal brain
regions, and lower in the superior frontal gyrus during
chemical exposure [80]. Using near-infrared spectroscopy
Azuma et al. did, however, find a higher prefrontal activity
Chemical Intolerance
in CI patients during odor exposure, compared with con-
trols [81, 82]. Orriols et al. also reported differences be-
tween CI cases and controls, assessed with single photon-
emission computed tomography. Fifteen to 30 minutes after
a chemical challenge, the CI group had a greater deactiva-
tion pattern (hypoperfusion) in the brain compared with
controls [83].
Common Ground for Several Theories?
Neural sensitization and neurogenic inflammation are,
according to their authors, complementary theories, empha-
sizing hyper-responsiveness in the brain and peripheral
mechanisms, respectively [2]. In combination, the two theo-
ries have much in common with central sensitization. The
limbic and mesolimbic pathways described in the neural sen-
sitization theory are mentioned as important brain regions in
central sensitization as well [62, 69, 70]. The increased reac-
tivity of C-fibers, and the neuropeptides that is suggested to
be involved in neurogenic inflammation, overlap to a large
degree with the suggested mechanisms of central sensitiza-
tion. The key difference between the last two theories is that
central sensitization is mainly described as a process on the
spinal level, whereas neurogenic inflammation focuses on
the trigeminal nerve [62, 73].
There are other theories of CI that are remarkably similar
to those described above. For instance, the elevated nitric
oxide/peroxynitrite theory describes CI as caused by a bio-
chemical process that is initiated by exposure to organic
chemicals, which initiates a vicious circle involving exces-
sive nitric oxide/peroxynitrate and hyper-sensitive N-methyl-
D-aspartate (NMDA) receptors [84, 85]. Yet another promi-
nent theoretical framework describes CI as the result of clas-
sical conditioning [86-88].
There is a dividing line in the scientific literature be-
tween on the one, hand neural sensitization, neurogenic
inflammation, and the elevated nitric oxide/peroxynitrite
theories, and, on the other hand, the theory of classical con-
ditioning. Bell and Meggs describe their theories as “direct
biological models”, in contrast to the theory of classical
conditioning, which is described as a psychological or
psychosomatic model [2]. The differences between the
theories have been the topic of rather heated debate [89,
90]. It is, however, not that easy to separate sensitization
from conditioning – neither as general concepts nor applied
to the CI case. At first glance, it may seem like the condi-
tioning theory and those describing the putative processes
on a physiological/biological level are discussing entirely
different mechanisms. However, conditioning is an inferen-
tial construct that can (and has been) operationalized using
the markers used by the other biological theories. For in-
stance, the synaptic and molecular basis of conditioning
involves the same processes that has been implicated by
other models of CI, such as NMDA-receptor-dependent
changes in synaptic transmission [91], nitric oxide as an
important messenger molecule [92], and even the involve-
ment of pro-inflammatory cytokines, such as interleukin
(IL)-1, IL-6 and tumor necrosis factor (TNF)- [93]. It is
possible that conditioning and sensitization (in its different
forms) constitute different mechanisms. It has, however,
been difficult to clearly separate them based on observa-
tions of underlying biological processes [94] .
Current Rheumatology Reviews, 2015, Vol. 11, No. 2 173
If this view would be embraced in the CI context, then
the major theories of the affliction, even conditioning, would
pertain to similar hypothesized underlying mechanisms. The
issue would not be whether CI is a psychological or organic
affliction, but rather whether the concept under scrutiny con-
stitutes inferential constructs (such as conditioning) or meas-
urable responses (such as substance P release). The issue
may seem academic, but in the case of CI, it lies at the very
heart of the controversy. For instance, conditioning is an
important theoretical framework, but should not be inter-
preted as a causal mechanism. Arguing that conditioning is a
“psychological force” that can cause symptoms, or that CI is
“psychogenic” implies a form of reification, and is thus an
incorrect use of an inferential construct.
Genetics
The importance of genetic factors in CI etiology still re-
mains unsettled. Most studies linking genetic polymorphisms
with CI have been based on the hypotheses that an impaired
ability to metabolize chemicals play a key role in the patho-
physiology, and that an increased vulnerability to external
chemical exposures is influenced by genetic polymorphisms
of enzymes involved in xenobiotic metabolism. These genes
include the paraoxonase/arylesterase 1 (PON1) gene, differ-
ent genes of the cytochromes P450 (CYP) superfamily, ary-
lamine N-acetyl- transferase 2 (NAT2) gene, superoxide
dismutase (SOD) 2 gene, glutathione S-transferase (GST)
genes, UDP-glucuronosyl Transferase (UGT) 1A1 gene and
the aryl hydrocarbon receptor (AHR) gene. A number of
variations in these genes are known to affect enzymatic ac-
tivity in different ways [95-97]. In addition, the panic disor-
der associated gene cholecystokinin 2 receptor (CCK2R) has
been included in two studies [98, 99] due to the frequently
observed association between anxiety and CI [46, 54, 100].
Moreover, two studies have included the methylene tetrahy-
drofolate reductase (MTHFR) gene. Variations in MTHFR
can cause increased levels of homocysteine and impaired
vitamin B12 metabolism, and vitamin B12 deficiency is as-
sociated with neurological symptoms similar to those experi-
enced in CI [99, 101]. The main findings of genetic varia-
tions in CI are listed in Table 4 and summarized in the fol-
lowing;
CYP: Allelic variations in genes encoding enzymes of
the CYP family have been examined in a total of four studies
[99, 101, 102], but with inconclusive results. De Luca et al.
and Berg et al. both failed to identify any case – control dif-
ferences in CYP genes although Berg et al. did notice a non-
significant trend towards a higher frequency of more meta-
bolic active CYPD6 phenotypes [99, 103]. In contrast,
McKeown-Eyssen et al. reported increased frequencies of
the active CYPD6 genotype and Caccamo et al found both
the active CYPD6 genotype and variations in the CYP2C9
and CYP2C19 genes to be more common in CI individuals.
All together, the findings on CYP variations as risk factors
for developing CI seem like an avenue for further investiga-
tion [101, 102].
NAT2: Three studies have examined frequencies of car-
rying either a slow, intermediate and rapid NAT2 metaboliz-
ing genotype in CI cases vs. controls. One study reported
more rapid NAT2 genotypes in CI [101] corresponding to a
174 Current Rheumatology Reviews, 2015, Vol. 11, No. 2 Dantoft et al.

Table 4. Main genotype studies on CI.

Gene vari- Study population Inclusion criteria Finding Comment Source

ant

PON1 25 gulf war veterans
Q(Gln192)/ (GWR) and 20 healthy
R(ARG192) army soldiers (10 who
had been deployed and 10
non-deployed)
GWR grouped into 3 GWR more likely to carry the The inclusion criteria employed is Haley et al.
neurologic symptom PON1 R allele (QR/or RR) unique for this study and a direct [109]
complex groups comparison with other studies of
CI and genetic polymorphism is
not possible

CCK- 11 patients with CI and Symptoms of at least Increased prevalence of panic Very low number of participants. Binkley et
B/CCK2R, 11 age, gender and eth- 3 months; symptoms disorder–related CCK-B recep- Case criteria similar to Cullen’s al. [98]
DRD4 nicity matched controls in at least 3 organ tor allele 7 in CI cases criteria
receptor systems including
gene exon CNS and sensitivity
III to at least 4 sub-
stances

CYP2D6, 203 female CI individuals Criteria implemented CI had higher odds of carrying Advantage that case definition is McKeown-
NAT1, and 162 healthy female in the University of the active CYP2D6 genotype based on features from the defini- Eyssen et
NAT2, controls Toronto Health and the NAT2 rapid genotype as tions presented by Nethercott et al. [101]
PON1-55, Survey [13] and well as being PON1-55 and al. and the 1999 Consensus [15].
PON1-195, Nethercott features PON1-192 heterozygous
PON2-148 [180].
and
MTHFR
C677T

NAT2, 273 CS subjects and 248 Self-reported CS CS had higher odds of carrying Advantage that the study used Schnaken-
GSTM1, control subjects using a modified the NAT2 slow genotype or QEESI based inclusion criteria berg et al.
GSTT1 and QEESI questionnaire having homozygous deletions of and a large study population [104]
GSTP1 GSTM1or GSTT1 genes

UGT1A1 42 patients with environ-
mental disease (CI and/or
FM and/or CSF/ME).
Number of controls not
provided
Patients from a prac- Increased frequencies of the Limited information on inclusion Müller et
tice for environ- UGT1A1 *28/*28 genotype criteria, the number of study par- al. [105]
mental medicine. associated with decreased glucu- ticipants with CI and general
Diagnostic criteria ronidation in patients background characteristics.
not provided.

5HTT, 59 self-reported CI cases Self-administrated No significant differences in Used a questionnaire that asks Wiesmüller
NAT1, and 40 control subjects standardized and allelic variation between cases questions about how strongly et al. [108]
NAT2, validated CI ques- and controls. substances induce physical and/or
PON1, tionnaire [182] psychical symptoms. No questions
PON2 and into life-style consequences and
SOD2 types of symptoms experienced.
Sample size limited.

CYP2D6, 96 CI patients and 1027
NAT2, controls.
PON1-55, Population subjects were
PON1-192, stratified for severity of
MTHFR CI in 4 groups.
and CCK2R
Population subject with
lowest CI score was used
for case-control study
with CI patients. Data
from the population sam-
ple was analyzed as a
cross sectional study
96 physician- No significant difference in
diagnosed CI pa- allelic variation in case-control
tients based on Cul- comparison, but an apparent
len’s criteria. Self- trend towards more active
reported CI based on CYP2D6 alleles and less PON1-
standardized ques- 55 alleles in CI patients.
tionnaire from the CCK2R allele 21 CT was asso-
populations sample ciated with CI using the entire
population sample as controls.
More NAT2 rapid genotype was
observed in the most severe CI
group.
The study did not confirm earlier Berg et al.
associations between CI and [99]
CYP2D6, NAT2 or PON1allele
variations. In the physician diag-
nosed CI group the study did find
a trend showing similar genotype
distribution for NAT2 and PON1-
55 as reported by McKeown-
Eyssen et al. (2014).
Chemical Intolerance Current Rheumatology Reviews, 2015, Vol. 11, No. 2 175

(Table 4) contd….

Gene vari- Study population Inclusion criteria Finding Comment Source

ant

CYP2C9, 110 CI subjects and 218
CYP2C19, controls were genotyped
CYP2D6, for CYP2C9, CYP2C19,
CYP3A5, CYP2D6, CYP3A5, and
UGT1A1, UGT1A1.
GSTP1, 144 CI subjects were
GSTM1 genotyped for GSTP1,
and GSTT1 GSTM1 and GSTT1 and
results compared to pub-
lished data from a large
Caucasian population.
Cullen´s criteria and The study did not find any dif- The author states that controls are De Luca et
a modified QEESI ference in genotype frequencies age and sex-matched but demo- al. [103]
score based on ques- between CI individuals and the graphic data reveal notable differ-
tions about 10 com- control group. ences in both the age and sex
mon environmental distribution between CI (119 F/14
exposures and 10 M, mean age 49) and controls
major symptoms (105F/113 M, mean age 36).

GSTM1, 47 CI and 1037 healthy Validated Japanese No difference in allelic distribu- Authors conclude that the geno- Fujimori
GSTT1, controls version of QEESI tion was identified between CI types examine are of little impor- [107]
ALDH2 [183] subjects and controls tance for the CI population in
and PON1- Japan.
192 The study has a high proportion of
male subjects in the CI group
(87%).

CYP2C9, 156 CI, 94 suspected CI Cullen´s criteria and The study report significant Findings strongly support the Caccamo
CYP2C19, patients and 113 sex and a modified QEESI increased frequency of proposed associated between et al. [102]
CYP2D6 age matched healthy score based on ques- CYP2C9*2, CYP2C9*3, specific cytochrome P450 geno-
and controls tions about 10 com- CYP2C19*2, CYP2D6*4 and typic variations and increased
AHR554 mon environmental CYP2D6*41 genotypes in CI susceptibility to develop CI.
exposures and 10 patients and significant in- Inclusion criteria for CI are the
major symptoms creased frequency of same as in De Luca et al., (2010).
CYP2C9*3, CYP2D6*4 and
CYP2D6*41 in suspected CI
patients.

GSTM1, 329 male paper pulp Validated Japanese The study reported a significant The number of individuals in the Cui et al.
GSTT1, factory workers grouped version of QEESI association between having a high CI group was limited to 11. [106]
GSTP1, into 208 controls, 67 with [183] high QEESI score and SOD2 The study included only male
ALDH2 low CI, 38 with middle CI polymorphisms. participants.
and SOD2 and 11 with high CI.

Dopamine receptor 4 (DRD4), paraoxonase/arylesterase 1 (PON1), Cytochromes P450 (CYP), arylamine N-acetyl- transferase 2 (NAT2), superoxide dismutase (SOD) 2, glutathione
S-transferase (GST), UDP-glucuronosyl Transferase (UGT) Aryl hydrocarbon receptor (AHR), cholecystokinin 2 receptor (CCK2R), methylene tetrahydrofolate reductase (MTHFR),
CI (chemical intolerance), chronic fatigue syndrome (CFS), fibromyalgia (FM), QEESI (Quick Environmental Exposure and Sensitivity Inventory)[27].

more metabolic active enzyme. Another study reported
higher frequency of the slow NAT2 genotypes [104] in CI
corresponding to a less metabolic active enzyme, and the last
study found no allelic differences in the case – control com-
parison [99].
UGT1A1: A sequence variation in the UGT1A1 gene
associated with decreased enzymatic capacity was found to
be more frequent in CI individuals in one study [105],
whereas another study subsequently failed to show any case-
control differences [103].
GST: A higher frequency of homozygous deletions of
GSTM1 or GSTT1 genes where reported in CI cases in one
study [104], but this association could not be confirmed in
three subsequent studies [103, 106, 107]. Notable methodical
differences in selected inclusion criteria and poorly matched
controls groups challenge a direct comparison of the differ-
ent study outcomes.
SOD2: A similar challenge is present when comparing
studies investigating SOD2 gene variations in CI [106, 108]
(Table 4). Wiesmuller et al. found no genotypic differences
between self-reported CI cases and controls, while Cui et al.
found a significant association between a SOD2 gene varia-
tion and CI. The two studies utilized similar inclusion crite-
ria’s, but their study populations differed significantly on a
number of important parameters, which might explain the
contradictory findings [106, 108].
PON1: CI related PON1 polymorphisms have been in-
vestigated in five studies [99, 101, 107-109]. Two North
American studies both reported increased frequency of
PON1 variations in the CI groups [101, 109], whereas two
European studies did not reveal any abnormal PON1 allele
176 Current Rheumatology Reviews, 2015, Vol. 11, No. 2
variations in CI [99, 108]. Additionally, no PON1 allele dif-
ferences were observed in a Japanese study [107].
CCK2R: One study found an increased prevalence of the
panic disorder associated allele with 22 CT repeats [98] in
individuals with CI, but with only 11 cases and 11 controls,
the study is underpowered. The association between CI and
CCK2R was partly reconfirmed by Berg et al. using a larger
group and similar inclusion criteria (Table 4) [99].
Based on the existing research of genetic variations in
CI, it is apparent that a reproducible and biochemically
meaningful phenotype is still lacking. Although several
studies have reported differences in allelic frequencies of
suggested risk genes in CI, one explanation could be that
CI associated phenotypes do not exist. However, identify-
ing one or more associated genotypes might be complicated
by natural variations in the frequencies of risk polymor-
phisms found across different populations. In a similar
way, the specific chemical exposures encountered by a cer-
tain population may also be essential for which gene mark-
ers that will constitute a potential risk for developing CI
[99]. This adds a regional, social and cultural layer to ge-
netic testing that needs to be accounted for when compar-
ing results from different studies. The different results ob-
tained for the PON1 gene between two North American and
two European studies could be a result of this phenomenon.
As suggested by Berg et al. a future strategy could be to
subgroup patients according to reported exposures and
symptoms as well as correlated biochemical profiling. This
strategy would make it possible to include more genetically
and metabolic homogenous populations that is easier to
reproduce by other researchers [99].
Immune Mechanisms
Chemically mediated immune dysregulation or heredi-
tary/acquired immunological deficits have been studied quite
frequently in CI [74, 110-114] and immunological hyper-
reactivity mediated by low level chemical stimulation can,
hypothetically, explain the diversity of symptoms in CI
[114]. Moreover, chemical substances often reported as
symptom-eliciting in CI, such as formaldehyde, hydrocar-
bons and organochlorines have been shown to cause abnor-
mal T-cell subset ratios and altered immunological regula-
tion in humans after prolonged low-dose exposure [115]. To
this date, immunological irregularities have been reported in
several unrelated studies. The immunological parameters
have included a broad variety of measures, such as white
blood cell and lymphocyte subset counts, serum complement
and immunoglobulin characterization, and immune regula-
tory mediators [100, 103, 114, 116, 117].
In early studies, increased levels of immunoglobulins,
complement, B-cell, or T-cell subsets were reported in CI
patients, indicating immunological hypersensitivity or dys-
function [111, 114, 118-120]. Kipen et al. (1992) reported an
increased T-cell ratio (CD4+/CD8+; low proportion of CD8+)
in MCS [119], and Levin and Byers (1992) found that severe
cases of CI have unstable T-cell ratio, with erratical varia-
tions in both directions. This was found to be more pro-
nounced in the early time-course of the condition, and the
ratio stabilized below normal range with time due to in-
creased CD8+ T-cell levels [111]. Heuser et al. observed
Dantoft et al.
similar irregularities in immune parameters, most signifi-
cantly for TA1 (CD26+), with cell counts above the normal
range in 66% of those with CI [118]. They also observed
high variation in T-cell ratio in both directions, and abnormal
levels of chemical-specific antibodies [118]. Rea et al. con-
cluded from more than 20.000 individuals with CI, that al-
though laboratory findings are highly inconsistent, a com-
mon feature is different signs of chronic or recurrent non-
specific inflammation, such as positive C-reactive protein,
abnormal complements parameters, impaired blastogenesis
and depressed C-tell count, including depletion of suppressor
T-cells [120]. However, Simon et al. failed to differentiate
CI from chronic musculoskeletal disorders (assumed not to
be immunologic) on lymphocytes surface markers (CD5+,
CD4+, CD8+, CD19, Ta1/CD26+), autoantibodies and IL-1
generation [121]. Ziem and McTamney reported increased
Ta1/CD26+, CD4+ and autoantibody levels and decreased B-
cell count in CI [122]. Similar to Kipen et al., Mitchell et al.
observed increased T-cell ratio, and Baines et al. reported
higher haemoglobin concentrations and lower total lympho-
cyte counts in CI [114, 119, 123]. Despite comorbidity in CI
with IgE-mediated hypersensitivity (atopy) [100, 124], se-
rum IgE levels show no abnormality in CI, suggesting that
CI it unlikely to be caused by specific IgE or cell-mediated
allergic mechanisms [100, 118, 119, 125, 126].
Kimata was first to report increased levels of several me-
diators often associated with neurogenic inflammation in CI
subjects. The study reported increased serum levels in CI of
substance P, vasoactive intestinal peptide (VIP) and nerve
growth factor (NGF) at baseline, and increased levels of sub-
stance P, VIP, NGF and histamine after exposure to volatile
organic compounds (VOC) [117]. The authors proposed a
role of neurogenic inflammation in CI etiology and induction
of neurogenic inflammation by VOC exposure [117].
Elberling et al. demonstrated increased non-IgE mediated
histamine release from basophile granulocytes in response to
incubation with perfume among patients suffering from per-
fume-related mucosal symptoms. These findings suggest that
perfume exposure can indeed induce a non-IgE-mediated
release of histamine from immune cells [127].
Recently, among an array of 27 immune regulatory me-
diators, De Luca et al. found elevated plasma levels of three
cytokines (interferon-, IL-8 and IL-10), a chemokine
macrophage (chemotactic protein 1), and two growth factors
(platelet-derived and vascular endothelial) in CI [103]. In a
similar setup, Dantoft et al. examined plasma levels of 14
cytokines, chemokines and growth factors in CI and controls.
The results showed increased levels of pro-inflammatory
cytokines (IL-1b, IL-2, IL-4, IL-6 and TNF-) and decreased
levels of IL-13, a cytokine with several Th2 associated me-
diator functions similar to those of IL-4 as well as anti-
inflammatory properties [100]. Noteworthy, no group differ-
ences were observed in levels of the six biomarkers found
elevated by De Luca et al. [100, 103]. Although the two
studies identified conflicting biomarker profiles, their find-
ings point towards an increased inflammatory plasma profile
in CI.
In summary, immunological testing has revealed several
immunological deviations in CI. However, there are also a
number of studies showing either no or inconsistent immu-
Chemical Intolerance
nological deviations. These inconsistencies are likely to be
a consequence of the variable case definitions used and
methodological shortcomings including absence of stan-
dardized protocols [128] and lack of statistical control for
known immune modulating variables. Furthermore, the
clinical relevance of the deviations is rarely discussed or
compared to other clinical conditions with similar immu-
nological profiles. For immunological testing to be useful
either as a research tool or to be used diagnostically, the
immunological differences have to be repeatable or of a
magnitude that are not only statistically significant, but also
clinically relevant.
To conclude, while several studies have identified immu-
nological deviations in CI, it still remains unsettled whether
and how the immune system is actually involved in the
pathophysiology of CI [116, 129]. Although many of the
markers described above are part of our defense against ex-
ternal chemicals, they are also part of the reaction to endoge-
nous alterations. In the case of neurophysiological deviations
reported by Kimata (2004), the inflammatory markers re-
ported elevated can be used as operationalizations for neuro-
genic inflammation taking place, but also for conditioning,
chronic low-grade inflammation or stress [100, 130-132].
Furthermore, it is difficult to use immunological deviations
as a clear argument for or against any specific explanatory
theory, and considering the complexities of CI, it is unlikely
that unaccompanied findings of abnormal immunological
parameters can be used alone to explain the pathophysiology
of the disorder. However, the amount of positive findings
supporting an immunological aspect of CI does make the
topic worth further investigation.
Altered Metabolic Capacity
It has also been suggested that CI can arise from a ge-
netically-based or acquired difference in individual capabil-
ity to metabolize xenobiotics and endogenous toxins. In
modern society, people are continuously exposed to an ex-
tensive array of different xenobiotics of both natural occur-
rence and industrially fabricated, and it is obvious that the
level and nature of exogenous exposures differ considerably
from what our ancestors would have encountered. Some of
the xenobiotics encountered are harmful, others completely
benign, and over time specialized metabolic pathways have
evolved to handle, detoxify and eliminate xenobiotic toxi-
cants as well as maintain homeostasis of toxic endogenous
metabolites [103, 133]. This system relies on optimal regula-
tions of an array of “stress responsive genes” coding for en-
zymes of the cytochrome P450 superfamily, uridine 5'-
diphosphate glucuronosyltransferases, catechol-O-
methyltransferase and glutathione S-transferases, just to
mention some. Consequently, it is recognized that the same
level of exposure to a chemical compound may give rise to
different biologic effects in different individuals. A reduced
capacity of the system is known to increase oxidative stress
with negative impact on general health, and dysfunctions of
the system correlates with the symptomatic pattern of CI
[133, 134].
Most studies investigating this possible mode of action
have tried to link genetic polymorphisms in genes encoding
enzymes of the metabolic partway with CI, as discussed in
Current Rheumatology Reviews, 2015, Vol. 11, No. 2 177
the genetics section and summarized in Table 4. Recently,
one study has pioneered in this area and provided the first
biochemical evidence pointing towards metabolic dysfunc-
tion in CI. The group assayed an array of metabolic blood
parameters in CI subjects and controls, and reported multi-
ple abnormalities comprising significantly altered activity
of key redox active and detoxifying enzymes as well as
increased nitric oxide production and glutathione depletion,
a pro-inflammatory cytokine plasma pattern and decreased
erythrocyte membrane polyunsaturated fatty acids compo-
sition and accelerated lipid oxidation [103]. The authors
proposed that these deviations were signs of a decreased
xenobiotic metabolizing capacity, thereby impairing the
body’s chemical defensive system, and that oxidative stress
and dysfunction of chemical defenses may play an essential
role in the etiology of CI. They also suggested, that the
increased vulnerability toward xenobiotic exposures is
more likely to be a result of epigenetic modifications in
gene expression levels than a consequence of an inherited
genetic susceptibility [103]. However, since experimental
and clinical evidence supporting this hypothesis is still
sparse, and have not been replicated, the role of altered
xenobiotic metabolism in CI needs to be elucidated further
in the future. The area would benefit from additional case-
control studies focusing on both genetic and blood bio-
markers involved in metabolism of xenobiotic and toxic
endogenous metabolites.
Do the Empirical Data Corroborate the Theories?
Several studies reveal significant differences between CI
sufferers and healthy controls in several domains, e.g. per-
ceptual, neurophysiological and immunological reactions. If
the results hold, an important question is what model they
corroborate. This is actually a problematic issue, as some
aspects of the theories are so broad that they cannot easily be
disproven. For instance, all theories described above assume
some kind of response amplification over time involving the
CNS [73] or limbic systems [70, 135, 136]. It is, however,
difficult to imagine a symptomatic state, caused by any dis-
ease or stressor that does not involve heightened reactions in
the brain or limbic system. Additionally, as most theories
share operationalizations, results from empirical studies ar-
guably corroborate all theories. For instance, if empirical
observations reveal that the reactions of the limbic system
deviate from that of controls, proponents of all theories can
use this as an argument that their model of CI is correct. This
is actually not only true for neurophysiological data. The
same argument can be made for, e.g. perceptual and immu-
nological deviations as well.
The above should not be interpreted as criticism. The
same issues characterize many other theories of disease, es-
pecially those where a causal mechanism has not been ob-
served [17]. It can, however, be read as a suggestion for fu-
ture scientific endeavors to downplay the differences be-
tween explanatory theories, if they cannot be separated on
the operational level. One of the main hurdles for CI suffer-
ers, or for that matter researchers and clinicians, is the in-
flamed discussion on the relationship between psyche and
soma. If this dichotomization can be replaced by a different
nomenclature, much would be gained.
178 Current Rheumatology Reviews, 2015, Vol. 11, No. 2
RISK FACTORS
Demographics
Despite the often held view that CI sufferers constitute a
heterogeneous group, which is likely due to the current lack
of etiological and pathophysiological understanding, and
thus poor delimitation of the disorder, demographic data of
CI has been quite consistent. A preponderance of women
among CI sufferers is almost consistently reported in popula-
tion-based studies [8, 20-23, 137, 138]. The effect of age on
CI is less clear, but epidemiological studies have reported
that persons above 60 years of age report less CI when com-
pared with other age groups [8, 18, 45]. Andersson et al.
conducted a study on the prevalence of CI in teenagers, and
found that this age group reported CI to a much lesser degree
than adults [46]. Almost three times as many in the age
group of 20 – 29 year, compared to the teenagers, reported
CI, i.e. “are you bothered by strong odors” [46]. Only little is
known about CI in children as only two case reports on the
subject have been published [139, 140]. Overall, these find-
ings suggest that CI may develop across the life span with a
minimized risk above 60 years of age. Socio-economic class
may possibly be a factor to consider as CI was found to be
more prevalent in low compared to high socio-economic
class in a Canadian [51] and an Australian [50] population-
based sample, whereas no difference in this respect was
found in an American sample [48].
Cognition and Emotional Regulation
A rather large number of studies point to an association
between CI and both trait and state anxiety in clinical as well
as non-patient groups, and it has been hypothesized that
anxiety is involved in various phases of CI [52, 54, 141-
143]. It has been suggested to constitute a dispositional vul-
nerability, and thereby facilitate development and contribute
to persistence of the condition [142]. As an example, Papo et
al. reported significantly higher trait and state anxiety in pa-
tients with CI compared to a healthy control group and a
group with self-reported CI [54]. However, no significant
differences were found on anxiety measures between the
control group and the group with self-reported CI, which led
the authors to suggest that a moderate degree of anxiety may
be characteristic of CI patients [54]. In a study including 38
healthy persons Orbaek et al. reported that trait anxiety in-
fluenced ratings of mucous membrane irritation, fatigue and
symptoms of environmental sensitivity in response to ex-
perimental chemical exposure [144]. In another study, a
group with high level of distress, compared to a group with
low level of distress, reported more symptoms and showed
poorer cognitive performance in response to chemical expo-
sure [145]. Findings of cognitive bias in CI [57, 146], e.g.
difficulty ignoring chemical stimuli, whereby attentional
priority is given to thoughts related to fear and somatic
symptoms, lends further support to a role of anxiety [147].
Bailer et al. hypothesized that CI is largely determined by a
self-perpetuating cycle of increased attention to environ-
mental factors and bodily sensations that result in biased
symptom perception and amplification [141]. Somato-
sensory amplification was initially described by Barsky et al.
as a mechanism in the maintenance of symptoms in func-
tional somatic disorders [148]. Bailer et al. reported signifi-
Dantoft et al.
cantly higher scores on measures of trait anxiety and symp-
tom attribution style when compared to a healthy control
group, whereas the CI group did not deviate from a somato-
form disorder group [141]. Two other studies have reported
an association with somato-sensory amplification [149, 150].
Altogether existing evidence supports a role of cognitive
factors and emotional regulation in CI, but whether suscepti-
bility to sensitivity reactions is a predisposing factor or
merely act as an amplifying factor remains to be clarified.
Psychiatric Co-morbidity
Psychiatric co-morbidity in CI is often reported, and fre-
quently in terms of major depression, somatoform disorders,
anxiety or panic disorder [151]. For example, Bell et al.
evaluated 28 middle-aged women with CI, and 68% of the
women reported a past diagnosis of depression, anxiety or
panic disorder. In contrast, 20% of a healthy control group
reported having past psychiatric diagnoses [149]. With the
aim of characterizing health complaints relevant for CI, 251
environmental outpatients were examined using a standard-
ized psychiatric interview (CIDI) [152]. Compared with a
general population group, environmental outpatients had
significantly higher rates of life-time psychiatric disorders,
and 76.5% compared with 36.9% of the general population
group fulfilled diagnostic criteria for at least one psychiatric
disorder (12-month prevalence). Psychiatric disorders pre-
existed their CI in the majority of the environmental outpa-
tients. Longitudinal data on CI are sparse, and the associa-
tion with psychopathology has largely been studied in cross-
sectional designs using self-report measures. In the evalua-
tion of the prevalence of psychiatric co-morbidity in CI, dif-
ferences in case definitions, study populations and self-report
measures should be taken into consideration since it may
question the comparability of data across studies. Some
authors have even cautioned against administering psycho-
logical or psychiatric tests to individuals with a poorly un-
derstood condition such as CI [153]. They argue that symp-
toms of psychopathology may be secondary to the condition
and that both research and treatment strategies may be pre-
maturely directed. In addition, evidence of efficacy of cogni-
tive or psychotherapeutic interventions and psychopharma-
cological drugs in CI is still needed [154].
Sociocultural Factors
Smeets and Dalton have proposed a model suggesting
that negative expectations of a health risk attributed to
chemical exposure may trigger a state of arousal and associ-
ated emotions such as anxiety, causing a behavioral response
in terms of aiming to avoid potential harmful effects of the
exposure [155]. That such beliefs about exposure risks may
influence reports of symptoms is supported by several stud-
ies [155-157]. Dalton and others have shown that persons
who are told that a chemical exposure is harmful report
symptoms to a greater degree, report the odor exposure to be
more unpleasant, and perform poorer on a cognitive task
than those who have been neutrally or positively biased to
the same exposure [158, 159]. Claeson et al. conducted a
study among a random sample of 1, 118 people living near a
biofuel facility in Southern Sweden [157], and found a statis-
tically significant association between perception of health
Chemical Intolerance
risk, annoyance, e.g. emotions and attitude towards the expo-
sure, and symptoms. Actual exposure levels were estimated
as being far below toxicity [157]. These results suggest that
at least some aspects of CI may be mediated by perceived
health risk related to chemicals.
TREATMENT MODALITIES, COPING AND SOCIAL
SUPPORT
The current lack of knowledge on CI extends to the ques-
tion of how to approach treatment. Evidence-based treatment
options are currently unavailable, but nevertheless highly
needed in light of the disabling consequences of CI. Mind-
body therapies have been tested in randomized trials, but so
far the effects have been limited [160-162]. A few case re-
ports have been published, whereof one described a positive
effect of electroconvulsive therapy [163], and others have
reported successful outcomes using selective serotonin reup-
take inhibitors [164] and/or desensitization therapy [165] or
pulsed electromagnetic fields (PEMF) [166]. In the case of
PEMF a randomized double-blind, placebo-controlled trial
has been conducted [68], which suggested some effect on
symptom severity (Tran MT et al. submitted manuscript).
Interestingly, post-hoc analyses revealed a reduction in cap-
saicin- induced secondary hyperalgesia in those who re-
sponded to the PEMF treatment, which may suggest that the
observed effect can be explained by PEMF acting on mecha-
nisms in the CNS. However, while these results are indeed
promising, more studies are needed to elucidate the neural
basis of PEMF.
Undoubtedly, more research is needed in terms of how to
approach treatment for CI. Based on the present knowledge
of the heterogeneous nature of CI in terms of symptoms,
symptom-eliciting exposures and probably also the relative
contributions of other factors, it may be argued that future
studies in this field must attempt to subgroup patients in or-
der to target more specific probable pathophysiological
mechanisms, e.g. central sensitization. Thus more individu-
ally tailored treatment approaches may be needed. Published
reports from treatment facilities specializing in CI and re-
lated disorders are few. Sampalli et al. have published sug-
gestions for a person-centered care model to improve health
outcomes in CI based on their experiences with these pa-
tients at the Nova Scotia Environmental Health Centre [167].
One of the major challenges identified by the authors is for
the patients to come to terms with the limited effectiveness
of current treatments for their various symptoms and to ac-
cept responsibility for self-management [167]. The model
proposed by Sampalli et al. offers a multidisciplinary ap-
proach where assessments of new patients by all involved
professional disciplines, i.e. physicians, psychologists, social
workers and dieticians, concludes in individualized care
plans [161]. Evaluations of the effects of this approach have
been promising, showing reduced numbers of physician vis-
its and decreased healthcare costs [167].
What can be done until more is known about effective
treatment for CI? A way to alleviate the discomfort is by
means of coping strategies and social support. Results from
qualitative [168-172] and quantitative [173] studies suggest
that persons with CI to a large extent use avoidance of the
chemical exposure as well as support from predominantly
Current Rheumatology Reviews, 2015, Vol. 11, No. 2 179
peers to cope with their intolerance. However, it has been
reported that persons with CI perceive the extent of social
support as lower than those of most other ill-health samples,
and show considerable variability [174]. Other commonly
used coping strategies in CI are detoxification and emotional
self-care [175]. In accordance with previous studies, results
from a study of 182 persons with CI show that avoiding
chemical environments and asking persons to limit their use
of odorous substances are the two most commonly used and
perceived as the most effective problem-focused coping
strategies [176]. Regarding emotion-focused strategies, ac-
cepting the situation and reprioritizing importance of differ-
ent things are the most commonly used, and those perceived
as the most effective. With respect to social support, indi-
viduals with CI perceived being provided with more emo-
tional (understanding) than instrumental (practical help) and
informative (help with information) support, and that the
support was provided predominantly from the partner and
other family members [176]. Although avoidance of chemi-
cal exposure can be considered an effective strategy for im-
mediate improvement, it is possible that it will aggravate the
symptoms in the long run. Among patients with CI who in a
study were advised to avoid specific chemical substances
under an average period of two years, only 4% improved
whereas 44% got worse [177]. With this in mind, emotion-
based strategies, such as accepting the situation and repriori-
tizing may possibly be more useful. However, more longitu-
dinal studies are needed to improve understanding of long-
term effects of coping and social support.
CONCLUSION
Coping with CI can be a daunting endeavor for the suf-
ferer and the current lack of a medical explanation often
leaves the patient to face the consequences of the illness
alone. In this review, we have aimed to provide a detailed
overview of the current status of research in this field, high-
lighting the studies that have shown the most promising pro-
gress towards an understanding of the pathophysiological
mechanisms underlying CI, as well as the most cited theo-
ries. It is, however, striking how limited positive effect these
findings have had for the patients battling the negative con-
sequences of CI on a daily basis. Since CI does not have a
medical definition, persons with CI are often met with skep-
ticism and experience being at a disadvantage when dealing
with the healthcare system and authorities. This lack of ac-
knowledgement is obviously a serious issue, and is by some
sufferers described as the aspect of CI which is most difficult
to deal with. From the perspective of the medical commu-
nity, practitioners often find it difficult to meet the needs of
the CI patients and often adopt a pragmatic approach in ad-
vising them to avoid problematic exposures being the only
tool they have available. In a similar manner, the ongoing
debate whether CI should be classified as a physical, somato-
form or psychiatric disorder seems fruitless or even damag-
ing in the process of designing future multifactorial person-
centered treatment and management solutions to ease the
degree of symptoms experienced by CI suffers and to im-
prove overall life quality.
In order to improve health care and gain a better under-
standing of CI and the underlying mechanisms, additional
research aiming to describe the pathophysiology of CI using
180 Current Rheumatology Reviews, 2015, Vol. 11, No. 2
a multifactorial approach is needed. And as CI is most likely
a result of an interplay between physiological and psycho-
logical factors the field would benefit from an increased col-
laboration between interdisciplinary groups approaching this
challenge without any strong pre-assumption of the underly-
ing modes of action. The area would also benefit from epi-
demiological studies examining selected physical, biochemi-
cal, psychological and sociological parameters that together
could reveal so far overlooked associations and interplays
between the included parameters. Additionally, as CI suffers
constitute a heterogeneous group examining clearly defined
subgroups may be the way ahead. Accumulated, longitudinal
interdisciplinary measures and subgroup analysis could pro-
vide essential knowledge in order to gain a deeper under-
standing of the course of the condition and help designing
better and more personalized health care and social support
for CI sufferers.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
This study was supported by grants from the Swedish
Council for Working Life and Social Research (2011-0396),
the Swedish Foundation for Humanities and Social Sciences
(M14-0375:1) and from the Danish Ministry of the Envi-
ronment.
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Accepted: June 11, 2015