臨床環境医学（第25巻第2号）

49

ReviewChemical Sensitivity-The Frontier of Diagnosis andTreatment
Kou Sakabe1, 2, 10), Minoru Kimura3, 10), Hayato Terayama1), Masashi Tsunoda4, 10),
Eriko Miyajima4, 10), Hirohisa Takano5, 10), Kenichi Azuma6, 10), Atsushi Mizukoshi6),
Tetsuya Matsuda7, 10), Chisato Mori8, 10), Satoshi Kawakami9), Mikio Miyata2),
Satoshi Ishikawa2), Yoshiharu Aizawa2, 4, 10)1) Department of Human Structure and Function, Tokai University School of Medicine
2) Environmental Medical Center, Kitasato Institute, Kitasato University3) Department of Molecular Life Science, Tokai University School of Medicine
4) Department of Hygiene, Kitasato University School of Medicine
5) Department of Environmental Engineering, Graduate School of Engineering, Kyoto University6) Department of Environmental Medicine and Behavioral Science, Kinki University Faculty of Medicine
7) Brain Activity Imaging Center, Tamagawa University Research Institute8) Department of Bioenvironmental Medicine, Graduate School of Medicine, Chiba University
9) Division of Oral and Craniofacial Anatomy, Graduate School of Dentistry, Tohoku University10) Chemical Sensitivity Study Promotion Committee, The Japan Ministry of the Environment

Abstract
The history of chemical sensitivity (CS) concept is quite old; it was established in the 1950s as part ofthe environmental illness. Following this, in the beginning of 1980s various respiratory symptoms withinduced inhalation, such as perfume inhalation, were identified through many reported cohort studies.
Thereafter, CS was relabeled as multiple chemical sensitivity (MCS). This was introduced in Japan in
the 1990s, but standardized diagnostic criteria or diagnostic guidelines were not yet established at thetime. However, despite the presence of CS symptoms in patients, the actual pathogenesis has not yetbeen developed, and the management of this condition will differ significantly depending on the medicalinstitution. As a biggest season for that, we would like to report on the considerable difficulty in establishing the causal relationship between exposures to small amounts of chemical substances in the environment compared to large amounts. Therefore, establishing and standardizing highly specified
objective diagnostic parameters is required. In this paper, we propose a scientific approach to the management of CS, by introducing the latest developments in diagnosis and treatment and provide insight
into requirements for future study.
《Key words》chemical sensitivity, olfactory stimulation, olfactory response, psychological-somaticsymptoms, methods of objective examination

Received 2016.29.Jan. Accepted 2016.27.Sep.
Corresponding Author: Kou Sakabe
Department of Human Structure, Tokai University School of Medicine
Shimokasuya 143, Isehara, Kanagawa 259-1193, Japan

50Ⅰ Introduction

Jpn J Clin Ecol（Vol.25 No.2 2016）

Chemical sensitivity (CS) is considered to be a
syndrome causing a variety of indefinite complaints due to contact with a very small amountof chemicals in the surrounding environment.
The definition by Cullen MR1) from Chicago
University is general and concludes as follows:“Group of clinical syndromes which are observed
after re-contact with the chemical substances ofa fairly small amount and the same quality as
chemical substances being in contact with thepatient over a long period or caused poisoning
symptoms in the past.” In other words, a patientdevelops hypersensitivity to the chemicals suchthat exposure to very small amounts in future
may cause a reaction.
The main symptoms include the following: 1)
mucous membrane irritation such as airway
hyper-reactivity; 2) headache, and dizziness,such as a somatoform autonomic dysfunction
and nausea; 3) neuropsychiatric symptoms and4) worsening of existing allergies. Although
there are a wide variety of organs being influenced differently, olfactory hypersensitivity isobserved in the majority of cases.
In addition, similarities to chronic fatigue
syndrome and fibromyalgia have been reported;some scholars have even described it as the condition of the Gulf War syndrome2). Many uncertainties regarding the relationship between avery small amount of chemical substance revelation and various malaises, but the psychosomatic stress caused by the syndrome may
significantly affect the psychosomatic relationand the course-outcome of this disease. It is
important to evaluate appropriately the influence of different stress factors on the patient’s
daily life3). The diagnosed cases were studied indetail from the standpoint of psychosomatic
medicine; regarding the onset, the possibility
that psychosocial stress may also influence thesymptoms along with chemical substances wassuggested, but the personality characteristics orstress coping-style were not taken into account.
It was assumed that those who developed thedisease did not have specific tendencies.

However, after a variety of mainly physicalsymptoms were observed, it was found that, inmany cases, the disease co-exists with mental
illness. That is to say that there is a close relation between the body and the psychologicalcondition3). In this paper, we summarize thelatest trends on unknown medical aspects ofthis disease, and we organized them to assist in
developing measures for the future.

Ⅱ Pathophysiology
In Japan, a recent large-scale epidemiologicalstudy reported4) that about 7.5% of the population has CS. Meggs WJ from the University ofSouth Carolina reported that 35% of the population is diagnosed with allergies, and 14% of
these allergic patients have CS in the UnitedStates5), with similar statistics in Japan.
Regarding the pathophysiology, there are still
many unknowns, and the rate of bronchialasthma, allergic rhinitis, and atopic dermatitis
co-existing with any of the allergic diseases suchas urticaria is very high at about 60-80%, which
is much higher than the rate of 30% for typicalallergic diseases in Japan6). Consequently, thepathophysiologically relevant responses of theimmune system to the allergic reactions weresuggested as follows7): 1) the critical form, 2)
skin, mucous membrane symptoms, and 3) the
effect of cause avoidance of substances. These
are the same for the CS disease and allergy. In
other words, immune sensitivity is strongly
associated with individual susceptibility at thedisease onset. Additionally, this disease is characterized by olfactory hypersensitivity symptoms8, 9), the limbic system relation andcharacteristic dysfunctions as expressed bypatients10). Thus, it is easy to imagine that CS
depends to some extent on the genetic or biochemical individual differences in chemical
metabolism. Based on this information,
Matsuzaka et al studied the genetic backgroundand 7 enzymes to understand the difference indetoxification enzymes of people who wereexposed to environmental chemicals and had
not contracted the disease, but they found臨床環境医学（第25巻第2号）

none11). However, a recent study investigatedpatatin-like phospholipase (PNPLAs) genes
which may influence the evaluation of sensitivity. The neuropathy target esterase (NTE)enzyme belonging to the PNPLA6 gene family
code is present in the nervous system (in thebrain) and the immune system (in lymphocytes);
it is involved in choline production and related
to the delayed impact of organophosphates. In
tracing exposure to environmental chemicals,
there is a difference in enzyme activity between
the group of people who developed the symptoms and those who did not, and a tendency was
found that the enzyme activity of Peripheral
Blood Mononuclear Cells (PBMCs) was high in
people in the highly sensitive group12). Moreover,regarding finding a genetic polymorphism associated with NTE enzyme activity, the result ofthe correlation analysis between NTE enzyme
activity and NTE genetic polymorphism in preparative lymphocytes from peripheral bloodindicated that the population with the genotype
A/A in the genetic polymorphism (rs480208)
which exists in intron21 of the NTE gene hadsignificantly lower NTE enzyme activity12).
Regarding the pathogenesis, the molecular biological approach is expected to be developed inthe future.

Ⅲ Clinical symptoms
Agricultural chemicals, exhaust gas, building
materials, products and furniture made withbuilding materials, volatile organic compoundsof daily necessities, combustion gas or heating,daily necessities (styling agents, perfumes, andsoftener), and others are included among substances that cause symptoms. Any contact witheven an extremely small amount of the substances listed above, which are tolerated byhealthy people, may cause symptoms for people
who have CS. Reactive symptoms include olfactory hypersensitivity, including irritation of theeyes, nose, and throat, erythema, itching of theskin, easy fatigue, headaches, poor concentration, dizziness, nausea, and others; there arealso a variety of non-specific symptoms along51

with autonomic symptoms13). In severe cases,
those with CS may also exhibit strong neuropsychiatric symptoms. Standardized diagnostic
criteria and diagnostic guidelines have yet to beestablished, but using the "Chemical Sensitivity:
Agreement of 1999" is convenient14). After rulingout other organic diseases which could explain
varying symptoms, the following six items areleft:(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 inmanifestations of the syndrome.
(4) ‌The symptoms improve or resolve when
the irritants are removed.
(5) ‌Responses occur to multiple chemicallyunrelated substances.
(6) ‌Symptoms involve multiple organ systems.
The paper to which Miller refers15) as theQuick Environmental Exposure Sensitivity
Inventory (QEESI) is used for auxiliary diagnosis. Scoring includes subjective symptoms (100points), intolerance scores against chemicals(100 points), and a masking score (10-pointscale); forty points and 4 points, respectively,
are the cut-off values. This is suitable for obtaining information about the resistance against
symptoms and chemical appeal of patients, andis useful for the initial diagnosis as well as tounderstand the conditions elapsed.

Ⅳ Clinical examination
Although auxiliary diagnosis for CS alreadyexists, objective examination leading to definitive diagnosis of the disease is not yet present.
However, based on the fact that many patientscomplain of unpleasant symptoms due to "olfactory hypersensitivity", evaluation methods ofthe olfactory pathway and limbic system in thebrain have attracted recent attention. Azuma etal16) compared the variation of cerebral bloodflow rate during odorous substance reaction inpatients with CS using common olfactory test
kits and near-infrared spectroscopy (NIRS)Jpn J Clin Ecol（Vol.25 No.2 2016）

52

Topographical maps of average scores for oxyHb between
patient with ＣＳ and controls (Ref.16)
Blood FlowControlsChemical Sensitivity
JCNO
JC: Japanese cypress
NO:non-odorantWith kind permission from Springer Science and Business Media:
Environmental Health and Preventive Medicine, 20(3):185-194, Azuma K. et al. Figure 4,
The Japanese Society for Hygiene 2015 (Adapted by author).
Figure 1(Figure 1). In patients with CS, the site of brain
blood flow at the time of recovery is when
odorous substance is loaded, load at the time ofthe prefrontal cortex (PFC), recovery at the timeof the orbitofrontal cortex (OFC); it has been
proven that this part has been strongly activated in patients with CS compared to healthy
individuals.
Additionally,accordingto17)
Chiaravalloti et al , the glucose consumption
in the cerebral cortex of each part during olfactory stimulation, has revealed different patterns in patients with CS and healthy
individuals.

Ⅴ Course, treatment and prognosis
There are many examples of poor prognosis inCS. In particular, regarding occupational exposure, if a history of poisoning symptoms in
response to the high concentration of chemical
exposure is present then the prognosis is poor; along period of time from the first visit to theavoidance of chemical exposure results in a poorprognosis. As noted above, since there are many
unknown aspects of the pathophysiology, specialized treatments for this disease have notbeen established. At the moment, the mosteffective remedy is to avoid the causative agent
that is believed to induce symptoms. Since there
is a high co-existence rate of allergic disease
with CS, it is also necessary to enhance the QOL
to fully control the allergic symptoms. In addition, since the co-existence rate of mental illness
with CS is as high as 80%, a psychosomatic andpsychiatric approach is also effective3).

Ⅶ

Future prospects

CS usually presents as a reaction to a small
amount of chemicals which would not induce
any toxicological effects. It is generally a disease
exhibiting the various symptoms, as defined

臨床環境医学（第25巻第2号）

above. In addition to the diversity of developmental factors, and the onset of symptoms andseverity, a method for diagnosing the disease isstill being established. Since it is the “smallamount effect” of chemicals, because of the socalled concept of addiction, it is difficult todescribe the conditions (dose-response relationship); additionally, individual differences are
considerable at the same time and certain tendencies for the patient are difficult to understand. In this paper, the disease was generally
described in the following question-answer
form, which is the subject theme of pros andcons: 1) Can CS be considered as a chemical
hypersensitivity, a mental illness, or otherwise?
2) Do the chemical exposure and appearance ofsymptoms match? 3) Can the allergic mechanisms incidentally be explained? 4) Do differences exist in gene analysis? We focused onthese questions and others.
According to recent research, 1) in groups ofpatients and healthy people, there is a possibility that differences from the brain physiology
point of view may appear, so, for the future, it isvery important to deepen the knowledge of thepsychosomatic approach if possible, and, 2)
when this disease is treated from the immunological aspects, the relationship between someimmune responses, mainly pathophysiologicallyallergic reactions, are strongly suggested to beclarified; 3) individual differences cause chemical sensitivity; it can be mentioned that geneticfactors (genomic information) are deeply
involved, so, in the future, focused basic researchis required with respect to these points, as it
would allow for the promotion of interdisciplinary clinical research.

Acknowledgement
This study was financially supported by ahealth science research grant (H25-5962, K.
Sakabe) from the Japan Ministry of theEnvironment and a Grant-in-Aid for Health andLabor Sciences Research Grand (H25-008, K.
Sakabe) provided by the Japan Ministry ofHealth, Labor and Welfare. This study was also53

financially supported by a Grant-in-Aid for
Scientific Research (ID: 25340050, K. Sakabe)provided by the Japan Ministry of Education,
Culture, Sports, Science and Technology.

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要約

化学物質過敏症の疾患概念の歴史はかなり古く、1950年代では、環境病（Environmental illness）の一つとして、概念的に捉えられていた。その後、1980年代に入り、化学物質曝露により主として呼吸器症状を呈した後 , 香水などの吸入に誘発されて多彩な症状を呈する一群の症例が数多く報告され、化学物質過敏症、あるいは多種化学物質過敏症（Multiple Chemical Sensitivity, MCS）と命名された。本邦においても、1990年代に紹介されたが、未だ標準化された診断基準・診断ガイドラインの作成・確立までには至っていない。しかしながら , 化学物質過敏症状を訴える患者が存在することは明らかであるにも関わらず , その病態解明が未だ進展していないために , 取り扱う臨床家・医療機関によって患者への対応は大きく異なっているのが実状である。 その最大の理由として , 環境中の大量ではなく , 極めて微量な化学物質との因果関係の証明が非常に困難であることがあげられる。そのため特異度の高い客観的な診断パラメータの抽出とその標準化が不可欠となっている。そこで本稿では、化学物質過敏症に対する脳科学的アプローチはじめとして、本症に関する診断と治療の最新動向を紹介し、今後のあるべき方策について提案した。
《キーワード》化学物質過敏症、嗅覚刺激、嗅覚応答、心身相関、客観的検査法