Trends in Analytical Chemistry, Vol. 26, No.

6, 2007

Trends

GC-MS and HPLC-MS analysis

of bioactive pharmaceuticals
and personal-care products
in environmental matrices
Chunyan Hao, Xiaoming Zhao, Paul Yang
We review analytical methods published between January 2001 and January 2007 using either gas chromatography (GC) or highperformance liquid chromatography (HPLC) separations and mass spectrometric (MS) detection technologies for the analysis of
bioactive pharmaceuticals and personal-care products (PPCPs) in environmental matrices. We emphasize sample preparation, the
pros and cons of available MS techniques, the benefits of using quality control and quality assurance (QC/QA) protocols during
routine analysis, and the difficulties associated with the matrix effect in the electrospray ionization (ESI) source. We discuss the
need for a concerted approach to determine numerical values associated with limits of detection in this emerging area of
environmental analysis, along with the use of QC/QA samples and low-level data qualifiers with recommended solutions.
Crown Copyright 2007 Published by Elsevier Ltd. All rights reserved.
Keywords: Chromatography; Detection limit; Mass spectrometry; Matrix effect; Pharmaceuticals and personal-care products; PPCPs; QA; QC;
Quality assurance; Quality control
Abbreviations: APCI, Atmospheric pressure chemical ionization; API, Atmospheric pressure ionization; ASE, Accelerated solvent extraction; BSTFA,
N,Obis(trimethylsilyl)trifluoroacetamide; DIN, Deutsches Institut fur Normung; EDC, Endocrine-disrupting chemical; EI, Electron impact; EOP,
Emerging organic pollutant; ESI, Electrospray ionization; EURACHEM, European Analytical Chemistry; GC, Gas chromatography; HFBA,
Heptafluorobutyric acid; HILIC, Hydrophilic interaction chromatography; HLB, Hydrophilic-lipophilic balanced; HPLC, High-performance liquid
chromatography; IDL, Instrument detection limit; ILC, Isotope-labeled compound; IT, Ion trap; IUPAC, International Union of Pure and Applied
Chemistry; LC, Liquid chromatography; LLE, Liquid-liquid extraction; LOD, Limit of detection; LOQ, Limit of quantitation; MAE, Microwave-assisted
extraction; MDL, Method detection limit; MRM, Multiple reaction monitoring; MS, Mass spectrometry; MSD, Mass-selective detector; MS2, Tandem
MS; MSTFA, NmethylN(trimethylsilyl)trifluoroacetamide; MTBSTFA, N(tertbutyldimethylsilyl)Nmethyltrifluoroacetamide; m/z, Mass-tocharge ratio; NSAID, Non-steroidal anti-inflammatory drug; NCI, Negative chemical ionization; PCI, Positive chemical ionization; PFB,
Pentafluorobenzyl; PFBBr, Pentafluorobenzyl bromide; PFBCl, Pentafluorobenzyl chloride; PLE, Pressurized liquid extraction; PPCPs, Pharmaceuticals and personal-care products; QA, Quality assurance; QC, Quality control; QqQ, Triple quadrupole; qTOF-MS, Quadrupole-time-of-flight mass
spectrometry; RT, Retention time; SD, Standard deviation; SIM, Selected ion monitoring; SNR, Signal-to-noise ratio; SPE, Solid-phase extraction;
SPME, Solid-phase microextraction; SRM, Selected reaction monitoring; TMSI, Ntrimethylsilylimidazole; TrBA, Tri-n-butylamine; TOF-MS, Timeof-flight mass spectrometry; UPLC, Ultra-performance liquid chromatography; USE, Ultrasonic solvent extraction; US EPA, US Environmental
Protection Agency; WWTP, Wastewater-treatment plant; XIC, Extracted ion chromatogram.

Chunyan Hao, Xiaoming Zhao, Paul Yang*

Applied Chromatography Section,
Laboratory Services Branch,
Ontario Ministry of the Environment,
125 Resources Road,
Etobiocke, Ontario,
Canada M9P 3V6

Corresponding author. Fax: +1 (416) 235 5900;

E-mail: paul.yang@ontario.ca

1. Introduction
This article reviews gas chromatographymass spectrometry (GC-MS) and liquid
chromatography-mass spectrometry (LCMS)-based analytical methods used for the
determination of bioactive pharmaceuticals and personal-care products (PPCPs) in
the environment. MS methods reviewed
may use single-quadrupole MS, magnetic
sector tandem MS (MS2), triple-quadrupole (QqQ) MS2, ion-trap MS (IT-MS),

0165-9936/$ - see front matter Crown Copyright 2007 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trac.2007.02.011

569

Trends

Trends in Analytical Chemistry, Vol. 26, No. 6, 2007

time-of-flight MS (TOF-MS), or hybrid quadrupole-TOFMS (qTOF-MS) in the analysis. PPCPs discussed in this
article refer to human and veterinary drugs and medical
diagnostic agents, as well as ingredients in personal-care
products (e.g., cosmetics, fragrances, food supplements,
shampoos, toothpastes, natural and synthetic compounds with endocrine-disrupting potency), and their
respective metabolites and transformation products.
Categorized as emerging organic pollutants (EOPs),
PPCPs have been the focus of global environmental
researchers attention since the late 1990s. PPCPs have
caused widespread concerns due to their extensive human and veterinary consumption, excretion or washing
off their hosts after their intended usages, and their entry
into the environment through effluents of wastewatertreatment plants (WWTPs), as well as surface-water runoffs and soil leaching after agricultural applications of
manure or treated sludge. As PPCPs were designed to
correct, enhance, or protect a specific physiological or
endocrine condition, their target effects in humans and/
or farm stocks are well understood and documented.
However, there is limited knowledge about their unintended effects in the environment. The fact that PPCPs
are in the environment and the lack of understanding in
their combined effects on non-target hosts is at the root
of the concerns that they cause.
To address the occurrence, the distribution and the
fate of PPCPs in the environment, efficient and reliable
analytical methods are needed. The relatively low concentration, high polarity, and thermal lability of PPCPs,
together with their interaction with a host of complex
environmental matrices, make their analysis challenging. Sample preparation followed by GC or HPLC separation, and qualitative and quantitative analysis using
various detectors has become the standard approach.
Compared to non-specific detectors (e.g., electron capture, ultraviolet or fluorescence), MS has the inherent
advantages of high selectivity, specificity, and sensitivity
and has been the technique of choice for PPCP analysis.
GC-MS, GC-MS2, LC-MS and LC-MS2 have become
indispensable tools for investigating PPCPs in environmental matrices. MS also allows the use of isotope-labeled compounds (ILCs), if available, to correct for matrix
effects and the uncertainty introduced during sample
preparation and analysis, further enhancing data
quality.
Since the first GC-MS determination of clofibric acid, a
metabolite of lipid-regulator clofibrate, in WWTP effluents [1], environmental scientists have reported the
occurrence of more than 80 PPCPs in the environment,
including soil, sediment, sludge (biosolid), manure,
treated and untreated sewage, surface water, groundwater, and drinking water. These PPCPs included
anti-inflammatory drugs, pain-killing drugs, cholesterollowering drugs, antibiotics, antiepileptic, anticonvulsants,
hormones, beta-blockers, lipid regulators, hypnotics,
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X-ray-contrast agents, caffeine, musks, and disinfectants.

This article focuses on the most recent developments and
applications of GC or LC separation and MS, MS2, or MS3
detection for the analysis of PPCPs in environmental
matrices, and how MS has helped to enhance the quality
of the analysis when used as for chromatographic
detection. We emphasize quality-control and qualityassurance (QC/QA) protocols, matrix effects, and the
requirements to enhance further the quality of data in
MS- or MS2-based PPCP analysis.

2. Sample preparation
Environmental concentrations of PPCPs are mostly in
the ng/Llg/L or pg/gng/g ranges, depending on
sample matrices. Analytes in samples therefore need to
be extracted and concentrated prior to instrumental
analysis. For aqueous sample matrices, solid-phase
extraction (SPE) has replaced traditional liquid-liquid
extraction (LLE) and become the sample-preparation
technique used most, as SPE allows sample extraction
and clean-up to be conducted at the same time. SPE
cartridges packed by different sorbents (e.g., C-18, nonpolar phase [2], ion-exchange phase [3], and polymeric
phase [4]) have been used to extract target PPCPs.
Waters Oasis HLB (Hydrophilic-Lipophilic Balanced)
cartridge has been the cartridge of choice for the preconcentration of both polar and non-polar compounds
using the same extraction conditions, a pre-requisite for
multi-residue analysis of different PPCPs. Novel polymer
sorbents have also been used in solid-phase microextraction (SPME), where smaller sample volumes and
shorter extraction times are required [5,6].
On-line, automated SPE procedures coupled with LCMS or LC-MS2 have been widely used in drug-discovery
laboratories to enhance data quality and operational
efficiency, and have been applied to the analysis of
PPCPs in aquatic environmental samples. This was done
by interfacing an automated SPE directly to LC-MS or
LC-MS2 to analyze low-ng/L levels of antibiotics in surface water, including sulfonamides [7], fluoroquinolones
and penicillins [8]. In addition, a new SPE-LC-MS2 system was also reported for the determination of estrogens
in natural waters with limits of detection (LODs) at the
ng/L levels [9]. On-line SPE eliminates time-consuming
and costly off-line SPE, enables higher throughput for
routine PPCP analysis, reduces human interactions with
the sample, and can be a useful tool to produce data
consistently with high quality.
For solid matrices (e.g., soil, sediment, sludge and fish
tissue), antibiotics are the most analyzed compound
class, although there are a few reports about other drugs
and endocrine-disrupting compounds (EDCs). Various
methods have been selected for the extraction of antibiotics and EDCs from solid matrices. These include initial

Trends in Analytical Chemistry, Vol. 26, No. 6, 2007

slurrying of samples into an aqueous matrix (sometimes

with added modifier) followed by liquid-liquid back
extraction of target analytes using various organic solvents [1012], accelerated solvent extraction (ASE) or
pressurized liquid extraction (PLE) [1318], ultrasonic
solvent extraction (USE) [15,19,20], and microwaveassisted extraction (MAE) [21], which have been employed to enhance extraction efficiency. Sample extracts
obtained from solid matrices are most of the time with
interfering co-extracts, which dictate an additional
clean-up before GC-MS, GC-MS2 and/or LC-MS or LCMS2 analysis. In this case, SPE is the method of choice
for sample clean-up [15,17].
Except for some neutral drugs and fragrance ingredients (musks), most PPCPs are polar, non-volatile, and
thermally labile compounds that are unsuitable for GC
separation. Derivatization of hydroxyl- and carboxylgroups prior to GC-MS or GC-MS2 analysis of PPCPs has
thus become a necessary step. This is a definite advantage of LC-based MS2 analysis, as no derivatization
would be required to achieve a good separation. Derivatization is usually done by using organic reactions (e.g.,
methylation, silylation, and acetylation) after analytes
are extracted and cleaned from the sample matrix.
Derivatization yield may be affected by different experimental parameters (e.g., temperature, reaction time and
different reaction agents used). Derivatization agents are
usually chosen according to their reactivity with the
analytes or the stability of their products so that
hydrolysis will be less likely to happen. In general, the
aromatic hydroxyl group would have the highest reactivity followed by the aliphatic hydroxyl group; and the
hydroxyl groups in position 17 of mestranol and 17aethinylestradiol, because of steric hindrance, will have
the lowest reactivity; N-methyl-N-(trimethylsilyl) trifluoroacetamide (MSTFA) would be the only known compound that can react with these two species for
quantitative GC-MS or GC-MS2 analysis [22].
Table 1 summarizes the agents that can be used to
derivatize sample extracts for GC-MS or GC-MS2analysis.
It is worth noting that, in using N,O-bis(trimethylsilyl)
trifluoroacetamide (BSTFA) and N-(tertbutyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA) to derivatize EDC estrone (E1) and 17a-ethynylestradiol (EE2),
two papers [23,24] reported that trimethylsilyl and
t-butyldimethylsilyl derivatives of EE2 were converted to
their respective E1 derivatives, either during derivatization or during chromatographic separation. Because of
this inter-conversion, results of E1 and EE2 can be biased
high and low, respectively, in samples analyzed. The use
of BSTFA and pyridine as derivatization agents and
hexane as the final solvent was therefore suggested to
get around E1 and EE2 inter-conversion for EDC analysis
[23]. It was also possible that, during acidic extraction,
diclofenac could be converted to 1-(2,6-dichlorophenyl)indolin-2-one, so that the quantitative results were

Trends

biased low for diclofenac [25]. It is therefore necessary to

investigate extraction and derivatization conditions to
avoid undesirable derivatization or extraction procedures
and to achieve reliable analytical results.
3. GC-MS and GC-MS2 studies
GC-MS was first used to determine PPCPs in the environment in 1976 [1]. GC-MS and GC-MS2 are still the
most commonly used techniques because of their wide
availability in environmental laboratories, the wellestablished electron-impact (EI) MS libraries, and the
superior sensitivity. With appropriate derivatization, GCMS or GC-MS2 is a sensitive, cost-effective technique
suitable for routine analysis. It is also worth noting that
GC-MS or GC-MS2 suffers less from the matrix effect that
is commonly observed in electrospray ionization (ESI)based LC-MS or LC-MS2 analysis [25], a phenomenon to
be discussed in further detail later. Table 1 lists MS and
MS2 operational parameters, matrix types, derivatization
agents, target analytes and their environmental concentrations in 16 GC-MS or GC-MS2 studies.
DB5, DB5 MS and HP5 MS (Agilent Technology, Palo
Alto, CA, USA) or their equivalents are commonly used
in the GC separation of PPCP targets. The column
dimension is usually 30 m 0.25 mm 0.25 lm, although longer or chiral separation columns have also
been used to achieve better separations of specific PPCPs
[26]. Helium is the carrier gas of choice and 13-lL
samples are injected into the GC using a split/splitless or
an on-column injector. Injection of a larger volume of
sample was reported to lower LODs of GC-MS analysis.
GC temperature is usually programmed to vary in the
range 50300C with a typical run time of 3045 min.
An EI source is the time honored, standard ionization
technique used for all GC-MS or GC-MS2 analysis of
PPCPs. At temperatures of 200250C and a standard
ionization energy of 70 eV, electrons are continuously
emitted from a heated filament and collide with gaseous
target compounds eluted from the end of the GC column
to produce molecular ions (if present), and more
importantly, characteristic fragment ions for each molecule. Computer libraries with several hundred thousands of standard mass spectra are commercially
available to help identify PPCPs and their metabolites in
the environment. Quantitative analysis is done by
acquiring compound-specific molecular ions and/or
fragment ions in selected ion monitoring (SIM) and selected reaction monitoring (SRM), respectively, for MS
and MS2, to increase the signal-to-noise ratio (SNR) of
the MS or MS2 experiment. Using data-processing software, one can transform SIM or SRM data to an extracted ion chromatogram (XIC) and integrate the XIC to
obtain retention time (RT) and intensity information for
qualitative and quantitative determination of a PPCP.
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Trends in Analytical Chemistry, Vol. 26, No. 6, 2007

Table 1. Summary of GC-MS and GC-MS2 methods for the quantitative analysis of PPCPs
Class/compound

Sample matrix

Derivatization agents

MS system

Environmental
concentrations (ng/L)

Ref.

Estrogens

Surface
water,wastewater

BSTFA

pptppb

[10]

Estrogens

Environmental water

0.165

[23]

Acidic drugs, triclosan

Various PPCPs

Wastewater
Surface & treated
water
Wastewater
Sewage water

Varian Saturn 2000 ion trap,

MS; Thermo Polaris ion trap,
MS2; full scan
Micromass Quattro Micro
triple quadrupole, MS; full
scan & SIM
Agilent 5971 MSD, MS; SIM
Agilent 5972 MSD, MS; SIM

1356
10107

[53]
[54]

Agilent MSD, MS; full scan

Agilent 5973 MSD, MS; full
scan & SIM
Varian Saturn 2000 ion trap,
MS2, full scan & SRM
Agilent 5973 MSD, MS; full
scan & SIM
Finnigan GCQ ion trap, MS;
full scan & SIM
Finnigan TSQ-7000 triple
quadruple, MS2; SRM (NCI)
Agilent 5973 MSD, MS; SIM

17313
3036,530

[55]
[56]

75400 ng/g

[21]

502,500

[32]

5560

[31]

1925,700

[28]

0.1135

[26]

Agilent 5985B quadrupole,

MS; SIM
Fisons MD 800 quadrupole,
MS; SIM
Thermal GCQ ion trap, MS;
full scan
Varian Saturn 2200 ion trap,
MS2; SRM
Varian Saturn 2200 ion trap,
MS; full scan

0.229

[27]

53500

[57]

101100

[58]

2.98059

[59]

30420

[60]

NSAIDs
Estrogens, acidic drugs,
personal-care products
Triclosan & related
compounds
Phenazone drugs
Pharmaceuticals
Estrogens
Estrogens
Estrogens
Acidic/neutral drugs
Acidic drugs
Acidic drugs/caffeine
Acidic/neutral drugs

MSTFA
MTBSTFA

Sludge & sediments

Groundwater &
drinking water
Sewage water

Acetic anhydride/
MTBSTFA
PFBBr

Groundwater, swine
lagoon
Surface & drinking
waters
surface & sewage
water
Surface & drinking
waters & wastewater
Groundwater

PFBBr/TMSI

Wastewater &
receiving water
Environmental water

PFBCl

Diazomethane

Methanol/BF3
Tetrabutylammonium
(TBA) salts

Sometimes negative chemical ionization MS (NCI-MS)

using methane as reagent gas is an alternative detection
technique for measuring pentafluorobenzyl (PFB) derivatives of estrogens [27,28]. Its sensitivity is proportional
to the electronegativity of the molecule analyzed, so NCIMS provides a sensitive, specific means for analyzing
estrogens in effluents and river waters [27]. It is worth
noting that NCI is a soft ionization technique, produces
simpler mass spectra than those obtained from an EI
source, and with fewer fragments. This may be beneficial
in achieving even better SNR in SIM analysis. However,
the lack of abundant fragment ions may be viewed as a
disadvantage for confirmation purposes.
Magnetic sector, single quadrupole, QqQ and IT-MS
have all been used in GC-MS and GC-MS2 study of
PPCPs. A magnetic sector instrument (VG Tribrid) was
employed to study the occurrence and the environmental behavior of diclofenac and ibuprofen [29], and
triclosan [30]. QqQ-MS was also used in two applications
[23,29] for the analysis of EDCs.
IT-MS was introduced for low-cost GC detection in
the 1980s. IT-MS was used predominantly for GC-MS
and GC-MS2 analysis because its unique ion-storage
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ability allowed the collection of high-sensitivity, fullscan MS spectra, high MS resolution, and the ability to
perform both MS and MS2 analysis functions. Following
IT-MS is the single quadrupole mass-selective detector
(MSD) because of its low cost and high availability in
environmental laboratories. Although GC-TOF-MS is
commercially available and has been used for environmental studies, it has not been applied for the
analysis of PPCPs. On the contrary, the application of
TOF-MS started to boom in the LC-MS and LC-MS2
analysis of PPCPs, especially after the advent of new
qTOF-MS.
In general, GC-MS analysis acquires data in full-scan
and/or SIM modes for identification and quantitation
purposes, respectively [23,31,32]. By carefully choosing
characteristic fragment ions with high intensity, unique
m/z, and low background (i.e., not being interfered by
column bleedings), GC-MS SIM analysis can provide
good sensitivity and selectivity for quantitative PPCP
analysis. However, when dealing with complex matrices
(e.g., sewage and sludge) where co-extracted components from the matrix may cause difficulty in GC-MS
quantitative analysis, GC-MS2 becomes the preferred

Class/compound

Sample matrix

Additive(s) in LC mobile
phase

MS system

Environmental
concentrations (ng/L)

Ref.

Analgesic compounds, lipid

lowering agent
Alcohol polyethoxylates,
nonylphenol, octylphenol

Surface water, wastewater

Formic acid

178,800

[39]

Wastewater, sludge

Acetic acid,
triethylamine

HP 1100 MSD single quadrupole, ESI(),

full scan, SIM
Finnigan SSQ 7000 single quadrupole,
ESI(+), full scan, ESI(), SIM

[10]

Soil, liquid manure, soil water,

groundwater
Manure

Formic acid, ammonium

acetate
Ammonium acetate,
acetic acid

3,100138,000
(water)1,3008,500
ng/g (sludge)
3.7198.7 ng/g

[11]

10270 ng/g

[12]

0.0822.8 ng/g

[19]

N/A

[20]

0.7 ng/g

[51]

580600

[38]

[47]

0.71,572

[44]

5295

[2]

10100

[3]

0.220.68

[9]

665,533

[36]

60170
1001300

[41]
[4]

103000

[7]

200450 ng/g

[14]

12197 ng/g

[15]

1.91200

[46]

Tetracyclines, tylosin
Sulfonamides & metabolites,
trimethoprim
Estrogens, progestogens

River sediment

Acidic drugs, antibiotics,

ivermectin
Macrolides, ionophores, tiamulin

Soil

Acetic acid, ammonium

acetate
Ammonium acetate

Tetracyclines, fluoroquinolones

River and well water

Acetic acid

Estrogens

Wastewater

Carbamazepine & metabolites

Wastewater, surface water

Estrogens, bisphenol A

River water, aquifer, drinking

water
Surface water, drinking water,
groundwater

Ammonium acetate,
formic acid

Various PPCPs

River sediment

Ammonium acetate

Finnigan-MAT LCQ ion trap, ESI(+), MS2,

MS3
Finnigan-MAT TSQ 7000 triple
quadrupole, APCI(+), MRM
HP 1100 MSD single quadrupole, ESI(+),
ESI(), SIM
PerkinElmer Sciex API 365 triple
quadrupole, APCI(), ESI(+), MRM
Finnigan-MAT TSQ 7000 triple
quadrupole, APCI(+), MRM
HP 1100 MSD single quadrupole, ESI(+),
SIM
Thermo Finnigan LCQ ion trap, ESI(),
MS2
Micromass Quattro LC triple quadrupole,
ESI(+), MRM
Single quadrupole, ESI(), SIM

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Micromasss Quattro Ultima triple

quadrupole, ESI(+), ESI(), MRM;Waters
q-TOF Ultima API, ESI(+), ESI(), MS2
Micromass Quattro LC triple quadrupole,
ESI(), MRM
Micromass Quattro LC triple quadrupole,
ESI(), MRM
LCQ Duo ion trap, ESI(+), MRM
Thermo Finnigan LCQ Advantage ion
trap, ESI(+), full scan MS and MS2

Surface water, drinking water

Acidic drugs, triclosan

Wastewater, surface water

Tri-n-butylamine

Tetracyclines, sulfonamides
Sulfonamides, trimethoprim,
fluoroquinolone, tetracyclines,
macrolides, caffeine
Sulfonamides, acetyl metabolites

Surface water
Surface water, groundwater

Formic acid
Formic acid

Surface water

Neutral and acidic

pharmaceuticals, iodinated
contrast media
Sulfonamides, macrolides,
trimethoprim
Estrogens, macrolides

Sludge

Formic acid, ammonium

acetate
Ammonium acetate,
acetic acid

Thermo Electron TSQ Quantum triple

quadrupole, ESI(+), MRM
PerkinElmer Sciex API 365 triple
quadrupole, ESI(+), APCI(), MRM

Sewage sludge

Formic acid

Wastewater

Ammonium acetate

Thermo Finnigan TSQ Quantum

Discovery triple quadrupole, ESI(+), MRM
AB API 2000 triple quadrupole, APCI(+),
ESI()

573

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Estrogens

Trends in Analytical Chemistry, Vol. 26, No. 6, 2007

Table 2. Summary of LC-MS and LC-MS2 methods for the quantitative analysis of PPCPs

574

[49]
[58]

10122,000

181860
251100

4. LC-MS and LC-MS2 studies

Wastewater, & river & tap water

Groundwater
NSAIDs
Various PPCPs

, No additive used; N/A, Not available.

Hospital effluent wastewater

Various PPCPs

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approach for additional selectivity and superior SNR

[21,29,33].
In MS2, not only specific parent ions (which can be a
molecular ion or fragment ion), but also the specific
daughter ions are monitored for a PPCP. Using particular parent/daughter-ion relationships, isomeric compounds could be distinguished by SRM with different
daughter ions.
GC-MS and GC-MS2 technologies have demonstrated
their capabilities in PPCP target-compound analysis.
However, target-compound monitoring cannot provide
sufficient information about the sample because nontarget PPCPs present in samples may also pose health
risks. With the available standard MS database, full-scan
GC-MS can be used for identifying non-target PPCPs
and/or their environmental transformation products.
This is best illustrated by the identification of six photodegradation products of diclofenac in water under
direct solar irradiation using GC-MS through the structural information provided by EI full-scan mass spectra
and the confirmation by the molecular mass in positive
chemical ionization (PCI) mass spectra [34].

Ammonium acetate

[48]

46215

Thermo Finnigan LCQ Advantage ion trap, ESI(+), full

scan MS2
Micromass Quattro triple quadrupole, ESI(+), ESI(),
MRM
Micromass Quattro triple quadrupole, ESI(), MRM
PE Sciex API 2000 triple quadrupole, ESI(+), ESI(),
MRM
Groundwater
Sulfonamides

Formic acid

[40]

530 ng/g
1105400
Thermo Electron TSQ triple quadrupole, ESI(+), MRM
Waters q-TOF-Micro, ESI(+), ESI(), MS, MS2
Aged agricultural soil
Wastewater

Acetic acid
Ammonium acetate,
acetic acid
Formic acid

[18]
[37]

[16]
[17]
0.0680.227 ng/g
155700 ng/g

Sulfonamides, penicillins
Tetracyclines, sulfonamides,
macrolides
Sulfonamides & metabolites
Various PPCPs

Formic acid
Formic acid

[35]
27215,500

Liquid hog manure supernatant,

run-off water
Sludge
Swine manure
Macrolides

Formic acid

[8]
54

Micromass Quattro LC triple quadrupole, ESI(+), MRM;

Micromass hybrid q-TOF, ESI(+)
Micromass Quattro Ultima triple quadrupole, APCI(+),
MRM
Micromass Quattro LC triple quadrupole, ESI(+), MRM
AB Sciex API 2000 triple quadrupole, ESI(+), MRM
Surface water, groundwater
Quinolones, penicillins

Formic acid

Sample matrix
Class/compound

Table 2 (continued)

Additive(s) in LC mobile
phase

Ref.
Environmental
concentrations (ng/L)

Trends in Analytical Chemistry, Vol. 26, No. 6, 2007

MS system

Trends

The technology using an atmospheric pressure ionization source (API) as an interface between an LC and an
MS or MS2 (i.e. the modern LC-MS or LC-MS2) has
gained great popularity due to its compatibility with
polar, non-volatile and thermally labile PPCPs since the
late 1980s. Over the past decade, various mass spectrometers have all been interfaced to liquid chromatographs, and applied to analyze PPCPs extracted from
aqueous and solid environmental matrices. Each MS
analyzer possesses its own specificity and applicability in
the qualitative confirmation and quantitative determination of the PPCP-target analytes; however, QqQ-based
LC-MS2 systems have the unique ability of doing SRM
with high SNR, have attractive price/performance ratio,
are relatively easy to maintain, and have become the
norm in PPCP analysis. Table 2 lists MS2 operational
parameters, matrix types, LC mobile phase, target analytes and their environmental concentrations in 30 LCMS and LC-MS2 studies.
Although MS provides a second dimension for the
confirmation of target analytes, LC separation is needed
to improve detection performance, especially when
dealing with isomeric chemicals. Reversed-phase (e.g.,
C18 and C8) analytical columns are most commonly used
in the separation of PPCPs. The inner diameter of 2 mm
is usually selected for analytical columns being used for
LC-MS or LC-MS2. The pH of the aqueous mobile phase is
normally adjusted with formic acid, acetic acid, ammonium hydroxide, ammonium formate and/or ammonium acetate, while the organic mobile phase employs

Trends in Analytical Chemistry, Vol. 26, No. 6, 2007

methanol, acetonitrile or a combination of these two

solvents. Sometimes, the organic mobile phase is also
modified with buffer solutions.
For very polar compounds (e.g., spectinomycin and
lincomycin), the application of hydrophilic interaction
chromatography (HILIC) has been reported [35] to improve LC retention.
For the separation of acidic drugs and triclosan, trin-butylamine (TrBA) was used as an ion-pairing agent
with a phenyl-hexyl adsorbent column to achieve stable
retention times [36].
Recently, the first application of ultra-performance liquid chromatography (UPLC) for the multi-residue
analysis of pharmaceuticals in wastewater was presented [37]. The major benefit of this type of column is
the increased column efficiency that resulted in shorter
analytical times, narrower peaks and improved separations. However, higher system back-pressure, requiring
special solvent-delivery units, has limited its operation in
routine analysis to date.
SIM is the mode used for the qualitative and quantitative analysis of the target analytes in single-quadrupole MS. Protonated ([M+H]+) and deprotonated
([M H] ) molecular ions and sometimes, fragment ions,
are collected in positive-ion and negative-ion modes
[38]. Determination of several analgesic drugs and one
lipid-lowering agent in surface-water and wastewater
samples was reported by la Farre et al. [39]. Using an LCMS, the full-scan mass spectrum was used to confirm the
target compounds along with their respective RT. Upon
positive identification of a specific compound, final
quantification was performed in the SIM mode using
external calibration.
LC-MS was also applied in the analysis of EDCs in
environmental matrices [2,10], in which the deprotonated molecular ion [M H] was used to quantify the
analytes. Using a similar approach, Lopez de Alda et al.
[19] studied the occurrence of estrogens and progestogens in river sediments using the deprotonated molecular ion [M H] and sodium adducts [M+Na]+ for
the determination of estrogens and progestogens,
respectively.
IT-MS has the unique ability to acquire high-sensitivity, full-scan mass spectra using MS2, and was applied
in the analysis of several sulfonamide antimicrobials in
private water wells in positive-ionization mode [40], and
to sulfonamides, tetracyclines, marcrolides and caffeine
in three water matrices [4]. High-SNR, full-scan MS and
MS2 data were collected using data-dependent scanning
with three time segments to ensure the collection of
useful mass ranges only. Full-scan MS2 data are more
valuable for identification than MRM/SRM because of
the presence of abundant fragment ions. This was
demonstrated by Yang et al. [41] for the quantitative
determination of tetracyclines and sulfonamides in
surface water using positive-ionization LC-IT-MS. The

Trends

unique ability of IT-MS to do multiple MSn makes it an

ideal candidate in identification and confirmation of
suspicious analytes of interest. The highly-selective MS3
technique was used to confirm the findings from the MS2
method in a liquid-manure sample [11].
It is worth noting that the much lower abundance of
fragment ions from an MS3 experiment implies both high
selectivity and inferior sensitivity, and that larger
amounts of samples would be required to achieve a
desirable SNR for the determination of the target
analytes.
As discussed earlier, QqQ is probably the most frequently used MS2 detector in the analysis of target
pharmaceutical and EDCs in environmental samples.
Recently published review papers [42,43] have contributed to the application of QqQ instrumentation for the
multi-residue analysis of pharmaceuticals in environmental samples, with particular focus on the discussion of fragmentation patterns, and details can be found
in those papers. QqQ LC-MS2 can be applied to the study
of native pharmaceuticals as well as their known
metabolites.
In the case of carbamazepine, the most frequently
detected pharmaceuticals in environmental waters, both
the native and its five metabolites were studied in
wastewater and surface water using LC-MS2 [44]. For
the determination, the precursor ion [M+H]+ and the
most intense product ion of each compound were selected to operate the mass spectrometer in SRM/MRM
mode.
LC-MS2-based SRM/MRM analysis is a sensitive tool
for the qualitative and quantitative determination of the
target analytes. However, using the RT of LC, a single
SRM/MRM transition without full-scan mass spectral
data can sometimes make identification and confirmation of the target analytes a task. This is why more than
one MRM transition needs to be used to avoid a false
positive being identified.
With the advent of a new hybrid quadrupole/linear IT
instrument [45], which combines the capabilities of QqQ
MS and IT technology on a single platform, true positive
analysis of target compounds in a suspicious sample
with higher confidence becomes possible. This is
achieved by running the MS2 in SRM/MRM mode, and
triggering the linear IT-MS to do an enhanced production scan with responses above preset criteria. The fullscan mass spectrum obtained can be compared to that in
the database library for identification with a high level of
confidence.
The advent of powerful data-acquisition and processing hardware has re-invented TOF-MS, and allowed the
development of qTOF for LC detection. Because of its
high-resolution capability, accurate mass can be obtained for both precursor and product ions in full-scan
spectra and be used for screening, qualitative and
quantitative analysis of PPCPs in complex matrices.
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Trends in Analytical Chemistry, Vol. 26, No. 6, 2007

Stolker et al. [3] compared QqQ and a qTOF-based

mass detector for LC screening and confirmation of
pharmaceutical residues in water. Based on the screening results obtained from two MRM transitions and the
ratio of their abundance on QqQ, four positive samples
were selected and subjected to analysis by LC-qTOF. The
identities of the target analytes were confirmed on
the basis of the ratios of two MS2-transition ions, and the
pseudo SRM/MRM data obtained from the accurate
masses monitored. It was shown that unequivocal
comparability between the qTOF and the QqQ can be
achieved in terms of the quantified concentrations of the
target analytes and true positive confirmation.
qTOF was also interfaced to UPLC and applied to the
multi-residue analysis of pharmaceuticals in wastewater
by Petrovic et al. [37]. The analysis was based on two
complementary approaches:
 quantitation was performed in TOF mode by setting a
narrow accurate mass interval to increase sensitivity
and to obtain reconstructed ion chromatograms (protonated or deprotonated molecular ions);
 identification and confirmation of the detected compounds was achieved by obtaining product-ion spectra using qTOF experiments under CID conditions.
It was also noted that the sensitivity of qTOF is suitable
for samples with levels of the target analytes as high as
those from WWTPs; however, for less contaminated
waters, the qTOF method needs to be complemented
with a sensitive quantitative analysis (e.g., QqQ-based
LC-MS2 operated in MRM mode). Nevertheless, the
advantages and the benefits of a qTOF instrument offer a
new perspective for trace analysis of PPCPs in environmental matrices and cannot be overlooked.

5. Matrix effect
The matrix effect exists in analysis by GC-MS, GC-MS2,
LC-MS and LC-MS2, and it affects the data quality of
target-compound analysis. It could be caused by those
co-eluted, interfering components in the sample extract
that have similar ions in the MS or MS2 experiment. It
might also arise from the interaction between the target
analytes and those co-extracted matrix components
(organic or inorganic) during sample preparation and in
the ionization chamber. The former is common in GC-MS
and GC-MS2 analysis, and might be encountered rarely
in LC-MS and LC-MS2 analysis. It can be resolved using a
non-interfered fragment ion or, where there are isomers
or chiral compounds, when MS or MS2 separation is
difficult to achieve, improving the GC or LC separation
would resolve the matrix effect problem.
The matrix effect, in the form of analyte and matrix
component interactions, is unique to ESI- and APCIbased LC-MS or LC-MS2 instrumentation. It can appear
as signal suppression or enhancement (when compared
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to a pure analytical standard), depending on the sample

matrix, a specific analyte or the mode of ionization. It
has become the most challenging issue for environmental analytical chemists.
Both signal suppression and/or enhancement were
observed in ESI, while only signal enhancement was
reported in APCI [12]. Highly-loaded environmental
samples (e.g., influent and sludge from WWTPs) present
a more severe matrix effect for the target analytes.
From the outset, ESI is more susceptible to matrix effect than APCI [46]. Since a majority of the applications
of LC-MS and LC-MS2 analysis of PPCPs use ESI as the
ionization technique, it is essential to address this issue
when developing and validating analytical methods in
environmental matrices.
The above discussion was best demonstrated by critical evaluation of ESI and APCI sources in the determination of sulfanomides and trimethoprim in manure by
QqQ-LC-MS2 by Pfeifer et al. [12]. They reported that
both ESI and APCI showed comparable ionization efficiency for the compounds investigated. However, ESI
could produced [M + acetonitrile+Na]+ adducts, while
APCI solely formed [M + H]+ ions. Depending on the
varying amount of sodium in the sample extract and
analytical system, inconsistent intensity of the adduct
ions was observed when compared to the [M + H]+,
hence the matrix effect. The varying amount of sodium
in the analytical system and/or samples will effect the
formation of different amounts of the sodium adduct ions
in the ESI source, and this made APCI the ionization
source of choice for the analysis of these target compounds in environmental matrix.
The analyses of acidic pharmaceuticals in river sediment and acidic pharmaceuticals extracted from sludge
by APCI-LC-MS2 were also reported [14,20].
LC-IT-MS analysis of steroid hormones in WWTP
effluents using both ESI and APCI sources in positiveand negative-ionization modes was evaluated [47]. It
was shown after optimization that the ESI negative
interface provided the best overall sensitivity for the
steroids of interest.
An LC-MS2 method using both ESI positive and APCI
negative interfaces for the study of steroid hormones and
hormone conjugates in WWTP influents and effluents
was also reported [46]. Clearly, APCI was preferred to
ESI as the ionization source for the analysis of steroid
hormones in wastewater samples because it has a less
pronounced matrix effect. Unfortunately, only a handful
of analytes could be ionized by APCI and analyzed by MS
or MS2, and most of the analytes had to be analyzed by
ESI-MS2.
Several operating strategies have been discussed to
circumvent the problems resulting from matrix components. Exhaustive sample clean-up may help remove
interfering components, but it is time-consuming and
runs the risk of losing analytes of interest. Better

Trends in Analytical Chemistry, Vol. 26, No. 6, 2007

chromatographic separation allows the analytes to be

eluted in an appropriate time interval, avoiding coeluting with the matrix components. Another strategy is
serial dilution of the final extract so that fewer matrix
components will be injected into the analytical system
[48,49]. Splitting the LC-eluent flow before entering the
mass spectrometer may also help eliminate the matrix
effect [50].
In most cases, the matrix effect cannot be eliminated,
despite the aforementioned operating strategies. Several
calibration methods [46] can be implemented to provide
more reliable, accurate analytical results. It was suggested that matrix-matched calibration standards be
used to establish a calibration curve [51]; however, this
approach requires the availability of uncontaminated
sample matrix to be used to prepare calibration standards and that can be difficult to obtain.
Another approach would be to use standard addition
[36], in which the calibration standards are added to the
samples to generate a calibration curve for each sample.
However, the process is tedious and impractical for
monitoring projects, where one must deal with a large
number of samples.
An effective approach to compensating for the matrix
effect is the application of ILCs. However, the poor
availability and the high cost of ILCs are disadvantages
of this approach.

6. Quality control/quality assurance and data

qualifiers
Environmental analysis provides long-term data and
there is an obligation to report and to qualify analytical
data in a consistent manner. For many years, environmental chemists have made efforts to provide consistent
estimation and use of low-level data qualifiers for data
reporting in various sample types.
Initial method validation will provide method-performance parameters, such as method recoveries, precision,
and LODs. Continual use of QC samples (e.g., method
blank, spiked samples, and standard reference materials)
are not only important to monitor and to maintain the
routine, batch-to-batch performance of the method but
also vital to ensure that there is minimal matrix effect for
the samples analyzed. Considering the unpredictable
nature of the matrix effect in API-based LC-MS and LCMS2 analysis and the lack of an effective strategy to deal
with this difficulty, it has become imperative to use
available QC data to document and to qualify the extent
of matrix effect encountered during the sample analysis.
QC samples represent only a small portion of the data
generated for any monitoring project, provide valuable
information on data quality, including matrix effect, are
associated with long-term method performance, and
should be implemented. Table 3 summarizes QC samples

Trends

used in each publication, the numerical values of LODs,

and the procedures used to determine the LODs.
GC-MS and GC-MS2 analysis are mature technologies
with established method-validation procedures that require routine QC samples to control the method performance.
Commonly
accepted
method-validation
procedures, QC samples, and QA practices have been
documented by various agencies, including the US
Environmental Protection Agency (US EPA), European
Analytical Chemistry (EURACHEM), and International
Union of Pure and Applied Chemistry (IUPAC).
LC-MS and LC-MS2 technologies, though relatively
new, could also benefit from such documentation to
establish a good method-validation protocol as well as
QC samples that should be used in routine analysis.
Unfortunately, most publications have neglected the
recommendations listed in these documents. From
Table 3, terms such as LOD, limit of quantitation (LOQ),
instrument-detection limit (IDL), and method-detection
limit (MDL) have been used in different publications to
qualify the low-level data reporting in the ppb (lg/L),
ppt (ng/L) and ppq (pg/L) ranges. A detailed, general
review gives the meaning of these terms and how they
were derived [52] and will not be repeated here. It is
worth noting that the passion to achieve the lowest
possible numerical values for the LOD still overrides
consistent estimation and use of low-level data qualifiers
for data reporting in various sample types. From
Table 3, four of the 14 GC-MS and GC-MS2 methods
used an instant SNR of the instrument, also the most
optimistic approach, to establish the lowest numerical
values possible and used them to qualify the data reported. Of the 30 LC-MS and LC-MS2 methods reviewed,
23 used a similar SNR approach to achieve the most
optimistic numerical values possible and used them to
qualify the data reported. Only four and two of the 44
methods listed in Table 3 used the US EPA MDL protocol and the DIN protocol 32 645, respectively, to
estimate numerical values of LODs.
Most publications mentioned little about available
method-performance data. The lack of an effective approach to resolve the difficulty arising from the matrix
effect can only be alleviated by meticulous documentation of method QC/QA data. Either the DIN 32645 or the
US EPA MDL protocol should be used as a minimal
requirement to establish numerical values of LODs, and,
preferably, the US EPA MDL protocol should be used for
method validation so that analytical data can be compared with high confidence.
Three types of QC samples (i.e. method blank, method
spike, and reagent blank) are used, respectively, to ensure that:
 no laboratory contamination was introduced during
complicated sample-preparation and analytical steps;
 the method performance was maintained for a specific
sample batch; and,
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Trends in Analytical Chemistry, Vol. 26, No. 6, 2007

Table 3. Terms, definitions, and numerical values of low level data qualifier and QC samples used in the method
Terms

Target analytes

Quality control

Numerical value (ng/L)

Definition

Ref.

Spikes

MS 0.520 (40-lL injection);

MS2 0.540 (2-lL injection)
0.30.7
0.6178
MS 26; MS213
MS 24 ng/mL; MS2 0.2 ng/mL
36
1.660
0.8
0.020.1

10 SD of lowest calibration
standard; SNR of 10
N/A
Serial dilution to SNR of 3
SNR of 10
SNR of 10
lowest calibration point
9 SD of blank noise
US EPA protocol
3 noise height

[10]
[23]
[54]
[33]
[21]
[32]
[31]
[28]
[26]

0.030.2
110
3.39.6
0.120
18

3 noise height
US EPA protocol
DIN 32645
US EPA protocol
SNR P 10

[27]
[57]
[58]
[59]
[60]

N/A

556

SNR of 3

[39]

Spikes

SNR of 10

[10]

Spikes
Spikes

100500 (water); 120 ng/g

(sludge)
12 ng/g (soil); 50 (water)
0.41.3 ng/g

SNR of 3
SNR of 3

[11]
[12]

Spikes
Spikes
Spikes
Blanks, spikes
Spikes
Spikes
Spikes
Spikes
Spikes
Spikes
Spikes
Spikes

0.041.00 ng/g
0.420 ng/g
0.21.6 ng/g
46
12
0.84.8 pg
0.5314.79
525
0.010.38
6198
3050
30190

[19]
[20]
[51]
[38]
[47]
[44]
[2]
[3]
[9]
[36]
[41]
[4]

Reagent blank,
blanks, spikes
Spikes

15

SNR of 3
2nd lowest calibration standard
SNR of 3
SNR of 3
SNR of 3
SNR of 3
SNR of 3
SNR of 10
SNR of 3
SNR of 3
SNR of 6, US EPA protocol
Concentration corresponding to
signal at the y-intercept plus
three times its SD
SNR of 3

2050 ng/g

[14]

Spikes

341 ng/g

Spikes
Blanks, spikes
Spikes
Spikes
Spikes

0.635
0.44.3
86,000
0.0010.27 ng/g
2.732.1 ng/g

2nd or 3rd lowest calibration

standard
SNR of 10 (PLE), 2nd lowest
calibration standard (USE)
SNR of 10
SNR of 3
SNR of 3
SNR of 3
SNR of 3

[46]
[8]
[35]
[16]
[17]

515 ng/g

SNR of 3

[18]

10500
2070

[37]
[40]

3.847
775
1.013

SNR of 3
Concentration corresponding to
signal at the y-intercept plus
three times its SD
SNR of 3
SNR of 3
DIN 32645

GC-MS and GC-MS analysis

LOQ
Estrogens
LOD
IDL
LOQ
LOQ
LOQ
LOQ
MDL
LOD

Estrogens
Various PPCPs
Estrogens
Triclosan & related compounds
Phenazone drugs
Pharmaceuticals
Estrogens
Estrogens

LOD
MDL
LOD
MDL
LOQ

Estrogens
Acidic/neutral drugs
Acid drugs
Acidic drugs/caffeine
Acidic/neutral drugs

LC-MS and LC-MS2analysis

LOD
Analgesic compounds, lipid lowering
agent
LOQ
Alcohol polyethoxylates,
nonylphenol, octylphenol
LOD
Tetracyclines
LOD
Sulfonamides & metabolites,
trimethoprim
LOD
Estrogens, progestogens
LOQ
Acidic drugs, antibiotics, ivermectin
LOD
Macrolides, ionophores, tiamulin
LOD
Tetracyclines, quinolones
LOD
Estrogens
IDL
Carbamazepine, metabolites
LOD
Estrogens, bisphenol A
LOQ
Various PPCPs
LOD
Estrogens
LOD
Acidic drugs, triclosan
MDL
Tetracyclines, sulfonamides
LOD
Sulfonamides, trimethoprim,
fluoroquinolone, tetracyclines,
macrolides, caffeine
LOD
Sulfonamides, acetyl metabolites
LOQ

Spikes
Spikes
Spikes
Spikes
Spikes
Spikes, blanks
Spikes
Spikes, blanks,
reagent blanks
Spikes, blanks
Spikes
Spikes, blanks
Spikes
Spikes

LOD

Neutral and acidic pharmaceuticals,

iodinated contrast media
Sulfonamides, macrolides,
trimethoprim
Estrogens, macrolides
Quinolones, penicillins
Macrolides
Sulfonamides, penicillins
Tetracyclines, sulfonamides,
macrolides
Sulfonamides & metabolites

MDL
LOD

Various PPCPs
Sulfonamides

Reagent blank,
blanks, spikes
N/A
N/A

MDL
LOD
LOD

Various PPCPs
NSAIDs
Various PPCPs

Spikes
Spikes
Spikes

LOQ
LOQ
LOD
LOQ
LOD
LOD

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[7]

[15]

[48]
[49]
[58]

Trends in Analytical Chemistry, Vol. 26, No. 6, 2007

 there is no carry-over from a standard or a high level

sample.
These three QC samples should be minimal requirements.
From Table 3, and for GC-MS and GC-MS2 methods,
one can note that only one publication [26] meets this
minimal requirement, while three publications used
method blanks and method spikes and the rest used only
method spikes. For LC-MS and LC-MS2 methods reviewed, there are only two publications [7,18] meeting
the minimal requirement. Two publications used method
blanks and method spikes and there are three publications that did not even mention the use of any QC
samples. This area could be easily improved to increase
the level of confidence in the data reported.

Trends

[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]

7. Conclusions
The quality of data of MS methods developed to deal with
PPCPs in aqueous and solid environmental matrices has
been improving since the 1990s. Target analytes are
detectable down to the sub-ng/L level by GC-MS, GCMS2, LC-MS and LC-MS2.
PPCP studies to date have covered removal from
WWTPs, mobility in the environment, and several surveillance programs focused on a limited number of
compound classes.
The matrix effect has been a difficult problem to resolve. In the future, we hope to see more practical approaches to resolve the problem of the matrix effect to
alleviate the uncertainty in reported data.
We hope to see more large-scale surveillance projects,
such as that carried out by the US Geological Survey, to
gain further understanding on the occurrence of not
only parent products but also transformation products to
allow the full assessment of environmental impact of
these EOPs. This will require environmental chemists to
make the best use of available resources and collaborative initiatives.
The need to have an agreed protocol for the development and the use of low-level data qualifiers, as well as
the use of sufficient QC samples with each reported study
to maintain the confidence level of environmental data,
should be viewed as an obligation instead of a resource
issue. This resolve will remove any concerns that we
might have on the data and augment our ability to
understand the eco-toxicological effects of both parent
compounds and their metabolites in the environment.

[12]
[13]
[14]
[15]

[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
[28]
[29]

[30]
[31]

References

[32]
[33]

[1] A.W. Garrison, J.D. Pope, F.R. Allen, GC/MS analysis of organic
compounds in domestic wastewaters, in: L.H. Keith (Editor),
Identification and Analysis of Organic Pollutants in Water, Ann

[34]

Arbor Science Publishers, Ann Arbor, MI, USA, 1976, pp. 517
556.
S. Rodrigues-Mozaz, M.J. Lopez de Alda, D. Barcelo,
J. Chromatogr., A 1045 (2004) 85.
A.A.M. Stolker, W. Niesing, E.A. Hogendoorn, J.F.M. Versteegh, R.
Fuchs, U.A.Th. Brinkman, Anal. Bioanal. Chem. 378 (2004) 955.
A.L. Batt, D.S. Aga, Anal. Chem. 77 (2005) 2940.
I. Rodrguez, J. Carpinteiro, J.B. Quintana, A.M. Carro, R.A.
Lorenzo, R. Cela, J. Chromatogr., A 1024 (2004) 1.
C. Basheer, A. Jayaraman, M.K. Kee, S. Valiyaveettil, H.K. Lee, J.
Chromatogr., A 1100 (2005) 137.
K. Stoob, H.P. Singer, C.W. Goetz, M. Ruff, S.R. Mueller, J.
Chromatogr., A 1097 (2005) 138.
O.J. Pozo, C. Guerrero, J.V. Sancho, M. Ibanez, E. Pitarch, E.
Hogendoorn, F. Hernandez, J. Chromatogr., A 1103 (2006) 83.
S. Rodriguez-Mozaz, M.J. Lopez de Alda, D. Barcelo, Anal. Chem.
76 (2004) 6998.
R. Jeannot, H. Sabik, E. Sauvard, T. Dagnac, K. Dohrendorf, J.
Chromatogr., A 974 (2002) 143.
G. Hamscher, S. Sczesny, H. Hoper, H. Nau, Anal. Chem. 74
(2002) 1509.
T. Pfeifer, J. Tuerk, K. Bester, M. Spiteller, Rapid Commun. Mass
Spectrom. 16 (2002) 663.
J.-J. Yang, C.D. Metcalfe, Sci. Total Environ. 363 (2006) 149.
T.A. Ternes, M. Bonerz, N. Herrmann, D. Loffler, E. Keller, B.B.
Lacida, A.C. Alder, J. Chromatogr., A 1067 (2005) 213.
A. Gobel, A. Thomsen, C.S. McArdell, A.C. Alder, W. Giger, N.
Thei, D. Loffler, T.A. Ternes, J. Chromatogr., A 1085 (2005)
179.
M.S. Daz-Cruz, M.J. Lopez de Alda, D. Barcelo, J. Chromatogr., A
1130 (2006) 72.
A.M. Jacobsen, B. Halling-Srensen, Anal. Bioanal. Chem. 384
(2006) 1164.
K. Stoob, H.P. Singer, S. Stettler, N. Hartmann, S.R. Mueller, C.H.
Stamm, J. Chromatogr., A 1128 (2006) 1.
M.J. Lopez de Alda, A. Gil, E. Paz, D. Barcelo, Analyst (Cambridge,
U.K.) 127 (2002) 1299.
D. Loffler, T.A. Ternes, J. Chromatogr., A 1021 (2003) 133.
S. Morales, P. Canosa, I. Rodrguez, E. Rub, R. Cela, J.
Chromatogr., A 1082 (2005) 128.
J. Carpinteiro, J.B. Quintana, I. Rodrguez, A.M. Carro, R.A.
Lorenzo, R. Cela, J. Chromatogr., A 1056 (2004) 179.
Z.L. Zhang, A. Hibberd, J.L. Zhou, Anal. Chim. Acta 577 (2006)
52.
A. Shareef, C.J. Parnis, M.J. Angove, J.D. Wells, B.B. Johnson,
J. Chromatogr., A 1026 (2004) 295.
K. Reddersen, T. Heberer, J. Chromatogr., A 1011 (2003) 221.
H.M. Kuch, K. Ballschmiter, Environ. Sci. Technol. 35 (2001)
3201.
X.-Y. Xiao, D.V. McCalley, J. McEvoy, J. Chromatogr., A 923
(2001) 195.
D.D. Fine, G.P. Breidenbach, T.L. Price, S.R. Hutchins, J.
Chromatogr., A 1017 (2003) 167.
H.-R. Buser, T. Poiger, M.D. Muller, Environ. Sci. Technol. 32
(1998) 3449;
H.-R. Buser, T. Poiger, M.D. Muller, Environ. Sci. Technol. 33
(1999) 2529.
A. Lindstrom, I.J. Buerge, T. Poiger, P.-A. Bergqvist, M.D. Muller,
H.-R. Buser, Environ. Sci. Technol. 36 (2002) 2322.
V. Koutsouba, T. Heberer, B. Fuhrmann, K. Schmidt-Baumler, D.
Tsipi, A. Hiskia, Chemosphere 51 (2003) 69.
S. Zuhlke, U. Dunnbier, T. Heberer, J. Chromatogr., A 1050
(2004) 201.
J.B. Quintana, J. Carpinteiro, I. Rodrguez, R.A. Lorenzo, A.M.
Carro, R. Cela, J. Chromatogr., A 1024 (2004) 177.
A. Aguera, L.A. Perez Estrada, I. Ferrer, E.M. Thurman, S. Malato,
A.R. Fernandez-Alba, J. Mass Spectrom. 40 (2005) 908.

http://www.elsevier.com/locate/trac

579

Trends

Trends in Analytical Chemistry, Vol. 26, No. 6, 2007

[35] K.M. Peru, S.L. Kuchta, J.V. Headley, A.J. Cessna, J. Chromatogr.,
A 1107 (2006) 152.
[36] J.B. Quintana, T. Reemtsma, Rapid Commun. Mass Spectrom. 18
(2004) 765.
[37] M. Petrovic, M. Gros, D. Barcelo, J. Chromatogr., A 1124 (2006)
68.
[38] S. Reverte, F. Borrull, E. Pocurull, R.M. Marce, J. Chromatogr., A
1010 (2003) 225.
[39] M. la Farre, I. Ferrer, A. Ginebreda, M. Figueras, L. Olivella, L.
Tirapu, M. Vilanova, D. Barcelo, J. Chromatogr., A 938 (2001)
187.
[40] A.L. Batt, D.D. Snow, D.S. Aga, Chemosphere 64 (2006) 1963.
[41] S. Yang, J. Cha, K. Carlson, Rapid Commun. Mass Spectrom. 18
(2004) 2131.
[42] M. Gros, M. Petrovic, D. Barcelo, Anal. Bioanal. Chem. 386
(2006) 941.
[43] M.S. Diaz-Cruz, D. Barcelo, Anal. Bioanal. Chem. 386 (2006)
973.
[44] X.-S. Miao, C.D. Metcalfe, Anal. Chem. 75 (2003) 3731.
[45] J.W. Hager, J.C. Yves Le Blanc, J. Chromatogr., A 1020 (2003) 3.
[46] M.P. Schlusener, K. Bester, Rapid Commun. Mass Spectrom. 19
(2005) 3269.
[47] V. Ingrand, G. Herry, J. Beausse, M.-R. de Roubin, J. Chromatogr.,
A 1020 (2003) 99.

580

http://www.elsevier.com/locate/trac

[48] M.J. Gomez, M. Petrovic, A.R. Fernandez-Alba, D. Barcelo, J.

Chromatogr., A 1114 (2006) 224.
[49] M.D. Hernando, E. Heath, M. Petrovic, D. Barcelo, Anal. Bioanal.
Chem. 385 (2006) 985.
[50] A. Kloepfer, J.B. Quintana, T. Reemtsma, J. Chromatogr., A 1067
(2005) 153.
[51] M.P. Schlusener, M. Spiteller, K. Bester, J. Chromatogr., A 1003
(2003) 21.
[52] C.Y. Hao, R. Clement, P. Yang, Anal. Bioanal. Chem. 387 (2007)
1247.
[53] P.M. Thomas, G.D. Foste, Environ. Toxicol. Chem. 24 (2005) 25.
[54] G.R. Boyd, H. Reemtsma, D.A. Grimm, S. Mitra, Sci. Total
Environ. 311 (2003) 135.
[55] T. Kosjek, E. Heath, A. Krbavcic, Environ. Int. 31 (2005) 679.
[56] H.-B. Lee, T.E. Peart, M.L. Svoboda, J. Chromatogr., A 1094
(2005) 122.
[57] S. Ollers, H.P. Singer, P. Fassler, S.R. Muller, J. Chromatogr., A
911 (2001) 225.
[58] F. Sacher, F.L. Lange, H.-J. Brauch, I. Blankenhorn,
J. Chromatogr., A 938 (2001) 199.
[59] S.S. Verenitch, C.J. Lowe, A. Mazumder, J. Chromatogr., A 1116
(2006) 193.
[60] W.-C. Lin, H.-C. Chen, W.-H. Ding, J. Chromatogr., A 1065
(2005) 279.