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Trends in Analytical Chemistry, Vol. 30, No. 4, 2011
Trace-level analysis of organic contaminants in drinking waters and groundwaters

M.J. Capdeville, H. Budzinski
We expect drinking water and groundwater samples to be contaminated very little, so they are subject to trace-level analysis. Due to the very low levels of contamination, this sort of analysis requires not only powerful analytical technologies to reach limits around the ng/L level, but also quality-control parameters (e.g., blank and spike samples) to monitor potential contamination or losses during sample treatment. Based on a literature review and laboratory experience, we discuss the problems linked to the difculties of calculating limits of detection, distinguishing instrumental from methodological limits and preventing false-positive results in cases of sample contamination, or false-negative results in cases of compound losses. When possible, we suggest solutions to compensate for, or to prevent, these problems. 2011 Elsevier Ltd. All rights reserved.
Keywords: Blank sample; Compound loss; Contamination; Drinking water; False negative; False positive; Groundwater; Limit of detection; Spike sample; Trace-level analysis
1. Introduction
M.J. Capdeville, H. Budzinski* ISM-LPTC, UMR 5255, CNRS Universite Bordeaux 1, 351 cours de la Liberation, 33 405 Talence cedex, France
Corresponding author. Tel.: +33 (0) 5 40 00 69 98; Fax: +33 (0) 5 40 00 22 67; E-mail: h.budzinski@ism. u-bordeaux1.fr
Contamination of environmental waters (e.g., surface waters and groundwaters) and of waters intended for human consumption by trace levels of organic substances is a subject of increasing concern in western countries. European regulations [1] on the quality of water intended for human consumption have xed quality limits of concentration for some substances, including polycyclic aromatic hydrocarbons (PAHs) [e.g., benzo[a]pyrene (0.01 lg/L)], pesticides [e.g., aldrin (0.03 lg/L)] or residues of food-contact materials [e.g., vinyl chloride (0.50 lg/L)]. Nevertheless, occurrence in groundwaters and drinking waters of some other unregulated substances have also been reported in the literature, including pharmaceuticals and personal-care products (PPCPs) (e.g., carbamazepine, caffeine and sulfamethoxazole), endocrine-disrupting compounds (EDCs) {e.g., nonylphenol and ame retardants} [e.g., TCEP (tris(2-chloroethyl) phosphate)] (Table 1). All these substances were detected in the range low lg/Lng/L. The evolution of the analytical devices allows us to improve instrumental sensi-
tivity, pushing scientists to publish protocols referring to lower limits of detection (LODs) and lower limits of quantication (LOQs). Unfortunately, in the eld of ultratrace analysis of organic contaminants, other factors, apart from the instrumental performance, have to be taken into account in determination of those limits. Indeed, the contamination of the water sample during its manipulation by some substances present in the working environment (e.g., naphthalene) or carried by the analyst (e.g., caffeine) can produce false-positive results. By contrast, the difculties of extracting small amounts from water, combined to the breakthrough-volume problems (e.g., paracetamol), can result in false-negative results. It is then necessary to take some precautions when manipulating such samples and it is also important to distinguish the instrumental LODs (IDLs) or instrumental LOQs (IQLs) from the real limits by considering the whole protocol, from sampling to pure analysis. This is even more the case for drinking waters and groundwaters that are very clean matrices requiring very low LODs and LOQs. This article deals with the complexity of reaching a reliable measure to qualify the contamination of a sample at the ultra-
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0165-9936/$ - see front matter 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.trac.2010.12.006
Table 1. Overview of organic compounds and their concentrations (ng/L) found in groundwater and drinking water worldwide. Only positive quantitative data, above the limits of quantification, are reported. Negative data (compounds not found, less than the quantification and detection limits) are not reported Ref. Sample type1 PPCPs2 EDCs (hormones, AkPs, BPA, phthalates)3 490 82 119 258 25 4 62 4.9 4.2 1.4 2.94 1.22.5 33.4 $80100 $1030 $100 $3200 $120 $90 $0.54 $24 $10 $30 $5 $4 $5 1170 320 360 1110 22 28 56 57 380 130 3110 BPA 420 DEET Prometon Pesticides4 Flame retardants5 66 96 TBEP TCEP TDIP TBP 350 99 250 100 Others
USA [2] Drinking water
[3]
Drinking water
[4]
Drinking water
AHTN HHCB Caffeine Carbamazepine Cotinine Dehydronifedipine Triethyl citrate Erythromycin Tylosin Roxithromycin Oxolinic acid Flumequine Sulfamethoxazole AHTN Camphor Triethyl citrate Carbamazepine Cotinine Caffeine Paracetamol Dehydronifedipine Cimetidine Codeine Diltiazem Diphenydramine Sulfathiazole 1,4-dichlorobenzene Lincomycin Sulfamethazine Sulfamethoxazole Dehydronifedipine Diltiazem Fluoxetine 1,7-dimethylxanthine Paracetamol Caffeine Ibuprofen
Anthraquinone Benzophenone Bromoform Tetrachloroethylene
72 130 21,000 100
BPA 4-NP OP2EO
$100300 $2 $100
DEET
$70 150
TDIP TBP TCEP
$100 $200 $80
Tetrachloroethylene
$30
[5]
http://www.elsevier.com/locate/trac
Groundwater
BPA Cholesterol Coprostanol
2550 1730 1290
DEET
13,500
TCEP
737
Naphthalene 5-methyl-1Hbenzotriazole Acetophenone Ethanol,2butoxyphosphate
1510 2080 2670 1340
Line missing
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Table 1. (continued) Ref. Sample type1 PPCPs2 EDCs (hormones, AkPs, BPA, phthalates)3 NP1EO NP2EO NP1EC NP2EC NP NP1EO NP2EO NP3EO NP4EO NP5EO NP6EO NP7EO NP8EO NP9EO BPA Di(2-ethylhexyl)phthalate Di-n-butylphthalate 503100 101400 1020,000 1015,000 6772 2430 4165 2543 47105 83122 156261 223414 269490 297551 0.450.76 103188 4650 Atrazine Deethylatrazine Deisopropylatrazine Cyanazine Simazine Europe [9] Tap water 1528 278 331 811 23.5 716 Pesticides4 Flame retardants5 Others
Canada [6] Drinking water
[7]
Drinking water
Clobric acid Carbamazepine Caffeine Cotinine Ooxacin Sulfamethoxazole
0.91.1 0.8135 6.8108 0.89 0.71.6 0.30.5
[8]
Tap water
Carbamazepine
5.6
Iopamidol Diatrizoate Diatrizoate Diatrizoate Iopromide Iomeprol Amitryptiline Caffeine Carbamazepine Diclofenac Ibuprofen Ketoprofen Naproxen Paracetamol
180 100 45 18 29 12 1.4 22.9 43.2 2.5 0.6 3 0.2 210
4-NP1EO 4-NP1EC Stigmasterol b-Sitosterol
2.52.6 1112 3863 99179
France [10] Drinking water before chlorination process
Line missing
tr-
[11]
Drinking water
Atenolol Bezabrate Carbamazepine Diclofenac Fenobric acid Ibuprofen Ketoprofen Metoprolol Naproxen Oxazepam Paracetamol Pravastatin Roxithromycin Salicylic acid Sulfamethoxazole Trimethoprime
0.42 0.32.2 2.132 0.21 0.21 1.3 0.67 0.31 0.5 1.22.5 0.745 0.2 18.1 0.819 0.8 1
Androstenedione Androsterone Oestrone Levonorgestrel Norethindrone Progesterone Testosterone
0.12.8 0.51 0.3 0.210 0.36.8 0.210.7 0.226.4
Germany [12] Groundwater
[13]
Drinking water
[14]
Drinking water
[15]
Drinking water
Sotalol Phenazone Diclofenac Iopamidol Amidotrizoic acid Carbamazepine Anhydro-erythromycin Sulfamethoxazole Phenazone Propiphenazone AMDOPH Clobric acid N-(phenylsulfonyl)-sarcosine Propiphenazone Phenazone Propiphenazone DP PDP AMDOPH AMPH
560 25 590 300 1100 900 49 410 400 120 900 1170 2105 80 300 90 1000 150 550 120 Simazine Atrazine Desisopropylatrazine Desethylatrazine Metolachlor 43 2562 2573 33 40
Spain [16] Drinking water
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Table 1. (continued) Ref. Sample type1 Tap water PPCPs2 EDCs (hormones, AkPs, BPA, phthalates)3 4-NP BPA Dimethylphthalate Diethylphthalate Di-n-butylphthalate Butylbenzylphthalate Di(2-ethylhexyl)phthalate BPA Di-n-butylphthalate BPA Diethylphthalate 4-NP NP NP1EC NP2EC BPA 24 625 34 3390 1632 1217 331 7 59 2 81139 78 85 12 10 5 Pesticides4 Flame retardants5 Others
[17]
[18]
Bottled water (PET) Bottled water (PE) Bottled water (glass) Drinking water
[19]
Drinking water
Simazine Atrazine
532 118
Israel [20] Groundwater

1 2
Sulfamethoxazole
20
Drinking water = water sampling at the end of the drinking water treatment before the distribution system; Tap water = water collected from residential tap water [8] or public fountain [17]. PPCPs, Pharmaceuticals and personal care products; AHTN, Acetyl hexamethyl tetrahydro naphthalene; HHCB, Hexahydrohexamethyl cyclopentabenzopyran; DP, 1,5-dimethyl-1,2-dehydro3-pyrazolone; PDP, 4-(2-methylethyl)-1,5-dimethyl-1,2-dehydro-3-pyrazolone; AMPH, 1-acetyl-1-methyl-2-phenylhydrazide; AMDOPH, 1-acetyl-1-methyl-2-dimethyloxamoyl-2-phenylhydrazide. 3 EDCs, Endocrine-disrupting compounds; AkPs, Alkylphenols; NP, Nonylphenol; NPEO, Nonylphenol polyethoxylate; NPEC, Nonylphenol carboxylate; BPA, Bisphenol A. 4 DEET, N,N-diethyltoluamide. 5 TBEP, Tris(2-butoxyethyl) phosphate; TBP, Tributyl phosphate; TCEP, Tris(2-chloroethyl) phosphate; TDIP, Tris(dichloroisopropyl) phosphate.
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ace level, in the eld of very pure matrices (e.g., drinking waters and groundwaters). We review the major analytical difculties at ultra-trace level (e.g., LODs, falsepositive and false-negative results), including literature advice and feedbacks from experience of our laboratory and know-how acquired in this eld.
2. General analytical validation parameters Before going in depth into the specic problems of the trace analysis, it is important to provide a brief reminder of the criteria essential to validation of a method, whatever the level of contamination studied: (1) Use of high-purity reference compounds (99%) [21]. If the purity is lower than 96%, the exact degree of purity of the product must be known to correct the concentrations [22]. The stock and working solutions must be prepared in solvents that are not too volatile; otherwise their evaporation can involve changes in concentrations [22]. (2) Identication of the compounds during the analysis by at least three characteristic parameters {e.g., retention time or the transition of quantication, as recommended by the European Commission (EC) [23,24]}. In mass spectrometry, it is better to have four identication points to ensure the identity of the compound: retention time, at least two ionic signals [one signal for quantication and one for conrmation, two ions in single-ion monitoring (SIM) mode in mass spectrometry (MS) or two transitions in multi-reaction monitoring (MRM) mode in tandem MS (MS2)] and the ratio between the two ionic signals [21]. (3) Evaluation of the linearity, the precision (repeatability and reproducibility) and the accuracy of the analytical answer [8,12,18,2427]. For most authors, the precision of a method was determined by repeated intra-day and inter-day analysis (successive injection of a standard solution in one day and in several successive days, respectively) and was expressed as the relative standard deviation of these replicate measurements [8,24,25]. The EC denes accuracy as the closeness of agreement between a test result and the accepted reference value, and accuracy is calculated by determining trueness and precision, with trueness being assessed through recovery of certied reference material or spiked samples [23]. (4) If possible, the addition of internal standards to evaluate the method performances [28]
3. Limits of detection and quantication As underlined by Glaser et al. [29], LODs are the most important criteria to evaluate the performance of a
method. The LOD corresponds to a minimal quantity or concentration, different from zero, which can be reliably detected with a certain degree of condence [29]. There are various ways of calculating the LOD [30]: (1) use of the signal-to-noise ratio (S/N); (2) statistical calculations based on the variation of the analytical response; (3) via the calibration curve obtained by spiking either pure water or the samples to take into account the matrix effect. When the LOD is dened from the signal-to-noise ratio, the response of the analytes is compared to that of the background noise. Usually, the LOD corresponds to the concentration that gives an S/N ratio equal to 3 and the LOQ to a concentration that gives an S/N ratio equal to 10 [3,17,18,25,27,31,32]. In other cases, the LOD corresponds to the variation (standard deviation) of the response of the successive injection of 710 replicates of a sample spiked at a very low concentration, multiplied by a factor of statistical condence. This method is used by the US EPA and USGS [5,21,28,33]. A third technique, which can be used for both LOD and LOQ, involves using a calibration curve. Wenzel et al. [9] determined their LOQ for iodinated contrast media, alkylphenol polyethoxylates (APEOs) and alkylphenol carboxylic acids (APECs) according to the DIN 32645 method, whereby the LOQ is calculated according to the condence interval at 99% of a calibration curve, obtained with a groundwater spiked with the compounds of interest. Because there is no universal standard method for the calculation of the LOD, the values of LOD can differ depending on the method used. This issue is illustrated for benzo[a]pyrene in meat [34]. For trace analyses, one sample may be considered as contaminated, or not, depending on the way that the LOD is calculated. In order to ensure reliable results, several authors modify their LODs with corrective factors. These modied LODs are more or less equivalent to LOQs. Barnes et al. [5] and Focazio et al. [28] would rather use the term reporting level, which corresponds to ve times the methodological LOD. These reported limits correspond to the value beyond which they can quantify the contamination and give the values with condence. In order to reduce the risks of a false positive, Furlong et al. [21], use interim reporting levels (IRLs) which correspond to twice the methodological LODs. Lastly, Garcia-ac et al. [8] used the term Method Detection Limits (MDLs) when the LODs are established on the transition of quantication, and the term Method Conrmation Limits (MCLs), when the LODs are established on the transition of conrmation. However, the EC [23] and the most recent guidelines on analysis by chromatography and MS recommend use of both transitions (quantitative and conrmatory) to establish the LODs and LOQs.
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In addition, once the way of calculating is dened for LOD and LOQ, it is necessary to understand the difference between the instrumental limits (IDLs or IQLs) and the methodological limits (MDLs or MQLs). The IDLs and IQLs are dened from the injection of standard solutions and are directly related to the sensitivity and to the performances of the analytical instruments. For example, the IDLs of ooxacin were 4759 pg, 214 pg and 2 pg injected, when it was analyzed, respectively, by: LC/UV (HPLC thermo pump P1500 spectraSystem, injector AS100 spectraSeries, detector DAD thermo UV6000; mobile phases: water + 0.03% TFA/acetonitrile + 0.03% TFA); LC/MS (HPLC Agilent 1100 series, MS Agilent 1100 series single quadrupole; mobile phases: water + 0.3% HCOOH/acetonitrile + 0.3% HCOOH); and, LC/MS2 (Rapid Resolution Liquid phase Chromatography Agilent 1200 series, MS/MS Agilent 6410 QQQ; mobile phases: water + 0.3% HCOOH/acetonitrile + 0.3% HCOOH). Globally, for various pharmaceuticals analyzed with these three instruments, a factor of 10 in sensitivity is obtained between LC/UV and LC/MS and another factor of 10 between LC/MS and LC/MS2. Petrovic et al. [18] also highlight the instrumental dependence of the IDL by comparing values obtained by LC/MS (liquid phase chromatography mass spectrometry) to those obtained in LC/MS2. The LODs of LC/MS2 are roughly three times lower than the LODs of LC/MS. Since these LODs are instrument-dependent, it was necessary to achieve technological improvements in order to be able to perform trace analyses, especially for polar and hydrophilic contaminants. The MDLs take into account both the instrumental sensitivity and the impacts of the sample-preparation protocols. The rst way of calculating them involves extrapolating the IDLs by taking into account the sample volume and the factor of reconcentration (theoretical IDLs). But this calculation supposes the absence of methodological error (i.e., no loss and no amplication phenomena during sample preparation and no matrix effect during the analysis). Another possibility involves applying the whole protocol (extraction, reconcentration and analysis) to pure water, spiked with very small quantities of compounds. These MDLs are then measured by taking into account all the possible impacts of the protocol but do not take into account matrix interferences during the extraction and the analysis. MDLs obtained by extrapolation of IDLs and considering a factor of reconcentration of 20,000 (extrapolated LODs) and MDLs obtained by the extraction of 1 L of drinking water spiked with targeted compounds (measured LODs) were compared for some pharmaceuticals in the laboratory. In drinking water, the matrix effects are low and the two MDLs have an equal order of magnitude. For example, for diclofenac, extrapolated and measured LODs were 592
0.5 ng/L and 0.9 ng/L, respectively. However, there are some differences, depending on the compounds: for carbamazepine, sample pre-treatment makes it possible to improve the measured MDLs (0.8 ng/L) compared to those extrapolated from the IDLs (2.5 ng/L); by contrast, when the handling of the sample causes compound losses, which is typically the case for caffeine, the measured MDLs (1.5 ng/L) are more important than those extrapolated from the IDLs (0.7 ng/L). Thus, although the extrapolated LODs are in most cases good estimators of MDLs, the last two examples justify interest in measuring them. Finally, there is a third kind of MDL, corresponding to the LODs measured from the analysis of various types of waters spiked with the targeted compounds. In this case, the potential problems brought during the samplepreparation step, and those related to the nature of the samples themselves, are both taken into account. The effects that the matrix can cause on the extraction recoveries or on the analytical sensitivity are integrated into those calculations. They are the most accurate MDLs, but, in the case of drinking water analyses, the disturbances brought by the matrix are unlikely. Table 2 illustrates the matrix impact on the MDLs for four types of water (i.e., raw tap water, surface water, marine water and wastewater-treatment-plant efuent). All were analyzed according to the same protocol: extraction of the compounds by solid-phase extraction (SPE) on Oasis MCX cartridges with ethyl acetate, ethyl acetate/acetone and ethyl acetate/acetone/ ammonium hydroxide as elution solvents; and, analysis with GC/MS with an HP5/MS capillary column and ultrapure helium as carrier gas [10]. It clearly highlights that the MDLs increase with increasing content of organic matter in water. Ternes [49] showed that the MQLs are instrument dependent and methodology dependent. The LOQs are 10 times lower for the antibiotic analysis when he used SPE rather than freeze-drying as extraction and reconcentration technique. He also highlighted the matrixdependent character of this parameter, since, from drinking water to groundwater, the estrogen LOQ increases by a factor of 2. Although in drinking-water analyses, the LODs are unlikely to be modied due to the matrix effect or signalextinction problems, they can be modied if contamination occurs. Indeed, if blanks are contaminated and the problem cannot be solved, the blank values must be taken into account to dene the LOQs. A contaminationbackground noise for bisphenol A of about 4 ng/L was noticed in the laboratory, by compiling a great number of experimental data. Consequently, any sample that potentially contains less than 4 ng/L BPA cannot be analyzed with condence, because the potential contamination of the sample is masked by the background
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Table 2. Influence of sample composition on the method limit of detection (MDL) (1L extracted for raw tap, surface and marine waters and 500 mL for wastewater effluent) of pharmaceutical compounds analyzed by GC/MS1 [10] Measured MDLs (ng/L) Raw tap water Amitryptiline Carbamazepine Diazepam Doxepine Imipramine Nordiazepam Aspirin Diclofenac Ibuprofen Ketoprofen Naproxen Clenbuterol Caffeine Gembrozil 0.7 0.8 0.4 0.7 0.7 0.4 0.2 0.9 0.1 0.3 0.1 0.6 1.5 0.1 Surface water 2.2 1.4 1.4 2.1 1.2 1.4 2.1 0.7 0.1 0.7 1.0 0.3 2.5 0.3 Marine water 2.6 2.2 1.9 2.4 1.6 1.9 2.1 2.6 1.7 1.8 2.1 1.2 2.3 1.2 Wastewater efuent 6.8 22.3 13.8 16.6 12.7 13.8 15.0 9.0 4.8 11.6 6.2 4.0 28.6 3.2
1 GC Agilent HP6890, MS Agilent 5973 single quadrupole; ionization by electronic impact at 70 eV; carrier gas ultrapure He; capillary column HP5/MS 5% diphenyl/95% dimethylsiloxane, 30 m 0.25 mm 0.25 lm lm thickness.
noise, in spite of an IDL extrapolated for the BPA at 1 ng/ L. In this case, the real LOD of the BPA should be at least 8 ng/L (i.e. twice the value of the background noise) to be able to be sure of getting rid of experimental pollution. In other cases, an analytical interference can mask the targeted compound. For example, the ketoprofen signal was shown to be interfered by a molecule that had the same retention time and the same quantication transition. The quantication of the signal in the blank gives a concentration equivalent to 2.5 ng/L. Then, in spite of an extrapolated LOD around 1 ng/L, any sample contamination lower than 3 ng/L will be hidden by the interference. Consequently, the LODs of ketoprofen should be raised to at least 5 ng/L. The last important point to dene LOD, is the signal considered. Few authors mention on which signal the LODs are established [3]. Generally, to ensure compound identication in MS, one must check its retention time, one ion or one transition of quantication and another one of conrmation, and the ratio between these two signals. The reliable identication of a compound is achieved when all these criteria match simultaneously. However, the signal of conrmation is often less intense than that of quantication. In the absence of this second signal, the presence of a compound in a sample cannot be certied. Thus, the LOD should be related to the response of the second signal. However, the potential presence of a compound in a sample cannot be completely ignored if the other criteria are fullled, especially when the ratio between the two signals is signicant. In this case, the LOD is dened according to the quantication signal. Then, to determine whether or not the sample is contaminated by the compound, it is necessary to take into account other parameters {e.g., the context (conditions in
which the sample was obtained, preserved and analyzed), the type of sample (e.g., surface water, or bottled water) and other indications [e.g., published results with similar samples or laboratory internal results (frequency and certainty of detection of this compound in this type of sample)]}. Finally, the sample cannot be certied as 100% contaminated or not contaminated. To sum up, although the LOD is the most important criterion for the trace analysis, it is the most variable parameter from one methodology to another. It depends on the compound, the technology, and the matrix. The ideal way of working for trace analysis is: to dene the MDL by taking into account the analytical instrument used, the whole protocol (extraction, reconcentration and analysis), the matrix effects; and, to specify the method of calculation adopted. Consequently, an accurate estimation of the LOD requires spiking at low level of one or several replicates of samples (nal concentration within the range of $10 ng/L) and making them undergo the whole protocol, whatever the mode of calculation chosen.
4. False positives Good sensitivity is an essential, but not exclusive, criterion to meet during the development of a methodology for trace-level analysis of organic compounds in water samples. Determining whether the sample contamination by targeted compounds originates from the sample or relates to its handling is another very important point. Indeed, although there is no natural background for human-made organic molecules, as there is for metals, they enter the composition of materials (e.g., plastics) or 593
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products for standard human consumption (e.g., cosmetics) and are present in our every-day environment. As a result, they can be transferred to the samples. The most common sources of sample contamination by organic molecules are: the atmosphere; equipment that is insufciently cleaned or made with materials inappropriate for the targeted compounds; bad care of the samples during the sampling and the transport (adapted USGS 2006) [35]. In practice, solvents, reagents, glassware, analytical instruments, equipment and work environment are the sources of contamination [22]. They make it possible to qualify a clean sample as contaminated. In the following paragraphs, we review the denition and the necessity to perform blanks in parallel to real samples as well as the various sources of pollution and the possible solutions from literature data and/or feedback from our laboratory experience. In addition to the blanks, the extraction recoveries can also reect pollution of the samples, when the recovery rates are much greater than 100%. For example, during one of their experiments, Furlong et al. [21] reported an extraction recovery up to 560% for caffeine, clearly proving the contamination of sample. As a result, blanks and extraction-recovery experiments must be performed in parallel. 4.1. Blanks To prevent false positives, many authors make blanks go through analysis in parallel with their samples. In general, they use water free from organic matter and free from the targeted analytes. Depending on the authors, various kinds of water are employed: water used for LC
mobile phases (e.g., HPLC grade [33]), ultra pure water (e.g., MilliQ water [17,32]), bottled spring water [37], bottled natural mineral water [38] or homemade water {distilled water [7], laboratory grade [2,36], water ltered on activated carbon [37]}. Several blanks can be made during sample treatment. They are introduced at different moments of the sample treatment, from the sampling to the injection on the analytical instrument, in order to identify the origin of the contamination such as the environment at sampling time, the equipment used for sampling, ltration or extraction, the needle of injection or the chromatographic solvent and gases. Table 3 adapted from USGS [35] lists the principal types of blank that can be realized to validate only the sampling step. In practice, the eld blank is the most complete, since it undergoes all the sampling stages (collection, transport and ltration) and makes it possible to validate the whole sampling step [28,32,36]. Berryman et al. [6] made these blanks by using eld bottles containing pure water and the same preservative agent that is added to each sample (formaldehyde). These bottles were opened during the collection step in the water-treatment plant, in order to evaluate the potential contamination brought by the equipment, the ambient air or transport. Nevertheless, the eld blank is not precise enough to identify the exact source of contamination. The second type of blank that must be integrated in a QC approach is known as laboratory blanks, which undergo the same treatment as the environmental samples [5,7,17,28]. They make it possible to be sure that the sample is not polluted in the laboratory. For Furlong et al. [21], these manipulation blanks correspond to water samples free from organic matter and spiked with
Table 3. Common types of blank samples and the questions they address [35] Type Field blank Equipment blank Targeted Source(s) of Bias1 Sample collection, processing and transport process Basic QC sample: Was my sample contaminated as a result of eld activities and exposure? Sample collection and processing equipment system Topical QC sample: Does an initial equipment assessment2 conrm the suitability of the equipment to provide samples within my data-quality requirements? Topical QC sample: Is my equipment-cleaning protocol adequate? Sampling device (e.g., the D-95 sampler, Fultz pump, or peristaltic-pump tubing) Topical QC sample: Is my sampling device the source of contamination? Filtration device (e.g., the capsule lter, in-line lter holder, aluminum plate lter) Topical QC sample: Is my ltration device the source of contamination? Exposure to atmospheric outfall or other conditions Topical QC sample: Was sample exposure to the atmosphere a contaminant source? The blank water used (e.g., IBW, PBW, or VPBW) Topical QC sample: Was my blank water tainted with respect to my analyte(s) of interest?
Sampler blank Filter blank Ambient blank Source-solution blank
[QC, Quality control; IBW, Inorganic-grade blank water; PBW, Pesticide-grade blank water; VPBW, Volatile-organic-compound and pesticidegrade blank water]. 1 The bias and variability measured include that from laboratory handling, processing, and analysis of the sample in addition to the targeted source listed. 2 An equipment blank is required for USGS investigations to determine the equipment suitability to provide the analyte data needed to meet study objectives.
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only internal standards. They are extracted and analyzed in parallel with a series of 10 environmental samples. Those blanks really reect what the handling can bring to a sample during processing, since they correspond to the processing of material, solvents, and gases used for the extraction or purication. They also take into account the atmosphere of the laboratory where the sample treatment is performed, because compounds present in the atmosphere and can be transferred to the solvents, can adsorb on glassware or in the phases that are used (e.g., in SPE methodologies). The last type of blank to be included in the QC approach is the injection blank [17,21,32,33]. Injection blanks make it possible to supervise a possible injectionto-injection carryover. This cross-contamination between injections can result from incomplete injection of the previous sample or insufcient washing of the injection needle. These blanks contain only solvent or water free of organic matter, plus internal and surrogate standards. They are placed directly on the rack of injection. Cahill et al. [33] inserted their injection blanks every 10 analyses, whereas Furlong et al. [21] analyzed them just after the calibration/verication sample (sample containing all the selected compounds). In Method 1694, the US EPA [37] also recommended placing an injection blank right after the analysis of samples containing the targeted analytes, in order to make sure that there is no transfer of pollutants. Even if many authors carry out analysis of blanks in parallel with their samples to ensure the validity of their environmental results, none of them exploit the information provided in the same way, when the blanks appear to be contaminated. Some authors {e.g., Casajuana and Lacorte [17], Chen et al. [7] or Garcia-Ac et al. [8]} subtracted the values of their laboratory and injection blanks from the values of their samples. By contrast, Furlong et al. [21] did not, as was also the case in US EPA methods 525.2 and 527 [22,39]. One should not subtract the values of the blank from those of the samples, because the concentrations in the blanks are variable. Others {e.g., Barnes et al. [5] or Focazio et al. [28]} would rather use these values to raise their LODs. Thus, Barnes et al. [5] reported that the concentration of compounds in the environmental samples were lower than their MDLs if the values were lower than at least 10 times the contamination of the blanks. Lastly, at the National Water Quality Laboratory (NWQL, USA), the presence of a compound in a sample is validated only if the concentration in the sample is 10 times that in the blank and the concentration in the sample is higher than the LOQs [21]. Other authors have decided on an individual basis, according to the compounds and the samples. Stackelberg et al. [2] specied that the quantities of compounds found in the blanks were either much lower than those found in the associated samples, or, on the contrary, that the compounds
identied in the blanks were not found in the associated samples. For example, carbamazepine was dosed at 0.3 ng/L in the eld blank whereas it was dosed with a value more than 100 times greater in the associated sample, or, by contrast, the sulfamethoxazole and the trimethoprim, respectively quantied at 0.9 ng/L and 0.1 ng/L in the eld blank, are not found in the associated samples. In both cases, they deduced that identication of these compounds in the eld blanks or in the laboratory blanks did not compromise qualitatively and quantitatively the results of their analysis. In general, the compounds that are the most frequently detected in the blanks are caffeine, phthalates and bisphenol A (BPA). Blanks of Focazio et al. [28] revealed frequent detection of caffeine, in the range 3 162 ng/L. They also underlined occasional detection of the metabolite of caffeine (1,7-dimethylxanthine), plasticizers (e.g., bisphenol A or triphenyl phosphate), or molecules that were constituents of cosmetics (e.g., 1,4dichlorobenzene or methyl salicylate). Furlong et al. [21] found at least once in the blanks 11 of the 14 pharmaceutical substances that they were looking for. Caffeine was found ve times out of 99 blanks analyzed, with an average concentration of 77.8 ng/L, and with a maximum concentration of 239 ng/L. Codeine is found three times out of 99 blanks analyzed, with an average concentration of 15 ng/L and with a maximum concentration of 33.4 ng/L. The authors concluded that the contamination of the blank by PPCPs is infrequent and that one laboratory blank every 10 environmental samples treated was enough, but yet essential, to evaluate it. 4.2. Contributions of the technician One of the sources of pollution during sample analysis is the technician. Some compounds [e.g., caffeine or cotinine (a nicotine metabolite), both found in standard products for human consumption like coffee or cigarettes, and acetyl hexamethyl tetrahydro naphthalene (AHTN) found in perfume, or aspirin, an anti-inammatory drug also found in dermatological creams] can be transferred to samples via the analyst. Tests have been carried out to compare the impact a coffee drinker can have on the transfer of caffeine to the samples. The same water analyzed by a coffee drinker contains 250 ng/L of caffeine, whereas it contains no more than 30 ng/L when it is analyzed by a person who does not drink coffee. This concentration even goes down to less than 5 ng/L if the analyst washes his hands carefully and wears gloves. Other compounds are also transferable. It has been noticed that the presence of phenanthrene or pyrene in laboratory blanks was characteristic of a smoking technician, as illustrated in Table 4. Also, an experienced technician, after working for several years on this problem, pollutes samples less than a beginner, as shown
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Table 4. Influence of the technician characteristics (experienced/inexperienced, smoker or not) on the detection of PAHs in experimental blanks (experienced technician technician used for several years to work on traces level samples; inexperienced technician technician working for the first time on such samples) Quantity (ng) of PAH compounds Naphthalene Acenaphthylene Acenaphthene Fluorene Phenanthrene Anthracene Fluoranthene Pyrene Benzo[a]anthacene Chrysene + triphenylene Benzouoranthene Benzo[e]pyrene Benzo[a] pyrene Perylene Indone[cd]pyrene Dibenzo[a,h + a,c]anthracene Benzo[ghi]perylene Sum Experienced non-smoker technician 6.47 0.13 0.52 0.54 1.78 0.09 0.39 0.55 nd 0.03 nd nd nd nd nd nd nd 10 Inexperienced non-smoker technician 9.53 0.06 0.05 1.16 13.35 nd 0.53 1.46 0.01 0.01 nd nd nd 4.27 nd nd nd 30 Experienced smoker technician 5.30 0.19 1.38 1.97 5.91 0.22 0.83 2.63 0.09 0.23 nd nd nd nd nd nd nd 19
with naphthalene and phenanthrene but also pyrene and perylene (Table 4). These two examples conrm that the technician can be the source of sample pollution. In the USGS handbook [35] about the quality of data acquisition for water analysis, chapter 4 on quality control (QC) lists the substances that people can introduce into the sample during sampling. It also applies to analysis of the sample itself. Caffeine, nicotine or N,N-diethyltoluamide (DEET, a mosquito repellent) can be transferred via dirty hands or gloves, alcohol can be brought by breath and many other substances can be transferred from clothes or hair. To reduce the risks of a technician polluting samples, Barnes et al. [5], Focazio et al. [28] and the USGS [35] recommended avoiding use of perfume or insect repellant (DEET) and not consuming products containing caffeine or tobacco when their components are also the target molecules. In conclusion, to limit the transfer of compounds from the technician to the sample, it is recommended to select the person according to their own characteristics (smoker or not, coffee drinker or not) and the targeted analytes. Wearing gloves, a laboratory coat and a mask throughout the process of sampling and analysis is recommended to reduce transfers. In addition, the experience of the analyst strongly contributes to reducing the risks of pollution during handling (Table 4). 4.3. Contributions of the working environment The environment of the laboratory is also a source of contamination. In our laboratory, a room has been dedicated to experiments on samples that are supposed to be highly contaminated [e.g., waters from sewage596
treatment plants (STPs)] and another room to experiments on samples that are not or only slightly, contaminated (e.g., groundwater or drinking water). Initially, the two rooms were the same, but, due to the constant treatment of contaminated samples in the rst one the work environment there is more likely to convey contaminants and could consequently pollute future samples for analysis. For this reason, this room was named the contaminated room. By contrast, the environment of the second room is supposed to be cleaner, so this second room is dedicated to analyses of traces and was named the clean room. Their respective ambient atmospheres are veried daily. PAHs were analyzed in blank samples carried out in parallel with environmental samples in each room. The average quantity of PAHs found in blank samples were 17 ng (n = 7) and 8 ng (n = 11) in the contaminated and clean room, respectively. In the same way, polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) were analyzed in blank samples carried out in parallel with environmental samples in each room (Fig. 1). Even if there is an overlap area between the quantities found in the blanks of these two rooms, it can noticed that, for the two classes of compounds and for a same parameter, as for PAHs, the values are systematically higher in the room dedicated to the contaminated matrices. These results perfectly reect the pollution that the laboratory environment itself can generate. As a result, we can strongly recommend to dedicate rooms and hoods to specic applications. Moreover, samples of different levels of contamination should not be analyzed during the same extraction series or at the same time, in the same room, even if they are in different
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sum PCB+PBDE (ng)
25 20 15 10 5 0
average
maximum
minimum
median
contaminated room (n=3) room type
clean room (n=9)
Figure 1. Impact of the room where the experiments are done on the quantity of PCBs and PBDEs detected in blank samples (Contaminated room means room where samples supposed to be highly contaminated are treated and clean room means room where only samples supposed not to be or only slightly contaminated are treated; in parallel, the ambient contamination is checked to verify levels for targeted contaminants to be analyzed).
extraction series. This will avoid cross-contamination between samples. Respecting this system of specic rooms according to the level of contamination implies doubling all necessary equipment to avoid changing rooms during the experiment. Consequently, it implies a certain cost, organizational rules and strict working methods. These practices are part of demanding QC procedures and methodologies [e.g., Good Laboratory Practice (GLP) or Hazard Analysis Critical Control Point (HACCP)]. Despite these precautions, if some compounds are identied in the laboratory blanks, it is necessary to distinguish the compounds brought by the sample treatment from those present initially. One strategy involves increasing the volume of the tested sample without changing extraction time signicantly. If the contamination comes from the sample, then the quantities extracted will increase in proportion to increases in the volume treated. However, if the contamination comes from the working atmosphere, then, whatever the volume treated, the quantity of extracted compounds will be the same. But increasing the sample volume is not always possible because matrix problems can increase or sample size can be limited. Caffeine was analyzed in eight raw waters (RWs) used in the production of drinking waters. With a sample volume of 100 mL, the contamination level of the laboratory blank (11.5 ng) and of the samples (11.2 22.7 ng) were roughly the same. In this particular case, it was impossible to know whether the caffeine analyzed in the samples came from the samples themselves or was the result of contamination during sample processing. Increasing the volume of the treated sample from 100 mL to 500 mL enabled going over the background noise (e.g., RW 4). Extraction of 100 mL and 500 mL of RW 4 gave 18.8 ng and 54.8 ng of caffeine, respectively, whereas extraction of 100 mL and 500 mL of blank samples gave 11.5 ng and 20.2 ng of caffeine, respectively. We can conclude that RW 4 probably contained
an average of 70 ng/L of caffeine, after subtraction of the blank. By contrast, the other samples always contained caffeine in the same proportions (4.227 ng for 500 mL extracted water) as the laboratory blanks (or even below). We can deduce that these waters initially did not contain caffeine and that the quantities analyzed resulted only from the pollution brought during handling. The differences between samples are due to the variability in ambient contamination. Generally, the more a sample is handled, the more it could be contaminated by the working atmosphere. To reduce this risk, there are certain techniques that can be used {e.g., direct injection [40,41], solid-phase micro-extraction (SPME) [42] or online SPE [8]}; they reduce both handling costs and risks of pollution. 4.4. Contribution of the laboratory equipment used According to the class of targeted contaminants, pollution of the laboratory blank is more likely to be caused by the working environment (e.g., naphthalene, caffeine), the technician (e.g., pyrene, caffeine) or the equipment. Indeed, when targeted compounds are components of plastics (e.g., alkylphenols, bisphenol A or phthalates), the equipment used for the analysis should be chosen carefully. To illustrate this point, on three occasions, two different volumes of the same drinking water were extracted, one by SPE with plastics pipes and one with glass Pasteur pipettes, in order to analyze BPA and 4-NP. The quantities of 4-NP and BPA were, respectively, 3 times and 100 times lower when the analysis was realized with glass Pasteur pipettes rather than plastics pipes. The contamination of the sample by the equipment was obvious. Moreover, with the same equipment employed, the quantities found were higher when greater volumes were extracted. For example, quantities of BPA were respectively 45.5 ng and 179.2 ng for 0.5 L and 1.5 L of drinking water extracted with plastics pipes, and 0.3 ng
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and 0.7 ng for 0.01 L and 0.1 L of the same drinking water extracted with glass Pasteur pipettes. The larger the volume of sample treated, the longer was the contact time and the greater was the quantity of BPA. Indeed, the equipment was not inert and the longer the sample was in contact with plastics, the more it absorbed BPA (and 4-NP), explaining why the quantities increased according to the increase in volume treated. Casajuana and Lacorte [17] observed that the contamination of their laboratory blanks, made in parallel for analysis of phthalates and other EDCs, could come from polypropylene cartridges and polyethylene frits during SPE. As the equipment used for SPE is a source of pollution, SPE does not seem to be an appropriate technique to analyze phthalates at low levels. Moreover, for the analysis of phthalates, we can notice that the less a sample is handled the less it is polluted. SPME should be preferred because it allows us to minimize the handling of aqueous samples. However, the average (n = 3) chromatographic peak areas for di(2-ethylhexyl)phthalate (DEHP) in an injected blank sample were 25,048 5235 and 73,791 12,979 with PDMS 100 lm and PDMS DVB bers, respectively, showing that, when DEHP was analyzed, laboratory blanks systematically contain the targeted analyte, whatever the type of ber employed. This unavoidable background noise can be managed by making a ber blank before the analysis of each sample. If the DEHP area in the sample is not at least twice as high as that in the previous blank, then it cannot be concluded that the sample is contaminated with DEHP. In addition, the state of the analytical system employed (more or less recently subjected to service and maintenance) and the type of ber chosen could affect the quantities of DEHP detected in
90000 80000 70000 60000 50000 40000 30000 20000 10000 0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324 new fibre + new elements
the blanks, and could vary from one day to another (Fig. 2). Fig. 2 shows the decrease in DEHP contamination observed in ber, which can be explained by the decrease in the pollution released from the ber or a decrease in analytical sensitivity. The impact of glassware on phthalate analysis was studied by SPME. The DEHP concentrations found were 4.2 2.1 ng/L, 3.7 1.2 ng/L, 3.3 1.6 ng/L and 1.5 0.2 ng/L in the same water analyzed with glassware used only for drinking-water analysis, new glassware, new glassware that had been baked and new glassware washed and baked, respectively. New, washed and baked glassware could reduce both the DEHP concentrations and concentration variations in the water analyzed. But, whatever the precautions taken, there was an unavoidable background noise of about 4 ng/L. This residual contamination masked all DEHP levels below 5 ng/L and imposed an LOD of at least 10 ng/L. The inuence of the state of the glassware on caffeine analysis was also highlighted in the laboratory. When the whole equipment used for extraction, reconcentration and analysis of caffeine was new, the caffeine level detected in the laboratory blank was $1 ng/L. But, if the equipment used was not new, even if it had been used for drinking-water analysis only and it had been cleaned with detergents and baked at 450C, traces of caffeine were quantied in the concentration range 330 ng/L. This is called the memory effect. The memory effect can be stronger if the equipment used for trace analyses is not clean enough or if it has already been used with contaminated samples. By contrast, the molecules can be lost if the equipment used is not adapted. For example, they can be adsorbed on the inside surface of the containers {e.g., some pesticides on plastic
area
1 2 3 4 5 6 7 8 same fibre after a break into the usage
1 2 3 4 5 6 7 8 9 101112 new fibre + same elements cleaned
1 2 3 4 5 6 7 8 9 101112 new fibre + new elements
Figure 2. Evolution of blank ber contamination depending on the analytical system and ber states (elements = glass insert SPME, gold plated inlet seal, column cutting).
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[43] or the tetracyclines on glass [44]}. Consequently, it is fundamental to pay attention to the choice of the material used and its cleaning at every step of the analysis protocol. For example, for the sampling step, almost all authors recommended use of amber or inactinic glass bottles, to prevent the photodegradation of the contaminants [2,3,16,20]. Furlong et al. [21] use stainless-steel containers. For handling, many authors recommended use of laboratory-glass material to limit pollution of the samples by the material employed [21,22,37,39]. For example Montiel [45] recommended use of Pyrex bottles, and Quintana et al. [16] borosilicate Pyrex bottles. Moreover, it is necessary to avoid pollution coming from caps by using Teon caps to close asks and bottles [21,22]. In addition, it is very important to pay attention to the products used for cleaning, as some detergents contain compounds [e.g., alkylphenol polyethoxylates (APEOs)]. Looking at the literature, each team seems to have its own cleaning protocol. To minimize the contamination of their material by APEOs, Wenzel et al. [9] cleaned their glassware with precautions, heating it at 250C for at least 24 hours, then rinsing it with organic solvents. They cleaned the caps of their injection vials for 24 h at 70C under reduced pressure (50 mbar). Boyd et al. [46] washed their glassware with soap, then soaked it in a solution containing a specic detergent for industrial and medical use and then in a hydrochloric-acid solution. To nish, they baked it at 450C. The Teon material was washed in the same way as the glassware except for the baking step. Ye et al. [3] washed their bottles with acid. The US EPA method 1694 [37] recommended washing the glassware with solvents and a solution of detergent, right after use. The various elements have to be disassembled before washing. To optimize elimination of substances, the glassware containing the solution of detergent can be sonicated for a few seconds, and, once washed, it was immediately rinsed with several solvents: methanol, hot water, methanol, acetone, and, lastly, methylene chloride. Finally, it was baked at 300500C. Montiel [45] forbade the use of detergents, but recommended washing with nitric acid and then rinsing the glassware with water, baking it for 30 min at 450C, and then rinsing it again with the extraction solvent of the compounds that were looking for. Nevertheless, re-use of a bottle can lead to pollution, because of the memory effect. As a result, a bottle that has contained highly polluted samples should not be used again for the analysis of trace materials. Depending on the target compounds, one possible option involves using single-use polyethylene bottles. Watkinson et al. [32] autoclaved their glassware before successively washing it with acetone, methanol and MilliQ water.
In addition to their glassware, Furlong et al. [21] also baked Pasteur pipettes and glass-ber lters at 450C for 4 h, in order to eliminate all organic-compound residues. Many authors recommended calcination of the glassware [2,9,21,45,46]. To sum up, except for certain particular pollutants, we advise working with glass containers and using Teon caps. The glassware must be washed with the extraction solvents of the compounds and/or adapted detergents and then baked at 450C for several hours. The caps must also be washed with adapted detergents. In addition to glassware, the SPE vacuum manifold used for the SPE extraction is another possible source of contamination. The same experiment was performed with and without an SPE manifold, for aspirin analysis. In both cases, SPE cartridges were conditioned with ethyl acetate, then with pure water. They were immediately eluted. In that way, the quantities detected exclusively reected the contamination brought by the equipment and particularly by the SPE manifold, since it was the only variable element between the two experiments. Blanks contained an average basis of 13 ng of aspirin when the analysis was carried out with the SPE manifold versus 5 ng when the experiment was carried out without the manifold. This clearly showed that the SPE manifold had an impact on sample contamination. The sample-reconcentration step under nitrogen ow can also be a source of pollution. Fluoranthene was detected in all the protocol blanks of various experiments at concentration in the range 0.21.4 ng. To identify the source of contamination, the experiment was divided into several steps and several blanks were analyzed after each step. The conclusion was that the problem came from the reconcentration stage under nitrogen ow and from the purity of the gases that were used. It is important to remember that working with analytical gases of high quality (purity superior to 99.999% for nitrogen or switch to argon) and excluding gases of industrial quality is of primary importance. Furlong et al. [21] used ultrapure quality nitrogen for the reconcentration stage. Another source of pollution identied in laboratories is linked to the purity of standard compounds, more particularly internal standards. Indeed, erythromycin was analyzed with concentrations in the range 0.66 ng/L in several drinking waters during various series. In parallel, it was observed that in the same series, concentrations were almost identical, at an average level of 6 0.6 ng/ L (n = 8) or 0.6 0.1 ng/L (n = 3) and that there was a link between the quantity of erythromycin-13C2 added to the samples and the concentration of erythromycin that was quantied. Finally, LC/MS2 injection of a solution containing only erythromycin-13C2 revealed the presence of erythromycin. Consequently, the erythromycin
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detected in drinking waters was caused by pollution coming from the internal standard. Stackelberg et al. [2] also noticed that adding erythromycin-13C2 was at the source of the pollution of their laboratory blank by erythromycin. Moreover, a similar observation was made for two molecules of the same class, lincomycin and clarithromycin, which were detected at very low concentrations, 2 ng/L and 4 ng/L, respectively, in drinking-water samples when their respective internal standards were added, whereas they were absent when these internal standards were not added. In these cases, the limits of the internal calibration were reached. To conclude, once the source of pollution is identied, the problem can be limited by taking great care of the quality and the purity of solvents, gases and analytical standards, by meticulously cleaning the equipment, adapting the equipment used to the targeted class of compounds and even using new glassware for each analysis, if necessary. 4.5. Contributions of the analytical system Finally, samples can be considered as false positives if they are contaminated during the ultimate analytical step, or if the analytical answers are spoiled by interferences that have exactly the same identication criteria as the targeted compounds. To prevent or to evaluate the cross-contamination between samples during analysis, one or more injection blanks can be inserted between each sample [17,22,39]. When interferences are due to the material employed and they co-elute with the targeted compounds, one possible way to try to separate one from the other is to modify the chromatographic gradient [e.g., with a fast 18-min gradient, the interfering compound present in the injection blank was eluted at the same time as ketoprofen, (7.59 min), but, by modifying the chromatographic gradient and extending the analysis time to 38 min, the interfering compound (14.59 min) was eluted before ketoprofen (14.85 min), which allowed us to differentiate the two analytes]. In the case of chromatographic interferences, another way of determining whether the compound observed is indeed the targeted compound is to change the analytical system or the mode of analysis. A sample suspected of containing carbamazepine was analyzed in LC/MS2 and GC/MS2. In both cases, the four identication criteria (retention time, signals of the two transitions, and good ratio between the two transitions) were met and made it possible to show the presence of carbamazepine in water. By contrast, a sample suspected of not containing carbamazepine was analyzed on the same machine but used once as a simple GC/MS (SIM mode) and then as GC/MS2 (MRM mode). Fig. 3 shows the results of this test. A chromatographic peak was systematically observed on the 600
total ionic chromatogram (TIC) at the expected retention time. But the compound that showed at carbamazepine ion 193 did not show at carbamazepine transition 193 165, which implied that the water was free of carbamazepine.
5. False negatives Injection or manipulation blanks allow study of contamination phenomena and then avoidance of the risks of false-positive results. By contrast, samples enriched with compounds of interest make it possible to study the phenomena of compound losses and avoid false-negative results, via the evaluation of quantication and extraction recoveries. The losses can be caused by photodegradation {e.g., anthracene, benzo[a]anthracene or benzo[a]pyrene, [22]}, oxidation {e.g., PAHs [22]}, absorption on the inside surface of the containers {e.g., tetracyclines, [44], metolachlor and atrazine, [43]}, their conversion into epimers or isomers {e.g., tetracyclines [47]} or inappropriate protocol. 5.1. Extraction and quantication recoveries To quantify the losses and to a lesser extent the gains of compounds, a water sample initially free from the targeted compounds and free from organic matter was spiked with the molecules of interest. The sample was then extracted and analyzed in parallel with a series of 1016 environmental samples, in order to estimate the recovery for each series. These recoveries make it possible to evaluate the method performance in the absence of matrix interferences, and to make sure that there are no large changes for a set of analyzed samples [5,21,28,32,33]. The recoveries can be evaluated at various steps of the method: extraction, analysis, extraction and reconcentration, or the overall procedure (i.e. extraction, reconcentration and analysis) [3,21]. Furlong et al. [21] introduced in their analytical sequence a continuing calibration verication standard, which was an aliquot of one of the points of their calibration curve that contained all the selected compounds, including surrogates and internal standard. This control enabled them to make sure that the compounds were always correctly identied and that the analytical response did not change during the sequence. Ye et al. [3] rst evaluated the recovery of the extraction step only, then the recovery at the extraction and reconcentration steps, and, nally, the overall recovery. This last step is the most important because it takes into account both potential interferences related to handling and those related to the matrix effects during the analysis. The important recoveries are those of the whole extraction methods, which give a clear idea of their performance.
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Figure 3. Chromatograms of the same standard solution of carbamazepine (top) and the same water for drinking water production (bottom) analyzed by GC/MS/MS1 used in SIR mode (left) and MRM mode (right) (1: GC Agilent 6890, MS/MS Waters Quattro Micro GC, column HP5/MS 30 m 0.25 mm, 0.25 lm).
According to Wenzel et al. [9], there are various ways of estimating extraction recoveries. For steroid hormones, they spiked groundwater free of the selected compounds, at different environmentally relevant levels (0.5 ng/L, 2 ng/L and 10 ng/L). They then realized the whole protocol (i.e. extraction, purication, derivatization and analysis). Subsequently, they evaluated the percentage of recovery, either directly or by comparing it with that of another compound, which only went through the derivatization step and the analysis. In the rst case, the recoveries were in the range 6288%, according to the spiking level, whereas, in the second case, the recoveries improved to 75103%. This highlighted the importance of the way of evaluating recoveries. Internal standards and native compounds should have the same behavior, as internal standards will not compensate for losses of native compounds. That is why the extraction recoveries of internal standards were also evaluated [21,46].
Usually, when the recoveries of some compounds were lower than 20%, these compounds were excluded from the analytical method [46] or their results were reported as estimates. 5.2. Losses during handling Some very volatile compounds [e.g., naphthalene (PAH) or caffeine (PPCP)] can be easily lost during the step of evaporation/reconcentration, if this step is too long or too sharp. Other molecules can be degraded by the heat required during this step {e.g., penicillin G, which was degraded at 75C and at low pH [50]}. Furlong et al. [21] recommended not exceeding the temperature or the pressure required during the reconcentration step, as it can negatively affect handling yields. For other compounds (e.g., antibiotics uoroquinolones or tetracyclines), reaching dryness can cause loss of these compounds. Indeed, for ciprooxacin and its internal standard,
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ciprooxacin-13C3-15N, recoveries decreased proportionally from 56% and 47% to 9% and 8%, respectively, with increase in the dryness level, whereas the recoveries of sulfamethoxazole and sulfamethoxazole-13C6 were not affected. Their recoveries varied only from 70% and 69% to 67% and 64%, respectively. Again, Furlong et al. [21] recommended not reducing the nal extract below 100 lL, otherwise this can negatively affect handling recoveries. However, the addition of an adapted internal standard (i.e. with an exactly similar behavior) can compensate for these losses (e.g., ciprooxacin and ciprooxacin-13C3-15N and sulfamethoxazole and sulfamethoxazole-13C6). The breakthrough volume, which denes the maximum volume that can be reconcentrated by SPE without affecting the extraction recoveries, is also a source of loss of compounds. As illustrated in Fig. 4 (top), the extraction recoveries of atenol-d7 and of paracetamol-d4 greatly decreased when the volume of water passed through the SPE increased, whereas those of propranolol-d7 and diazepam-d5 were almost unchanged. The effects of breakthrough volume can also be compensated for by adding the internal standard corresponding exactly to the compound of interest [e.g., atenolol extraction recoveries evaluated according to atenolol-d7 were always around 100% [Fig. 4 (bottom)], whatever the percolated volume of water was, whereas it decreased strongly when calculated by external calibration. This was also true in the case of a measurement made with an inappropriate internal standard (e.g., paracetamol compared to diazepam-d5). However, in the extreme situations, the internal standard could someatenolol-d7 125 recovery (%) 100 75 50 25 0 (quantification method accuracy n=2) 5 ml (n=1) 100 ml (n=2) 200 ml (n=2) 300 ml (n=2) propranolol-d7
times act not exactly as the stable isotope, causing the recovery to be over-evaluated [Fig. 4 (bottom), 1500 mL]. To conclude on these two cases (i.e. evaporation and breakthrough volume), the loss of compounds can be compensated for only by adding an internal standard behaving exactly like the targeted molecule. The isotopic analogues of the studied compounds are the preferred choice [21]. However, where labeled isotopes do not exist, it is important to study these phenomena to understand their impact on the molecules of interest. Once the limits of the protocol have been established, it is necessary to ensure that they are not exceeded, in order to optimize extraction recoveries, even for the compounds without an isotopic analogue. 5.3. Losses due to inappropriate protocol Some parameters (e.g., pH) are well known to inuence extraction recoveries. In order to get optimal extraction conditions, it is important to study the effect of pH on water spiked with the targeted molecules. However, other elements can interfere with the recovery rate [e.g., chlorine or divalent cations (e.g., calcium or magnesium)]. The addition of ethylene-diamino-tetra-acetic acid (EDTA), a chelator of these divalent ions, allows us to improve signicantly the extraction recoveries of antibiotics (e.g., tetracyclines or uoroquinolones) (Fig. 5, top) by avoiding their irreversible binding to such ions or onto the glass surface. The addition of EDTA in water with pH stabilized at 7 makes it decrease to 5, but, as shown in Fig. 5, optimization of the extraction yields of these antibiotics
paracetamol-d4 100 75 50 25 0 (quantification method accuracy n=3) 100 ml (n=3) 500 ml (n=3) 1500 ml (n=3) diazepam-d5
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percolated water volume (quality assurance)

external calibration 100 recovery (%) 75 50 25 0 (quantification 100 ml 200 ml method accuracy n=2) percolated water volume (quality assurance) 300 ml internal calibration (atenolol/atenolol-d7)
percolated water volume (quality assurance)

paracetamol / diazepam-d5 paracetamol / paracetamol-d4
150 175 125 100 75 50 25 0

(quantification 100 ml 500 ml method accuracy (n=3) (n=3) n=3) percolated water volume (quality assurance) 1500 ml (n=3)
Figure 4. Impact of the breakthrough volume on the recovery (top) and its compensation via the addition of the appropriate internal standard versus external calibration for atenolol (left), or versus calibration by an inappropriate internal standard for paracetamol (right) (bottom) (h-blockers: SPE on Oasis HLB cartridges and analyze in ESI+ with LC/MS/MS, RRLC Agilent 1200 series and MS/MS 6410 QQQ; other medicaments: SPE on Oasis MCX cartridges and analyze in ESI+ with LC/MS/MS, RRLC Agilent 1200 series and MS/MS 6410 QQQ).
602
recovery (%)
Trends
was not linked to this change in pH, but to the addition of EDTA. In the presence of chlorinated water, we recommend neutralizing this disinfecting agent, because it can degrade organic compounds. US EPA method 525.2 [22] recommended addition of sodium sulte for the quantication of PAHs, PCBs, phthalates and some pesticides, as did Boyd et al. [46] for the quantication of PPCPs. However, US EPA method 527 [39] for the quantication of some pesticides and brominated ame retardants recommended the addition of ascorbic acid, because the other reducing agents degraded the targeted compounds. Ye et al. [3] also used addition of ascorbic acid to prevent degradation by chlorine of EDCs (e.g., BPA) and antibiotics. Finally, US EPA method 1694 [37] for the quantication of PPCPs recommended the addition of sodium thiosulfate, as did Quintana et al. [16] for the quantication of some pesticides. Fig. 5 (bottom) highlights the optimization of extraction recoveries when sodium thiosulfate was added. The extraction yields of diclofenac-d4, paracetamol-d4 and gembrozil-d6 were null in chlorinated waters, and were clearly improved by addition of sodium thiosulfate, reaching values almost equivalent to those obtained in reference water. By contrast, extraction recoveries of diazeapm-d5 and of ibuprofene-d3 did not vary for the three conditions, indicating that diazepam and ibuprofen were not impacted by the presence of chlorine. Thiosulfate had no effect on the improvement of their recoveries in this case.
5.4. Analytical losses If the presence of chromatographic interferences can produce false-positive results, they can also mask compounds of interest. This can be highlighted if the peak of a compound is distorted in a spiked water sample compared to the peak of the same compound in a standard solution. In this case, the interfering compound prevents the correct integration of the compounds and a correct quantication. As for false positives, the solution recommended in this case is either to change the chromatographic gradient, in order to move the retention time of both substances, or to switch to another analytical technique (e.g., GC/MS2 or LC/MS2), when possible.
6. Condence in published results If contaminants are detected in samples without exactly fullling all the criteria of method validity, because their extraction recoveries are not good enough, the LODs are too high, or they are detected in the blanks, it is difcult to claim that they are indeed present and to give a concentration level. But, they cannot be neglected. In order to make decisions in these zones of uncertainty, criteria of validity of a method need to be established. For example, the results presented by some authors {e.g., Focazio et al. [28]} can be trustworthy, since they specied that, for each treated sample series, they analyzed in parallel, blanks, spiked pure water and spiked samples, but they also duplicated some samples in order to evaluate the extraction recoveries, the problems of
tetracycline recovery (%) 150 125 100 75 50 25 0 (quantification method accuracy)
oxytetracycline
ciprofloxacin
ofloxacin
pH 5
pH 7 + EDTA
pH 7
tested condition (quality assurance)
recovery (%)
100 75 50 25 0 reference water (n=3)
diclofenac-d4 paracetamol-d4 gemfibrozil-d6
ibuprofene-d3 diazepam-d5
chlorinated water water type
chlorinated water + thiosulfate
Figure 5. The improvement of the recovery of tetracycline and uoroquinolones antibiotics by adding EDTA in spiked-water samples (top) and improvement of the recovery of some other pharmaceutical compounds by adding sodium thiosulfate in chlorinated water, in comparison with the reference water spiked with the internal standards (bottom) (Top: SPE on Oasis HLB cartridges + analyze with LC/MS/MS, RRLC Agilent 1200 series and MS/MS Agilent 6410 QQQ; Bottom: SPE on Oasis MCX + analyze with LC/MS/MS, RRLC Agilent 1200 series and MS/MS Agilent 6410 QQQ).
603
Trends
matrix effect, the reproducibility and the laboratory contamination. Moreover, they added internal standards to their samples, which allowed us to estimate the method performances. All these precautions, when detailed, allow us to have condence in the published results. In their review, Hao et al. [48] conrmed the necessity to have at least three minimal QC parameters (method blank, method spike and reagent blank) to have condence in results. They reviewed the QC parameters of 44 publications and concluded that only three of them specied these three criteria. Otherwise, analyzing the same sample using various methods and different analytical techniques is another way to be sure of the presence and the concentration of a compound [5,28]. Apart from the validation parameters of the analytical method and respect for QC principles (e.g., the blanks and the spikes treated in parallel with the environmental samples), another factor can also affect the results: the preservation of the samples. Although the authors are aware of the crucial importance of this factor towards the results, they have chosen not to discuss this subject here, since it does not strictly concern the analytical eld. Nevertheless, they underline that storage and preservation conditions should not be neglected to make sure of the validity of the results and avoid false-negative results (samples kept in darkness, at 4C or 20C, with or without the addition of a preservative (e.g., formaldehyde or methanol), time of conservation between sampling and treatment, and between extraction and analysis). Conversely, when compounds resulting from a
degradation reaction were being studied (e.g., nonylphenol, bacterial degradation by-product of APEOs), the concentrations could have been higher if the sample had been badly preserved.
7. Conclusion Seen from a distance, working with drinking waters and groundwaters can appear easy, because matrix effects at the analytical level are weak, and there are few risks (e.g., plugging the SPE cartridges). However, many other constraints make it very difcult to produce reliable measurements. Table 5 summarizes problems and solutions of such analysis, as found in the literature review and from our own experience. The biggest constraint for ultra-trace analysis involves avoiding risks of external contamination. We could see that, from sampling to analysis, many sources of pollution exist (e.g., glassware, solvents, ambient air, technicians, experimental equipment or measurement devices). In order to produce trustworthy results, it is of prime importance to prepare several blanks throughout the handling of samples and to be ready to criticize the results obtained. Moreover, due to the very low level of contamination looked for, it is very important to make sure that there is no loss of the analytes during the treatment process. It is equally important to prepare spiked waters not only during methodological development, but also in parallel with each series of analyses, in order to evaluate the recovery rates.
Table 5. Probems encountered during trace-level analysis and their solutions Problems Analytical performance Identication Solutions Use new (recent) analytical systems [e.g., LC/MS(/MS), GC/MS(/MS), on line SPE LC/MS/MS] Use several criteria (two transitions in MRM mode, ...) and, for the future, generalize the use high-resolution mass spectrometer [e.g., LC/TOF, GC/TOF, LC/MSn]
Pollution Linked to technician Linked to equipment Linked to reagent Linked to working environment
Wear lab coat, gloves and mask, select technician in relation to targeted compounds (e.g., smoker or not) Dedicate glassware, use adapted detergents for cleaning, baked glassware, choose materiel in relation to targeted compounds (e.g., glass bottles for BPA analysis) Use high-purity, quality standards, gases and solvents (e.g., HPLC grade, ultrapure water) Dedicate rooms, hoods and laboratory equipment in relation to the level of contamination of the sample (e.g., water from STP or drinking water)
Losses Due to Due to Due to Due to Due to Due to
degradation adsorption chlorine cations breakthrough volume evaporation
Prevent photodegradation (e.g., glass amber bottles) Use plastic or glass bottle depending on molecules looked for Use sodium thiosulfate, sodium sulte or ascorbic acid Use EDTA Use isotopic analogues as internal standards (e.g., 13C, 15N or deuterated) Avoid dryness and use labeled isotopes
Interferences Analytical Experimental
Change chromatographic gradient, use different analytical system (e.g., LC/MS/MS and GC/MS/MS), use different mode (e.g., SIM and MRM) Increase sample volume
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Trends
Table 6. How to report a value depending on the fulfilment of analytical criteria (RT, Retention time; MQL, Method limit of quantification; R, Extraction recovery; TRUE, Identification and quantification certified; FALSE, No compound; ESTIMATED, Identification sure but quantification uncertain; DETECTED, Identification sure but no quantification possible)
Also, the sensitivity of the method developed is a key factor in carrying out such analyses successfully. Instruments (e.g., mass spectrometers, simple or in tandem) can reach LODs in the ng/L range, but such analytical performances are uninteresting if the sample handling is not surrounded by safeguards. In conclusion, it appears from the literature and from our own observations that particular precautions must be taken when analyzing organic pollutants present at trace levels in groundwaters and drinking waters: X four identication points (retention time, one ionic signal for quantication and another one for conrmation, and the ratio between them); X standards, reagents, gases, solvents and water of high quality and purity; X appropriate internal standards; X eld, laboratory, reagent and injection blanks; X spiked waters at relevant concentration (ng/L); X glassware, equipment, rooms and hoods dedicated to trace analysis; X careful cleaning (appropriate detergent and calcination) and equipment maintenance; X wear laboratory coat, gloves and mask; X avoid smoking, drinking coffee, wearing perfume, dermatological cream and other everyday cosmetics when there constituents are in targeted compounds; and, X keep a critical eye on the results (e.g., sample concentrations in parallel with blank concentrations). Finally, inspired by the precautions exposed by Barnes et al. [5] when reporting the results of their study on groundwaters in USA (<RL, UC, nd), we propose in
Table 6 a way of reporting the data as a function of the quality criteria they meet.
Acknowledgements This work was supported by the EFBW (European Federation of Bottled Waters). Aquitaine Region is also acknowledged for financial support with respect to analytical equipment.
References
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Trends

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Trace-level analysis of organic contaminants in drinking waters and groundwaters

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

USA [2] Drinking water

Anthraquinone Benzophenone Bromoform Tetrachloroethylene

72 130 21,000 100

BPA 4-NP OP2EO

TDIP TBP TCEP

$100 $200 $80

BPA Cholesterol Coprostanol

2550 1730 1290

Naphthalene 5-methyl-1Hbenzotriazole Acetophenone Ethanol,2butoxyphosphate

1510 2080 2670 1340

Canada [6] Drinking water

Clobric acid Carbamazepine Caffeine Cotinine Ooxacin Sulfamethoxazole

0.91.1 0.8135 6.8108 0.89 0.71.6 0.30.5

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

180 100 45 18 29 12 1.4 22.9 43.2 2.5 0.6 3 0.2 210

4-NP1EO 4-NP1EC Stigmasterol b-Sitosterol

2.52.6 1112 3863 99179

France [10] Drinking water before chlorination process

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Androstenedione Androsterone Oestrone Levonorgestrel Norethindrone Progesterone Testosterone

0.12.8 0.51 0.3 0.210 0.36.8 0.210.7 0.226.4

Germany [12] Groundwater

Spain [16] Drinking water

Israel [20] Groundwater

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Sampler blank Filter blank Ambient blank Source-solution blank

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

sum PCB+PBDE (ng)

contaminated room (n=3) room type

clean room (n=9)

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

1 2 3 4 5 6 7 8 same fibre after a break into the usage

1 2 3 4 5 6 7 8 9 101112 new fibre + same elements cleaned

1 2 3 4 5 6 7 8 9 101112 new fibre + new elements

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

percolated water volume (quality assurance)

percolated water volume (quality assurance)

150 175 125 100 75 50 25 0

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

tetracycline recovery (%) 150 125 100 75 50 25 0 (quantification method accuracy)

tested condition (quality assurance)

100 75 50 25 0 reference water (n=3)

diclofenac-d4 paracetamol-d4 gemfibrozil-d6

chlorinated water water type

chlorinated water + thiosulfate

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011

Losses Due to Due to Due to Due to Due to Due to

degradation adsorption chlorine cations breakthrough volume evaporation

Interferences Analytical Experimental

Trends in Analytical Chemistry, Vol. 30, No. 4, 2011