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Trends in Analytical Chemistry 123 (2020) 115423 Contents lists available at ScienceDirect Trends in Analytical Chemistry journal homepage: www.elsevier.com/locate/trac Towards a comprehensive analytical workflow for the chemical characterisation of organofluorine in consumer products and environmental samples Alina Koch, Rudolf Aro, Thanh Wang, Leo W.Y. Yeung* Man-Technology-Environment Research Centre (MTM), School of Science and Technology, Orebro University, SE-70182, Orebro, Sweden ARTICLE INFO Article history: Available online 28 February 2019 Keywords: Fluorine mass balance Extractable organofluorine (EOF) Per- and polyfluoroalkyl substances (PFASs) Combustion ion chromatography (CIC) Particle-induced gamma-ray emission spectrometry (PIGE) Inductively coupled plasma MS/MS (ICPMS/MS) ABSTRACT This review summarizes and discusses eight analytical methods for organofluorine (OF) analysis, which offer detection limits suitable for consumer products and environmental samples. Direct sample analysis of OF only applies to some techniques on consumer products, whereas others require sample pretreatment or concentration before measurements. Comparison between methods for OF analysis were found to be difficult because of different selectivity (between OF and fluoride), sensitivity and type of samples (bulk, extract, surface) analysed. Neither inter-laboratory comparison on OF analysis nor suitable certified reference materials have been used for method validation, which makes data comparability between studies challenging. A top down approach for the comprehensive assessment of OF is proposed, where OF/extractable OF is first measured, followed by target analysis to obtain unquantifiable OF concentrations using the mass balance approach. For further identification of unquantifiable OF, approaches such as total oxidizable precursor assay, suspect and non-target screening are briefly discussed. 0 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction While fluorine in its inorganic form is the most abundant halogen in the Earth's crust, only about a dozen natural organofluorine substances have been isolated from a few subtropical and tropical plants [1]. Therefore when measuring organofluorine in the environment one can assume that it originates from an anthropogenic source. Organofluorines have strong C--F bonds which gives them chemical and thermal stability making them useful in a wide range of commercial products and industrial processes. It has been estimated that 25% of pharmaceuticals [2] and approximately 30-40% of agrochemicals [3], including 25% of licensed herbicides [4], contain fluorine. The introduction of a perfluoroalkyl moiety (C,,F2ni --) to a substance provides unique properties such as high surface activity at low concentration, strong acidity, hydrophobicity and/or lipophobicity [5]. A specific group of organofluorines that mostly or partly consists of perfluoroalkyl moieties are known as per- and polyfluoroalkyl substances (PFASs). They have been produced since the 1950s, for food contact materials, cosmetics, surface coatings, aqueous film forming foams * Corresponding author. E-mail address: oru.se (L.W.Y. Yeung). (AFFF) and many other applications [6]. However, the useful properties of PFASs could also lead to undesired environmental consequences. For example, a subclass of PFAS5, the perfluoroalkyl acids (PFAAs), are known to be extremely resistant to degradation which have led to widespread occurrence in the global environment, and their long-chain homologues are bioaccumulative [7]. Due to evidence regarding adverse health effects, the production of the most common PFAA, perfluorooctanesulfonic acid (PFOS) and its precursors, were phased out by the major producer 3M in 2001 [8]. Later PFOS and its salts were added to the Stockholm Convention on Persistent Organic Pollutants (POPs) in 2009 (SC-4/17), while perfluorooctanoic acid (PFOA) and certain related substances have been regulated by the European Union (EU 2017/1000) in 2017. Declining trends of PFOS and PFOA concentrations in human blood in different countries have been reported after their phaseout [9-11]. However, alternative PFAS5 have been introduced into the global market, which may lead to increased human exposure to unidentified PFASs [12,13]. Therefore, declining concentrations of PFOS and PFOA in human blood do not necessarily correspond to reduced exposure to PFAS5. Furthermore, these and other unidentified substances (e.g. impurities, intermediates and precursors) may account for some of the 4730 PFAS-related CAS-numbers that https://doi.org/10.1016/j.trac.2019.02.024 0165-9936/ 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.orgilicensesiby/4.0/). 2 A. Koch et al. / Trends in Analytical Chemistry 123 (2020) 115423 have been identified [14]. However, no single analytical method is versatile and robust enough to identify and quantify the vast number of PFASs, as well as other fluorine-containing agrochemicals or pharmaceuticals that might be present in a sample. In order to tackle these challenges, analytical methods that are able to identify and to quantify the vast number of compounds are needed. Various instrumental methods have been used to measure the levels of total fluorine (TF) and organofluorine (OF), such as 19F nuclear magnetic resonance (NMR) spectroscopy, particle-induced gamma-ray emission spectrometry (PIGE), combustion ion chromatography (CIC) and continuum source molecular absorption spectrometry (CS-MAS). The difference between OF and the sum of quantified PFASs, expressed as fluorine equivalents (F-equivalents), indicates the presence of unquantifiable fluorinated substances in a sample. This concept is also known as fluorine mass balance analysis (Fig. 1) and has been used in numerous studies [15e24]. As the need to estimate and identify unidentified organofluorine is growing, this review will discuss existing analytical methodologies (instrumental techniques and sample pre-treatments) for OF analysis with a focus on those with sufficient detection limits for consumer products and environmental samples. Approaches on how to address the determination of unquantifiable OF will also be discussed. Finally, an analytical workflow is proposed for a comprehensive assessment of OF. 2. Terminology for the mass balance approach Several terms have been used to describe different fractions of fluorine in the mass balance approach (Fig. 1). TF is equal to the sum of inorganic fluorine (IF, including F, fluoride salts and metal complexes) and organofluorine (OF, compounds that contain one or several CeF bonds). Earlier methods measured TF and IF, and determined OF as the difference between TF and IF. Several studies have used modified extraction methods (see Section 4), either extracting OF or removing IF from a sample to determine the levels of extractable organofluorine (EOF). Conceivably, different extraction procedures isolate different amounts of OF, therefore distinguishing between non-extractable fluorine (NEOF) and EOF is needed. Organofluorine analysis entails the analysis of the EOF fraction, which consists of quantifiable OF and unquantifiable OF. Unquantifiable OF can be further divided into unidentified (hence unquantified) OF and identified (but yet to be quantified, tentative or semi-quantified) OF. 3. Instrumentations for total fluorine/organofluorine analysis The development of analytical methods for fluorine analysis started in the early 1900s with traditional titration [25]. Before the 1990s, fluoride was mainly measured in coal [26] and blood samples (for dental research) [27,28]. Defluorination, such as ashing or oxygen bomb, was used to cleave the CeF bond in order to convert OF into fluoride before detection. Instruments such as aluminum monofluoride MAS (AIF-MAS), PIGE, ion chromatography (IC) and several fluoride ion selective electrode (F-ISE) detection methods have been used for total fluorine determination [29e32]. After 2000, several methods have been developed for TF/OF analysis for different matrices in the context of PFAS research [17,18,22,33e35]. The following sections will discuss selected analytical methods with the focus on OF measurements. Only methods which offer limits of detection (LODs) suitable for consumer products (Table 1(a)) and environmental analysis (<500 ppb F, Table 1(b)) are discussed. 3.1. Direct analysis of OF in consumer products 3.1.1. Particle-induced gamma-ray emission spectroscopy (PIGE) PIGE a long-established ion beam technique was recently adapted for the quantitative determination of TF/OF in textiles and paper in the context of PFAS research [18]. In PIGE, an ion beam of accelerated protons excites the nucleus of atoms in the sample. The gamma rays emitted from fluorine are distinctive and yield an emission count that is proportional to the number of fluorine atoms on the sample surface. The method has the advantages of being non-destructive, having high throughput (>20 samples per hour), no matrix effects and acceptable sensitivity (ppm levels) [18]. In addition, no sample pre-treatment is needed for the analysis of solid surfaces (assuming that contribution from IF is negligible), which eliminates potential bias from sample extraction [19]. However, some materials could be treated with wood treatment agents that contain IF such as ammonium hydrogen fluoride or sodium fluoride, which would lead to overestimation of the OF [16]. PIGE measures surface material to a depth of up to 250 mm, thus is commonly used for solid samples, although powders can be compressed into pellets [18] and liquid samples could also be analysed using a solid support (e.g. sorbent). As PIGE is non-selective between IF and OF, the removal of IF is needed for other complex matrices such as soil, sediment and biota for OF analysis. Other drawbacks are the need for a neutron activation source and highly specialized operators to use the instrumentation. Total uorine analysis, TF Organouorine analysis, OF Inorganic uorine, IF + Non-extractable Extractable uorine, NEOF organouorine, EOF Quanable Idened OF OF Unquanable OF Unidenied OF Fig. 1. Mass balance analysis of fluorine. 3.1.2. X-ray photoelectron spectroscopy (XPS) X-ray photoelectron spectroscopy (XPS) is another direct anal- ysis method which was recently adapted for OF analysis by quantifying the atomic percentage of fluorine (at % F) in consumer products [37]. XPS spectra are acquired by irradiating the surface of a material with an X-ray under high vacuum while simultaneously recording the number of electrons emitted and their kinetic energy, which is specific to certain chemical states (e.g. CF2 at ~292 eV and CF3 at ~293 eV groups). Thus, this technique can confirm the presence of perfluoroalkyl moieties. Tokranov et al. [37] demonstrated that CF2 and CF3 can be selectively quantified with high resolution C 1s scans (1s e atomic orbital). This was further confirmed using F 1s scans showing a peak of ~689 eV corresponds to the binding energy of fluorinated carbon groups (CF2 and CF3). Both scans can be used to distinguish between IF and OF, which gives XPS an advantage compared to PIGE and instrumental neutron activation analysis (INAA). XPS is limited to a surface depth of 0.01 mm; however depth profiles have been made by intervals of A. Koch et al. / Trends in Analytical Chemistry 123 (2020) 115423 3 Table 1 Overview of studies on organofluorine, listed are types of instrumentation, types of sample treatment, removal of fluoride (yes or no), forms of fluorine detected, sample matrices, concentration factors, LODs listed in the reference (with their original unit), converted LODs (in ppb) and the studies references. Instrumentation Type of sample treatment Removal of fluoride a) Direct analysis of OF in consumer products PIGE Direct analysis No PIGE Direct analysis No Forms of fluorine detected Matrix F Papers Textiles F Food packaging XPS Direct analysis No F, CF3, CF2 Consumer products INAA Direct analysis No F Food packaging CIC Direct analysis for No F Food packaging TF Yes Extraction for EOF CIC b) Analysis of EOF 19F NMR 19F NMR CS-MAS Potentiometric detection Fluorimetric detection RP-HPLC UV GC-FID GC-ECD GC-MS ICP-MS-MS Direct analysis for No TF Yes Extraction for EOF in environmental samples Extraction No Extraction No Online HPLC/ No pyrolysis Defluorination/pre- No conc. Defluorination/pre- No conc. Defluorination/ No derivatization/pre- conc. Defluorination/ No derivatization/pre- conc. Defluorination/ No derivatization/pre- conc. Defluorination/ No derivatization/pre- conc. Online HPLC No ICP-MS-MS CIC CIC CIC CIC Extraction/online Yes HPLC Extraction Yes Extraction Yes Extraction Yes Extraction Yes a Polyatomic F (138Ba19F and138Ba19F(14NH3)3). F Cosmetic products CF3 CF3 GaF F F TPSiF TPSiF TPSiF TPSiF Polyatomic Fa Polyatomic Fa F F F F Surface water Rain water Groundwater Spiked aqueous solution Spiked aqueous solution Spiked aqueous solution Spiked aqueous solution Spiked aqueous solution Spiked aqueous solution Spiked aqueous solution River water Water Several waters Blood Blood Concentration factor LOD listed in the reference Converted LOD (ppb) References No concentration 13 nmol F/cma e [18] 24e45 nmol F/cma No concentration 38 mg/g in 100 mg 38 000 [35] sample No concentration 1 atomic % (~1.6 wt (~16 000) [37] % F) No concentration 20 mg/g in 100 mg 20 000 [35] sample No concentration 0.8 mg/g in 100 mg 800 [35] Not applicable sample 6.61 mg/g in 290 mg 6 610 sample No concentration 91.1 mg/g 91 100 [20] 20 1.02e6.65 mg/g 1020e6650 200 500 No concentration Not applicable Not applicable 1000 10 mg/L 16 ng/L 1 ng F/mL 103 mg/L 40 mg/L 14 ng F/L 10 [44] 0.016 [46] 1 [48] 103 [40] 40 [40] 0.014 [39] 50 dilution with 0.02 mmol/L 5.57 [41] buffer solution 50 dilution with buffer solution 0.3 mmol/L 83.52 [41] 50 dilution with 0.003 mmol/L 0.84 [41] buffer solution No concentration 0.11 mg/L 110 [49] 2000e6000 0.49 mg F/L 490 [34] 800 1 ng F/L 0.001 [17] 500 0.1 mg F/L 0.1 [22] 2 3 mg F/L 3 [47] 2 6e32 ng F/mL 6e32 [24] etching and XPS analysis of the material [37]. In comparison to PIGE, XPS instruments are more common in research laboratories. 3.1.3. Instrumental neutron activation analysis (INAA) In the 1950s, the use of NAA began in the field of archaeology and is now used in a wide range of sample matrices and research fields. It is a non-destructive multi-element analysis for both major and trace elements and can perform both qualitative and quantitative identification [38]. In INAA a bulk sample is bombarded with neutrons and radioactive isotopes are produced. The radioactive emission and the radioactive decay are element specific and can be used to determine the elements. Recently, Schultes and co-workers [35] applied INAA to consumer products for the first time to measure their EOF, and the results were comparable with those achieved by PIGE and CIC. However, interferences from e.g. aluminium were found for the tested certified reference material (CRM), making INAA unsuitable for that matrix. INAA has advantages of being a non-selective high throughput method and can measure bulk samples as well as liquid and solid matrices. 3.2. Analysis of OF/EOF in environmental samples 3.2.1. Defluorination with sodium biphenyl (SBP) and various fluoride detection methods The most commonly used reagent for defluorination is sodium biphenyl (SBP) as the reaction can be carried out at room temperature and acceptable recoveries have been reported [39]. However, defluorination efficiencies have been found to decrease with increasing chain length of PFASs and SBP becomes deactivated in the presence of 1e2% of water [31,40]. To overcome the deactivation of SBP, a carbon based sorbent has been used to concentrate water samples followed by drying of the sorbent prior to SBP defluorination [40]. The extract was then analysed by a flowinjection system with either fluorimetric or potentiometric detection. Another method added an extra step where the fluoride was, after defluorination, derivatized with triphenylhydroxysilane (TPSiOH) and analysed by reversed phase LC-UV or gas chromatography (GC) coupled with a flame ionization detector (FID), electron capture detector (ECD) or mass spectrometer (MS) [39,41]. 4 A. Koch et al. / Trends in Analytical Chemistry 123 (2020) 115423 The GC derivatization methods showed comparable LODs to those of fluorimetric or potentiometric methods, whereas LC-UV reached lower LOD after 1000 times concentration (Table 1). However, the derivatization products were shown to only be stable up to 10 days [39]. In general, relatively high background contamination of IF in the commercial SBP reagent limits trace level analysis of OF in environmental samples [42]. 3.2.2. 19F nuclear magnetic resonance (NMR) spectroscopy 19F Nuclear magnetic resonance (NMR) spectroscopy has been employed for the quantitative determination of PFASs in human blood [27], rat serum [43] and surface water [44]. The identification of PFASs is based on the chemical shift of fluorine atoms under NMR. The quantification of total PFASs was carried out using the peak area of the terminal CF3 groups and a calibration curve constructed from the standard of a single compound such as PFOS [45]. NMR is therefore selective and can also determine the degree of branched isomers [23]. However, extensive pre-concentration or prolonged acquisition time (45 or 60 min) are usually required for environmental samples due to the low sensitivity of the 19F NMR technique (Table 1) [44,46]. 3.2.3. Combustion ion chromatography (CIC) Several studies used the CIC method to estimate the amount of EOF in different matrices after sample extraction [20,22,24]. CIC can also be applied for direct measurement of TF in a sample. In CIC a solid, liquid or gaseous sample undergoes pyrolysis and thermal oxidation in a moisturized oxygen stream at a high temperature (900e1050 C) to convert all OF into hydrogen fluoride (HF). The HF is then absorbed in aqueous media (e.g. MilliQ water or hydroxide peroxide) and the free anions (e.g. F) are determined by conductivity [47]. A drawback for the CIC analysis is that removal of chloride may be needed, as samples with high chloride content may interfere with the chromatographic peak of fluoride during IC analysis due to displacement of fluoride ions in the column by chloride ions. Additionally, sample with high levels of some alkaline earth elements (e.g. potassium, calcium) may cause the devitrification of the combustion tube (quartz) and may affect the combustion process leading to an underestimation of OF in the sample. 3.2.4. Continuum source molecular absorption spectrometry (CSMAS) CS-MAS uses online pyrolysis and formation of metal monofluorides (e.g. AlF, InF, or GaF) at high temperatures [48]. Monofluorides absorb light between 200 and 900 nm. Qin and coworkers [48] combined a reverse phase-high performance liquid chromatograph (RP-HPLC) to both ESI-MS and CS-MAS in parallel to identify and quantify novel PFASs in environmental samples. The detection of fluoride was based on the molecular formation of gallium fluoride (GaF), at 1150C, after pyrolysis at 550C. The absorption from GaF was monitored at 211.248 nm. The CS-MAS detected the presence of fluorine in a chromatographic peak, whereas ESI-MS generated the mass spectra. However, the online pyrolysis and subsequent fluoride detection took about 90 s, and thus the fluoride signal produced from CS-MAS may corresponded with several different OF compounds. Therefore, better separation of individual compounds for the CS-MAS would be needed to improve identification of OF. 3.2.5. Inductively coupled plasma tandem mass-spectrometry (ICPMS/MS) ICP-MS is a powerful tool for speciation analysis of elements, metals, proteins and biomolecules. Detection of fluoride with common ICP-MS instruments is not feasible for two main reasons: the high ionization potential of fluorine (17.4 eV) which leads to insufficient formation of F ions in the argon plasma; and the isobaric interferences from polyatomic ions such as 38Ar2, 16O1H3 and 18O1H [49,50]. Instead of directly measuring F, attempts have been made to produce polyatomic fluorine ions (e.g. AlF2, BaF) and to reduce interfering polyatomic ions (such as [16O1H3] or [18O1H]) by utilizing a collision cell in MS/MS mode [49]. Polyatomic fluorine ions are formed by mixing either Ba or Al solution with the sample prior to introduction into the nebulizer [51]. Jamari et al. [49] first demonstrated OF detection with a fluoroacetate standard using the formation of BaF (Table 1). Recently this method was further developed for PFASs, where a RP-HPLC method was coupled with ICP-MS/MS for fluorine-specific detection and the simultaneous analysis of target PFASs by electrospray MS (ESIMS) [34]. Spiked river water (sub-ppb level) was tested using sample extraction prior to instrumental analysis with acceptable recoveries (Table 1). In order to measure trace levels of fluorine with the ICP-MS/MS instrument, the instrument needs to be equipped with an "s-lens" (extraction lens) instead of the more commonly used "x-lens" [52]. Furthermore, Jamari et al. [34] argued the need for negative mode ICP-MS/MS in order to reach even higher sensitivity (sub-ppb levels) for trace analysis. 4. Sample preparation on EOF analysis As most of the instrumental methods discussed above do not distinguish OF from IF in the sample, removal of IF or separation of these two fractions is needed. Commonly used sample preparation methods, optimized for fluorine mass balance analysis, are solidphase extraction (SPE) and liquid-liquid extractions such as ion pair extraction (IPE). For SPE extraction, fluoride has been found to be enriched onto the sorbent. Miyake et al. [17] adjusted the SPE extraction for water samples by adding an extra washing step (20 mL of 0.01% NH4OH/H2O followed by 3 10 mL of MilliQ water) onto the weak-anion exchange (WAX) cartridges, which could remove 99.995% of the spiked fluoride. Another method enriched OF by using synthetic polystyrenedivinylbenzene-based activated carbon (AC) and used 50 mL of sodium nitrate to remove up to 99.97% of the spike fluoride [22]. The IPE uses an ion pair reagent, tetrabutylammonium (TBA), to separate IF in the aqueous phase and OF, as stable ion-pairs (TBAPFASs) and other neutral OF to the organic phase. IPE has some disadvantages such as co-extraction of matrix components [53], which could interfere during instrumental analysis, and bias could be introduced due to the formation of unstable ion pairs resulting in different recoveries for different PFASs [54]. While IPE can be applied to various matrices, SPE is mainly for liquid samples, although SPE with the IF removal step can also be used as a cleanup method for solid samples after sample treatment (e.g. alkaline, acid digestion or IPE). Besides IPE, liquid-liquid extractions with hexane or methyl-tert-butyl ether (MTBE) could also separate OF and IF. A recent study on OF in consumer products showed that methanol extraction with alkaline digestion and graphitized carbon clean-up could efficiently remove IF [20]. To our knowledge no studies has compared different extraction methods for the determination of EOF. A. Koch et al. / Trends in Analytical Chemistry 123 (2020) 115423 5 5. Remarks on current organofluorine methods Comparison between methods for OF analysis is challenging, as they vary in terms of selectivity, sensitivity and type of samples (bulk, extract, surface) analysed A number of OF methods can reach fairly low LODs (Table 1), compared to MS/MS methods they are still high, therefore sample pre-concentration is needed (e.g. 800 times concentra- tion of water resulted in 0.001 mg F/L (ppb) LOD with CIC [17]). Direct sample analysis of OF only applies to PIGE, XPS, INAA and CIC. PIGE, XPS and INAA are non-destructive high-throughput methods mainly used for solid surfaces, although analysis of liquid samples is possible by using solid support. Their LODs are sufficient for consumer products whereas analysis of environmental samples may be challenging Most instrumental methods measure OF indirectly (CIC: OF is converted to fluoride; GC-MS/HPLC-UV: sample is derivatized; CS-MAS: monofluorides; ICP-MS/MS: polyatomic fluorine ions). Only XPS and 19F NMR are selective between OF and IF. 19F NMR is selective and gives structural information on the compound, low LODs can only be reached by extensive preconcentration or prolonged acquisition time. For those non-selective methods, EOF can be determined with appropriate sample extraction after the removal of IF. Bias due to extraction may be introduced to EOF determination. For example, IPE has been shown to extract only a portion of OF. The choice of the extraction method should be carefully considered. The choice of OF methods (extraction and instrumental) is matrix dependent. Suggested instrumentation based on type of samples: o Consumer products: PIGE and XPS for surfaces, CIC and INAA for bulk samples. o Gaseous samples: CIC. o Extracted liquid and solid samples: CIC, ICP-MS/MS, 19F NMR, CS-MAS, HPLC-UV, GC-MS. GC-MS/FID/ECD or HPLC-UV are fairly common instrumentation in research laboratories and can be used to measure OF after defluorination and subsequent derivatization. However, the derivatization products might be unstable after a few days. Combined techniques such as HPLC-CS-MAS [48] and HPLCICPMS/MS-ESI-MS [34] can allow the simultaneous detection of OF and their identification. Most studies on OF analysis have utilized the CIC method. Contamination from different instrument parts before the combustion unit needs to be identified and reduced in order to obtain low detection limit. Many but not all (e.g. HPLC-UV, GC-FID/ECD/MS) of these methods are able to measure TF and IF. 6. Data comparability Several standardized methods for measuring TF/EOF using CIC have been issued [55e58]. However, to the best of our knowledge, there is no inter-laboratory comparison on these methods. Most studies (Table 1) use spiked "OF" as their quality control. Only a couple of studies used CRMs as their quality control making data comparison difficult [11,35]. One of the studies utilized CRM (BCR461, fluorine in clay) to compare three instrumental methods (CIC, PIGE and INAA) for TF and EOF analysis [35]. Their results showed good data comparability between CIC and PIGE; however, INAA was not able to determine F due to the high aluminium content in clay. In the same study, the results of fortified filters and food packaging analysis showed agreement in the measured levels of F. The nature of the sample matrices have great effect on the measurement. For example, CIC and INAA measure F content in bulk samples, whereas PIGE and XPS only measure the surface F content which may give different results, as the measurement of F depends on the penetration depth. In general, each method (Table 1) measures a certain fraction of OF/EOF present in a sample, mostly dependent on which extraction method is applied. Also, different instrumental methods give results in different units (Table 1). For example, results on TF/ TOF in paper are reported in ug/g (PIGE) or nmol F/cm2 (PIGE) while results from XPS is presented in atomic % F, and thus direct comparison is difficult. Furthermore, isotope labelled standards are commonly added to samples in target analysis by MS to correct for matrix effects and to assess recoveries. However, these standards cannot be used in TOF/EOF-CIC analysis, because the signal generated from F is indistinguishable between native and isotopically labelled compounds. This could lead to further issues such as inconsistencies in mass balance calculations. In order to solve this issue, it is recommended to frequently analyze a QC sample containing or spiked with PFOS or PFOA within each batch to monitor the combustion efficiency as well as changes in combustion recovery during the sample sequence. As the sample matrix could significantly affect the combustion recovery, it is also important to analyze the sample in duplicate when using CIC or re-analyze the sample extract at 2 or 5 time dilution to ensure that same results can be obtained. 7. Analytical approaches for quantifiable and unquantifiable organofluorine 7.1. Target analysis Target analysis for PFAS is well established and at least two standardized protocols exist, the ISO 25101 [59] method and the standard operational procedure (SOP) developed by UNEP [60]. Besides the commonly analysed PFAAs, a wide range of other PFASs may also be present in environmental samples, such as ultrashort C2eC3 PFASs (e.g. trifluoroacetate (TFA)), intermediate compounds (e.g. 6:2/8:2 fluorotelomer (unsaturated) carboxylic acids (FTUCAs), 5:3/7:3 FTCAs) and poorly ionized compounds (e.g. 6:2/8:2 FTCA). Measuring a wide range of target PFASs can be challenging. For example, ultrashort PFASs are poorly separated using a reversed phase (RP)-HPLC method. Alternative methods using an ion exchange column [61] and/or convergence chromatography (CC) [62] have shown acceptable separation. 7.2. Total oxidizable precursor assay (TOPA) Total oxidizable precursor assay (TOPA) is a method to reveal the presence of any PFCA and PFSA precursors, and several studies have used this approach for surface-, ground- and wastewater [63e65]. The assay has also been adapted by a number of commercial laboratories in different countries to provide alternative risk assessment of PFASs [66,67]. This method converts PFAA precursors (e.g. N-ethyl perfluorooctane sulfonamidoethanol or fluorotelomerbased compound, 6:2 FTSA) into the persistent PFAAs via oxidation using hydroxyl radicals [68,69]. The concentrations of common target PFASs are measured before and after oxidation, and if PFAA precursors are present in the sample, the measured PFAA concentrations will increase after oxidation. The development of a reliable TOPA method can be challenging as the amounts of the base and oxidizing agent (mainly persulfate) need to be optimized for each sample type. The sample matrix can affect the pH and/or react with the hydroxyl radicals which may slow down the persulfate thermolysis due to low pH, or leave some 6 A. Koch et al. / Trends in Analytical Chemistry 123 (2020) 115423 PFAA precursors intact due to reduced numbers of radicals. One option to reduce these matrix effects is to conduct TOPA after sample extraction [64], but additional biases may be introduced as some PFAA precursors may not be extracted from the sample. Another approach can be the addition of a 13C labelled precursor. The reaction is deemed to be complete if all the added mass labelled precursor is consumed, assuming that the mass labelled precursor has a higher concentration than other precursor compounds. The third approach could be to perform the TOPA in duplicate with one of the extracts being 10 times diluted. If the measured levels of PFAA between the original and diluted samples are the same, then the oxidation process is presumed to be completed. 7.3. Suspect screening analysis In suspect screening analysis (SSA), the accurate mass of molecular features obtained from high resolution mass spectrometry (HRMS) are compared to databases with known PFASs, such as the USEPA CompTox Chemistry Dashboard and NORMAN Suspect List Exchange. Screening criteria have been proposed and adopted in several studies [70,71] as follows: after suspect peaks are detected with the exact mass within 0.01 Da, positive hits will further be selected by (i) a signal-to-noise ratio > 3, (ii) intensity > 1000, (iii) an accurate mass error < 5 ppm, and (iv) isotope ratio difference < 10%. Further confirmation of the structure will then be compared with available mass spectra from literature and databases, such as the MassBank (www.massbank.eu). Apart from PFAS, fluorinated pharmaceuticals and pesticides should also be included in the suspect list to ensure comprehensive coverage of the total OF. 7.4. Non-target analysis Non-target analysis (NTA) applies different data mining techniques to identify compounds without the use of suspect lists, and is increasingly used for the identification of contaminants of emerging concern and their transformation products (reviewed in Ref. [72]). Several studies have outlined the workflow for NTA and how to report the level of confidence in identification [70,73]. Since the generated mass spectra contain significant amount of data, selection criteria must be specified to reduce the number of features in order to facilitate the identification process. A number of selection criteria have been used to identify new PFASs, in which detected peaks are filtered out that fulfil [74]: (1) S/N > 3 and (2) peak width of the chromatographic separation. Detected peaks should have a minimum fold change of 10 (e.g. peak height or peak area) when compared with the corresponding peak in the procedural blank or control group. The next step is to detect compounds that contain fluorine by using mass defect analysis of the extracted peak list. Instead of using the Kendrick mass scale (CH2 14.0000 Da), a normalized mass defect plot is constructed using the CF2 (49.99681 Da) or CH2CF2 (64.01246 Da) mass scale, since [CF2] and [CH2CF2] are common repeating units of many PFAS homologues to identify fluorinated compounds [75,76]. The HF (20.006343 Da) mass scale can also be applied to filter out polyfluorinated compounds [75]. 8. Towards a comprehensive analytical workflow for the assessment of organofluorine An ideal analytical method for OF analysis should readily distinguish between IF and OF without sample treatment. However most OF methods are non-selective and thus require sample pre-treatment, and different treatment methods varies in their capabilities to extract different portions of OF. In order to increase the specificity, the OF methods could be combined with target analysis and/or TOPA, suspect screening or non-target screening (also suggested in Ref. [77]). For example two studies have utilized such a comprehensive workflow, where RP-HPLC was coupled with parallel CS-MAS and ESI-MS [48] and SPE extraction prior to RP-HPLC that was coupled online to ICP-MS/MS and simultaneous to ESI-MS analysis [34]. Alternatively, characterisation of unquantifiable EOF could be facilitated by additional fractionation of the extract by an HPLC fractionator or various sample preparation [76]. Here a general workflow for comprehensive OF assessment is suggested (Fig. 2); a top down approach where the OF/EOF is determined prior to target analysis. In this workflow three matrix categories are suggested, consumer products (e.g. textiles, paper, food packaging), water (e.g. surface-, drinking- and wastewater) and biota (e.g. blood, animal tissue, plants). First sample treatment should be applied if needed. Generally sample pre-treatment is required for most matrices in order to remove IF from the sample. However direct sample analysis may be applied for samples with negligible IF content (e.g. food packaging and textiles) or for rapid screening. If mass balance is investigated, duplicate samples may be prepared, with one extract analysed for OF and the other one kept for later target analysis. Then, the instrumental method for OF analysis should be chosen depending on the sample matrix and availability. For example, radiation techniques such as PIGE, XPS, and INAA, but also CIC, may be chosen for surface coated consumer products. However, these techniques (except CIC) may not be as suitable for environmental samples due to their higher LODs compared to other techniques. Based on the results from the OF analysis, "samples of interest" can be selected to limit the number of samples as the comprehensive workflow could be tedious and time consuming. Guideline values might useful, though only PFAS guidelines exist. For example, the EU annual average environmental quality standard (AA-EQS) for inland surface water is 0.00065 mg/L for PFOS. Converted to F equivalents this would equal to 0.00042 mg F/L. How- ever, as PFOS might only contribute to a small fraction of EOF in a sample, this guideline value might not be representative for the EOF analytical workflow. Furthermore, the guideline values for individual or a small number of PFASs, when converted to F equivalents, are usually far below the LOD for the OF methods mentioned in this review. The lack of guideline values is therefore a major shortcoming but is also a difficult task since it would involve risk assessment of complex OF/EOF mixtures. The Danish Food and Veterinary Administration suggested an indicator value of 10 mg/dm2 OF for food packaging, where fluorine concentration in paper below this value can be assumed to not be treated with OF. That value could represent a first guidance for OF analysis. Other selection criteria may be more study specific depending on the research questions, e.g. choosing only the top 20% samples with the highest concentrations or those that have largest fraction of unknown EOF. After OF/EOF analysis and the selection of "samples of interest" target PFAS analysis may follow to set up a mass balance in order to estimate the amount of unquantifiable OF. For samples with a large proportion of unquantifiable OF, approaches such as TOPA with LCMS/MS, suspect screening and/or non-target analysis can be applied to identify the unquantifiable OF. It is important to note that the OF concentration in samples doesn't necessarily correspond to toxicities of OF compounds. Nevertheless we believe that the mass balance approach of OF can be an important tool to achieve a non-toxic environment objective [78], by characterizing OF in environmental samples and identifying potential toxic substances, as most OF are likely of anthropogenic origin. A. Koch et al. / Trends in Analytical Chemistry 123 (2020) 115423 7 Consumer Products Water Biota Direct sample analysis PIGE XPS INAA Sample treatment in duplicates for EOF and target analysis Solvent extracon SPE IPE SPE Organouorine analysis INAA CIC CIC ICP-MS/MS CS-MAS CIC ICP-MS/MS Selecon of samples of interest Sample treatment Solvent extracon Target analysis LC-MS/MS GC-MS/MS Mass balance fracon of unquanable/unknown organouorine Approaches for idencaon of unquanable/unknown organouorine TOPA with LC-MS/MS Suspect screening with HRMS Non-target with HRMS Fig. 2. Proposed workflow for a comprehensive organofluorine assessment. Acknowledgements The authors acknowledge support from the Swedish Research Council Formas (project numbers: 2015-00320 and 2016-01158) and the Knowledge Foundation (KKS) for funding the project within the Enforce Research Project (20160019), Sweden. References [1] D. O'Hagan, D.B. Harper, Fluorine-containing natural products, J. Fluorine Chem. 100 (1) (1999) 127e133. [2] J. Wang, et al., Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001e2011), Chem. Rev. 114 (4) (2014) 2432e2506. [3] A.M. Thayer, Fabulous Fluorine - having fluorine in life sciences molecules brings desirable benefits, but the trick is getting it in place and making sought-after building blocks, in: Chemical and Engineering News C&EN, 2006. [4] T. Fujiwara, D. O'Hagan, Successful fluorine-containing herbicide agrochemicals, J. Fluorine Chem. 167 (2014) 16e29. [5] Z. Wang, et al., A never-ending story of per- and polyfluoroalkyl substances (PFASs)? Environ. Sci. Technol. 51 (5) (2017) 2508e2518. [6] KemI, Occurrence and Use of Highly 717 Fluorinated Substances and Alternatives, Swedish Chemicals Agency, 2015. [7] J.P. Giesy, K. Kannan, Global distribution of perfluorooctane sulfonate in wildlife, Environ. Sci. Technol. 35 (7) (2001) 1339e1342. [8] 3M, Phase-Out Plan for POSF-Based Products. U.S. EPA Docket AR226-0600, U.S. Environmental Protection Agency, Washington DC, 2000. [9] A. Glynn, et al., Perfluorinated alkyl acids in blood serum from primiparous women in Sweden: serial sampling during pregnancy and nursing, and temporal trends 1996e2010, Environ. Sci. Technol. 46 (16) (2012) 9071e9079. [10] L.S. Haug, C. Thomsen, G. Becher, Time trends and the influence of age and gender on serum concentrations of perfluorinated compounds in archived human samples, Environ. Sci. Technol. 43 (6) (2009) 2131e2136. [11] L.W.Y. Yeung, S.A. Mabury, Are humans exposed to increasing amounts of unidentified organofluorine? Environ. Chem. 13 (1) (2016) 102e110. [12] S. Wang, et al., First report of a Chinese PFOS alternative overlooked for 30 Years: its toxicity, persistence, and presence in the environment, Environ. Sci. Technol. 47 (18) (2013) 10163e10170. [13] Z. Wang, et al., Fluorinated alternatives to long-chain perfluoroalkyl carboxylic acids (PFCAs), perfluoroalkane sulfonic acids (PFSAs) and their potential precursors, Environ. Int. 60 (Supplement C) (2013) 242e248. [14] OECD, Towards a new comprehensive global database of per-and ployfluoroalkyl substances (PFAS): Summary report on updating the OECD 2007 list of per-and ployfluoroalkyl substances (PFAS), in Series on Risk Management, 2018. [15] D. Borg, J. Ivarsson, Analysis of PFASs and TOF in Products, Nordisk Ministerrd, 2017. [16] K. Granby, G.A. Pedersen, Vurdering Af Metode Til Bestemmelse Af Total Organisk Fluor (TOF) I Fdevarekontaktmaterialer Og Bestemmelse Af Baggrundsniveau for TOF I Pap Og Papir, Technical University of Danmark, 2018. [17] Y. Miyake, et al., Determination of trace levels of total fluorine in water using combustion ion chromatography for fluorine: a mass balance approach to determine individual perfluorinated chemicals in water, J. Chromatogr. A 1143 (1) (2007) 98e104. [18] E.E. Ritter, et al., PIGE as a screening tool for Per- and polyfluorinated substances in papers and textiles, Nucl. Instrum. Methods Phys. Res. Sect. B Beam Interact. Mater. Atoms 407 (2017) 47e54. 8 A. Koch et al. / Trends in Analytical Chemistry 123 (2020) 115423 [19] A.E. Robel, et al., Closing the mass balance on fluorine on papers and textiles, Environ. Sci. Technol. 51 (16) (2017) 9022e9032. [20] L. Schultes, et al., Per-and polyfluoroalkyl substances and fluorine mass balance in cosmetic products from the Swedish market: implications for environmental emissions and human exposure, Environ. Sci.eProcess. Impacts 20 (12) (2018) 1680e1690. [21] M. Trojanowicz, et al., Determination of Total Organic Fluorine (TOF) in environmental samples using flow-injection and chromatographic methods, Anal. Methods 3 (5) (2011) 1039e1045. [22] A. Wagner, et al., Determination of adsorbable organic fluorine from aqueous environmental samples by adsorption to polystyrene-divinylbenzene based activated carbon and combustion ion chromatography, J. Chromatogr. A 1295 (2013) 82e89. [23] B. Weiner, et al., Organic fluorine content in aqueous film forming foams (AFFFs) and biodegradation of the foam component 6: 2 fluorotelomermercaptoalkylamido sulfonate (6: 2 FTSAS), Environ. Chem. 10 (6) (2013) 486e493. [24] L.W. Yeung, et al., Perfluorinated compounds and total and extractable organic fluorine in human blood samples from China, Environ. Sci. Technol. 42 (21) (2008) 8140e8145. [25] R.J. Rowley, H.V. Churchill, Titration of fluorine in aqueous solutions, Ind. Eng. Chem. 9 (12) (1937) 551e552. [26] G. Gao, B. Yan, L. Yang, Determination of total fluorine in coal by the combustion-hydrolysis/fluoride-ion selective electrode method, Fuel 63 (11) (1984) 1552e1555. [27] W. Guy, Organic fluorocompounds in human plasma: prevalence and characterization, in: Biochemistry Involving Carbon-Fluorine Bonds: Symposium at the 170th Meeting of the American Chemical Society, 1975, 1976, American Chemical Society, 1976. [28] D.R. Taves, Normal human serum fluoride concentrations, Nature 211 (5045) (1966) 192e193. [29] I. Roelandts, et al., The application of proton-induced gamma-ray emission (PIGE) analysis to the rapid determination of fluorine in geological materials, Chem. Geol. 54 (1) (1986) 35e42. [30] C.Y. Wang, J.G. Tarter, Determination of halogens in organic compounds by ion chromatography after sodium fusion, Anal. Chem. 55 (11) (1983) 1775e1778. [31] P. Venkateswarlu, Sodium biphenyl method for determination of covalently bound fluorine in organic compounds and biological materials, Anal. Chem. 54 (7) (1982) 1132e1137. [32] P. Venkateswarlu, Determination of fluoride in bone by aluminum monofluoride molecular absorption spectrometry, Anal. Chim. Acta 262 (1) (1992) 33e40. [33] W. Guo, et al., Method development for the determination of total fluorine in foods by tandem inductively coupled plasma mass spectrometry with a massshift strategy, J. Agric. Food Chem. 65 (16) (2017) 3406e3412. [34] N.L.A. Jamari, et al., Novel non-targeted analysis of perfluorinated compounds using fluorine-specific detection regardless of their ionisability (HPLC-ICPMS/ MS-ESI-MS), Anal. Chim. Acta 1053 (2018) 22e31. [35] L. Schultes, et al., Total fluorine measurements in food packaging: how do current methods perform? Environ. Sci. Technol. Lett. 6 (2) (2019) 73e78. [37] A.K. Tokranov, et al., How do we measure poly- and perfluoroalkyl substances (PFASs) at the surface of consumer products? Environ. Sci. Technol. Lett. 6 (1) (2018) 38e43. [38] M.D. Glascock, Overview of Neutron Activation Analysis, n.a. [cited 2019 02/ 14]; Available from: http://archaeometry.missouri.edu/naa_overview. html#method. [39] J. Musijowski, et al., Determination of fluoride as fluorosilane derivative using reversed-phase HPLC with UV detection for determination of total organic fluorine, J. Sep. Sci. 33 (17e18) (2010) 2636e2644. [40] J. Musijowski, et al., Flow-injection determination of total organic fluorine with off-line defluorination reaction on a solid sorbent bed, Anal. Chim. Acta 600 (1e2) (2007) 147e154. [41] M. Koc, et al., Application of gas chromatography to determination of total organic fluorine after defluorination of perfluorooctanoic acid as a model compound, Croat. Chem. Acta 84 (3) (2011) 399e406. [42] M. Trojanowicz, et al., New analytical methods developed for determination of perfluorinated surfactants in waters and wastes, Croat. Chem. Acta 84 (3) (2011) 439e446. [43] D.F. Hagen, et al., Characterization of fluorinated metabolites by a gas chromatographic-helium microwave plasma detectordthe biotransformation of 1H,1H,2H,2H-perfluorodecanol to perfluorooctanoate, Anal. Biochem. 118 (2) (1981) 336e343. [44] C.A. Moody, et al., Determination of perfluorinated surfactants in surface water samples by two independent analytical Techniques: liquid chromatography/tandem mass spectrometry and 19F NMR, Anal. Chem. 73 (10) (2001) 2200e2206. [45] C.A. Moody, J.A. Field, Perfluorinated surfactants and the environmental implications of their use in fire-fighting foams, Environ. Sci. Technol. 34 (18) (2000) 3864e3870. [46] D.A. Ellis, et al., Development of an 19F NMR method for the analysis of fluorinated acids in environmental water samples, Anal. Chem. 72 (4) (2000) 726e731. [47] Y. Miyake, et al., Trace analysis of total fluorine in human blood using combustion ion chromatography for fluorine: a mass balance approach for the determination of known and unknown organofluorine compounds, J. Chromatogr. A 1154 (1e2) (2007) 214e221. [48] Z. Qin, et al., Fluorine speciation analysis using reverse phase liquid chromatography coupled off-line to continuum source molecular absorption spectrometry (CS-MAS): identification and quantification of novel fluorinated organic compounds in environmental and biological samples, Anal. Chem. 84 (14) (2012) 6213e6219. [49] N.L.A. Jamari, et al., Novel non-target analysis of fluorine compounds using ICPMS/MS and HPLC-ICPMS/MS, J. Anal. At. Spectrom. 32 (5) (2017) 942e950. [50] Y. Zhu, K. Nakano, Y. Shikamori, Analysis of fluorine in drinking water by ICPQMS/QMS with an octupole reaction cell, Anal. Sci. 33 (11) (2017) 1279e1284. [51] M.M. Bayon, et al., Indirect determination of trace amounts of fluoride in natural waters by ion chromatography: a comparison of on-line post-column fluorimetry and ICP-MS detectors, Analyst 124 (1) (1999) 27e31. [52] Aglient, Agilent 8900 Triple Quadrupole ICP-MS - Technical Overview, Aglient Technologies, 2016. [53] S.P. Van Leeuwen, et al., Struggle for quality in determination of perfluorinated contaminants in environmental and human samples, Environ. Sci. Technol. 40 (24) (2006) 7854e7860. [54] W.K. Reagen, et al., Comparison of extraction and quantification methods of perfluorinated compounds in human plasma, serum, and whole blood, Anal. Chim. Acta 628 (2) (2008) 214e221. [55] ASTM D5987-96, Standard Test Method for Total Fluorine in Coal and Coke by Pyrohydrolytic Extraction and Ion Selective Electrode or Ion Chromatograph Methods. 2015, ASTM International, West Conshohocken, PA, 2015. www. astm.org. [56] ASTM D7359-14a, Standard Test Method for Total Fluorine, Chlorine and Sulfur in Aromatic Hydrocarbons and Their Mixtures by Oxidative Pyrohydrolytic Combustion Followed by Ion Chromatography Detection (Combustion Ion Chromatography-CIC). 2014, ASTM International, West Conshohocken, PA, 2014. www.astm.org. [57] DIN 51723, Testing of Solid Fuels - Determination of Fluorine Content, Deutsches Institut fr Normung, 2002. [58] UOP991-17, Trace Chloride, Fluoride, and Bromide in Liquid Organics by Combustion Ion Chromatography (CIC). 2017, ASTM International, West Conshohocken, PA, 2017. www.astm.org. [59] ISO 25101, Water Quality - Determination of Perfluorooctanesulfonate (PFOS) and Perfluorooctanoate (PFOA) - Method for Unfiltered Samples Using Solid Phase Extraction and Liquid Chromatography/mass Spectrometry, International Organization for Standardization, 2009. [60] UNEP, Procedure for the Analysis of Persistent Organic Pollutants in Environmental and Human Matrices to Implement the Global Monitoring Plan under the Stockholm Convention-Protocol 1: The Analysis of Perfluorooctane Sulfonic Acid (PFOS) in Water and Perfluorooctane Sulfonamide (FOSA) in Mothers' Milk, Human Serum and Air, and the Analysis of Some Perfluorooctane Sulfonamides (FOSAS) and Perfluorooctane Sulfonamido Ethanols (FOSES) in Air, United Nations Environment Programme (UNEP), Geneva, Schwitzerland, 2015. [61] S. Taniyasu, et al., Analysis of trifluoroacetic acid and other short-chain perfluorinated acids (C2eC4) in precipitation by liquid chromatographyetandem mass spectrometry: comparison to patterns of long-chain perfluorinated acids (C5eC18), Anal. Chim. Acta 619 (2) (2008) 221e230. [62] L.W.Y. Yeung, C. Stadey, S.A. Mabury, Simultaneous analysis of perfluoroalkyl and polyfluoroalkyl substances including ultrashort-chain C2 and C3 compounds in rain and river water samples by ultra performance convergence chromatography, J. Chromatogr. A 1522 (Supplement C) (2017) 78e85. [63] X. Dauchy, et al., Per- and polyfluoroalkyl substances in firefighting foam concentrates and water samples collected near sites impacted by the use of these foams, Chemosphere 183 (2017) 53e61. [64] E.F. Houtz, et al., Persistence of perfluoroalkyl acid precursors in AFFFimpacted groundwater and soil, Environ. Sci. Technol. 47 (15) (2013) 8187e8195. [65] E.F. Houtz, et al., Poly- and perfluoroalkyl substances in wastewater: significance of unknown precursors, manufacturing shifts, and likely AFFF impacts, Water Res. 95 (2016) 142e149. [66] iEnvironmental Australia, TOPA and PFAS Precursor Detection, 2018, 2018/08/ 01]; Available from: https://www.ienvi.com.au/topa-and-pfas-precursordetection/. [67] TestAmerica Laboratories, PFAS Total Oxidizable Precursor (TOP) Assay, 2018, 2018/11/22]; Available from: http://www.testamericainc.com/services-weoffer/services-we-offer-by-method-group/ultra-trace-level-organics/pfastotal-oxidizable-precursor-top-assay/. [68] E.F. Houtz, D.L. Sedlak, Oxidative conversion as a means of detecting precursors to perfluoroalkyl acids in urban runoff, Environ. Sci. Technol. 46 (17) (2012) 9342e9349. [69] K.R. Rhoads, et al., Aerobic biotransformation and fate of N-ethyl perfluorooctane sulfonamidoethanol (N-EtFOSE) in activated sludge, Environ. Sci. Technol. 42 (8) (2008) 2873e2878. [70] E.L. Schymanski, et al., Identifying small molecules via high resolution mass spectrometry: communicating confidence, ACS Publications, 2014. [71] N. Yu, et al., Non-target and suspect screening of per- and polyfluoroalkyl substances in airborne particulate matter in China, Environ. Sci. Technol. 52 (15) (2018) 8205e8214. A. Koch et al. / Trends in Analytical Chemistry 123 (2020) 115423 9 [72] T. Ruan, G. Jiang, Analytical methodology for identification of novel per- and polyfluoroalkyl substances in the environment, Trac. Trends Anal. Chem. 95 (Supplement C) (2017) 122e131. [73] K.J. Jobst, et al., The use of mass defect plots for the identification of (novel) halogenated contaminants in the environment, Anal. Bioanal. Chem. 405 (10) (2013) 3289e3297. [74] Y. Wang, et al., Suspect and nontarget screening of per- and polyfluoroalkyl substances in wastewater from a fluorochemical manufacturing park, Environ. Sci. Technol. 52 (19) (2018) 11007e11016. [75] K.A. Barzen-Hanson, et al., Discovery of 40 classes of per-and polyfluoroalkyl substances in historical aqueous film-forming foams (AFFFs) and AFFF-impacted groundwater, Environ. Sci. Technol. 51 (4) (2017) 2047e2057. [76] L.A. D'Agostino, S.A. Mabury, Identification of novel fluorinated surfactants in aqueous film forming foams and commercial surfactant concentrates, Environ. Sci. Technol. 48 (1) (2014) 121e129. [77] C.A. McDonough, G.J.L. Higgins, P. Christopher, Measuring total PFASs in water:the tradeoff between selectivity and inclusivity, Curr. Opin. Environ. Sci. Health (2018) (in press) [online since August 2018]. [78] European Commission, Towards a non-toxic environment strategy, 2013, 2017/09/27 [cited 2018/11/28; Available from: http://ec.europa.eu/ environment/chemicals/non-toxic/index_en.htm.