Pharmacological Reports

Copyright 2010
by Institute of Pharmacology
Polish Academy of Sciences

2010, 62, 12431249

ISSN 1734-1140

Short communication

Effects of ethylene glycol ethers on cell viability

in the human neuroblastoma SH-SY5Y cell line
Magdalena Regulska1, Bartosz Pomierny2, Agnieszka Basta-Kaim1,
Andrzej Starek2, Magorzata Filip3, Wadysaw Laso1, Bogusawa
Budziszewska1,2


Department of Experimental Neuroendocrinology, Institute of Pharmacology Polish Academy of Sciences,

Smtna 12, PL 31-343 Krakw, Poland
!

Department of Biochemical Toxicology, Department of Toxicology, Jagiellonian University, Medical College,

Medyczna 9, PL 30-688 Krakw, Poland
Correspondence: Bogusawa Budziszewska, e-mail: budzisz@if-pan.krakow.pl

Abstract:
Ethylene glycol ethers (EGEs) are a class of chemicals used extensively in the manufacture of a wide range of domestic and industrial products, which may result in human exposure and toxicity. Hematologic and reproductive toxicity of EGEs are well known
whereas their action on neuronal cell viability has not been studied so far. In the present study, we investigated the effects of some
EGEs on cell viability and on the hydrogen peroxide-induced damage in the human neuroblastoma (SH-SY5Y) cells. It has been
found that 2-phenoxyethanol in a concentration-dependent manner (525 mM, 24 h) increased the basal and H O -induced lactate
dehydrogenase (LDH) release and 3-[4,5-dimethylthiazol-2-yl]2,5-diphenyl tetrazolium bromide (MTT) reduction. 2-Butoxyethanol
given alone did not affect LDH release and MTT reduction but concentration-dependently enhanced the cytotoxic effect of H O . 2Isopropoxyethanol significantly and concentration-dependently (125 mM) increased the basal LDH release and attenuated MTT
reduction, but did not potentiate the cytotoxic effect of H O . Contrary to this, 2-methoxyethanol did not show a cytotoxic effect
while 2-ethoxyethanol at high concentrations intensified the hydrogen peroxide action. This study demonstrated that among the
EGEs studied, 2-phenoxyethanol showed the most consistent cytotoxic effect on neurons in in vitro conditions and enhanced the hydrogen peroxide action. 2-Isopropoxyethanol had also a potent cytotoxic effect, but it did not enhance the hydrogen peroxide action,
whereas 2-butoxyethanol only potentiated cytotoxic effect of H O . It is concluded that the results of the present study should be confirmed in in vivo conditions and that some EGEs, especially 2-phenoxyethanol, 2-butoxyethanol and 2-isopropoxyethanol, may be responsible for initiation or exacerbation of neuronal cell damage.
Key words:
ethylene glycol ethers, neurotoxicity, lactate dehydrogenase, MTT assay, SH-SY5Y cells

Introduction
Ethylene glycol ethers (EGEs) are a class of chemicals which, because of their useful physical properties, are widely used as solvents of paints, inks and

varnishes, components of cooling liquids, preparations of

household cleaners and cosmetics. The most wellknown EGEs include 2-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol, 2-propoxyethanol, 2-isopropoxyethanol and 2-phenoxyethanol. The chemical
structure of a particular EGE affects its physico-

Pharmacological Reports, 2010, 62, 12431249

1243

chemical properties and in consequence biological effects. These compounds can be absorbed through the
skin, the respiratory system and the digestive tract and
are more toxic than propylene glycol ethers [4].
A number of epidemiological and experimental studies have shown that EGEs can cause adverse reproductive, developmental, immunological and hematological effects through inhalation or dermal absorption and ingestion. Hematologic and reproductive
toxicity of EGEs is relatively well known. It has been
found that 2-methoxyethanol evoked leukopenia, pancytopenia, decreased the hemoglobin concentration
and the number of red blood cells in humans [15]. In
experimental animals, 2-butoxyethanol and 2-isopropoxyethanol showed the most potent hemolytic activity
[20]. Contrary to the hematopoietic system, the most
potent reproductive toxicity was exerted by 2-methoxyethanol and 2-ethoxyethanol. In men, the reduction in
sperm count whereas in women the disturbance of the
menstrual cycle have been observed [10, 24]. In experimental animals, these compounds caused degeneration of spermatocytes and reduced the number of
spermatocytes and spermatides in males, whereas in
females they disturbed the function of the corpus luteum and inhibited the ovulation [6, 22]. The molecular
mechanism of EGEs toxic effect is not fully known,
but it has been postulated that testicular toxicity induced by these compounds can result from oxidative
stress. It was evidenced by the fact that 2-ethoxyethanol decreased glutathione level, superoxide dismutase and catalase activity but increased glutathione
S-transferase and malondialdehyde levels in the rat
testes [1]. Moreover, it has been found that 2-methoxyethanol activates mitochondrial pathway of apoptosis
in spermatocytes by increasing the expression of
proapoptotic factors (Bax and Bak), induction of cytochrome c release and activation of caspase-3 and
caspase-9 [3].
The effects of EGEs on the central nervous system
(CNS) are expected, but are not well known. EGEs
rapidly cross the blood-brain barrier and acute intoxication with these compounds in humans evoked disturbances of motor coordination, headaches, permanent cognitive dysfunction, CNS depression and occasionally convulsions [2, 16]. In a study concerning the
mechanism of EGE action on synaptic transmission, it
has been found that 2-phenoxyethanol reduces
NMDA-induced currents [17], however, the effect of
these drugs on neuronal viability has not been studied
so far. Based on the data from peripheral organs,
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Pharmacological Reports, 2010, 62, 12431249

which indicate that EGEs attenuate antioxidant defense system and increase lipid peroxidation, their
similar effect in the brain, especially in structures particularly sensitive to damage, can lead to neuronal cell
damage. The present study aimed to investigate the
effects of some EGEs on cell viability and on the hydrogen peroxide (oxidative stress)-induced damage in
the human neuroblastoma (SH-SY5Y) cells. For this
study, we chose 2-methoxyethanol and 2-ethoxyethanol, i.e., the compounds with the most potent reproductive toxicity, 2-butoxyethanol and 2-isopropoxyethanol solvents with strong hemolytic activity and
2-phenoxyethanol, which reduces NMDA-induced currents. SH-SY5Y cell line represents a well-established
experimental model to study neurotoxic potential of
chemical compounds in vitro [8, 11, 13, 23].

Materials and Methods

Cell culture

The SH-SY5Y neuroblastoma cell line was obtained

from the American Type Culture Corporation (ATCC).
Cells were cultured in Dulbeccos modified Eagles
medium (Gibco-BRL, Germany) supplemented with
10% fetal bovine serum (FBS, Gibco-BRL, Germany),
100 units/ml of penicillin and 100 g/ml of streptomycin (Sigma-Aldrich Ltd.), and kept in humidified
atmosphere of 5% CO /95% O at 37C.
Treatment of cells

One day before the experiment, the cells were seeded

at 15,000 cells per well in 96-well plates in the
medium containing a reduced amount of serum (1% FBS).
The SH-SY5Y cells were treated with 2-methoxyethanol,
2-ethoxyethanol, 2-isopropoxyethanol, 2-butoxyethanol
and 2-phenoxyethanol (Sigma-Aldrich Ltd.) at concentrations from 0.1 to 25 mM alone or with hydrogen peroxide (0.5 mM) for 24 h. 2-Methoxyethanol,
2-ethoxyethanol, 2-butoxyethanol, 2-isopropoxyethanol
and 2-phenoxyethanol were added to culture medium
in the volume of 10 l.
Lactate dehydrogenase (LDH) test

Cell death was detected, as described previously [14],

by measuring the efflux of LDH into the culture me-

Neurotoxicity of ethylene glycol ethers

Magdalena Regulska et al.

dia 24 h after the treatment with EGEs alone or together with hydrogen peroxide. Cell-free culture supernatants were collected from each well and LDH
activity was determined using a colorimetric method
(Cytotoxicity Detection Kit, Roche Diagnostic GmbH),
according to which the amount of colored hydrazone,
formed in the reaction of pyruvic acid with 2,4dinitrophenylhydrazine, is inversely proportional to the
LDH activity in the sample and was quantified by measuring the absorbance at 490 nm.
3-[4,5-dimethylthiazol-2-yl]2,5-diphenyl tetrazolium bromide (MTT) reduction assay

Cell viability was measured, as described previously

[12], by determining the cellular reducing capacity,
estimated through the extent of MTT reduction to the
insoluble intracellular formazan, which depends on
the activity of intracellular dehydrogenases and is independent of changes in the integrity of the plasma
membrane. Briefly, culture medium was removed and
SH-SY5Y cells were incubated with MTT (0.15
mg/ml) for 1 h at 37C. MTT was prepared in PBS
and added at a final concentration of 0.15 mg/kg.
Then, the crystals of formazan were dissolved in
DMSO and the absorbance of each sample was measured at 570 nm in a plate reader (Multiscan, Labsystem). The results were expressed as a percentage of
control cells incubated in the absence of EGEs and
HO.
Statistical analysis

The data were obtained in three independent experiments, each performed in 34 wells and were presented as the percentage of control SEM. The significance of differences between the means was
evaluated by the Duncans test following a one-way
analysis of variance.

Results
Cytotoxic effect of EGEs was examined by LDH release and MTT reduction. There were no fundamental
differences between these tests. Exposure of SH-SY5Y
cells to 2-phenoxyethanol for 24 h produced cytotoxicity, as assessed by LDH release and MTT test.

2-Phenoxyethanol at concentrations 5, 10 and 25 mM

significantly and concentration-dependently increased
the basal and H O -induced LDH release (Fig. 1A, B).
At the same concentrations, this compound inhibited
the reduction of MTT, whereas at concentrations of 10
and 25 mM 2-phenoxyethanol enhanced H O induced MTT reduction (Fig. 1C, D). 2-Butoxyethanol
when given alone at a concentration between 0.125 mM
did not affect the basal LDH release and only in the
highest examined concentration (25 mM) inhibited
MTT reduction (Fig. 2A, C). However, this compound
in a concentration-dependent manner enhanced the
cytotoxic effect of H O in the LDH release test (5, 10
and 25 mM) and in the MTT test (10 and 25 mM)
(Fig. 2B, D). Contrary to 2-butoxyethanol, 2-isopropoxyethanol exerted a small effect on the H O induced damage, because it did not alter H O action
in the MTT test and only at the highest concentration
tested (25 mM) it raised H O -induced LDH release
(Fig. 3B, D). On the other hand, 2-isopropoxyethanol
given alone significantly and concentrationdependently (125 mM) increased the basal LDH release
and MTT reduction (Fig. 3A, C). 2-Methoxyethanol did
not show a cytotoxic effect because in the concentration range from 0.1 to 25 mM it had no effect either
on basal or on H O -induced LDH-release and MTT
reduction (Tab. 1). Also 2-ethoxyethanol alone did
not induce cytotoxic effect in SH-SY5Y cells, as assessed by the LDH and MTT assay (Tab. 1). However,
this compound at concentrations of 10 and 25 mM enhanced H O -induced LDH release and at the highest
concentration used (25 mM) it potentiated the action
of H O on MTT reduction.

Discussion
This study has demonstrated that the examined EGEs
markedly differ between themselves in their effect on
SH-SY5Y cell damage. Among EGEs under study,
2-phenoxyethanol showed the most consistent
cytotoxic effect on neurons in in vitro conditions. Its
toxicity involved cell membrane disruption, as
evidenced by the LDH release and mitochondrial
dysfunction, as assessed by the MTT assay. 2-Phenoxyethanol in a concentration-dependent manner
increased both the basal and hydrogen peroxideinduced damage of the cell membrane and inhibited

Pharmacological Reports, 2010, 62, 12431249

1245

Fig. 1. Effect of 2-phenoxyethanol on

basal (A) and H O -induced (B) LDH
release and basal (C) and H O induced (D) MTT reduction in SHSY5Y cells. Results are shown as
a percentage of control cells incubated in the absence of 2-phenoxyethanol and H O (A, C) or in the
presence of H O only (B, D). The significance of differences between the
means was evaluated by Duncans
test following a one-way analysis of
variance (* p < 0.05 vs. control culture;
 p < 0.05 vs. cells treated with H O ;
n = 12)

Fig. 2. Effect of 2-butoxyethanol on basal (A) and H O -induced (B) LDH release and basal (C) and H O -induced
(D) MTT reduction in SH-SY5Y cells.
Results are shown as a percentage of
control cells incubated in the absence
of 2-butoxyethanol and H O (A, C) or
in the presence of H O only (B, D).
The significance of differences between the means was evaluated by
Duncans test following a one-way
analysis of variance (* p < 0.05 vs.
control culture;  p < 0.05 vs. cells
treated with H O ; n = 12)

the basal and hydrogen peroxide-induced mitochondrial function. The statistically significant cytotoxic
effect of this compound was evident at 5 mM concentration. 2-Isopropoxyethanol already in a concentration of 1 mM caused cell membrane disruption and
mitochondrial dysfunction, however, it did not intensify
damages caused by hydrogen peroxide. Contrary to
2-isopropoxyethanol, 2-butoxyethanol alone had no
cytotoxic effect, but strongly enhanced the effect of

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Pharmacological Reports, 2010, 62, 12431249

hydrogen peroxide, which indicated that this

compound could be important in intensifying the
effect of some harmful agents, but alone it did not
induce neurodegenerative processes. Two remaining
investigated EGEs, 2-methoxyethanol and 2-ethoxyethanol had no clear cytotoxic effect because only
2-ethoxyethanol in a higher concentration enhanced
the hydrogen peroxide action. Comparison of the
intensity of action of the investigated monoalkyl- and

Neurotoxicity of ethylene glycol ethers

Magdalena Regulska et al.

160

LDH release
% of control

120

10

25

100
80
60
40
20
0

H2O2
2-isopropoxyethanol -

MTT reduction
% of control

Fig. 3. Effect of 2-isopropoxyethanol

on basal (A) and H O -induced (B)
LDH release and basal (C) and H O induced (D) MTT reduction in SHSY5Y cells. Results are shown as
a percentage of control cells incubated in the absence of 2-isopropoxyethanol and H O (A, C) or in the
presence of H O only (B, D). The significance of differences between the
means was evaluated by Duncans
test following a one-way analysis of
variance (* p < 0.05 vs. control culture;
 p < 0.05 vs. cells treated with H O ,
n = 12)

140

0.1

120

100

+
-

+
0.1

+
1

+
5

+
10

+
25 [mM]

+
1

+
5

+
10

+
25 [mM]

D
*

80

25

+
-

60
40
20
0

H2O2
2-isopropoxyethanol -

0.1

10

+
0.1

Tab. 1. Effect of 2-methoxyethanol and 2-ethoxyethanol on basal and H O -induced LDH release and MTT reduction in SH-SY5Y cells

Treatment

LDH

MTT

Treatment

Vehicle

100.0 1.2

100.0 2.4

Vehicle

2-methoxyethanol 0.1 mM

100.5 3.4

101.3 2.9

2-methoxyethanol 1 mM

99.8 3.2

2-methoxyethanol 5 mM

LDH

MTT

100.0 1.1

100.0 2.4

2-ethoxyethanol 0.1 mM

99.0 1.9

95.2 5.9

110.2 2.3

2-ethoxyethanol 1 mM

99.5 2.7

106.6 5.1

100.6 2.5

109.5 3.9

2-ethoxyethanol 5 mM

98.0 0.3

108.7 4.3

2-methoxyethanol 10 mM

99.2 1.6

112.4 3.2

2-ethoxyethanol 10 mM

98.4 1.5

106.9 5.5

2-methoxyethanol 25 mM

92.0 3.2

109.1 3.1

2-ethoxyethanol 25 mM

99.4 1.3

101.2 8.1

Vehicle + H O

128.6 2.3*

76.0 3.9* Vehicle + H O

128.0 2.1*

77.0 4.2*

2-methoxyethanol 0.1 mM+ H O

140.8 8.4

72.9 0.6

2-ethoxyethanol 0.1 mM + H O

131.4 7.5

96.9 1.0

2-methoxyethanol 1 mM+ H O

138.2 4.4

70.2 9.2

2-ethoxyethanol 1 mM + H O

131.4 4.2

77.6 4.4

2-methoxyethanol 5 mM+ H O

131.0 2.7

79.5 8.6

2-ethoxyethanol 5 mM + H O

139.7 6.9

74.7 6.8

2-methoxyethanol 10 mM+ H O

128.7 3.8

86.5 4.0

2-ethoxyethanol 10 mM + H O

145.9 5.8

64.4 8.7

2-methoxyethanol 25 mM+ H O

129.4 2.9

86.0 5.0

2-ethoxyethanol 25 mM + H O

162.5 1.2

47.6 3.2

The SH-SY5Y cells were treated with saline, 2-methoxyethanol or 2-ethoxyethanol at concentrations from 0.1 to 25 mM alone or with hydrogen
peroxide (H O , 0.5 mM) for 24 h. Cytotoxic effect was determined by measuring the efflux of lactate dehydrogenase (LDH) into the culture media and by the MTT assay. The significance of differences between the means was evaluated by Duncans test following a one-way analysis of
variance (* p < 0.05 vs. control culture;  p < 0.05 vs. cells treated with H O ; n = 9)

Pharmacological Reports, 2010, 62, 12431249

1247

monoaryl-EGEs suggests that lipophilicity may play

a key role in their neurotoxic action. 2-Methoxyethanol
and 2-ethoxyethanol are hydrophilic compounds,
whereas 2-butoxyethanol and 2-isopropoxyethanol
are weakly lipophilic [21]. The monoaryl ether, 2phenoxyethanol, with the most potent cytotoxic
action in the present study, is also the most lipophilic.
Therefore, it is possible that the intensity of
neurotoxic action of these compounds rises with the
increase in their lipophilicity, which in turn may
enhance their concentration inside the neuron. The
present results indicate also that 2-methoxyethanol
and 2-ethoxyethanol, i.e., the compounds which exert
the most potent toxic effect on gonadal cells do not
cause damages in neuronal cells, at least in in vitro
conditions. The demonstration of a potent reproductive
and developmental toxic action of 2-methoxyethanol
and 2-ethoxyethanol resulted in the limitation of their
use, whereas the production of 2-butoxyethanol and
2-phenoxyethanol, considered to be safer, increased
[7]. In consequence, at present, about a half of economic
chemistry preparations contain 2-butoxyethanol. However,
on the basis of the present study, 2-phenoxyethanol
and 2-butoxyethanol do not appear to be a safe substitute for 2-methoxyethanol and 2-ethoxyethanol. Moreover, recent data indicate that 2-butoxyethanol had
high hemolytic activity [20]. It should be stressed,
however, that there are no data concerning EGEs
metabolism in the brain or in the SH-SY5Y cells, so
the results of the present study should be confirmed
under in vivo conditions before drawing the final
conclusion about their neurotoxic action. In the liver,
testicles and skin, EGEs are primarily metabolized via
alcohol dehydrogenase and aldehyde dehydrogenase
to respective alkoxyacetic acids, which are considered
to be responsible for hemolytic and gonadotoxic
effects [25]. Although it is assumed that central
effects of EGEs are exerted by parent compounds, this
was never confirmed, so the differences between
EGEs metabolism in the brain and SH-SY5Y cells can
potentially affect their neurotoxic effect. Also, the fact
that 2-methoxyethanol and 2-ethoxyethanol did not
induce SH-SY5Y cell damage did not completely
exclude their detrimental effect on neuronal cells in
vivo. Moreover, because there are no data on the brain
levels of EGEs in humans, the concentrations of the
compounds used in the present study were chosen on
the basis of other in vitro experiments and reflected
their levels in blood in experimental animals [5, 9, 18,
19]. Nevertheless, since it is predicted that much
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Pharmacological Reports, 2010, 62, 12431249

lower concentrations may be active in chronic

exposures than in short-time in vitro experiments, and
clinical symptoms of neurodegenerative disorders,
like Alzheimer's or Parkinson's diseases are evident
many years after the process of apoptosis had begun,
it is possible that some EGEs, especially 2-phenoxyethanol, 2-butoxyethanol and 2-isopropoxyethanol,
may be responsible for initiation or exacerbation of
the harmful action of oxidative stress or aging on
neuronal damage. The demonstration of EGE neurotoxic effect in in vivo condition should lead to the
limitation of their use (e.g., by replacing them with
propylene glycol ethers to a greater degree) and to
correction of the value of the maximum admissible
concentration (MAC) in occupational conditions.

Acknowledgments:
This study was supported by the grant No. K/ ZDS/ 001507 from
the Collegium Medicum Jagiellonian University, Krakw, Poland
and by the Statutory Funds of the Institute of Pharmacology of the
Polish Academy of Sciences, Krakw, Poland.

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Received:
September 7, 2010; in the revised form: October 22, 2010.

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