Pharmacological Reports Copyright 2010

2010, 62, 12431249 by Institute of Pharmacology

ISSN 1734-1140 Polish Academy of Sciences

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 indus-
trial 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 . 2-
Isopropoxyethanol 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 hy-
drogen 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 con-
firmed in in vivo conditions and that some EGEs, especially 2-phenoxyethanol, 2-butoxyethanol and 2-isopropoxyethanol, may be re-
sponsible for initiation or exacerbation of neuronal cell damage.

Key words:
ethylene glycol ethers, neurotoxicity, lactate dehydrogenase, MTT assay, SH-SY5Y cells

Introduction varnishes, components of cooling liquids, preparations of

Ethylene glycol ethers (EGEs) are a class of chemi-
cals which, because of their useful physical proper-
ties, are widely used as solvents of paints, inks and
household cleaners and cosmetics. The most well-
known EGEs include 2-methoxyethanol, 2-ethoxy-
ethanol, 2-butoxyethanol, 2-propoxyethanol, 2-isopro-
poxyethanol 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 ef-
fects. 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 stud-
ies have shown that EGEs can cause adverse repro-
ductive, developmental, immunological and hemato-
logical effects through inhalation or dermal absorp-
tion and ingestion. Hematologic and reproductive
toxicity of EGEs is relatively well known. It has been
found that 2-methoxyethanol evoked leukopenia, pan-
cytopenia, decreased the hemoglobin concentration
and the number of red blood cells in humans [15]. In
experimental animals, 2-butoxyethanol and 2-isopro-
poxyethanol showed the most potent hemolytic activity
[20]. Contrary to the hematopoietic system, the most
potent reproductive toxicity was exerted by 2-methoxy-
ethanol 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 ex-
perimental animals, these compounds caused degen-
eration of spermatocytes and reduced the number of
spermatocytes and spermatides in males, whereas in
females they disturbed the function of the corpus lu-
teum 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 in-
duced by these compounds can result from oxidative
stress. It was evidenced by the fact that 2-ethoxy-
ethanol decreased glutathione level, superoxide dis-
mutase and catalase activity but increased glutathione
S-transferase and malondialdehyde levels in the rat
testes [1]. Moreover, it has been found that 2-methoxy-
ethanol activates mitochondrial pathway of apoptosis
in spermatocytes by increasing the expression of
proapoptotic factors (Bax and Bak), induction of cy-
tochrome 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 intoxi-
cation with these compounds in humans evoked dis-
turbances of motor coordination, headaches, perma-
nent cognitive dysfunction, CNS depression and occa-
sionally 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,
1244 Pharmacological Reports, 2010, 62, 12431249
which indicate that EGEs attenuate antioxidant de-
fense system and increase lipid peroxidation, their
similar effect in the brain, especially in structures par-
ticularly 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 hy-
drogen peroxide (oxidative stress)-induced damage in
the human neuroblastoma (SH-SY5Y) cells. For this
study, we chose 2-methoxyethanol and 2-ethoxy-
ethanol, i.e., the compounds with the most potent re-
productive toxicity, 2-butoxyethanol and 2-isoprop-
oxyethanol solvents with strong hemolytic activity and
2-phenoxyethanol, which reduces NMDA-induced cur-
rents. 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 strepto-
mycin (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 con-
centrations from 0.1 to 25 mM alone or with hydro-
gen 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-

dia 24 h after the treatment with EGEs alone or to-
gether with hydrogen peroxide. Cell-free culture su-
pernatants 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 2,4-
dinitrophenylhydrazine, is inversely proportional to the
LDH activity in the sample and was quantified by meas-
uring the absorbance at 490 nm.
3-[4,5-dimethylthiazol-2-yl]2,5-diphenyl tetra-
zolium 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 in-
dependent 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 meas-
ured at 570 nm in a plate reader (Multiscan, Labsys-
tem). 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 experi-
ments, each performed in 34 wells and were pre-
sented as the percentage of control SEM. The sig-
nificance 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 re-
lease and MTT reduction. There were no fundamental
differences between these tests. Exposure of SH-SY5Y
cells to 2-phenoxyethanol for 24 h produced cytotox-
icity, as assessed by LDH release and MTT test.
Neurotoxicity of ethylene glycol ethers
Magdalena Regulska et al.
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-isopro-
poxyethanol 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 concentration-
dependently (125 mM) increased the basal LDH release
and MTT reduction (Fig. 3A, C). 2-Methoxyethanol did
not show a cytotoxic effect because in the concentra-
tion 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 as-
sessed by the LDH and MTT assay (Tab. 1). However,
this compound at concentrations of 10 and 25 mM en-
hanced 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-Phen-
oxyethanol in a concentration-dependent manner
increased both the basal and hydrogen peroxide-
induced damage of the cell membrane and inhibited
Pharmacological Reports, 2010, 62, 12431249 1245

the basal and hydrogen peroxide-induced mitochon-
drial function. The statistically significant cytotoxic
effect of this compound was evident at 5 mM concen-
tration. 2-Isopropoxyethanol already in a concentra-
tion 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
1246 Pharmacological Reports, 2010, 62, 12431249
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 SH-
SY5Y cells. Results are shown as
a percentage of control cells incu-
bated in the absence of 2-phen-
oxyethanol and H O (A, C) or in the
presence of H O only (B, D). The sig-
nificance 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 ba-
sal (A) and H O -induced (B) LDH re-
lease 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 be-
tween 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)
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-ethoxy-
ethanol 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
A B
#
140 *
Fig. 3. Effect of 2-isopropoxyethanol *

LDH release
120 * * *

% of control
on basal (A) and H O -induced (B) 100
LDH release and basal (C) and H O -
80
induced (D) MTT reduction in SH-
60
SY5Y cells. Results are shown as
a percentage of control cells incu- 40

bated in the absence of 2-isoprop- 20

oxyethanol and H O (A, C) or in the 0
presence of H O only (B, D). The sig- H2O2 - - - - - - + + + + + +
nificance of differences between the 2-isopropoxyethanol - 0.1 1 5 10 25 - 0.1 1 5 10 25 [mM]
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 ,
120 C D
n = 12)
100 * *
80
* * *
MTT reduction
% of control

60

40

20

H2O2 - - - - - - + + + + + +
2-isopropoxyethanol - 0.1 1 5 10 25 - 0.1 1 5 10 25 [mM]

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 LDH MTT

Vehicle 100.0 1.2 100.0 2.4 Vehicle 100.0 1.1 100.0 2.4

2-methoxyethanol 0.1 mM 100.5 3.4 101.3 2.9 2-ethoxyethanol 0.1 mM 99.0 1.9 95.2 5.9

2-methoxyethanol 1 mM 99.8 3.2 110.2 2.3 2-ethoxyethanol 1 mM 99.5 2.7 106.6 5.1

2-methoxyethanol 5 mM 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 me-
dia 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, 2-
phenoxyethanol, 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 substi-
tute for 2-methoxyethanol and 2-ethoxyethanol. More-
over, 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
1248 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-phen-
oxyethanol, 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 neuro-
toxic 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.
Pharmacological Reports, 2010, 62, 12431249 1249