Journal of Analytical Toxicology, Vol. 22, July/August 1998
Identification Limitsfor Volatile Organic
Compoundsin the Blood by Purge-and-TrapGC-FTIR
Ilkka Ojanper~i, Katja Pihlainen, and Erkki Vuori
Department of Forensic Medicine, P.O. Box 40, FIN-O0014 University of Helsinki, Helsinki, Finland
Abstract
An analysismethod for volatile organic compoundsin blood
based on purge-and-trap extraction coupled with gas
chromatography-Fourier transform infrared spectroscopy
(GC-FTIR) was developed. The sample volume was 5 mL, and the
internal standard was diethyl ketone. The chromatographic
separation was carried out on a PoraPLOT Q capillary column,
and the effluent was first directed to the FTIR and then to a flame
ionization detector (FID). FTIR identification limits were measured
for 27 volatile organic compounds;the criteria for the limit were
that the first hit-list position should be obtained againstthe Sadtler
library, which contains 3240 spectra, and that the correlation
value should exceed 0.5. It was required that the peak be seen by
FID but not necessarilyby a Gram-Schmidt chromatogram. The
FTIR identification limits, rangingfrom 0.01 mg/L for ethyl
acetate, methylethyl ketone, and sevofluraneto 24 mg/L for
methanol, generally allowed the detection of volatile-substance
exposure at a lower level than is acutely toxic. Quantitative
calibration data were presentedfor selected substances,based on
the FID response,which showsthat the method is also amenable
to quantitative analysis. The throughput of the method without
additional automation is five samples per day, the purge-and-trap
stage being the limiting factor.
Introduction
A considerable number of volatile organic compounds of toxicological relevance remain outside the routine alcohol determination of biological specimens performed by established
headspace gas chromatographic (GC) techniques. Because of
the high throughput requirements for such an alcohol analysis,
the methods usually focus only on ethyl alcohol and some congeners, such as methanol, isopropyl alcohol, acetone, tertbutanol, methylethyl ketone, and 2-butanol (1,2).
Important compounds that should be included in a broader
screening for volatiles in the blood are diethyl ether, ethyl
acetate, hexane, toluene, xylene, and some halogenated hydrocarbons, which are all common industrial and laboratory chem290
icals with a potential for abuse by sniffing (3). Methyl-tert-butyl
ether, which is used as an octane booster in gasoline, is a sensitive indicator of gasoline exposure (4,5). The liquefied petroleum
gas consisting of propane or butane or a mixture has been
involved in suicides and accidents, whereas butane, which is
used in cigarette lighters, has been abused by sniffing (3). The
currently used inhalation anaesthetics, desflurane, enflurane,
halothane, isoflurane, and sevoflurane (6), should be analyzed,
particularly in cases of death during anesthesia, and these substances have also been abused by hospital personnel (7).
GC is by far the most frequently used technique for the separation of volatile organic compounds, but both the extraction
and detection steps of the analysis can be carried out in several
ways. Recent studies usually used one of the following extraction
techniques: headspace (8), purge and trap (9), pulse heating (10),
or solid-phase microextraction (11). Polar compounds may even
be analyzed directly (12). In broad-scale screening procedures,
detection has usually been carried out with traditional GC detectors, such as the combination of flame ionization (FID) and
electon capture (ECD) (13), or with mass spectrometry (MS) (14).
In a recent paper from this laboratory (5), a method involving
purge-and-trap PoraPLOT Q-capillary GC coupled with Fourier
transform infrared spectroscopy (FTIR) was introduced with
several examples of actual forensic toxicological casework. In the
present paper, an improved sensitive method using current FTIR
instrumentation is described.
Materials and Methods
Materials
The blood used for the identification limit and linearity studies
was mixed porcine/bovine blood containing 1% NaF. The case
blood samples, which contained 1% NaF, were taken at forensic
autopsies.
The internal standard (IS) solution was a 0.25 g/L aqueous solution of diethylketone. The standard solutions of the volatile substances investigated were prepared in methanol by adding the
substances under the liquid surface with a gas-tight syringe. All of
Reproduction (photocopying) of editorial content of this journal is prohibited without publisher's permission.
Journal of Analytical Toxicology, Vol. 22, July/August 1998
the solutions were stored under refrigeration (4~ The standard
blood samples or standard mixtures of two to six substances with
differing retention times were prepared by adding 5-10 IJL of the
methanolic solutions to 5-50 mL of blood with a gas-tight syringe.
the FTIR light pipe and then was directed to the FID.
The spectral library was the Enhanced EPAVapor Phase Select
Database, which contained 3240 spectra (Bio-Rad Sadtler, Hemel
Hempstead, U.K.), or an in-house library, which contained 50
spectra.
Apparatus
Extraction
The purge and trap concentrator was a Tekmar 3000 (Cincinnati, OH) equipped with a 1/8-in. x 12-in. Tenax trap. The heated
transfer line from the concentrator entered the GC through a
septum needle adapter. The GC was a Perkin Elmer 8600 (Norwalk, CT), equipped with an FID. The instrument was operated
using the software revision C.01 (Perkin Elmer).
The FTIR spectrometer was a Perkin Elmer Spectrum 2000
equipped with a system 2000 GC-IR interface and an external
narrow band MCT detector. The spectrometer was operated
using Spectrum 1.10 and Spectrum Search 1.50B software
(Perkin Elmer). The interface was operated using the TR-IR
1.00 software. The column flow from the GC first passed through
Internal standard solution (100 IJL) was added to a sample of
blood (5 mL) with a syringe under the liquid surface to obtain a concentration of 5 mg/L. The sample was placed into a 5-mL sparger,
and a drop of Antifoam B emulsion (Sigma, St. Louis, MO) was
added. The room-temperature extraction was performed according
to the Tekmar default procedure (15) with modifications in the
line, valve, and mount temperatures, purge time, and dry purge
time. The helium sample flowwas 38 mlJmin. The sample pressure
was 140 kPa, and the trap pressure was 50 kPa. The trap TurboCool
temperature was -20~ The purge time was 15 min, and the dry
purge time was 6 min. The desorption temperature was 225~
and the desorption time was 2 rain. The line and
valve temperature was 150~ and the mount temTable I. Relative Retention Times and FTIR Identification Limits for
perature was 80~
Volatile Organic Compounds in Blood
Compound
Mean
RRT*
CV%
Idenlification
limit (mg/L)t
Propene
Propane
Methanol
Acetaldehyde
Butane
Ethanol
Desflurane
Acetonitrile
Acetone
Isopropyl alcohol
Sevoflurane
Diethyl ether
n-Propanol
lsoflurane
Enflurane
tort-Butanol
Methylethyl ketone
Halothane
Methyl-tort-butyl-ether
Ethyl acetate
Isobutanol
Hexane*
1,1,1-Trichloroethane
Benzene
n-Butanol
Diisopropyl ether
1,1,2-Trichloroethene
Diethyl ketone
Methylisobutyl ketone
Toluene
m-Xylene
0.390
0.408
0.477
0.512
0,616
0.636
0.651
0.665
0.726
0.741
0.758
0.766
0.803
0.817
0.831
0.834
0.862
0.871
0.901
0.902
0.922
0.922
0.932
0.941
0.951
0.970
0.995
1.000
1.07
1.08
1.19
0.38
0.32
0.34
0,22
0.41
0.29
0.55
0.30
0.14
0.53
0.80
0.27
0.56
0.34
0.25
0.25
0.17
0.49
0.31
0.05
0.28
0.57
0.42
0.60
0.25
0.22
0.59
0.14
0.33
0.21
24
0.5
t0
0.13
20
0.6
0.6
0.01
0.05
5
0.5
0.7
1
0.01
0.07
0.02
0.01
1.5
0.04
0.08
0.2
10
0.03
0.08
0.05
0.02
0.08
* 1-he mean RRT and CV% are based on five measurements of single concentration blood samples over a
five-week period.
The identification is based on two criteria: #1 hit-list position and a correlation value > 0.5 with the
corresponding spectrum in the Sadtler spectrum library. For the anesthetics, the in-house library was used.
Not always the #1 hit-list position because of other hydrocarbons with similar spectra.
Chromatographicconditions
The analytical column was a PoraPLOT Q (25 m
x 0.32 ram, 10-1Jm film thickness, Chrompack,
Middelburg, The Netherlands). The carrier gas was
helium with a flow rate of 3.8 mL/min at 30~ The
injector was operated without carrier gas splitting
or septum purge. The oven temperature was initially held at 30~ for 2 min, then increased by
15~
to 250~ and held at the final temperature for 5 rain. The injector and detector temperatures were 250 and 270~ respectively.
Spectrometer and interface conditions
The resolution was 8 cm-1, the spectral range
was 4000-700 cm-1, and the scan speed was 2
cm/min. The interferogram type was double-sided
bidirectional, and the strong Norton-Beer apodization was used. In addition to storing all the scans
throughout the run, co-added spectra for the chromatogram peaks detected with a threshold value of
100 were stored. An automatic baseline-correction
procedure that picks baseline regions on either side
of peaks and subtracts the baseline spectrum from
each peak spectrum based on a linear interpolation
between the baseline regions was used. The baseline
spectra contained eight co-added scans similar to
the original background spectrum. Occasionally,a
manual baseline correction was used. The light pipe
heated zone temperature was 250~ The makeup
gas was helium at a flow rate of 0.5 mL/min.
Identification limits
The criteria for establishing the FTIR identification limit were that the euclidean search hit-list
position against the Sadtler library should be
number one and that the spectral correlation with
291
Journal of Analytical Toxicology, Vol. 22, July/August 1998
the correct library spectrum should be over 0.5. It was not
required that a signal should be seen in the Gram-Schmidt
chromatogram because the more sensitive FID revealed the
peak position in each case.
obtained using an in-house library. The euclidean search proved
to be the best among the search procedures provided by the software, and this was even more pronounced at low concentrations.
Figures 1 and 2 show the analysis of a blood sample fortified
with isopropyl alcohol (4 mg/L), halothane (0.25 rag/L), and
toluene (0.5 mg/L) in methanol. Although the compounds could
not be seen at these concentrations in the Gram-Schmidt chromatogram, they could be clearly detected at the FID and positively identified by their FTIR spectra using either library. The
concentrations reflect such levels that may be obtained by
inhalation during occupational exposure. When no exogenous
volatile organic compounds were present in the blood, the FID
chromatogram was easy to interpret, revealing only some acetone, acetaldehyde, and ethyl acetate, and, in putrefied cases,
alcohols, aldehydes, and sulfides as well (16).
Table II shows the regression equations and correlation coefficients for selected volatile compounds based on the FID. The
coefficient of variations (CV) for quantitation were generally
2-10% and 10-20% in within-day (n = 5) and day-to-day (n ---5
over a five-week period) studies, respectively. The
best linearity and precision were obtained with
A
carbonyl compounds, but the lowest were
obtained with low molecular weight alcohols: the
day-to-day CVs of acetone and isopropyl alcohol
were 10 and 25%, respectively. The purge-andtrap stage had the largest influence on precision,
judging from comparisons with unextracted sampies, and regular baking and gas flushing of the
trap and concentrator lines were needed to maintain the performance of the instrument. A blank
run between samples was necessary to prevent
carry-over, especially when concentrated samples
were analyzed, and this limited the throughput of
the method to five samples per day.
Results
The relative retention times (RRT), related to diethyl ketone,
and their day-to-day precision for 30 common volatile substances analyzed by the present method are listed in Table I.
Table I shows the FTIR identification limits of the substances
against the Sadtler library. Although the correlation limit was set
to 0.5 in the criteria for the identification limit (see Materials and
Methods), the actual correlation values obtained were generally
over 0.8 at the identification limit, with the hit-list position being
the determining factor. At the given identification limits, top hitlist positions and nearly equal correlation values were also
9i
Discussion
I
Int
B
lOO0.
327.0
0
,
2
,
4
,
6
,
8
Time
,
1
,
12
,
1
,
16
(rnin)
Figure 1. Analysis of a 5-mL blood sample fortified with isopropyl alcohol 4 mg/L (peak 2),
halothane 0.25 mg/L (peak 3), and toluene 0.5 mg/L (peak 5)in methanol (peak 1) and with
the IS diethyl ketone 5 mg/L (peak 4). Detection by (A) FID and (B) FTIR(Gram-Schmidt chromatogram).
292
"
The precision of the RRT was highest for the
carbonyl compounds, as would be expected with a
ketone IS possessing related polarity. Satisfactory
precision was obtained in general, which suggests
there is no need to frequently recalibrate the RRT
values. Diethyl ketone has advantages as an IS: it
is water soluble and thus easy to handle, it is rarely
encountered in biological specimens, and its
polarity properties are close to low molecular
weight ketones, aldehydes, and esters.
Most of the present identification limits are considerably better than those obtained in the previous study (5); they now generally allow the
detection of a much lower level of solvent exposure
than acutely toxic. Although the criteria for establishing the limit are different from the previous
study, the improvement is largely due to the more
sensitive spectrometer, the modified extraction
method, and, particularly, the more appropriate
Journal of Analytical Toxicology, Vol. 22, July/August 1998
design of the GC-FTIR interface. In the present
instrument, the capillary column directly enters
the narrow-bore light pipe without any junctions
that may cause peak broadening and adsorption.A
low identification limit is associated with the high
hydrophobicityand volatility of the compound and
especially with the presence of a strong IR absorbing functional group. The background noise
from the blood and from the instrumentation also
have an effect on the measurements. For acetone,
acetaldehyde, and ethyl acetate, even lower identification limits than reported here could be
obtained if these compounds did not alwaysexist in
the blood at low concentrations.
In order to increase the reliability of volatile
substances screening by solely chromatographic
methods, parallel columns of different polarity,
retention indices, or two different detectors have
been used (13,17-19). Such methods, however,
need frequent qualitative calibration to prevent
the substances from moving out from their narrow
detection windows. Combined chromatographicspectrometric methods are easier to maintain in
Table II. Quantitive Calibration Data for Selected Volatile Organic
Compounds in Blood*
Regression
equatio#
Compound
Correlation
coefficient
Range
(rag/L)*
0.993
0.999
0.983
0.973
0.982
0,862
0.999
0.994
0.979
0.999
0.999
0.966
0.986
0.985
0.983
0.5-30
0.1-30
20-100
1-50
0.1-20
10-100
0.1-20
2-50
20-200
0.3-50
0.1-50
0.02-20
1-20
1-20
1-20
Acetaldehyde
y = 0.087x + 0.48
Acetone
y = 0.096x + 0.060
Acetonitrile
y = 0.067x- 0.035
tert-Butanol
y = 0.040x- 0.066
Diethyl ether
y = 0.55x + 0.42
Ethanol
y = 0.0052x + 0.10
Ethyl acetate
y = 0.23x + 0.040
Isopropyl alcohol
y = 0.016x + 0.034
Methanol
y = 0.0056x- 0.065
Methylethyl ketone
y = 0.16x - 0.044
Methylisobutyl ketone
y = 0.31 x + 0.19
Sevoflurane
y = 0.13x- 0.041
Toluene
y = 0.68x- 0.21
1,1,1-1richloroethane
y = 0.19x- 0.079
m-Xylene
y = 0.49x- 0.15
*
Basedon the FID response.
(area of analyte)/(area of IS).
Concentrations range of [inearity study; 5-7 concentrationsanalyzed in duplicate.
* Variables: x = c o n c e n t r a t i o n (mg/L), y =
*
A
100.0
2~
;000
4000.0
u'oo
lobo
sob.o
cm-1
I00.0 .
.
.
.
B
~
%T 60
40
20
I0,0
4000.0
3000
2000
1500
1000
700.0
Cm-1
C
I00,0
20 J
10.0 I
4oo0.0
v
3o~o
2o'00
u'oo
cm-1
lobo
500.0
0.768 EL0520 ISOPROPYL ALCOHOL
0.570 EL2485 ACETALDEHYDE,DIETHYL ACETAL
0.531 EL0422 PROPANE,2..CHLORO-2-METHYL-,
0.515 EL0117 BUTANE, 2..CHLORO-,
0.497 EL0915 BUTANE, 2~HLORO-2-METHYL-,
0.495 EL0370 BUTYL ALCOHOL,TERT-,
0.495 EL2478 PROPANE,2-CHLORO-,
0.475 EL0058 2-BUTANOL,2-METHYL-,
0.459 EL0998 3-PEN'I'EN-2-OL,4-METHYL-,
0.459 EL0290 2-PROPANOL, I,IPR..OXYDI-,
0.449 EL0436 3-PENTANOL,3-ETHYL-,
0,448 El.0401 2-PROPANOL, I..CHLORO-,
0.444 EL0286 PROPANE, 1-BROMO-3-CHLORO-2-METHYL-,
0.433 EL0390 3-PENTANOL
0.432 EL1636 2,3-BUTANEDIOL
0,429 EL1223 PROPANE, 1,2-EPOXY-3-1SOPROPOXY-,
0.428 ELI037 2,4-PENTANEDIOL
0 428 EL2143 SULFIDE~ETHYl. ISOPROPYL.
0.423 EL0211 2-BUTANOL.3-METHYL-,
0.422 EL0782 2-PENTANOL.2-METHYl.-,
0.868 GC0390 HALOTHANE
0.514 GC0370 ENFLURANE
0.409 GC0130 CHLOROFORM
0.374 GC0100 ACETONE
0.341 GC0470 TERT.BUTYLMETHYL EIHER
0.293 GCO180 1,2-DICHLOROETHANE
0.248 GC0360 I,I,I-TRICHLOROETHANE
0.246 OC0080 ETHYL ACETATE
0.246 GC0550 TETRAHYDROFURAN
0.241 GC0380 ISOFLURANE
0.237 CRC0240BUTYL ACETATE
0.229 GCO010 ETHANOL
0.228 GC0490 DESFLURANE
0.220 GCO120 I -PROPANOL
0.219 GC0520 DIISOPROPYL ETHER
0.200 GC0420 NITROUS OXIDE
0.200 GC0340 DIETHYL ETHER
0.173 GC0050 1-BI I T A N O L
0.155 GC0560 TR IETHYLAMINg
O,139 GCO190 2.2,2-TRICtlLOROETItA NOL
0901 EL0026 BENZENE, METIIYI.-,
0.731 E1,1692ACETONITRILE,PHENY[.-.
0 723 El.1205 BIBENZYL
0.702 EL2686 PROPANE. 1,3-DIPHENYI.-,
0.701 EL2609 BUTANE, I-BROMO-2.4-DIPH~NYL-,/PLUS/-,
0.675 EL0g06 O-XYLENE
0.675 EL1g52 ETHYLAMINE, 1.2-DIPHENYL-,
0.663 EL3238 BENZENE, CYCLOPROPYL-,
0.648 EL3062 BENZYI. ALCOIIOL, O-BENZYL-,
0.635 EL2642 ISOQUINOLINE. I-BENZYL- 1,2,3,4-TFYFRAHYDRO-.
0631 EL0479 BIPH~/YL, 3-METIIYL.,
0.618 EL1873 BENZYL MERCAPTAN
0611 EL0795 SULFIDE. pHENYL 3-PHENYLPROPYL,
0610 ELI751 SULFIDE, PtIENETHYL PIIENYL,
0599 EL2610 HEXANE, 1,3.5-TRIPHENYL-,/KACEMIC/-,
0 594 EL1917 METHANE, CHLORODIPHENYL-,
0594 EL3078 O-CRESOL, A-PHENYL-,
0.584 EL2430 BIPHENY1. 4-METHYL-.
0 575 EL1890 2.BUTENE. I-PIIE.NYL-.
0574 EL034? I-PROPANOI., 3.3-DIPHENYL .
Figure 2. Sample FTIR spectra superimposed with the library spectra and library search results for the analyles of Figure I : (A) isopropyl alcohol (Sadtler library),
(B) halothane (in-house library; substance not included in the Sadtler library), (C)toluene (Sadtler library),
293
Journal of Analytical Toxicology,Vol. 22, July/August1998
this respect because more weight can be put on the spectral
analysis, which is usually more reproducibie than the chromatographic analysis. Consequently, a number of methods that
combine GC with MS have been published (14,20-24), and, if
the purge-and-trapextraction is combined, extremely low detection limits can be achieved (4,9,25,26). The main advantageof the
FTIRidentificationis the high information content of the spectra
of low molecular weight compounds, which allows the ready
recognition of the substance class, whereas homologues can be
further differentiated by the chromatographic RRT.
The quantitative evaluation showed that the present method
is amenable to quantitative analysis of apolar and medium-polar
compounds in the blood. However, optimal extraction conditions
were not obtained for methanol and ethanol at the concentration
level studied becauseof their irreproducible adsorption behavior
in the purge-and-trap concentrator. The problems associated
with quantitative analysis of polar analytes in aqueous matrices
by purge and trap have been recently investigated (27).
Toxicologically interesting volatile organic compounds are
numerous, but the prevalence of findings in forensic toxicology
is low compared with drugs and alcohol. This is partly due to the
technical fact that volatile compounds require a special method
that is not necessarily applied to every case without indicative
background information. In clinical cases, the substances may
not be detected in the blood because of rapid elimination
through the lungs. Regardless of the relatively low prevalence,
statistics from many countries, such as the U.K. (28), show that
volatile substance abuse is an established problem, and, consequently, the systematic analysis of these substances should be
performed more regularly in connection with forensic toxicological investigation (29). The present method, although not
well suited for high-throughput screening, has proved to be an
invaluable tool in the analysis of volatile substances from
propane to xylene in suspected cases. The earlier paper from this
laboratory (5) and this paper are the only published studies on
purge-and-trap GC-FTIR in analytical toxicology.
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