HEMAPHERESIS

Donor exposure to the plasticizer

di(2-ethylhexyl)phthalate during plateletpheresis
Christoph Buchta, Claudia Bittner, Paul Hcker, Maria Macher, Rainer Schmid, Christoph Seger,
and Markus Dettke

BACKGROUND: Di(2-ethylhexyl)phthalate (DEHP) is

a plasticizer that is contained in most PVC devices,
including apheresis disposables. Because DEHP can
be extracted from apheresis disposables as the blood
passes through the apheresis device, DEHP exposure
was determined in healthy donors undergoing plateletpheresis performed with commercially available apheresis systems.
STUDY DESIGN AND METHODS: The study population consisted of 36 healthy PLT donors undergoing
plateletpheresis with either continuous or discontinuous
apheresis devices. Serum concentrations of DEHP
were determined from peripheral blood obtained before
and after plateletpheresis, with gas chromatographymass spectroscopy.
RESULTS: Plateletpheresis performed with standard
collection disposables resulted in a median increase of
232 percent of serum DEHP compared to levels before
apheresis, corresponding to a total amount of DEHP
exposed during a single apheresis of a median of 6.46
(range, 1.8-20.3) mg per kg of body weight. Endogenous levels of triglycerides showed a positive correlation with the amount of DEHP released. Increase in
serum DEHP was short-term as serum DEHP rapidly
returned to levels obtained before apheresis within 3
hours after completion of the apheresis course. Donor
exposure to DEHP led to no variation in liver cell function within 48 hours after plateletpheresis.
CONCLUSION: Commercial plateletpheresis disposables release considerable amounts of DEHP during
the apheresis procedure, but the total dose of DEHP
retained by the donor is within the normal range of
DEHP exposure of the general population.

wide variety of medical devices are manufactured from PVC. Because PVC is hard and
brittle at room temperature, plasticizers such
as di(2-ethylhexyl)phthalate (DEHP) are added
to make the physical properties of the material more suitable.1 Based on the high flexibility, the high resistance to
shear stress, and the possibility of being sterilized, PVC
plasticized with DEHP found wide use in medical appliances used in transfusion medicine, including fluid bags,
tubing sets, or plastic bags used for the collection and
storage of blood and blood components. One disadvantage of DEHP is that the plasticizer is not bound to the PVC
polymer.2 By contact with liquids, including blood, DEHP
can be extracted from PVC.3-6 Increased blood levels of
DEHP have been described in recipients of blood components,7 although the human health risks posed by medical
devices containing DEHP remain uncertain.8,9 To minimize transfusion-associated exposure to DEHP, most
recently the FDA has recommended the consideration of
the use of PVC devices that do not contain DEHP, at least
in selected high-risk groups including neonates or pregnant women.10
The collection of single-donor PLT concentrates by
automated apheresis devices is a routine procedure per-

ABBREVIATION: DEHP = di(2-ethylhexyl)phthalate.

From the Department of Blood Group Serology and Transfusion
Medicine and the Institute for Medical and Chemical Laboratory Diagnostics, Vienna General Hospital, University of Vienna,
Medical School, Vienna; and the Department of Pharmacognosy, University of Innsbruck, Innsbruck, Austria.
Address reprint requests to: Markus Dettke, MD, Department for Blood Group Serology and Transfusion Medicine,
Vienna General Hospital, University of Vienna, Medical School,
Whringer Grtel 18-20, 1090 Vienna, Austria; e-mail:
markus.dettke@univie.ac.at.
Parts of this study were supported by a grant of the
Hochschuljubilumsstiftung der Stadt Wien, Vienna, to M.D.
Received for publication December 16, 2002; revision
received April 19, 2003, and accepted April 14, 2003.
TRANSFUSION 2003;43:1115-1120.
Volume 43, August 2003 TRANSFUSION

1115

BUCHTA ET AL.

formed in many blood banks and transfusion services.

During plateletpheresis, donor blood passes through the
collection disposables of the apheresis device before the
blood returns to the donor. Parts of these collection disposables are manufactured with PVC containing DEHP.
During blood passage through the apheresis instrument,
DEHP can be resolved in the blood, leading to leaching of
DEHP into the donor. To assess DEHP exposure associated
with PLT donation, in the present study we analyzed
the serum levels of DEHP in donors undergoing routine
plateletpheresis.

MATERIALS AND METHODS

Study population and plateletpheresis procedures
Thirty-six healthy PLT donors (23 men, 13 women) participated in the study after written informed consent was
obtained. Seventeen donors underwent plateletpheresis
with continuous (double-needle) apheresis machines;
in 19 donors PLT collection was performed with discontinuous (single-needle) cell separators. Plateletpheresis
was performed with different systems (in 5 subjects, the
Spectra apheresis system [Gambro Cobe BCT, Inc., Lakewood, CO] with the LRS 000-777-120 Spectra dual-needle
extended-life PLT set with LRD chamber [Gambro BCT
Ltd., Quedgeley, UK]; in 6 donors, the Com.Tec cell
separator and the C5L PLT set [Fresenius HemoCare,
Bad Homburg, Germany]; and in 6 donors, the Amicus
cell separator with the R4R2314 Amicus double-needle
apheresis kit [Baxter Healthcare Corporation, Deerfield,
IL]). Discontinuous plateletpheresis was performed with
the following system (MCS + LN 9000-220-E [Haemonetics Corporation, Braintree, MA], with the 994 CF-E
extended storage PLT and apheresis set [Haemonetics UK
Ltd., Bothwell, UK]). Detailed donor characteristics and
apheresis related key data are summarized in Table 1.

Collection of blood samples

and acetonitrile were purchased in from Merck (Darmstadt, Germany), n-heptane was obtained from Fluka
(Buchs, Switzerland), and n-decane 99+ percent was purchased from Aldrich (Steinheim, Germany). Deionized
water was prepared by a water purification system (MilliQ, Millipore; Vienna, Austria).

Extraction procedure
For extraction of DEHP from serum samples, a method
described elsewhere4 was modified. In brief, 500 mL of
serum was transferred to a 10-mL glass tube, and 2.1 mL
of 5 percent aqueous methanol was added. Proteins were
precipitated with 2.5 mL of acetonitrile, and 50 mL of internal standard was added before shaking the mixture on a
vortex. DEHP and the internal standard were extracted
into 2.5 mL of n-heptane by shaking for 10 minutes. After
centrifugation at room temperature (1000 g; 10 min), the
organic layer containing DEHP was removed. After addition of n-decane, the samples were evaporated to a final
volume of 200 mL. One microliter of the final extract was
injected into the gas chromatography system.

DEHP analysis
Serum samples were analyzed with gas chromatographymass spectrometry. Separation was achieved on a gas
chromatograph (Fisons GC 8000, Fisons Instruments SpA,
Milan, Italy), with a 5 percent diphenyl-95 percent dimethylpolysiloxane capillary column (25 m length, 0.2 mm
inner diameter, 0.2 mm film thickness; Optima 5MS,
Macherey-Nagel, Dren, Germany). The helium flow rate
was set at 3.0 mL per minute. The following operating settings were used: an injector temperature of 280C and an
oven temperature programmed from 160C (held for
1 min) at 30C per minute to 200C and at 6C per minute
to 280C (held for 10 min). DEHP was quantified with a
mass spectrometer (QMD 1000, Carlo Erba, Milan, Italy).
Mass spectrometry conditions were selective ion monitoring of the ions m/z 279, 167, and 149 for DEHP and m/z
328, 326, and 254 for the internal standard. The ion source
was operated in the electron ionization mode (70 eV,
250C). The limit of detection was 10 ng of DEHP per mL
of serum.

Peripheral blood was sampled before and after completion of plateletpheresis. In four donors, additional blood
sampling was performed at 1, 3, 6, 24, and 48 hours after
completion of the apheresis course. To avoid any secondary contamination with DEHP derived from syringes
manufactured with PVC, blood was
taken through metal canulas and collected in glass tubes. After collection,
TABLE 1. Patient characteristics and apheresis-related key data
the blood was centrifuged and the
Single-needle devices
Double-needle devices
serum was stored at -20C.
Number of donors (male/female)
19 (14/5)
17 (9/8)

Chemicals
DEHP was used as internal standard
and was obtained from Dr Ehrenstorfer
GmbH (Augsburg, Germany). Methanol
1116 TRANSFUSION Volume 43, August 2003

Total blood volume (L)*

Total plasma volume (L)*
Inlet blood flow (mL/min)*
Total blood volume processed (L)*
Total apheresis time (min)*
* Data are expressed as median (range).

5.0 (3.3-6.1)
2.9 (2.1-3.5)
68 (56-80)
3.3 (2.9-4.0)
79 (48-89)

4.4 (3.4-5.7)
2.6 (2.1-3.3)
72 (60-80)
3.7 (2.6-4.7)
70 (38-81)

DEHP EXPOSURE DURING PLATELETPHERESIS

Estimation of total amount of DEHP exposed

during plateletpheresis

800

Given a recovery of 100 percent in plasma, the individual

amount of DEHP exposed during plateletpheresis was
estimated according to the formula
Total amount of DEHP exposed = (a - b) c,

Statistical analysis
Data are expressed as median and range. Differences in
serum DEHP as assessed before and after plateletpheresis
were compared by t test for paired samples and by U test,
when appropriate. A p value of less than 0.05 was considered significant.

DEHP (ng/mL)

where a is the serum level of DEHP as determined after

apheresis, b is the serum level of DEHP as determined
before apheresis, and c is the donors total plasma volume.

600

400

200

RESULTS
Increase in serum DEHP after plateletpheresis
To assess the effect of plateletpheresis on serum DEHP
levels, we compared DEHP levels obtained after completion of the apheresis procedure to those obtained before
apheresis (Fig. 1). Plateletpheresis resulted in a marked
increase in serum DEHP. Median serum levels of DEHP
increased from baseline levels of 92.2 (range, 5.9-219.6) to
213.8 (range, 7.3-716.1) ng per mL, corresponding to a
median DEHP exposure of 6.46 (range, 1.8-20.3) mg per kg
of body weight. DEHP was independent of the apheresis
technology used. In single-needle apheresis machines, the
median DEHP exposure was 6.4 (range, 1.9-19.5) mg per kg
of body weight compared to 7.2 (range, 2.0-20.3) mg per kg
of body weight when continuous apheresis machines
were used (p = 0.85). There was no association between
increase in serum DEHP and apheresis-related modifications of the apheresis procedure. Serum DEHP increased
independently of the inlet blood flow (p = 0.82), total
amount of blood processed (p = 0.89), or total apheresis
time (p = 0.79) (data not shown).
Follow-up kinetic analysis of serum DEHP revealed
that the increase of DEHP was short-term. DEHP levels
returned to values obtained before apheresis within 3
hours after plateletpheresis and remained at baseline
levels within the following 48 hours after completion of
the apheresis setting (Fig. 2).

Correlation between increase in serum DEHP and

endogenous serum lipid concentration
To assess whether endogenous factors can influence
DEHP release during plateletpheresis, we correlated the
concentration of serum triglycerides and serum cholesterol to the amount of DEHP released. There was a weak

0
Before

After
Plateletpheresis

Fig. 1. Increase in serum DEHP associated with plateletpheresis. There was a marked increase in serum DEHP after apheresis compared to DEHP levels obtained before plateletpheresis
(p < 0.0001).

association between the concentration of serum triglycerides and the relative increase in serum DEHP (Fig. 3;
r2 = 0.24, p = 0.03). In contrast, no correlation existed
between increase in DEHP and the concentration of
serum cholesterol (r2 = 0003; p = 0.8) (data not shown).

No changes in liver function measures

after plateletpheresis
To assess possible changes in liver enzymes after exposure
to DEHP, we monitored the serum levels of the liver parameters glutamic oxaloacetate transaminase, glutamic
pyruvic transaminase, gamma-glutamyltranspeptidase,
and cholinesterase for up to 48 hours after completion of
plateletpheresis. None of these measures showed any significant variations during the observation period (n = 8
donors; Table 2).

DISCUSSION
DEHP is a ubiquitous plasticizer that can leak from PVCderived materials.3 Because disposables used for plateletVolume 43, August 2003 TRANSFUSION

1117

2.5

5
*

2.0

4
Serum triglycerides (g/L)

Relative increase in serum DEHP compared to baseline (=1)

BUCHTA ET AL.

3
*

1.5

1.0

0.5

0.0
0
Before
After
Apheresis

3
6
24
Hours after apheresis

48

Fig. 2. Kinetics of serum DEHP after plateletpheresis. Serum

levels of DEHP declined to baseline within 3 hours after completion of the apheresis. Data shown represent the relative
variation of serum DEHP compared to baseline (=1). *p < 0.05
compared to baseline.

100
200
300
400
500
Relative increase in serum DEHP (%)

600

Fig. 3. Association between serum triglycerides and increase

in serum DEHP. There was a significant correlation between
serum triglyceride levels and the relative increase in serum
DEHP as obtained after plateletpheresis (r2 = 0.24; p = 0.03).

TABLE 2. Variations in liver function measures

Baseline*
After plateletpheresis
24 hr after plateletpheresis
48 hr after plateletpheresis

GOT (U/L)
12 (9-18)
10 (9-15)
10 (9-18)
11 (10-16)

GPT (U/L)
13 (10-35)
11 (7-33)
13 (9-37)
13 (11-28)

g-GT (U/L)
23 (8-42)
20 (8-30)
22 (7-39)
22 (8-39)

Cholinesterase (kU/L)
6.4 (3.5-7.8)
5.6 (2.9-7.4)
6.2 (3.2-8.6)
5.5 (3.3-8.5)

* Data are expressed as median (range).

GOT = glutamic oxaloacetate transaminase; GPT = glutamic pyruvic transaminase; g-GT = gamma-glutamyltranspeptidase.

pheresis are manufactured from PVC containing DEHP,

the aim of the present study was to determine the exposure to DEHP in normal donors undergoing plateletpheresis. Plateletpheresis caused up to a 10-fold increase
in serum DEHP compared to levels before apheresis.
Given a 100 percent recovery of DEHP in serum, the
median amount of DEHP exposed during a single plateletpheresis procedure was estimated to be 6.5 mg per kg
of body weight, with a broad interindividual variation
ranking from 1.8 to 20.3 mg per kg of body weight. Despite
this significant exposure to DEHP, the total amount of
DEHP leaching during plateletpheresis is at least 3 log
lower than the estimated DEHP exposure of 14.8 mg per
kg per day during hemapheresis previously calculated
by Doull et al.11 Furthermore, DEHP exposure during
plateletpheresis is low when compared to the DEHP exposure described in other medical settings (Table 3). For
1118 TRANSFUSION Volume 43, August 2003

example, during hemodialysis, the total dose of DEHP

retained by the patients is up to 3.1 mg per kg of body
weight.15 One explanation for the discrepancy between
hemodialysis and plateletpheresis is that in hemodialysis
the total blood volume processed is between 20 and 30 L,
which is 4 to 10 times higher compared to the 3 to
5 L of total blood volume processed during normal
plateletpheresis.
We observed a positive association between the levels
of serum triglycerides and the amount of DEHP retained
by the donors. This can be explained by the chemical
properties of the plasticizer. As a lipophilic substance,
leaching of DEHP is enhanced at higher plasma lipid
levels, as already demonstrated in other clinical settings.4,21 Variations in the apheresis course, such as modifications in inlet blood flow or the total blood volume
processed, showed no significant influence on the

DEHP EXPOSURE DURING PLATELETPHERESIS

TABLE 3. Estimated DEHP exposure during various medical settings

Hemodialysis
Blood transfusion in adults
Extracorporeal membrane
oxygenation in infants
Cardiopulmonary bypass

Total exposure DEHP (mg)

0.5-360

DEHP (mg/kg body weight)

0.01-7.2

14-600

0.2-8.0
42.0-140.0

References
Gibson et al.,13 Lewis et al.14
Pollack et al.,15 Schneider et al.16
Jacobson et al.,17 Kevy and Jacobson18
Schneider et al.16

2.3-168

0.03-2.4

Barry et al.,19 Jeger and Rubin20

12

* Modified from Tickner et al.

amount of DEHP released. These data are not in contrast

to previous findings demonstrating a time and temperature dependency on the extraction rate of DEHP.4,22
Plateletpheresis was performed at ambient room temperature, and the total apheresis time varied only marginally
between the different apheresis settings (Table 1). The
influence of physical factors on the DEHP extraction rate
might therefore be too small to be detected in our setting.
The small variations in total apheresis time may also
explain the lack of differences in the amount of DEHP
released from tubing sets of the various apheresis systems
tested, despite the increased contact surface area between
blood and tubing sets in continuous apheresis machines
compared to discontinuous cell separators.
Kinetic analysis revealed that the increase in serum
DEHP was only short-term. DEHP levels returned to
values obtained before apheresis within 3 hours after
completion of plateletpheresis. DEHP is converted by
plasma and liver enzymatic actions to mono(2-ethylhexyl)phthalate, and this metabolite is more toxic than
DEHP.23 In a animal model, the t50 of DEHP has been
reported to be 30 minutes.24 The observed rapid disappearance of DEHP from circulation is therefore in agreement with the quick metabolism of DEHP, although it
should be concerned that serum levels of mono(2-ethylhexyl)phthalate were not determined in the present study.
An alternative explanation may involve a multicompartment model where DEHP is accumulated in various
tissues, including the spleen, the liver, the lungs, and
abdominal fat.20
Toxicity associated with acute administration of
DEHP appears not to be very important.25 In accordance
with these findings, we did not observe any short-term
effects of DEHP exposure on liver cell function after
plateletpheresis. However, animal studies on the chronic
exposure to high doses of DEHP suggest a broad range of
effects on several organ systems. This includes adverse
effects in the reproductive tract, the kidneys, the lungs,
and the heart.12 Furthermore, DEHP can induce changes
in hepatic morphology and biochemical functions,11,26 and
chronic DEHP exposure is associated with an increased
incidence of liver tumors in DEHP-treated animals.27,28
Although these data implicate potential hazards of prolonged exposure to high doses of DEHP, it should be a

concern that DEHP is a ubiquitous environmental contaminant.29 In the general population, the total amount
of DEHP exposure is estimated to be in the range of 3 to
30 mg per kg of body weight and per day.8,11 Based on these
data and in view of our results assuming a median DEHP
exposure of 6.5 mg per kg of body weight during plateletpheresis, the additional DEHP uptake can be calculated to
be in the range of 5 to 20 percent above the daily exposure.
In some donors, the additional exposure might even
exceed 50 percent of the normal daily ingested and
inhaled uptake. However, this estimation has some limitations. Our calculation is based on the assumption of a
single-compartment model with a 100 percent recovery of
DEHP in serum and does not include the possibility of an
accumulation of DEHP in tissue. Furthermore, this estimation does not include any DEHP metabolism during
the time of the apheresis donation. However, despite these
uncertainties, it should be concerning that the FDA has set
the tolerable intake value of DEHP at 600 mg per kg of body
weight and per day.2 This value is approximately 30 times
higher than the highest serum levels of DEHP determined
in the present study. Our data therefore gave no evidence
for a critical DEHP exposure during plateletpheresis.
However, for safety issues, longitudinal studies must
exclude any potential hazard of repeat DEHP exposure in
repeat plateletpheresis donors.
ACKNOWLEDGMENT
The continuous help of the staff of the Department of Transfusion Medicine is acknowledged.

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