488

Journal of Health Science, 57(6) 488–496 (2011)— Review —Immunotoxic Effects of Trichloroethylene andTetrachloroethylene
Makoto Seo,∗, a, b Ryo Kobayashi, b and Hisamitsu Nagase ba

Department of Biochemistry, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Iruma-gun, Saitama 350–
0495, Japan and b Laboratory of Hygienic Chemistry and Molecular Toxicology, Gifu Pharmaceutical University, 1–25–4 Daigakunishi,
Gifu 501–1196, Japan(Received September 6, 2011)

Allergic diseases have been increasing worldwide in industrialized countries. The interplay of genetic andenvironmental factors is involved in the induction and progression of several types of allergic diseases. Recently,
there have been many reports that the increase and spread of allergic diseases are related to chronic exposure toseveral environmental pollutants, such as diesel exhaust particles and formaldehyde. Trichloroethylene (TCE) andtetrachloroethylene (PCE) are categorized into chlorinated organic compounds, and are the most widely used extensively in various industrial processes. As a consequence of their widespread use, TCE and PCE are becoming
environmental pollutants. Generally, TCE and PCE exposure causes organ toxicological effects on the liver, kidney,
and the central nervous system; however, studies of TCE and PCE exposure-induced immune modulations are limited. In this review, we summarize research into immunotoxic effects, such as allergy hypersensitivity, autoimmune
disease, and immunosuppression, of TCE and PCE from experimental animal studies and human epidemiologicalstudies.
Key words —— trichloroethylene, tetrachloroethylene, immunotoxic effect, allergy, autoimmune disease

INTRODUCTION
Allergic diseases have been increasing in westernized countries1) and are caused by both genetic
and environmental factors.2, 3) Recently, there havebeen many reports that environmental pollutants,
such as diesel exhaust particles and formaldehyde,interact with the immune system and, in humans
and experimental animals, have also been shownto cause immunological changes and to increase
several allergic diseases.4–10) There may be several reasons for this, including increased allergen
exposure levels and exposure to allergy-promoting(adjuvant) chemicals and environmental pollutants.
Therefore, to increase allergic sensitization, an increase in allergen-specific IgE in humans and in animal studies may be used for hazard identificationof an adjuvant chemical effect.
∗

To whom correspondence should be addressed: Department of Biochemistry, Faculty of Medicine, Saitama Medical
University, 38 Morohongo, Moroyama, Iruma-gun, Saitama
350–0495, Japan. Tel. & Fax: +81-49-276-1155; E-mail:mkt.s.lev5060@gmail.com

Several chlorinated organic compounds are wellknown to disturb the central nervous system and induce changes in the parenchymal organs, especiallythe liver and kidneys.11, 12) High levels of exposure
to chlorinated organic compounds are mainly responsible for toxic effects,13) whereas moderate exposure induces inflammatory responses.14)
Among all of the chlorinated organic compounds, trichloroethylene (TCE) and tetrachloroethylene (perchloroethylene; PCE) are themost widely used extensively in various industries, such as metal degreasing processes, drycleaning agents, paint removers, and componentsof adhesives and lubricants. As a consequenceof their widespread use, TCE and PCE are becoming environmental contaminants and arefound in groundwater, drinking water, soil, andindoor/outdoor air in the U.S.A.,15–18) and inappropriate waste disposal has been associated withlinkages and emissions that are potentially harmful
to human health and the natural environment.19, 20)
The main exposure routes of TCE and PCE are
inhalation (e.g., indoors and outdoors), ingestionC 2011 The Pharmaceutical Society of Japan

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Table 1. Animal Studies of Allergy and Hypersensitivity
Authors
Seo et al.
(2008)
Seo et al.
(2008)

Speicies
rat

Kobayashi et al.
(2010)
Tang et al.
(2002, 2008)
Chen et al.
(2005)

mice

rat

guinea pig
swine

Experimental method
Intraperitoneal treatment with TCE
and PCETCE (0.3, 3 mg/ml) and PCE (0.1,
1 mg/ml) exposure from drinking water for 2 and 4 weeks
TCE (0.3, 3 mg/ml) exposure fromdrinking water for 2 and 4 weeks
TCE and TCE metabolize intradermal injection
TCE and PCE exposure for swine trachea directly(e.g., contaminated drinking water, breast milk,
and daily products), and dermal absorption (e.g.,bathing in contaminated water). Chronic exposure
to TCE and PCE is accompanied by many severe
toxicological and pathological problems. The general toxic effects of their exposure are associatedwith disturbances in the central nervous systemand changes in the parenchymal organs in theliver and kidneys.21–23) Recently, there has been
increasing epidemiological and clinical evidence
that chronic exposure to several environmental
pollutants at levels too low to be overtly toxic canharm human health by altering immune function.
Adverse effects on the immune system resulting
from environmental pollutants exposure fall within
the following immunotoxic effects: allergy hypersensitivity, autoimmunity, and immunosuppression(host resistance). In this review, we summarize theresearch into the immunotoxic effects of TCE and
PCE from experimental animal studies and humanepidemiological studies.

ALLERGY AND HYPERSENSITIVITY
Animal Studies
Evidence of the increasing effect of allergy
and hypersensitivity by TCE and PCE exposure
is limited (Table 1). Seo et al. examined the effect of several chlorinated organic compounds on
histamine release and inflammatory cytokines production from antigen-stimulated rat mast cells.24)
TCE and PCE exposure significantly increased histamine release and inflammatory cytokines, interleukin (IL)-4 and tumor necrosis factor (TNF)-α,secretion from antigen-stimulated mast cells; moreover, both TCE and PCE administration intraperitoneally enhanced passive cutaneous anaphylaxis

Results
Enhancement of histamine release, increase of IL-4 andTNF-alpha secretion, enhancement of PCA reaction
Enhancement of PCA reaction, increase of infiltration ofmononuclear leukocytes into dermal skin lesion, increase of mast cell accumulation perivascularly
Enhancement ACA reaction, enhancement of antigenstimulated splenocyte proliferation
Skin edma and erythema, skin sensitazation rate 66–71%
Increasing prostaglandin E release from swine trachea(PCA) reaction in rats. In two other in vivo studies, Seo et al. examined the enhancing effect of low
concentrations of TCE (0.03 or 3 mg/l) or PCE (0.01
or 1 mg/l) ingestion from drinking water on antigenstimulated allergic responses.25, 26) TCE or PCE ingestion from drinking water increased the infiltration of mononuclear leukocytes into dermal skin lesions and increased mast-cell accumulation perivascularly, and then enhanced PCA reactions. This
was a result of T helper (Th) 1/Th2 cell imbalance
and the increase of total IgE in serum. In addition
to these adjuvant-like effects of TCE, TCE ingestion from drinking water increases antigen-specific
T cell proliferation, and alters antigen-specific IgE
and cytokine production from antigen-specific T
cells.27) In the development of immune responses,
activated local B cells can act as antigen-presenting
cells for CD4+ and CD8+ T cells.28) CD4+ T cells
that recognize major histocompatibility complex(MHC) class II molecules are of two functional
types: Th1 and Th2. Th1 cells are specialized toactivate macrophages that are promoted by, or haveingested, pathogens. Th2 cells are specialized for
B cell activation.29) There are two main components of the immune response leading to IgE production. The first consists of signals that favor thedifferentiation of naive Th0 cells to the Th2 phenotype. The second involves the action of cytokinesand co-stimulatory signals from Th2 cells that stimulate B cells to switch to producing IgE antibodies. Th2 cells produce IL-4, IL-5, IL-10, and IL13, and these responses are down-regulated by Th1
cytokines, interferon-γ (IFN-γ), TNF-α, and IL2.30–32) IL-4 plays crucial role as an inflammatory
mediator in allergic asthma by inducing Th2 inflammation and IgE synthesis.
Tang et al. examined TCE-induced delayed hypersensitivity using the guinea pig maximization

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Table 2. Human Studies of Allergy and Hypersensitivity
Authors
Lehmann et al.
(2002)

Location
Germany

Lehmann et al.
(2001)

Germany

Iavicoli et al.
(2005)

Italy

Tanios et al.
(2004)
Kimijima et al.
(2007)U.S.A.
Asia

Source of data (period, sample size, age etc.)
85 neonates (4 weeks of age), indoor air
samples (including TCE and PCE),
cytokine-secreting CD3+ cord-blood Tcells
28 children (3 years of age), indoor air
samples (including TCE and PCE),
cytokine-secreting CD3+ and CD8+ Tcell populations from blood samples
35 male workers (mean ∼33 years of age),
workplace TCE measures, serum cytokine levels
Female worker (42 years of age), historicaland physical examination
260 Asian patients, TCE concentraiotion

test. In this test, sensitization rates of 66–71% andskin edema and erythema were observed.33, 34) Inflammatory cell infiltration was found with an acuteintradermal dose of 4500 mg/kg TCE.34)
In addition to the increase of histamine release from mast cells, TCE and PCE increased
prostaglandin release from the tracheal epithelium,
particular prostaglandin E2 from swine tracheal epithelium, by modulating the influence of enzyme,
cyclooxygenase, or prostaglandin biosynthesis.35)
Thus, TCE and PCE appear to enhance the release of arachidonic acid metabolites, promoting inflammation. Further study is required to elucidate
whether prostaglandin production from airway epithelia exposure to TCE and PCE results in airway
inflammation.
Human Studies
Allergy and hypersensitivity have not been extensively studied with respect to the effects of TCE
or PCE exposure. The available data from studies
in humans suggested an association between TCE
or PCE exposure and inflammatory cytokine secretion, which represents immune function (Table 2).
Lehmann et al. examined cord blood samples
from 85 healthy, full-term neonates (4 weeks of age)for cytokine-secreting CD3+ (or CD3+ and CD8+ )T-cells and associated them with indoor air samples (including TCE and PCE). TCE exposure data
showed a decrease of IL-4-secreting T-cells and anincrease of IFN-γ-secreting T-cells, whereas PCE
exposure data showed a significant decrease of IFNγ-secreting T-cells.36) Another study examining indoor air samples (including TCE and PCE) and

Results
TCE: Decrease of IL-4 secreting T-cells, increase of
IFN-γ secreting T-cells
PCE: Decrease of IFN-γ secreting T-cells
PCE: No relation between PCE exposure and allergic sensitazation to egg white

TCE: Decrease of IL-4 secretion, increase of IFN-γ
secretion
PCE: Hypersensitivity pneumonitis
Skin disorderallergic sensitization and cytokine secretion in 28
children (3 year of age) at high risk for the development of allergic disease (e.g., low birth weight,
high cord blood IgE, family history of atopy) foundno association between PCE exposure and allergic
sensitization to egg whites, and an elevated but nonsignificant association between PCE exposure andallergic sensitization to milk.37) Iavicoli et al. measured cytokine levels in 35 male workers exposed to
TCE from a painting area in a factory. Occupational
exposure to TCE resulted in significantly increased
serum levels of the T cell-derived proinflammatory
cytokine IFN-γ.38) These studies provide weak evidence of an effect of TCE or PCE exposure duringchildhood on allergic sensitization or exacerbationof asthma; however, the observation of an association between increased TCE or PCE exposure andthe decrease of IFN-γ in cord blood samples may
reflect a sensitive period of development, and points
to the current lack of understanding of the potential
immunotoxic effects of prenatal exposure.
Occupational exposure to TCE or PCE has been
associated with severe, generalized skin disorderthat is distinct from contact dermatitis. PCE exposure may result in immune-mediated organ-specificor systemic effects, as decribed in a case report ofhypersensitivity pneumonitis in a 42-year-old female dry cleaning worker.39) Recently, an increasing number of cases TCE-induced hypersensitivity
dermatitis in TCE-exposed workers have been reported. Kamijima et al. reviewed case reports describing 260 Asian patients with TCE-induced generalized skin disorders.40) The measured concentration of TCE ranged from 50 to 4000 mg/m3 , and

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Table 3. Animal Studies of Autoimmune Disease
Authors
Gilbert et al.
(1999)

Strains
MRL+/+ mice

Griffin et al.
(2000)

MRL+/+ mice

Griffin et al.
(2000)

MRL+/+ mice

Khan et al.
(1995, 2001)

MRL+/+ mice

TCE and TCE metabolizes exposure
from drinking water

Blossom et al.
(2004, 2006)

MRL+/+ mice

TCE and TCE metabolizes exposure
from drinking water

Cai et al.
(2008)
Green et al.
(2001)

MRL+/+ mice

TCE (0.5 mg/ml) exposure fromdrinking water for 48 weeks
PCE (5 mmol/kg) for 24 hr or every
fourth day for 6 weeks

MRL-lpr/lpr andMRL+/+ mice

Experimantal method
TCE (2.5, 5 mg/ml) exposure fromdrinking water for 4, 8, and 22
weeks
TCE (2.5, 5 mg/ml) exposure fromdrinking water for 4, 8, and 22
weeks
TCE (0.1, 0.5, 2.5 mg/ml) exposure
from drinking water for 4 and
32 weeks

exposure scenarios included inhalation only and inhalation with dermal exposure. Disease manifestation generally occurred with 2–5 weeks of initial exposure, with some intervals of up to 3 months.

AUTOIMMUNE DISEASE
Animal Studies
Several mouse strains spontaneously develop
conditions resembling systemic lupus erythematosus seen in humans. MRL+/+ mice have been extensively used in mechanistic research pertaining todisease pathogenesis and are also most often used inexperimental studies of TCE exposure (Table 3).
The initial drinking water study used relatively
high TCE concentrations of 2.5 and 5.0 mg/ml,
with serologic measurements of antinuclear antibodies (ANA) and IgG levels and assays of activation of CD4+ T cells from splenocytes.41, 42) Another study examined lower TCE exposure levels(0.1, 0.5, and 2.5 mg/ml) and extended the observation to 32 weeks.43) These studies demonstrated
an acceleration of the autoimmune response. T
cell activation peaked at 4–8 weeks in the highdose experiment and at 32 weeks in the lower doseexperiment. The higher dose study showed evidence of a reversal of the effects at 22 weeks, withlower levels of CD4+ T cell expression and IFN-γ

Results
Increase of ANA and IgG level in serumat 4 and 8 weeks
Enhancement of activation of CD4+ cells
and increase of IFN-γ secretion at 4
weeks
Increase of IFN-γ secretion at 4 weeks,enhancement of activation of CD4+
cells and increase of ANA at 32
weeks
Increase of ANA level and inflammatory
cytokine secretion, enhancement ofT cell activation
Increase of ANA level and inflammatory
cytokine secretion, enhancement ofT cell activation
Infiltration of leukocytes in the portal
vein of the liver
Detecting trichloroacetylated protein
adducts formed in the liverin exposed mice compared with controls. Moreover, several studies demonstrated the involvementof one or more potential metabolites of TCE, such asdichloroacethyl chloride, trichloroacetaldehyde hydrate, and trichloroacetic acid, in the autoimmune
response seen in MRL+/+ mice: acceleration of
ANA expression, T cell activation, and secretionof inflammatory cytokines.44–47) Chronic TCE exposure was shown to induce autoimmune hepatitis,
characterization by lymphocytic infiltration aroundthe portal vein, in MRL+/+ mice.43, 48)
This evidence of immunological alterations following TCE exposure provides suggestive evidence
against PCE, a halogenated solvent that shares somecommon metabolites with TCE. To date, similar
studies in MRL+/+ mice have not been conductedwith other solvents, so the extent to which thesefindings pertain to PCE is limited. Only one report
has shown the detection of trichloroacetylated protein adducts formed in the liver of MRL-lpr/lpr andMRL+/+ mice treated with tetrachloroethylene.49)
Human Studies
Exposure to organic solvents or chlorinated solvents has been associated with a 2- to 3-fold increased risk of systemic sclerosis (scleroderma)
in epidemiological studies summarized in a recent meta-analysis50) and in subsequent studies (Table 4).51, 52)492Vol. 57 (2011)

Table 4. Human Studies of Autoimmune Disease
Authors
Aryal et al.
(2001)
Garabrant et al.
(2003)

Location
U.S.A.

Maitre et al.
(2004)

FranceByers et al.
(1988)
Kilburn et al.
(1992)

U.K.

Nietert et al.
(1998)
Lacey et al.
(1999)
Beaudreuil et al.
(2005)U.S.A.

U.S.A.

U.S.A.
U.S.A.
FranceSource of data (period, sample size, age etc.)
Case control study and one cohort study, period 1989–1998
Structured interview, 660 cases and 2227
frequency-matched controls, period
1980–1992
10 men and 83 women diagnosed with scleroderma and 206 age- and sex-matched
controls, period 1995–1999
23 family members of the patients withleukemia with particular emphasis
362 subjects exposed toTCE and PCE etc. inwater obtained from wells
Structured interview, 178 cases mean age
45.2 years, period 1995–1997
Structured interview, 205 cases and 2095
population controls, period 1980–1992
Structured interview, 60 cases of ANCApositive patients, period 1999–2000

A number of epidemiological reports and casestudies have suggested that chronic exposure to lowlevel TCE relates to a variety of autoimmune diseases in humans, including lupus, scleroderma, bullous pemphigoid, diabetes, and immune-mediatedhepatitis.53– 55) Byers et al. collected serum samples
from 23 family members of leukemia patients in
Woburn53) to assess the presence of several autoantibodies, such as ANA, anti-smooth muscle, antiovarian, anti-thyroglobulin, and anti-microsomal
antibodies, in the family member samples and compared the results with laboratory reference values.
None of the serum samples from family members
contained anti-thyroglobulin or anti-microsomal antibodies, but ANA was detected in samples from
10 family members (compared with < 5% expectedbased on the reference value).
Three case-control studies of undifferentiatedconnective tissue disease,56) scleroderma,51) and antineutrophil cytoplasmic antibody (ANCA)-relateddiseases57) provide data concerning dry cleaning
work or PCE exposure. As expected in populationbased studies, the exposure prevalence is low, withapproximately 4% of controls reporting work in dry
cleaning and 1% reporting exposure to PCE. The
observed associations are generally weak (odds ratios for dry cleaning around 1.5 in 3 large studies ofwomen) and none of the individual studies were statistically significant. The results seen for exposure
to PCE in the three studies that attempted this type

Results
2–3 fold increased risk of scleroderma
2–3 fold increased risk of scleroderma

2–3 fold increased risk of scleroderma

Altered ratios of T lymphocyte subpopulations, increased incidence of autoantibodies
Increased symptoms of lupus erythematosus as perceived by the ARA score and the increased
ANA titers
Incidence of scleroderma associated with occupational solvent exposure
Increase of the risk of developing undifferentiatedconnective tissue disease
ANCA in plasma partially be related with occupational exposureof assessment were more varied.

IMMUNOSUPPRESSION
Animal Studies
A number of animal studies have examined immunosuppression and host resistance against infection in relation to TCE or PCE exposure by various routes and concentrations. Immunological parameters ware altered in B6C3F1 mice administereda chemical mixture of 25 groundwater contaminants. After 14 or 90 days of exposure, immunosuppressive evidence was observed in immunological parameters with a dose-related decrease in antibody response to sheep red blood cells and decreased host resistance to subsequent challenge to
Plasmodium yoeli. There was no change in lymphocyte number, T cell subpopulations, natural killer
cell activity, or in challenge listeria monocytgens.58)
CD1 mice exhibited increased susceptibility to infectious agents (e.g., Streptococcus zooepidimicus,
Klebsiella pneumoniae) with short-term inhalationof TCE ranging from 2.6 to 48 ppm.59) In anotherstudy, after 3 days of single intraperitoneal injections of TCE in Sprague-Dawley (SD) rats at 0.05,
0.5, or 5 mmol/kg per day and B6C3F mice at
10 mmol/kg per day, natural killer cell activity in theliver was depressed in rats given the highest dose
(22% lower than control levels, p < 0.05); in mice,

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a smaller decrease was reported (14% lower thancontrol levels, no significant difference).60)
Human Studies
Data on the immunosuppressive effects in humans are very limited. In 1982, Lagakos et al.11)
conducted a telephone survey of Woburn residents
to collect information on the residential history andhistory of 14 medically diagnosed conditions. Thissurvey included 4978 children born since 1960 who
had lived in Woburn before they reached 19 yearsof age. The exposure information was based on estimates of the contribution of water from contaminated wells (including TCE and PCE) in various
zones within the town, and this information wasused to estimate cumulative exposure based on eachchild’s length of residence in Woburn. A higher cumulative exposure measure was associated with ahistory of kidney and urinary tract disorders (primarily kidney or urinary infection) and with lungand respiratory disorders (asthma, chronic bronchitis, or pneumonia).

CONCLUSION
Several animal models have been tested to identify chemical allergy;61) however, although environmental chemical allergens tend to have weak,minimal immunogenicity, these methods have focused on the detection of strong allergic reactions.
Although allergic effects of environmental chemical exposure have been studied extensively, allergic
effects at low doses remain unknown;62–64) therefore, there is a need for protocols for the treatment and detection of weakly immunogenic andlow doses allergic reactions. A low level of environmental chemical exposure causes breathingproblems such as asthma and other allergic reactions.65, 66) Recently, environmental chemical exposure was found to induce significantly altered expression in genes regulated through the Toll-likereceptor signaling pathway, T cell receptor signaling pathway cytokine-cytokine receptor interaction,and natural killer cell-mediated cytotoxicity.67) This
genome-wide expression profile approach will provide a novel mechanism of environmental chemicalinduced immunotoxic effects in the future.
In this review, we have discussed several reports on the immunotoxicity of chlorinated organic
compounds, especially TCE and PCE; however additional data from inhalation, oral, and dermal ex-

posure of different durations are needed to assess
the potential immunotoxicity of TCE and PCE frommultiple viewpoints, including immunosuppression,
autoimmunity, and allergic sensitization. The lackof data together with the concern that other structurally related solvents are associated with immunotoxicity contributes to uncertainty in the databasefor TCE and PCE.
Furthermore, many environmental pollutants
generally coexist with other chemicals and are exposed to human and animals. Recently, there
was a report that coexposure to methylmercury
aggravates TCE-induced autoimmune hepatitis in
MRL+/+ mice compared with single exposure with
TCE;68) therefore, further studies are needed to clarify the immunotoxic evaluations about not only single exposure to TCE or PCE but also coexposure toother environmental pollutants.

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