Environmental Mass Spectrometry: Emerging Contaminants and Current Issues

Environmental Mass Spectrometry: EmergingContaminants and Current Issues

Susan D. Richardson

National Exposure Research Laboratory, U.S. Environmental Protection Agency, Athens, Georgia 30605

Review Contents

Background 4373Mass Spectrometry Detection Trends 4373Sampling and Extraction Trends 4374Chromatography Trends 4374Online Analysis 4375Detection Limits 4375Emerging Contaminants 4375

General Reviews 4376Nanomaterials 4376PFOA/PFOS and Other Perfluorinated Compounds 4377Pharmaceuticals, Hormones, and EndocrineDisrupting Compounds 4379

Pharmaceuticals 4380Drinking Water Studies 4380Fate and Transport Studies 4381Methods for Antibiotics/Antimicrobials 4381Veterinary Pharmaceuticals 4381Studies of Illicit Drugs 4382Other Occurrence Studies 4382Other Pharmaceutical Methods 4383Endocrine Disrupting Compounds and Hormones 4383New Methods for EDCs 4383Biological Samples 4383Other EDC Methods and Studies 4383

Drinking Water and Swimming Pool DisinfectionByproducts 4384

Drinking Water DBPs 4384Emerging Halogenated and N-DBPs 4385Other Methods 4386New Human Exposure Studies 4386New Swimming Pool Research 4387Other Occurrence Studies 4387Discovery Research for High Molecular WeightDBPs 4387DBPs of Pollutants 4387

Sunscreens/UV Filters 4389Brominated Flame Retardants 4390

Human Exposure Studies 4390Other PBDE Studies 4391

Benzotriazoles 4391Dioxane 4392Naphthenic Acids 4392Chiral Contaminants 4393Algal Toxins 4394Perchlorate 4395Pesticide Degradation Products and New Pesticides 4397

Occurrence Studies 4397Measurements in Foods 4398Fate Studies 4398

Arsenic 4398Literature Cited 4399

BACKGROUNDThis biennial review covers developments in environmental

mass spectrometry for emerging environmental contaminants overthe period of 2006-2007. A few significant references that

appeared between January and February 2008 are also included.Analytical Chemistry’s current policy is to limit reviews to amaximum of 250 significant references and to mainly focus onnew trends. As a result, as was done in the previous 2006environmental mass spectrometry review (1), this 2006 reviewwill be limited to new, emerging contaminants, and environmentalissues that are driving most of the current research. Even with amore narrow focus, only a small fraction of the quality researchpublications could be discussed. Thus, this review will not becomprehensive but will highlight new areas and discuss repre-sentative papers in the areas of focus. I write a similar reviewarticle on water analysis, which also focuses on emergingcontaminants (2). That review article is somewhat different fromthis one, in that it covers other analytical techniques in additionto mass spectrometry, and it focuses only on the analysis of water.This review on Environmental Mass Spectrometry focuses onmethods and occurrence/fate studies utilizing mass spectrometry,but also includes the study of air, soil/sediment, and biologicalsamples, in addition to water. I welcome any comments you haveon this review ([email protected]).

Numerous abstracts were consulted before choosing the bestones to present here. Abstract searches were carried out usingWeb of Science, and in many cases, full articles were obtained. Atable of acronyms is provided (Table 1) as a quick reference tothe acronyms of analytical techniques and other terms discussedin this review.

Mass Spectrometry Detection Trends. There is a tremen-dous increase in the use of time-of-flight (TOF)-mass spectrometry(MS) and quadrupole (Q)-TOF-MS for structural elucidation andcompound confirmation. TOF-MS and Q-TOF-MS provide in-creased resolution capability (typically 10 000-12 000 resolution),which allows precise empirical formula assignments for unknownsand also provides extra confidence for positive identifications inquantitative work. This benefit of TOF-MS and Q-TOF-MS canbe seen particularly in the sections on pharmaceuticals, endocrinedisrupting compounds (EDCs), and pesticide degradation prod-ucts. Nearly all new research on the identification and study ofenvironmental transformation products has involved Q-TOF oranother form of high-resolution MS. In addition, liquid chroma-tography (LC)/electrospray ionization (ESI)- and atmosphericpressure chemical ionization (APCI)-MS methods continue todominate the new methods developed for emerging contaminants,and the use of multiple reaction monitoring (MRM) with MS/MS has become commonplace for quantitative environmentalanalysis. The use of LC/MS/MS allows the identification of highlypolar organic pollutants without derivatization, down to nanogram

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10.1021/ac800660d Not subject to U.S. Copyright. Publ. 2008 Am. Chem. Soc. 4373Analytical Chemistry, Vol. 80, No. 12, June 15, 2008Published on Web 05/23/2008

per liter levels in environmental samples. Also, the use of MRMprovides increased selectivity and sensitivity, greatly reducing thechemical background in LC/MS analyses. Researchers are alsoincreasingly using isotopically labeled standards (deuterated or13C-labeled) to allow more accurate quantitation in a variety ofsample matrixes (especially for wastewater and biological samples,where matrix effects can be substantial). Atmospheric pressurephotoionization (APPI) is also increasingly being used with LC/MS, because it provides improved ionization for more nonpolarcompounds, such as nanomaterials (e.g., fullerenes) and polybro-minated diphenyl ethers (PBDEs).

Sampling and Extraction Trends. Trends in sampling andextraction include increased use of stir bar sorptive extraction andhollow-fiber microextraction. Examples of stir bar sorptive extrac-tion presented in this review include the extraction of UV filtersand polybrominated diphenyl ethers (PBDEs); the use of hollowfiber extraction can be seen in this review in the section onbrominated flame retardants. Stir bar sorptive extraction involvesthe use of a sorbent-coated stir bar, which is stirred in the aqueoussample to extract the analytes of interest. The analytes are thenthermally desorbed and analyzed by gas chromatography (GC)/MS. Hollow-fiber microextraction is similar to traditional SPME,except that a polypropylene hollow fiber is attached to the tip ofa syringe that contains an extraction solvent (typically, a nonpolarsolvent, such as decane). The membrane is then used to extractthe aqueous sample, the solvent is drawn back into the syringe,the fiber discarded, and the solvent injected directly into a GC orLC instrument. Traditional solid phase microextraction (SPME),which eliminates the need for organic solvents in extraction, hasnow become commonplace, and examples are presented through-out this review. In addition, Oasis HLB solid phase extraction(SPE) cartridges have become very popular for extracting highlypolar compounds from water, especially in pharmaceutical research.

Chromatography Trends. One of the fastest growing trendsin chromatography is the use of ultraperformance liquid chroma-tography (UPLC). UPLC is a recently developed LC techniquethat uses small diameter particles (typically 1.7 µm) in thestationary phase and short columns, which allow higher pressuresand, ultimately, narrower LC peaks (5-10 s wide). In addition toproviding narrow peaks and improved chromatographic separa-tions, UPLC can also dramatically shorten analysis times, oftento 10 min or less. Waters Corp. was the first company to developthis technology, but other companies are now offering similarsystems. An example of UPLC presented in this review is themeasurement of illicit drugs in environmental samples. Othersignificant chromatography trends include the use of two-dimensional GC (GC × GC) and hydrophilic interaction chroma-tography (HILIC). GC × GC enables enhanced separations ofcomplex mixtures through greater chromatographic peak capacityand allows homologous series of compounds to be easily identi-fied. It also enables the detection of trace contaminants that wouldnot have been identified through traditional GC. TOF-MS is oftenused as the detector for GC × GC because of its rapid acquisitioncapability. An example of GC × GC presented in this reviewincludes the analysis of complex mixtures of disinfection byprod-ucts (DBPs) and polybrominated diphenyl ether (PBDE) flameretardants. HILIC is a new LC technique that provides improvedseparation and detection for highly polar compounds. The station-

Table 1. List of Acronyms

APCI atmospheric pressure chemical ionizationAPPI atmospheric pressure photoionizationBH benzhydrolBM-DBM butyl methoxydibenzoylmethaneBP-3 benzophenone-3CCL Contaminant Candidate ListCE capillary electrophoresisDBPs disinfection byproductsDHB dihydroxybenzophenoneDHMB 2,2′-dihydroxy-4-methoxybenzophenoneE1 estroneE2 17�-estradiolE3 estriolEE2 17R-ethinylestradiolECD electron capture detectionEDCs endocrine disrupting compoundsEI electron ionizationELISA enzyme-linked immunosorbent assayEMHC ethylhexyl methoxycinnamateEPA Environmental Protection AgencyESA ethane sulfonic acidESI electrospray ionizationFAIMS high-field asymmetric waveform ion mobility

spectrometryFT Fourier transformFTOHs fluorinated telomer alcoholsGC gas chromatographyHAAs haloacetic acidsHBP 4-hydroxybenzophenoneHILIC hydrophilic interaction chromatographyHMB 2-hydroxy-4-methoxylbenzophenoneIC ion chromatographyICR ion cyclotron resonanceICP inductively coupled plasmaLC liquid chromatographyMALDI matrix-assisted laser desorption ionization4-MBC 4-methylbenzylidene camphorMCL maximum contaminant levelMIMS membrane introduction mass spectrometryMRM multiple reaction monitoringMS mass spectrometryMX 3-chloro-(4-dichloromethyl)-5-hydroxy-2(5H)-

furanoneNCI negative chemical ionizationNDMA nitrosodimethylamineN-EtPFOSA N-ethylperfluorooctane sulfonamideNMR nuclear magnetic resonanceNOM natural organic matterOC octocryleneODPABA octyl-dimethyl-p-aminobenzoic acidPBSA phenylbenzimidazole sulfonic acidPCBs polychlorinated biphenylsPBDEs polybrominated diphenyl ethersPFCs perfluorinated compoundsPFBS perfluorobutanesulfonatePFCAs perfluorocarboxylic acidsPFDA perfluorodecanoic acidPFHA perfluorohexanoic acidPFHpA perfluoroheptanoic acidPFHS perfluorohexanesulfonatePFNA perfluorononanoic acidPFOA perfluorooctanoic acidPFOS perfluorooctane sulfonatePFOSA perfluorooctane sulfonamidePFUnDA perfluoroundecanoic acidSPE solid phase extractionSPME solid phase microextractionTHB trihydroxybenzophenoneTHMs trihalomethanesTOF time-of-flightTOX total organic halogenUCMR-2 the second Unregulated Contaminants Monitoring

RuleUPLC ultraperformance liquid chromatographyVOCs volatile organic compounds

4374 Analytical Chemistry, Vol. 80, No. 12, June 15, 2008

ary phase in HILIC columns has a polar end group (such as anamino group), and retention is based on the affinity of the polaranalyte for the charged end group of the column stationary phase.An example of the use of HILIC in this review includes themeasurement of veterinary pharmaceuticals in agricultural runoffwaters.

Online Analysis. There is also a trend toward more onlineanalysis of contaminants. For example, there is a new multiresiduemethod reported for measuring antibiotics, using online SPE-LC/MS/MS. The use of online preconcentration-LC/MS/MS usuallynot only allows for more rapid screening but improves theprecision of the analysis.

Detection Limits. New analytical methods continue to pushdetection limits lower. Just a few years ago, microgram per literdetection limits were common. Today, it is unusual to seedetection limits that are not at least low-nanogram per liter. Thereare even some examples in this review of picogram per literdetection limits. As instruments and extraction techniques con-tinue to improve and new types of instruments are developed,detection limits will likely continue to drop, allowing the detectionof analytes not previously possible. Another advantage of lowerdetection limits is in the study of transformation processes. Forexample, the study of wastewater treatment to remove pharma-ceuticals is greatly aided by a technique that can measure low- orsubnanogram per liter detection limits. Pharmaceuticals aregenerally present at nanogram per liter to low-microgram per literlevels in wastewater influents, and detection limits at the low- orsubnanogram per liter level allow the percentage removal to bedetermined. Low detection limits also benefit human exposurestudies, where amounts of biological samples are generally limited(microliter to milliliter).

Emerging Contaminants. Three new classes of emergingcontaminants are added to this environmental mass spectrometryreview this year: nanomaterials, 1,4-dioxane, and swimming poolDBPs. Nanomaterials are probably the hottest topic in researchtoday. They are already being used in a variety of commercialproducts (particularly cosmetics), and there is significant concernabout their potential human and ecological effects. Nanomaterialsare the focus of a new initiative at the U.S. EnvironmentalProtection Agency (EPA), where research on their fate, transport,and health effects is being investigated. Nanomaterials researchin environmental samples is in its infancy, but there are now afew published studies, and this area is expected to grow expo-nentially in the next few years. 1,4-Dioxane is a widespreadcontaminant in groundwater and is a probable human carcinogen.Dioxane is a high production chemical and is used as a solventstabilizer in the manufacture and processing of paper, cotton,textile products, automotive coolants, cosmetics, and shampoos.The U.S. EPA has recently listed dioxane on the new (3rd)proposed Contaminants Candidate List (CCL-3) (www.epa.gov/safewater/ccl/ccl3.html#ccl3). The CCL is a list of priority,unregulated contaminants that the U.S. EPA is considering forregulation. This list is used to prioritize research and datacollection efforts to help in deciding whether to regulate acontaminant. Finally, swimming pool DBPs have become a hotresearch topic, as epidemiologic research has shown increasedincidence of asthma with exposure in indoor pools and alsoincreased incidence of bladder cancer. Because swimming pools

have additional precursors (including components of humansweat, urine, sunscreens, etc.) for the formation of DBPs withchlorine or other pool disinfectants, unique byproducts can beformed.

Other areas covered in this review again include perfluorooc-tanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and otherperfluorinated compounds (PFCs), pharmaceuticals, hormones,EDCs, drinking water DBPs, sunscreens/UV filters, brominatedflame retardants (including polybrominated diphenyl ethers),benzotriazoles, naphthenic acids, chiral contaminants, algal toxins,perchlorate, pesticide degradation products and new pesticides,and arsenic. These continue to be intense areas of research. Atrend for these ongoing research areas is the study of theirtransformation in drinking water or wastewater treatment. Forexample, the chlorination and ozonation of pharmaceuticals,personal care products, and pesticides are represented in thisreview, as researchers try to find ways to remove these contami-nants from source waters. However, new research is discoveringthat most of these compounds are not completely mineralized butare transformed into other compounds that may be less toxic ormore toxic than the parent compounds. The reaction of ozonewith nanomaterials is also reported in this review. Other fatestudies include the study of the microbial degradation, hydrolysis,and photolysis of emerging contaminants, as well as the measure-ment of in vivo metabolites in human exposure studies.

I continue to be fascinated by the creative human exposurestudies that are conducted. There is a huge growth in the numberof human exposure studies conducted in the last 2 years. Forexample, PFCs were measured in more than 2000 human serumsamples as part of the U.S. National Health and NutritionExamination Survey, and they were also measured in the serumof retired fluorochemical production workers to investigate theirhalf-lives in the human body. The toxicokinetics of a UV filter(4-methylbenzylidene camphor, 4-MBC) was investigated bymeasuring it in human plasma and urine after dermal application(simulating sunscreen exposure). PBDE flame retardants, whichare now being found in biological samples all over the world, weremeasured in serum from residents living in an electronicsdismantling region in China, as well as in human milk samplesfrom women in Australia. Perchlorate has been measured inamniotic fluid from pregnant women in the United States.Trihalomethane DBPs were measured in the blood and breath ofpeople carrying out common household water use activities. Algaltoxins (microcystins) were measured in stored human tissuesfrom a lethal poisoning episode in Brazil, where hemodialysispatients were exposed through tap water contamination.

Finally, one of the most comprehensive studies of an emergingcontaminant (perchlorate) in foods and beverages is discussedin this review. In this study, >350 foods and beverages that wereproduced or harvested in more than 50 countries were analyzedfor perchlorate. Most foods had measurable levels, some with highmicrogram per kilogram levels, revealing that perchlorate con-tamination is not limited to the United States but is a worldwidephenomenom. Foods and beverages analyzed included fresh andcanned fruits and vegtables, baby foods, wine, beer, tea, milk, andfruit juices.

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GENERAL REVIEWS

This section includes general reviews relating to environmentalmass spectrometry and emerging contaminants. Reviews thatrelate to specific areas (e.g., pharmaceuticals, EDCs, DBPs, orchiral contaminants) can be found in those specific sections. Manyreviews have been published over the last 2 years that relate toenvironmental mass spectrometry, and a few focus specificallyon emerging contaminants. The previous biennial environmentalmass spectrometry review published in 2006 contained 200references and discussed advances in research for emergingcontaminants and issues, including PFCs (e.g., PFOS and PFOA),pharmaceuticals, hormones, endocrine disruptors, drinking waterDBPs, sunscreens/UV filters, benzotriazoles, PBDEs and newflame retardants, chiral contaminants, algal toxins, pesticidedegradation products, naphthenic acids, perchlorate, arsenic, andmicroorganisms (1). This review covered developments from2004-2005.

A biennial review on water analysis published in 2007 includeda discussion of emerging contaminants and current issues thatare important for water, as well as a discussion of new regulationsand regulatory methods that have been developed (2). This wateranalysis review covered developments from 2005-2006.

Emerging environmental contaminants were the focus of arecent issue of Environmental Science & Technology (December1, 2006), where current research on emerging chemical andmicrobial contaminants was highlighted. This is a must-read issue,and several of those papers will be discussed in this review. Theguest editors of this issue also published an excellent perspectiveon “What is emerging?” as a lead-off editorial to this issue, whichpoints out that the longevity of a contaminant’s “emerging” statusis typically determined by whether the contaminant is persistentand/or has potentially harmful human or ecological effects (3).It is often the case that emerging contaminants have actually beenpresent in the environment for some time (in some cases,decades), but it is the onset of new technologies (such as LC/MS) that have enabled their discovery and measurement in theenvironment for the first time. Petrovic and Barcelo presented anice perspective on emerging environmental contaminants andemphasized that the term “emerging contaminants” does notnecessarily mean new substances (i.e., newly introduced) but canalso include naturally occurring compounds with previouslyunrecognized adverse effects on ecosystems (4). In fact, algaltoxins and hormones, two classes of emerging contaminantsincluded in the current environmental mass spectrometry review,fall into this category of being naturally occurring yet can haveadverse human or ecological impacts. Petrovic and Barcelo alsoprovide a list of several compounds considered to be emergingand discuss LC/MS instrumentation for their analysis, along withthe identification point (IP) system used for identification andconfirmation of environmental contaminants in the EuropeanUnion. In another review, Muir and Howard discuss a procedurefor determining whether there are other persistent organicpollutants that should be addressed beyond those currently beingstudied (5). The authors point out that only a small fraction ofthe approximately 30 000 chemicals widely used in commerceare currently being investigated, and they list 30 chemicals withhigh predicted bioconcentration factors and low rates ofbiodegradation, along with 28 chemicals with long-range

atmospheric transport potential, that could be candidates forenvironmental monitoring.

The journal Trends in Analytical Chemistry published a specialissue in January 2007 for their 25th anniversary on LC/MS inenvironmental analysis. In this issue, Barcelo and Petrovic gavean overview of the challenges and achievements of LC/MS inenvironmental analysis over the last 25 years (6). This article alsodiscusses more recent advancements in triple quadrupole, linearion trap, Q-TOF, and Orbitrap mass spectrometers in the mea-surement of emerging contaminants. Emerging pollutants was thefocus of another review by Wells et al., which summarizedoccurrence and fate studies published in 2006 (7). Morley et al.summarized emerging chemicals and analytical methods (includ-ing MS) published in 2005 (8). Peck reviewed analytical methodsfor antimicrobials, UV filters, inspect repellents, synthetic muskfragrance compounds, and parabens in water, sediment, sewagesludge, air, and aquatic biota (9).

With increasing popularity of TOF and Q-TOF mass spectrom-eters (due to increased resolution and use for identifying unknown,nontarget contaminants), there are increased publications using thesetechniques and also increased review articles. One such reviewdiscussed applications of LC/Q-TOF-MS for environmental analysis,with examples of target pharmaceuticals and pesticides and theidentification of unknown compounds, including biodegradation andphotodegradation products (10). Another review by Williamson andBartlett discussed the rationale for using TOF and LC detection anddescribed many methods currently used for quantifying pharmaceu-ticals, environmental pollutants, explosives, and phytochemicals (11).Atomic analysis reviews are also published annually. Two reviewshighlighted here include one by Butler et al., which includes recentpapers on the analysis of air, water, soils, plants, and geologicalmaterials (12), and another by Wang, which focuses on the use ofLC/inductively coupled plasma mass spectrometry (ICPMS) formeasuring various elements (13).

NANOMATERIALSThere is currently a research boom in the area of nanomate-

rials, with many companies, agencies, and universities expandingtheir efforts. New university departments are being developedaround the study of nanomaterials, and government investmentin nanotechnology has dramatically increased in the last 5-6years. Most research is centered on developing new uses fornanomaterials and new products with unique properties, but onthe other side of this, there is also significant concern regardingnanomaterials as environmental contaminants. As such, nanoma-terials are the focus of a new initiative at the U.S. EPA, whereresearch on their fate, transport, and health effects is beinginvestigated. Nanomaterials are 1-100 nm in size and can haveunique properties, including high strength, thermal stability, lowpermeability, and high conductivity. Nanomaterials are alreadybeing manufactured and used in many products, includingcosmetics, sunscreens, clothing, paints, automobile tires, tennisrackets, lubricants, electronics, soaps, shampoos, and detergents(14). Zero-valent iron nanoparticles are also being used forgroundwater remediation (14). In the near future, nanomaterialsare projected to be used in areas such as chemotherapy, drugdelivery, and labeling of food pathogens (“nanobarcodes”). Thechemical structures of nanomaterials are highly varied, includingfullerenes and functionalized fullerenes (formed in hollow spheres,


ellipsoids, or tubes), quantum dots, metal oxanes, TiO2 nanopar-ticles, and zerovalent iron nanoparticles.

Most environmental concerns center on the potential humanand ecological effects of nanomaterials. An early health effectsstudy of fullerene nanomaterials was published in the December2006 issue of Environmental Science & Technology on emergingcontaminants. Dhawan et al. measured the genotoxicity of colloidalC60 fullerenes in human lymphocytes (15). The C60 fullerenesshowed a genotoxic response at concentrations of 2.2 µg/L, andresults indicate that the mechanism of DNA damage may be dueto the electron accepting ability of C60. Recently, Jennifer Field’sgroup has developed an LC/ESI-MS method (negative ion mode)for measuring fullerenes (C60 to C98) (16). For their method,isotopically enriched 13C60 was used as an internal standard, anddetection limits of 0.02 µg/L were achieved. This method wassubsequently used to measure the uptake of C60 by embryoniczebrafish. Kawano et al. developed an LC/APPI-MS method(negative ion mode) for measuring fullerenes (C60 and C70) (17).Zero-grade air was found to improve their analysis, indicating thatoxygen was involved in the ionization process by APPI. Finally,Fortner et al. used laser desorption ionization-MS, matrix-assistedlaser desorption ionization (MALDI)-MS, 13C nuclear magneticresonance (NMR) spectroscopy, Fourier transform infrared (FT-IR) spectroscopy, UV-vis, and X-ray photoelectron spectroscopy(XPS) to investigate the reaction of C60 fullerene with ozone (18).C60 fullerene reacted with ozone to form a highly oxidizedfullerene, with an average of ∼29 oxygen additions per molecule,arranged in repeating hydroxyl and hemiketal functional groups.These results demonstrate how easy C60 can be functionalizedand highlight the importance of investigating functionalizedfullerenes, beyond C60, in environmental studies.

PFOA/PFOS AND OTHER PERFLUORINATEDCOMPOUNDS

Perfluorinated compounds (PFCs), also referred to as fluo-rotelomer acids, alcohols, and sulfonates, have been manufacturedfor more than 50 years and have been used to make stainrepellents (such as polytetrafluoroethylene and Teflon) that arewidely applied to fabrics and carpets. They are also used in themanufacture of paints, adhesives, waxes, polishes, metals, elec-tronics, and caulks, as well as grease-proof coatings for foodpackaging (e.g., microwave popcorn bags, french fry boxes,hamburger wrappers, etc.). PFCs are unusual chemically, in thatthey are both hydrophobic (repel water) and lipophobic (repellipids/grease), and they contain one of the strongest chemicalbonds (C-F) known. Because of these properties, they are highlystable in the environment (and in biological samples), and theyare expected to have unique distribution profiles in the body.During 2000-2002, an estimated 5 million kg/year were producedworldwide, with 40% of this in North America. Two of these PFCs,perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid(PFOA), are currently receiving a great deal of attention asemerging contaminants in the United States. PFOS was once usedto make the popular Scotchgard fabric and carpet protector, andsince 2002, it is no longer manufactured due to concerns aboutwidespread global distribution in the blood of the generalpopulation and in wildlife, including remote locations in the Arcticand North Pacific Oceans. However, other fluorinated surfactantslike PFOA are still manufactured. Like PFOS, PFOA appears to

be ubiquitous at low levels in humans, even in those living farfrom any obvious sources (2).

Most Americans have about 5 ppb of PFOA in their blood(www.epa.gov/opptintr/pfoa/pubs/pfoarisk.pdf), and potentialhealth concerns include developmental toxicity, cancer, andbioaccumulation (19, 20). Research questions include understand-ing the sources of PFOA and other PFCs, their environmentalfate and transport, pathways for human exposure and uptake, andpotential health effects. It is currently hypothesized that thewidespread occurrence of PFOA and other fluoro acids is likelydue to the atmospheric or oceanic transport of the more volatilefluorinated telomer alcohols (FTOHs), and subsequent transfor-mation into PFOA and other fluoro acids via metabolism andbiodegradation. New studies seem to offer support for thishypothesis (19, 21). PFOS, PFOA, and other PFCs are nowincluded in the National Health and Nutrition Examination Surveybeing conducted by the Centers for Disease Control and Preven-tion (CDC) to provide a better assessment of the distribution ofthese chemicals in the human population (www.cdc.gov/nchs/nhanes.htm). The National Toxicology Program will also becarrying out toxicity studies on PFOA and several other perfluo-rcarboxylic acids and perfluorosulfonates to better understand thetoxicity of these chemicals and their persistence in human blood(http://ntp.niehs.nih.gov).

In January 2005, the U.S. EPA issued a draft risk assessmentof the potential human health effects associated with exposure toPFOA (www.epa.gov/opptintr/pfoa/pubs/pfoarisk.htm), and inJanuary 2006, the U.S. EPA invited PFC manufacturers toparticipate in a global stewardship program on PFOA and relatedchemicals (www.epa.gov/oppt/pfoa/pubs/pfoastewardship.htm).Participating companies have agreed to commit to reducing PFOAfrom emissions and product content by 95% by 2010 and to worktoward eliminating PFOA in emissions and products by 2015. TheU.S. EPA has now listed PFOA on the new proposed CCL-3(www.epa.gov/safewater/ccl/ccl3.html#ccl3). There is currentlyno regulation in the European Union that directly targets PFOAor other PFCs.

While PFOS and PFOA were the first fluorinated surfactantsto receive considerable attention, research is expanding beyondthese two contaminants to other long-chain perfluorinated acidsand alcohols. LC/MS and LC/MS/MS are the most commonanalytical techniques used for their measurement; however, it isdifficult to obtain clean analytical blanks, due to inherent con-tamination in LC systems (fluoropolymer coatings on seals, etc.).As a result, GC/MS and GC/MS/MS are sometimes used. Mostresearch being conducted on PFCs is focused on determining theirsources, fate, and transport. Previous studies have focused onmeasurements in biota and wastewaters. Current studies includesurface waters, rainwater, and drinking water.

There were several good reviews published on PFCs in thelast 2 years. Lau et al. discussed recent advances in the toxicologyand mode of action for perfluorocarboxylic acids (PFCAs), as wellas new monitoring data on environmental, wildlife, and humansamples (20). Future directions were also outlined, including theneed for more standardized methods to understand historical andfuture trends in exposure, the sources and pathways for PFCAs,environmental data for PFCAs beyond PFOA, and a betterunderstanding of toxicological effects. In another review, Preve-


douros et al. discussed the sources, fate, and transport of PFCAsin the environment, with a special focus on PFOA (21). De Voogtand Saez outlined analytical methods for measuring PFCs inenvironmental samples, which included LC/MS(/MS) and GC/MS, along with issues involved in measuring PFCs (22). A reviewof LC/MS/MS methods for PFCs was the focus of another reviewby Villagrasa et al. (23). Sample pretreatment and analysisconditions are also discussed, as well as problems that can beencountered. Finally, Houde et al. reviewed the biological moni-toring of PFCs in wildlife and humans, compared concentrationsand contamination profiles among species and locations, evaluatedtheir bioaccumulation/biomagnification in the environment, anddiscussed possible sources (24). Knowledge gaps related totransport, accumulation, biodegradation, temporal/special trends,and PFC precursors were also discussed.

Many studies of biological samples have been published thelast 2 years, including several human studies. Researchers fromthe CDC reported results from the U.S. National Health andNutrition Examination Survey from 1999-2000 (25) and 2003-2004(26), which included the measurement of 11 PFCs in 1562 and2094 human serum samples, respectively. Isotope dilution-LC/MS/MS was used to measure these PFCs at detection limits of0.05-0.2 ng/mL. In the 1999-2000 samples, PFOS, PFOA,perfluorohexanesulfonate (PFHS), and perfluorooctane sulfona-mide (PFOSA) were detected in all samples analyzed; 2-(N-ethylperfluorooctane sulfonamide) acetic acid, 2-(N-methyl-perfluorooctane sulfonamide) acetic acid, and perfluorononanoicacid (PFNA) were detected in >90% of the samples. Highereducation of participants was associated with higher concentra-tions of PFOS and PFOA. In the 2003-2004 study, PFOS, PFOA,PFHS, and PFNA were present in >98% of the samples. Geometricmean concentrations were significantly lower for PFOS (20.7 µg/L), PFOA (3.9 µg/L), and PFHS (1.9 µg/L) but higher for PFNA(1.0 µg/L) than previous levels measured in 1999-2000. De-creases in PFOS and PFOA were also observed in a survey ofAmerican Red Cross blood donors (27). In the 100 serum samples,geometric means were 33.1 and 15.1 µg/L for PFOS and PFOA,respectively. The half-lives of PFOS, PFOA, and PFHS in humanserum was the focus of another study of retired fluorochemicalproduction workers (28). The geometric mean half-lives were 4.8,3.5, and 7.3 years, for PFOS, PFOA, and PFHS, respectively. LC/MS/MS was used for their measurement.

Apelberg et al. measured 10 PFCs in umbilical cord serumsamples from babies born between 2004 and 2005 in Baltimore,MD (29). Online SPE with LC/MS/MS revealed geometric meanconcentrations of 4.9 and 1.6 µg/L for PFOS and PFOA, respec-tively. PFOS and PFOA were detected in 99 and 100% of theumbilical cord sera, respectively; the other 8 PFCs were detectedless frequently and at lower concentrations. De Silva and Maburyused GC/negative chemical ionization (NCI)-MS (also called GC/electron capture negative ionization-MS) to examine structuralisomer patterns of PFCAs in human blood to investigate theirsources (30). Profiles showed primarily the linear isomer for eachPFCA, which is suggestive of a strictly linear perfluoroalkyl source.Similarities in branched isomer patterns of PFOA and PFNA inthe blood were observed with electrochemically generated PFOA.Maestri et al. developed an LC/MS method utilizing trifunctionalC18 and strong anion-exchange SPE cartridges to measure PFOA

and PFOS in human liver, kidney, adipose tissue, brain, basalganglia, hypophysis, thyroid, gonads, pancreas, lung, skeletalmuscle, and blood (31). Detection limits were 0.1 ng/g in alltissues except adipose, where limits were 0.2 ng/g. PFOA andPFOS ranged from 0.3 to 13.6 ng/g in these tissues.

Marine mammals and other wildlife continue to be active areasof research with PFCs. Butt et al. measured several PFCs in Arcticringed seals and found that these seals and their food web arerapidly responding to the phase out of PFOS-related compoundsin the United States (32). The relatively short doubling times ofthe PFCAs, in addition to the PFOS disappearance half-livessupport the hypothesis of atmospheric transport as the maintransport mechanism of PFCs to the Arctic. Smithwick et al.reported temporal trends of PFCs in polar bears from the Arctic(33). Liver tissue samples were collected from 1972 to 2002.Concentrations of PFOS and PFCAs with carbon chain lengthsfrom C9 to C11 showed an exponential increase between 1972 and2002. Perfluorooctane sulfonamide (PFOSA) showed decreasingconcentrations, and other PFCs did not show any trend. Thedoubling time for PFOS was similar to the doubling time ofproduction of perfluorooctylsulfonyl fluoride-based products dur-ing the 1990s. Sinclair et al. reported the occurrence of PFCs inwater, fish, and birds from New York State (34). PFOS, PFOA,and PFHS were ubiquitous in the water samples, and PFOS wasthe most abundant PFC found in fish and bird samples. Overall,average concentrations of PFOS in fish were 8850× greater thanin surface water, and an average biomagnification factor of 8.9was estimated. Most research on PFCs has been conducted inNorth America, where they were first identified in the environ-ment, but increasingly, new studies are being conducted in Europeand Asia. For example, van de Vijver et al. reported PFCs in harborporpoises from the Black Sea (35). PFOS was the predominantPFC detected, accounting for approximately 90% of the measuredPFC load; these levels were comparable to levels found inporpoises from the German Baltic Sea and from coastal areas nearDenmark. PFNA, perfluorodecanoic acid (PFDA), perfluoroun-decanoic acid (PFUnDA), and perfluorododecanoic acid weredetected in approximately 25% of the porpoises (livers), but PFOA,perfluorobutanoic acid, and perfluorobutanesulfonate (PFBS) werenot detected.

Drinking water has recently been investigated for PFCs.Skutlarek et al. carried out one of the first such studies where 12PFCs were measured in drinking waters and in surface watersfrom Germany with SPE and LC/MS/MS (36). A relatively highmaximum concentration of total PFCs was found in drinking water(598 ng/L), with the major component being PFOA (519 ng/L).Higher concentrations were found in surface waters, with amaximum of 4385 ng/L in the Moehne River at Heidberg. PFOAwas the major component (3640 ng/L), followed by perfluoro-hexanoic acid (PFHA) (247 ng/L), PFOS (193 ng/L), perfluoro-heptanoic acid (PFHpA) (148 ng/L), and perfluoropentanoic acid(93 ng/L). Loos et al. examined PFOS and PFCAs (includingPFOA) in drinking waters in Northern Italy (37). SPE with LC/MS/MS was used for analysis. PFOS and PFOA were found at 9and 3 ng/L, respectively, in drinking water at levels almostidentical to those found in lake source waters, indicating thatdrinking water treatment (chlorination and sand filtration) did notremove them.


Several researchers are examining precipitation (rainwater)and snow to test for the atmospheric transformation of FTOHsas a source of PFOA and other PFCAs. To this end, Scott et al.developed a method to measure PFCAs in surface waters and inprecipitation using GC/MS with large-volume sampling (38). ThePFCAs were derivatized with 2,4-difluoroaniline and N,N-dicyclo-hexylcarbodiimide to form 2,4-difluoroanilide derivatives. Thisenabled detection limits of 0.5 ng/L (and large volume extractioncould achieve 0.01 ng/L). Young et al. used SPE with LC/MS/MS to measure PFCAs in Arctic snow collected from 1996-2005(39). PFCAs were observed in all of the samples collected, withconcentrations in the low to midpicogram per liter range. Adecrease in PFOS levels over time was observed, indicating a rapidresponse to its phase-out in the United States.

Wastewater studies continue to be popular, as researchers tryto understand the fate and potential sources of PFCs. For example,Schultz et al. investigated PFC mass flows in a municipalwastewater treatment plant (40). Results showed that PFOS andperfluorodecane sulfonate increased in mass flow throughout thewastewater plant, with both increasing in concentration aftertrickling filtration. All four perfluoroalkyl sulfonamides measuredhad increased mass flows, which were attributed to the degrada-tion of precursors during the activated sludge process. No trendswere observed for the PFCAs, and conventional treatment wasnot effective for removing them. In fact, PFNA levels increasedfollowing wastewater treatment.

Foods were the focus of a Canadian Total Diet Study,conducted from 1992-2004 (41). PFCs have been used as coatingsfor paper packaging of foods, and the PFOSAs that are likelybreakdown products were measured in this study: N-ethylper-fluorooctane sulfonamide (N-EtPFOSA), PFOSA, N,N-diethylper-fluorooctane sulfonamide, N-methylperfluorooctane sulfonamide,and N,N-dimethylperfluorooctane sulfonamide. Liquid-liquid ex-traction was used with GC/MS for their measurement. Picogramper gram to low nanogram per gram of these PFCs were detectedin all food groups tested: baked goods, candy, dairy, eggs, fastfood, fish, meat, and foods to be prepared in packaging. Thehighest levels of the PFOSAs were found in fast foods (up to 27.3ng/g). Concentrations of N-EtPFOSA decreased over the samplingperiod (1992-2004) in French fries and other fast foods; no trendwas observed in the other foods. With the use of these data, anexposure level of 73 ng/person/day was estimated.

New occurrence studies in Asia include recent measurementsof 14 PFCs in river water (from tributaries of the Pearl River andthe Yangtze River) in China (42). PFOS and PFOA were the mostfrequently detected PFCs, with maximum levels of 99 and 260ng/L, respectively. Lower levels were observed for the other PFCs(PFBS, PFHS, PFOSA, PFHA, PFHpA, PFNA, PFDA, and PFUn-DA). Highest levels for most PFCs were in water samples fromthe Yangtze River near Shanghai, the major industrial and financialcenter in China.

Air has been the focus of some new studies. Barber et al. usedboth GC/positive ion CI-MS and LC/TOF-MS to measure PFCsin air from Northwest Europe (43). High-volume air samplerscontaining glass fiber filters and glass columns with polyurethanefoam were used for sampling. PFOA was the predominant PFCfound in particulates (up to 818 pg/m3); 8:2 FTOH and 6:2 FTOHwere the predominant PFCs found in the gas phase (up to 243

and 189 pg/m3, respectively). These three PFCs were ubiquitousin the air samples collected. Jahnke et al. measured PFCs in airsamples collected onboard a ship cruising between Germany andSouth Africa (44). GC/MS was used to measure the PFOHs andN-alkylated fluorooctane sulfonamides (FOSAs) and sulfonami-doethanols (FOSEs). Most PFCs were found in the NorthernHemisphere, at a maximum of 190 pg/m3. Lower levels wereobserved off the coast of Africa (up to 14 pg/m3).

Other new methods include those for measuring FTOHs andother PFCs in water, wastewater, serum, and biological tissues.Szostek et al. used LC/MS/MS to measure FTOHs in water, with90 ng/L detection limits (45). Zhao et al. reported a method usingmixed hemimicelle-based SPE (with cetyltrimethylammoniumbromide-coated silica and sodium dodecyl sulfate-coated alumina)to preconcentrate six PFCs in river and wastewater samples (46).Concentration factors of 500 were achieved, and samples wereanalyzed using LC/ESI-MS/MS. Finally, Henderson et al. devel-oped a GC/MS method for simultaneously quantifying volatile andnonvolatile PFCs in biological matrixes (serum and mammaliantissues) (47). Liquid-liquid extraction and diazomethane deriva-tization were used, and detection limits below 50 ng/mL (serum)or ng/g (liver) were achieved. This method offered the advantageof an all-in-one method for volatile and nonvolatile PFCs incomplex matrixes and a simple GC/MS method for laboratoriesthat do not have LC/MS/MS instruments.

PHARMACEUTICALS, HORMONES, ANDENDOCRINE DISRUPTING COMPOUNDS

Pharmaceuticals, hormones, and EDCs have become importantemerging contaminants, due to their presence in environmentalwaters (following incomplete removal in wastewater treatment orpoint-source contaminations), threat to drinking water sources,and concern about possible estrogenic and other effects, both towildlife and humans. A major concern for pharmaceuticals alsoincludes the development of bacterial resistance (creation of“super bugs”) from the release of antibiotics in the environment.It is estimated that approximately 3000 different substances areused as pharmaceutical ingredients, including painkillers, antibiot-ics, antidiabetics, �-blockers, contraceptives, lipid regulators,antidepressants, and impotence drugs. However, only a very smallsubset of these compounds (∼150) has been investigated inenvironmental studies. Pharmaceuticals are introduced not onlyby humans but also through veterinary use for livestock, poultry,and fish farming. Various drugs are commonly given to farmanimals to prevent illness and disease and to increase the size ofthe animals. One lingering question has been whether the lowenvironmental levels of pharmaceuticals (generally nanograms perliter) would cause adverse effects on humans or wildlife. Whilehealth effects studies are still limited, estrogenic effects and renaleffects have been reported for R-ethinylestradiol (EE2) anddiclofenac, respectively, at low environmentally relevant concen-trations (1).

Many pharmaceuticals, hormones, and EDCs are highly polar,which necessitates the use of either LC/MS(/MS) or an efficientderivatization procedure combined with GC/MS(/MS) for theiranalysis. These mass spectrometry methods can typically measurepharmaceuticals at low nanogram per liter levels in environmentalsamples. ESI and atmospheric pressure chemical ionization(APCI) are the most commonly used LC interfaces, but APPI and


sonic spray ionization (SSI) are sometimes used. Increasingly,tandem-MS and multiple reaction monitoring (MRM) are beingused with both LC/MS and GC/MS to provide added selectivityand sensitivity to these analyses. Innovations have also been madein rapid online extraction, microextraction, and online derivatiza-tion techniques used in combination with GC/MS/MS detection.

Pharmaceuticals. Research on pharmaceuticals continues togrow exponentially, and this is especially evidenced by the vastnumber of reviews that have been written on them, as well as thenumber of the special issues of journals covering them (e.g.,Analytical and Bioanalytical Chemistry, February 2007). Fent etal. recently reviewed the ecotoxicology of human pharmaceuticals(48). While most pharmaceuticals have an acute or chronic effecton aquatic and other organisms, most of the lowest observed effectconcentrations (LOECs) are substantially above the environmentalconcentrations that have been observed (nanogram per liter tolow microgram per liter). Those pharmaceuticals whose chronictoxicity LOECs approach levels observed in wastewater effluentsinclude salicylic acid, diclofenac, propranolol, clofibric acid,carbamazepine, and fluoxetine. For example, for diclofenac, theLOEC for fish toxicity was in the range of wastewater concentra-tions, and the LOEC of propranolol and fluoxetine for zooplanktonand benthic organisms was near the maximum measured inwastewater effluents. The contraceptive EE2 has the greatestpotential for estrogenic effects of the pharmaceuticals studied, asit can induce estrogenic effects at extremely low concentrations(low and subnanogram per liter). Effects include alteration of sexratios and sexual characteristics and decreased egg fertilizationin fish. Acute effects documented include those from fluoxetine,which has a LOEC concentration of 20 µg/L.

Fatta et al. reviewed analytical methods for measuring phar-maceuticals in water and wastewater (including LC/MS and GC/MS methods) (49), and Buchberger reviewed methods formeasuring pharmaceuticals in water, wastewater, and sludge(including GC/MS, LC/MS, and capillary electrophoresis (CE)/MS methods) (50). LC/MS/MS was the focus of several reviewson pharmaceuticals. For example, Hao et al. covered developmentsover the last 10 years and included sample preparation, chro-matographic separation, and MS detection (51). Gros et al.reviewed LC/MS/MS methods for the simultaneous determina-tion of acidic, neutral, and basic pharmaceuticals in water andwastewater (52). Pozo et al. wrote an excellent review detailingthe achievements and pitfalls of LC/MS/MS for antibiotic andpesticide analysis (53). Pitfalls included the use of nonspecificMRM transitions (such as those involving the loss of water), whichcan result in false-positive findings. On the other hand, falsenegatives are possible if coeluting isobaric interferences arepresent. The authors suggest that good chromatographic separa-tions are essential for assuring accuracy in LC/MS/MS. Themeasurement of lipid regulators and their metabolites (e.g.,clofibric acid and fenofibric acid) by LC/MS was reviewed byHernando et al. (54). Occurrence patterns of pharmaceuticals inwater was the subject of another review by Nikolaou et al., whichalso discussed the fate of many in the environment (55). Analyticalmethodologies for studying the fate and removal of pharmaceu-ticals in wastewater treatment were reviewed by Radjenovic et al.(56).

Drinking water treatment studies of pharmaceuticals areincreasing. Zwiener reviewed the occurrence and analysis ofpharmaceuticals and their transformation products in drinkingwater treatment (57). Examples of pharmaceuticals found indrinking waters from Germany, Italy, the United Kingdom, theUnited States, or Canada include the lipid regulators clofibric acid,bezafibrate, and gemfibrozil; the antiepileptic drug carbamazepine,and the analgesics diclofenac, phenazone, propylphenazone, andibuprofen. The likelihood of the presence of other pharmaceuticalsin drinking water is also discussed, including the antibioticssulfamethoxazole and erythromycin, the �-blocker sotalol, andiodinated X-ray contrast media (e.g., diatrizoate, iopamidol, oriopromide). These compounds are likely to be present due to theiroccurrence in surface waters and groundwaters and due to theirchemical properties.

GC/MS and LC/MS methods for measuring NSAIDs (non-steroidal anti-inflammatory drugs) in water were reviewed by Farreet al. (58). These drugs include ibuprofen, ketoprofen, naproxen,diclofenac, aspirin, and others. Because of their high polarity,these NSAIDs are not removed well during wastewater treatment.Future directions outlined include the need to measure newNSAIDs, such as COX-2 inhibitors. X-ray contrast media are aconcern for the environment, due to high amounts excreted(grams per liter) in urine and their wide use for medical imaging.Perez and Barcelo reviewed their fate and occurrence in theenvironment and included a discussion of the microbial degradatesthat have been found in laboratory studies (59). Research needsoutlined include the need for comprehensive characterization ofbiodegradation products (including exact mass measurements andMS/MS for providing fragmentation pathways) and verifyingwhether microbial degradates observed in laboratory studies arealso found under real environmental conditions.

Drinking Water Studies. To that end, some new research isusing exact mass measurement and MS/MS to structurallyidentify degradates and metabolites of pharmaceuticals in envi-ronmental samples. For example, Perez et al. used ion trap-MSwith H/D exchange to elucidate the structures of the X-raycontrast agent iopromide’s metabolites formed during biodegrada-tion in activated sludge (60). Three metabolites were producedby the oxidation of the primary alcohols (forming carboxylates)on the side chains of iopromide. The iodinated ring remainedintact during biodegradation in sludge. In another study by Perezet al., MS/MS data from quadrupole-linear ion trap-MS and exactmass data from Q-TOF-MS were used to elucidate photodegra-dation products of enalapril (a hypertensive cardio drug) (61).Structures for the three photodegradates were proposed, whichformed by the loss of formaldehyde from the proline residue,cleavage of the central amide bond, and migration of the ethylesterside chain.

Drinking water samples have been included in pharmaceuticalstudies, and new research is investigating illicit drugs and theirmetabolites. Hummel et al. used LC/ESI-MS/MS to measureseveral psychoactive drugs and their metabolites in drinking water,surface water, groundwater, and wastewater in Germany (62).These drugs included opioids, tranquilizers, antiepileptics, thecocaine metabolite benzoylecgonine, the antidepressant doxepin,as well as the calcium channel blocker verapamil. In drinkingwater, only carbamazepine, its metabolite 10,11-dihydroxy-10,11-


dihydrocarbamazepine, and primidone were present (up to 0.020µg/L). Most analytes (15 of 20) were found in raw and treatedwastewater, as well as in surface water. The cocaine metabolitewas found at a maximum of 78, 49, and 3 ng/L in wastewaterinfluents, effluents, and surface water, respectively. Vanderfordand Snyder measured 15 pharmaceuticals, 4 pharmaceuticalmetabolites, 3 EDCs, and 1 personal care product in drinkingwater, surface water, and wastewater (63). Only 2 of the 15pharmaceuticals were detected in finished drinking water, mep-robamate and dilantin, at levels of 5.9 and 1.3 ng/L, respectively.Other pharmaceuticals were found to degrade in drinking watertreatment using ozone and chlorination. In the wastewater influ-ents, seven pharmaceuticals were detected at levels above 1 µg/L(the highest being naproxen at 22.5 µg/L); levels were substan-tially lower in the wastewater effluents, with only one pharma-ceutical above 1 µg/L (1.27 µg/L for meprobamate). In surfacewaters, atenolol was found at the highest level (0.86 µg/L) of thepharmaceuticals measured. Rabiet et al. measured 16 pharma-ceuticals in drinking water, surface water, and wastewater inFrance using GC/MS (64). Seven of the pharmaceuticals werefound in the drinking water (supplied by wells), with paracetamoland carbamazepine found at the highest levels (211 and 43.2 ng/L, respectively). Higher levels were found in surface waters andwastewater effluents (up to 11 300 ng/L of paracetamol).

Fate and Transport Studies. Several excellent fate andtransport studies have been published in the last 2 years. Someof these involve fate in the environment (in waters, sediments,wetlands), and others involve fate in wastewater treatment. Buergeet al. investigated the occurrence and fate of the chemotherapydrugs cyclophosphamide and ifosfamide in wastewater and surfacewaters (65). These compounds were detected in untreated andtreated wastewater at concentrations of <0.3-11 ng/L, and nosignificant degradation was observed in environmental samples.Concentrations were lower in surface waters (<50-170 pg/L) andwere several orders of magnitude lower than levels that wouldcause acute ecotoxicological effects; however, a final risk assess-ment could not be made because of the lack of data for chroniceffects on aquatic organisms. Fono et al. investigated the naturalattenuation rates of a suite of wastewater-derived contaminants(including several pharmaceuticals) in a river during a periodwhen wastewater effluent accounted for nearly the entire flow ofthe river (66). The X-ray contrast agent was constant over the 2week travel time in the river, but concentrations of gemfibrozil,ibuprofen, metoprolol, and naproxen decreased significantly(60-90%) as the water flowed downstream. GC/MS/MS was usedfor their detection. Results indicated that natural attenuation canresult in significant decreases in concentrations of wastewater-derived contaminants in large rivers. Barbiturates were the focusof another occurrence and fate study by Peschka et al. (67). AGC/MS method was developed to measure them (butalbital,secobarbital, hexobarbital, aprobarbital, phenobarbital, and pen-tobarbital) at a detection limit of 1 ng/L, using Oasis HLBcartridges for extraction. These barbiturates were not detectedin several rivers in Germany (Main, Rhine, Elbe) but weredetected up to 5.4 µg/L in the River Mulde. Results indicated apoint source contamination, potentially from an older landfill orfrom veterinary use of these substances.

Wastewaters from European countries were the focus of amulti-investigator study, which measured 36 polar pollutants(including pharmaceuticals) in eight municipal wastewater treat-ment plants from four countries (68). Three of these plants werefollowed over 10 months. Some pharmaceuticals (e.g., diclofenac,carbamazepine) showed mean concentrations in the 1-10 µg/Lrange, and many of the polar compounds were not significantlyremoved in tertiary wastewater treatment. These authors proposeda water cycle spreading index (WCSI), which is calculated froma compound’s effluent concentration and its normalized removal,to be used as an indicator for the potential of a polar pollutant tospread in an aquatic environment and for its expected concentra-tion level. Of the polar analytes investigated, diclofenac andcarbamazepine were the pharmaceuticals that would have thehighest WCSI. Lindberg et al. studied the fate of three fluoroqui-nolones (norfloxacin, ofloxacin, and ciprofloxacin), one sulfona-mide (sulfamethoxazole), and trimethoprim in a sewage treatmentplant from Sweden (69). More than 70% of the norfloxacin andciprofloxacin passing through the treatment plant sorbed to thedigested sludge. Trimethoprim was found in the final effluent atnearly the same level as in the influent, indicating that it was notdegraded in treatment.

Sludge left over from wastewater treatment (biosolids) is oftensold commercially for use as fertilizer on farm fields. The presenceof pharmaceuticals in these biosolids is a recent concern. In anew study, nine different biosolids products produced at waste-water treatment plants in seven different states in the U.S. wereanalyzed for 87 organic contaminants, including pharmaceuticals(70). Carbamazapine (an antiepileptic), diphenhydramine (anantihistamine), and fluoxetine (an antidepressant) were found inall nine biosolids, at a maximum or 1200, 22 000, and 4700 µg/kg, respectively.

The behavior and fate of the antibiotic tetracycline was studiedin rivers and wetlands in Canada (71). UV-vis irradiation andthe type of water matrix were important in catalyzing the removalof tetracycline in the waters. Jones-Lepp investigated the abilityof the antibiotic azithromycin and the human waste markerurobilin to serve as chemical markers of human waste contamina-tion (72). Source waters were collected from 21 sites in NewEngland, Nevada, and Michigan, extracted using Oasis HLB SPEcartridges, and analyzed using LC/ESI-MS. Azithromycin, whichis prescribed for human use only, was detected in many of thosewaters, up to 77 ng/L. It was suggested that azithromycin andurobilin could be used to track human waste contamination.

Methods for Antibiotics/Antimicrobials. Antibiotics havereceived increasing attention, and two recent reviews focus onanalytical methods for measuring them in environmental samples.Samanidou and Evaggelopoulou outlined analytical strategies formeasuring antibiotic residues in fish and focused on thoseantibiotics used in aquaculture (fish farming) (73). Diaz-Cruz andBarcelo provided an overview of LC/MS/MS methods for mea-suring antibacterial agents in surface water, groundwater, andwastewater (74). One of the new methods developed for antibioticsincludes a multiresidue method using online SPE-LC/MS/MS formeasuring 16 antibiotics in water (75). Detection limits rangedfrom 0.4 to 4.3 ng/L.

Veterinary Pharmaceuticals. Veterinary pharmaceuticalshave been gaining interest, as they are widely used to treat disease


and protect the health of farm animals, as well as to promote theirgrowth rate. There is concern regarding the excreted drugs andmetabolites getting into the environment, through runoff intorivers, entry into groundwater, and use of animal waste as fertilizer.Antibiotics are of particular concern, as the majority given toanimals is excreted unchanged into the feces and urine, and thereis potential for antibiotic resistance (76). Sarmah et al. publishedan excellent review on the use, sales, exposure pathways,occurrence, fate, and effects of veterinary antibiotics (76). Fourof the most popular veterinary antibiotics, tylosin, tetracycline,sulfonamides, and bacitracin, are discussed, and recommendationsfor future research are given. Diaz-Cruz and Barcelo publishedanother review outlining LC/MS methods for veterinary drugsin soil, sediment, and sludge samples (77).

Several new studies of veterinary pharmaceuticals have alsobeen recently published. Peru et al. developed a new method tomeasure spectinomycin and lincomycin in liquid hog manuresupernatant and in runoff samples (78). SPE with a weak cation-exchange resin (Oasis WCX) or an Oasis HLB cartridge was usedto extract spectinomycin and lincomycin, respectively. HILIC wasused with APCI-MS/MS for separation and detection. Whentraditional C8 or C18 LC columns were used, there was little orno retention of spectinomycin, but the use of HILIC increased itsretention and separation from other matrix interferences. A silica-based Altima HP hydrophilic interaction column was used for theLC separation. Lincomycin was detected at submicrogram per literlevels in runoff samples, and both spectinomycin and lincomycinwere detected in high microgram per liter levels in liquid hogmanure. The impact of a concentrated animal feeding operation(CAFO) on well water was investigated by Batt et al., whomeasured veterinary sulfonamide antibiotics (79). A previouslydeveloped SPE-LC/MS/MS method was used for their measure-ment. Two veterinary antibiotics, sulfamethazine and sulfadimethox-ine, were present in all samples collected, at levels up to 0.22 and0.068 µg/L, respectively. In another study, Kim and Carlsonmeasured the occurrence of 15 antibiotics belonging to 3 differentclasses: tetracyclines, sulfonamides, and macrolides, using LC/MS/MS for their measurement (80). Results for aqueous andsediment samples showed differing concentrations depending onthe sampling location and time periods. The highest concentra-tions of the antibiotics were found in the winter, indicating thatlow-flow conditions and cold water temperatures may enhancetheir persistence.

Studies of Illicit Drugs. Illicit drugs have been receivingincreased interest since Fanelli and collaborators from the MarioNegri Institute in Italy first reported their occurrence in the PoRiver and in wastewater in 2005. Their measurement in environ-mental waters can not only provide concentration data for potentialecological and other effects, but it can also provide an indirectmeasurement of the drug usage by the population. Illicit drugsare now being measured in several countries, including the UnitedStates, Germany, Italy, Spain, the U.K., Switzerland, and Poland.Wastewater was the focus of an illicit drug study by Castiglioniet al. (81). Cocaine, amphetamines, morphine, cannabinoids,methadone, and some of their metabolites were measured usingLC/MS/MS with isotope dilution. Low nanogram per liter detec-tion limits were achieved, and these drugs and metabolites werefrequently detected in the wastewater plant influents and effluents

from Milan (Italy) and Lugano (Switzerland). Cocaine and ben-zoylecgonine (a metabolite) were the most abundant, withconcentrations of approximately 0.5-1 µg/L for benzoylecgonineand 0.2-0.4 µg/L for cocaine. Concentrations of other cocainemetabolites were lower (4-36.6 ng/L). Morphine was also presentat relatively high concentrations (80-200 ng/L), but most otherdrugs were lower than 20 ng/L. Concentrations were lower inthe effluents than in the influents, suggesting extensive degrada-tion or sorption in the wastewater treatment plant. However,significant amounts of illicit drugs and metabolites were stillpresent in the effluent from the Lugano plant, and traces ofamphetamines and methadone were present in the plant fromMilan. Methamphetamine and 3,4-methylenedioxymethamphet-amine (MDMA, ecstacy) levels were similar to those previouslyobserved in wastewater effluents in the United States.

UPLC/MS/MS methods were developed by other researchersfor analyzing illicit drugs in environmental samples (82, 83). Therecent development of UPLC has allowed vastly improved chro-matographic resolution (as compared to conventional LC) andallows very short run times (often less than 10 min). Huerta-Fontela et al. developed a SPE-UPLC/MS/MS method usingisotope dilution for measuring cocaine, amphetamine-relateddrugs, LSD, ketamine, PCP, fentanyl, and many of their metabo-lites, as well as noncontrolled drugs, in wastewater and surfacewater (82). Limits of quantification ranged from 0.1 to 3.1 insurface waters and 0.2 to 4.0 ng/L in wastewaters. A total of 10 ofthe 15 target compounds were found in the 16 wastewatertreatment plants sampled in Northeast Spain. Cocaine and itsmetabolite, benzoylecgonine, were found in 85% of the wastewaterinfluents and in 69% of the effluents. Mean concentrations of 79and 810 ng/L for cocaine and benzoylecgonine were found ininfluent samples, respectively, while 17 and 216 ng/L were foundin the effluents. River water samples contained 10 and 111 ng/L,respectively. Amphetamine 3,4 -methylenedioxyethamphetamine(MDEA), and MDMA were found in 30% of the influents and in23% of the effluents. Only 15% of the incoming MDMA waseffectively removed, leading to relatively high effluent levels (67ng/L) and a river mean concentration of 3 ng/L. Among the othercontrolled drugs, only ketamine was found at a mean concentra-tion of 41 and 19 ng/L in influent and effluent samples, respec-tively. Noncontrolled drugs, nicotine and caffeine, were found inall influent samples up to 13 and 23 µg/L, respectively. Kasprzyk-Hordem et al. published another SPE-UPLC/ESI-MS/MS methodfor measuring illicit drugs and basic/neutral pharmaceuticals insurface water (83). Method detection limits ranged from 0.3 to50 ng/L. Cocaine and benzoylecgonine were not detected in theriver waters from the U.K. or Poland, but amphetamine wasdetected at 6-9 ng/L in river water from the U.K.

Other Occurrence Studies. Another study reported the firstmeasurement of six glucocorticoids (prednisone, prednisolone,cortisone, cortisol, dexamethasone, and 6R-methylprednisolone)in wastewater treatment plants and receiving rivers in Beijing,China (84). LC/ESI-MS/MS was used for their measurement.Average concentrations in the influents ranged from 0.62 to 39ng/L, and their removals ranged from 78 to 100%. In some cases,levels in the rivers were much higher than levels in the wastewaterplant effluents, indicating a random discharging of untreatedwastewaters into these rivers.


Other Pharmaceutical Methods. Other UPLC methodsinclude one using Q-TOF-MS for measuring 32 biologically activecompounds in tap water and wastewater (85). Compoundsmeasured included anti-inflammatories, analgesics, lipid regula-tors, psychiatric drugs, antiulcer agents, antibiotics, �-blockers,and phytoestrogens. Limits of quantification ranged from 0.1 to15 ng/L in tap water and 2 to 300 ng/L in wastewater. UPLCallowed the analysis to be completed in 14 min. Carbon nanotubeswere used as the sorbent material for a new SPE-CE-MS methodto measure tetracyclines in surface water (86). Detection limitsranged from 0.3 to 0.69 µg/L for a 10 mL water sample.

Endocrine Disrupting Compounds and Hormones. Certainsynthetic and natural chemicals have the ability to mimic hor-mones, and thus, are able to interfere or disrupt normal hormonalfunctions. Endocrine disrupting compounds (EDCs) are of con-cern due to their ecotoxicological and toxicological potencies. Avariety of natural compounds and anthropogenic chemicals areknown or predicted to influence the endocrine system, such asnatural estrogens (e.g., 17�-estradiol, estrone), natural androgens(e.g., testosterone), phytosteroids (e.g., 17�-sitosterol), isofla-venoids (e.g., daidzeine), synthetic estrogens (e.g., 17R-ethi-nylestradiol), pesticides (e.g., atrazine), phthalates, alkylphenolethoxylate surfactants, dioxins, coplanar polychlorinated biphenyls(PCBs), parabens (hydroxybenzoate derivatives), bisphenol A, andorganotins. Because of the large number of chemicals withdifferent modes of action and different affinities to hormonalreceptors, their EDC potencies differ substantially. In wildlife,EDCs are suspected in the decline of certain species (e.g., possibleincreased sterility in the American alligator), change of sex infish and shellfish, and other problems. EDCs are also suspectedin declining sperm counts in humans, although this has not beenproven. Both natural estrogens and synthetic EDCs can reach theaquatic environment through wastewater discharges. Fish andwildlife can be exposed, and humans can become exposed throughthe intake of this water into drinking water treatment plants. GC/MS and GC/ion trap-MS/MS are still being used for EDCmeasurements, but increasingly, LC/MS and LC/MS/MS arebeing used. The main benefits of LC/MS/MS, in comparison toGC/MS, are lower statistical errors and no need for derivatization.However, when higher chromatographic resolution is needed toseparate isomers or congeners (such as for PCBs, dioxins, orbrominated flame retardants), GC/MS/MS systems are still themethod of choice.

Several reviews on EDCs have recently been published. Stuartpublished a nice review on GC/MS developments for measuringEDCs (87). Also discussed in this review are derivatizing agents,extraction techniques, and new chromatographic methods (includ-ing GC × GC-TOF-MS) for analyzing EDCs. Wang et al. publisheda comprehensive review of analytical methods for estrogens infood and environmental samples (88). GC/MS and LC/MSmethods are detailed, as well as other methods using enzyme-linked immunosorbent assays (ELISAs), bioassays, and GC andLC. LC/MS methods for the analysis of surfactants in wastewaterwere the focus of another review by Gonzalez et al. (89). Methodsinclude the use of LC/triple quadrupole, ion trap, Q-TOF, andMALDI-TOF-MS. The identification of polar metabolites producedduring biodegradation in wastewater treatment is also discussed.

Recent studies have also used mass spectrometry to identifynew estrogenic compounds. For example, Noguchi et al. used LC/MS/MS to identify 2,6-dimethyl-4-nitrophenol and 1-hydroxy-pyrene as estrogenic compounds in diesel exhaust (90). Boitsovet al. used GC/MS (with EI and NCI) to identify three newestrogenic alkylphenols in produced water from offshore oilinstallations (91). These long-chain para-substituted alkylphenolswere identified as 4-(1,1-dimethylbutyl)phenol), 4-(1,2,2-trimeth-ylpropyl)phenol and 4-(1,1-dimethylpentyl)phenol.

New Methods for EDCs. Several new methods have beendeveloped for various hormones and EDCs. Trenholm et al.created a comprehensive method utilizing a single SPE step, alongwith GC/MS/MS and LC/MS/MS, to measure a broad range ofEDCs and pharmaceuticals in water (92). Detection limits rangedfrom 1 to 10 ng/L and recoveries from 50 to 112% for 58 EDCs.In one of the more innovative methods, Bovet et al. developed achip-based nano-ESI-MS method for detecting noncovalent ligandbinding to a human estrogen receptor (93). This approach allowedfor rapid screening of EDCs. Farre et al. reported a new UPLC/Q-TOF-MS method for measuring EDCs at nanogram per literlevels in wastewater, river water, and groundwater (94). Theseincluded estrogens, estrone (E1), 17�-estradiol (E2), estriol (E3),and 17R-ethinylestradiol (EE2), and the isoflavones daidzein,genistein, and biochanin A. This UPLC/Q-TOF-MS method wasfound to be more sensitive than LC/MS/MS (with a triplequadrupole mass spectrometer). In addition, analysis times (16min) were less than traditional LC/MS/MS methods (45 min).Yang et al. reported a fully automated SPME/on-fiber derivatiza-tion method (with GC/MS) for simultaneously measuring threeEDCs and five steroid hormones in aqueous and biologicalsamples (95). Quantification limits of 4-413 ng/L were achieved.This method provided better precision as compared to traditional,manual SPE methods, and analysis time was shortened.

Biological Samples. EDCs continue to be measured inbiological samples. For example, Markman measured four EDCs:E2, dibutylphthalate, dioctylphthalate, and bisphenol A in earth-worms that had been exposed to sewage effluents (worms livingin sewage percolating filter beds and garden soil) (96). Signifi-cantly higher levels of these EDCs were found in the worms fromsewage percolating filter beds, suggesting that earth wormsaccumulate these chemicals and that they could be used asbioindicators for EDCs. Derivatization with bis-(trimethylsilyl)-trifluoroacetamide (BSTFA) and GC/MS was used for theiranalysis. In another paper, Ahn et al. developed a new GC/MSmethod that utilized a lipid freezing filtration to eliminate lipidsin fish samples and allow 0.02-0.41 ng/g detection limits for eightalkylphenols and bisphenol A (97). Further purification involvedthe use of an HLB sorbent and Florisil SPE cartridges.

Other EDC Methods and Studies. Sarmah et al. carried outa survey of natural and synthetic estrogens in sewage and animalwaste effluents in a dairy farming region of New Zealand (98).Dairy farm effluents contained high levels of E2 (19-1360 ng/L)and its breakdown product, E3 (41-3123 ng/L) compared to pigor goat farm effluents. The combined load for the five estrogensmeasured varied from 60 to >4000 ng/L. The synthetic estrogenEE2 was detected only in one wastewater sample, at a trace level.Hutchins et al. measured estrogens and estrogen conjugates inlagoons associated with swine, poultry, and cattle operations using


GC/MS/MS and LC/MS/MS (99). Several estrogens wereidentified, and estrogen conjugates accounted for at least one-third of the total estrogen equivalents. In another study, the fateof natural estrogens (E1 and E2), a synthetic estrogen (EE2), andestrogen conjugates (estrone-3-sulfate, estrone-3-glucuronide, and17�-estradiol-glucuronides) was investigated in three pilot-scaleand two laboratory-scale membrane bioreactors (100). Becausewomen primarily excrete estrogens as conjugates, it was arguedthat it could be important to measure these conjugates becausethey can be cleaved to reform the original estrogens in theenvironment. E1 was removed with high efficiency (80-91%) andE2 less so (49-67%). However, the estrogen conjugates passedthrough treatment without significant degradation.

Air was the focus of a new method for measuring bisphenolA, tetrabromobisphenol A, 4-tert-octylphenol, 4-nonylphenol, andpentachlorophenol (101). LC/MS/MS with isotope dilution al-lowed low quantification limits of 0.1 ng/m3. Measurement ofEDCs in cereals was the focus of another method (102). Pres-surized liquid extraction was used with LC/ESI-MS to measureseven EDCs (bisphenol A, 4-tert-butylbenzoic acid, 4-nonylphe-nol, 4-tert-butylphenol, 2,4-dichlorophenol, 2,4,5-trichlorophenol,and pentachlorophenol) at detection limits of 0.003-0.043 µg/g. Loos et al. used SPE with LC/MS/MS to measure octyl- andnonylphenols, their ethoxylates, and carboxylates in textileindustry effluents, wastewater treatment plant effluents, andsurface waters (103). Alkylphenol ethoxylate surfactants areused heavily in the textile industry in pretreatment formulationsand as additives in detergents or wetting agents for woolscouring, hydrogen peroxide bleaching, and dyeing. Two ofthe carboxylates (NPE1C and NPE2O) showed the highestconcentrations, up to 4.5 µg/L in a wastewater effluent, and3.6 µg/L in river water. The highest nonylphenol levels werein receiving rivers (up to 2.5 µg/L). The predicted no-effectconcentration for nonylphenol is 0.33 µg/L, and this level wasoften exceeded, suggesting the potential for adverse effects tothe aquatic environment. Gatidou et al. created an integratedmethod for the simultaneous measurement of nonylphenol,nonylphenol ethoxylates, triclosan, and bisphenol A in waste-water and sewage sludge (104). SPE was used for extraction,and BSTFA derivatization was used with GC/MS for detection,at limits of 0.03-0.41 µg/L in wastewater and 0.04-0.96 µg/kg in sludge. Endocrine disrupting pesticides were the focusof another SPE-GC/MS method developed by Nevado et al.(105). Atrazine, simazine, propazine, ametryn, prometrun,terbutryne, and three chloro-s-triazine degradation products,deethylatrazine, deisopropylatrazine, and deethyldeisopropy-latrazine, could be measured in surface waters at quantificationlimits of 2.3-115 ng/L.

DRINKING WATER AND SWIMMING POOLDISINFECTION BYPRODUCTS

Drinking Water DBPs. New areas in drinking water DBPresearch include the study of highly genotoxic DBPs that havebeen recently identified, issues with increased formation of manyof these with the use of alternative disinfectants (e.g., chloraminesand ozone), and other routes of exposure besides ingestion(including inhalation and dermal absorption from showering,bathing, and swimming activities, which are now being recognizedas important). A new review article discusses the occurrence,

genotoxicity, and carcinogenicity of regulated and emerging DBPsin drinking water and also identifies data gaps and provides aroadmap for future research (106). Three categories of DBPs areidentified for priority toxicity testing and decision-making, basedon the combination of occurrence, genotoxicity, and carcinogenic-ity data: (1) DBPs that have some or all of the toxicologicalcharacteristic of human carcinogens, (2) DBPs that occur atmoderate concentrations and are genotoxic, and (3) DBPs thatoccur at moderate concentrations but for which little of notoxicology data are available. Areas for future research includethe need for (1) more occurrence, genotoxicity, and mechanismsof action for priority DBPs that have moderate occurrence andare genotoxic, (2) systematic quantitative genotoxicity data forclasses of DBPs, (3) understanding the route of exposure andthe role of genotype, (4) identifying the unknown fraction of DBPsin drinking water, (5) the evaluation of DBPs from alternativedisinfectants (including new ones like UV disinfection), (6) theevaluation of source water contamination and the potential forthese contaminants to form DBPs, and (7) the toxicologicalevaluation of DBPs in real, complex mixtures.

Toxicologically important DBPs include brominated, iodinated,and nitrogen-containing DBPs (“N-DBPs”). Brominated DBPs aregenerally more carcinogenic than their chlorinated analogues(106), and new research is indicating that iodinated compoundsare more toxic than their brominated analogues (106). Brominatedand iodinated DBPs form due to the reaction of the disinfectant(such as chlorine) with natural bromide or iodide present in sourcewaters. Coastal cities, whose groundwaters and surface waterscan be impacted by salt water intrusion, and some inland locations,whose surface waters can be impacted by natural salt depositsfrom ancient seas or oil-field brines, are examples of locationsthat can have high bromide and iodide levels. A significantproportion of the U.S. population and several other countries nowlive in coastal regions that are impacted by bromide and iodide;therefore, exposures to brominated and iodinated DBPs areimportant. Early evidence in epidemiologic studies also givesindication that brominated DBPs may be associated with repro-ductive and developmental effects, as well as cancer effects.Brominated and iodinated DBPs of interest include iodo acids,bromonitromethanes, iodo trihalomethanes (THMs), brominatedforms of MX (MX is 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone), haloaldehydes, and haloamides. Iodinated DBPs areincreased in formation with chloramination, and bromoni-tromethanes are increased with the use of preozonation. Besideshaloamides, other N-DBPs of interest include nitrosodimethy-lamine (NDMA) and other nitrosamines, which can form witheither chloramination or chlorination (if nitrogen-containingcoagulants are used in treatment). Five nitrosamines (NDMA,N-nitrosodiethylamine, N-nitrosodipropylamine, N-nitrosodiphe-nylamine, and N-nitrosopyrrolidine), as well as formaldehyde(which is a DBP from ozone, chlorine dioxide, or chlorine), arecurrently listed on the new proposed CCL-3 (www.epa.gov/safewater/ccl/ccl3.html#ccl3). Chloramination has become apopular alternative to chlorination for plants that have difficultymeeting the regulations with chlorine, and its use is expected toincrease with the advent of the new Stage 2 Disinfectants (D)/DBP Rule (www.epa.gov/safewater/disinfection/stage2).


Emerging Halogenated and N-DBPs. Bromonitromethanes,iodo-THMs, brominated forms of MX (so-called BMXs), haloam-ides, as well as other priority DBPs, were the focus of a U.S.Nationwide DBP Occurrence Study, which was recently publishedin Environmental Science & Technology (107). This NationwideOccurrence Study focused on approximately 50 priority DBPs thatwere selected from an extensive prioritization effort (accordingto predicted cancer effects). In this study, haloacetaldehydesrepresented the third major class formed on a weight basis(behind THMs and haloacetic acids [HAAs]). An important findingwas that while the alternative disinfectants significantly loweredthe formation of regulated DBPs (THMs and HAAs), other priorityDBPs were increased. For example, iodinated DBPs (iodo-THMsand iodo acids) were increased in formation with chloramination,dichloroacetaldehyde was highest at a plant using chloraminesand ozone, and preozonation increased the formation of haloni-tromethanes. This has important implications for drinking watertreatment, as many plants in the United States have switched orare switching to alternative disinfectants to meet the Stage 1 and2 D/DBP Rule requirements. This study also reports the highestlevels of MX analogues to-date, with MX analogues and BMXanalogues frequently found at levels >100 ng/L, and in two plants,the sum of these analogues reached ppb levels. Haloamides werealso quantified for the first time in this study and were found upto 16 µg/L, individually. Finally, 28 new, previously unidentifiedDBPs were reported, including brominated and iodinated acids,a brominated ketone, and chlorinated and iodinated aldehydes.Despite the fact that more than 90 DBPs were measured in thisstudy, only about 30% and 39% of the total organic halogen (TOX)and total organic bromine (TOBr) were accounted for, respec-tively, by the sum of the measured DBPs. This is consistent withearlier studies that have shown that there is more TOX accountedfor in chlorinated drinking water, as compared to drinking watertreated with alternative disinfectants.

Haloamides were the subject of another recent study, wherea new iodinated haloamide was identified for the first time inchloraminated drinking water using GC/electron ionization (EI)-MS: bromoiodoacetamide (108). This standard was synthesized,and key mass spectral ions were analyzed under selected ionmonitoring (SIM) conditions to maximize detection. Bromoiodoac-etamide was detected in chloraminated drinking waters from 12treatment plants (from 6 U.S. states). This iodinated haloamidewas extremely cytotoxic and genotoxic in mammalian cells, aswere several of the other haloamides studied. In another studyof N-DBPs, Lee et al. assessed the formation of dichloroacetoni-trile, trichloronitromethane (chloropicrin), and NDMA, along withchloroform, in a controlled laboratory study, where chloraminesor chlorine was reacted with natural organic matter (NOM)fractions (hydrophobic, transphilic, hydrophilic, and colloidal)(109). GC/NCI-MS and GC/electron capture detection (ECD)were used for analysis. Compared to chlorination, chloraminationformed 10× lower chloroform levels, but 5× higher dichloroac-etonitrile. NDMA was only formed with chloramines and notchlorine. Chloropicrin was formed in equal amounts with chlorineor chloramines and correlated with the amino sugar content inthe NOM. Haloacetonitriles, including dichloroacetonitrile, havebeen found to be potent genotoxins and cytotoxins in mammaliancells, and as a class, are more toxic than the regulated carbon-

based (non-nitrogen containing) DBPs (110). Yang et al. alsoinvestigated the formation of N-DBPs (haloacetonitriles, chloropi-crin, and cyanogen halides), along with haloketones with chlo-ramination of NOM (111). Membrane introduction-MS (MIMS)and GC/ECD were used to measure the DBPs. Linear relation-ships were observed between the formation of dichloroacetonitrile,cyanogen chloride, 1,1-dichloropropanone, or chloroform and thedose of monochloramine. Highest DBP levels were formed at pH5-6. The mechanism and kinetics of cyanogen chloride formationfrom the chlorination of glycine was the focus of another paperby Na and Olson (112). Glycine has been found to be an importantprecursor for the formation of cyanogen chloride, and the authorsfound that the anionic form of N,N-dichloroglycine was animportant intermediate in its formation.

Nitrosamines have become a hot area of research in recentyears, since they were discovered to be DBPs in 2002. NDMA isa probable human carcinogen, and there are also concernsregarding other nitrosamines. NDMA was initially discovered inchlorinated drinking waters from Ontario, Canada, and has sincebeen found in other locations. The detection of NDMA in U.S.waters is largely due to improved analytical techniques that haveallowed its determination at low-nanogram per liter concentrations.NDMA is generally present at low-nanogram per liter levels inchloraminated/chlorinated drinking water, but it can be formedat much higher levels in wastewater treated with chlorine. NDMAis not currently regulated in the United States for drinking waterbut is included on the second Unregulated ContaminantsMonitoring Rule (UCMR-2), along with five other nitrosamines(N-nitrosodiethylamine, N-nitrosodibutylamine, N-nitrosopro-pylamine, N-nitrosomethylethylamine, and N-nitrosopyrroli-dine), where drinking water occurrence data is being collectedon a national scale (www.epa.gov/safewater/ucmr/ucmr2/basicinformation.html#list). As mentioned earlier, NDMA andfour other nitrosamines are also listed on the current proposedCCL-3. Ontario has issued an interim maximum acceptableconcentration for NDMA at 9 ng/L (www.ene.gov.on.ca/envision/gp/4449e.pdf).

Until recently, all methods for measuring NDMA used GC/MS(/MS) or GC/ECD, including the EPA method created tomeasure nitrosamines (EPA Method 521). Zhao et al. created thefirst LC/MS/MS method to measure nitrosamines, and in doingso, identified two new nitrosamine DBPs in drinking water,N-nitrosopiperidine and N-nitrosodiphenylamine (113). LC/MS/MS was essential for detecting N-nitrosodiphenylamine, as it isthermally unstable and cannot be measured by GC/MS. Anisotopically labeled NDMA standard was used as the surrogatestandard for determining recovery, and isotopically labeled N-nitrosodipropylamine was used as an internal standard forquantification. Detection limits ranged from 0.1 to 10.6 ng/L.Measurements in a drinking water distribution system revealedthat nitrosamine concentrations increased with increasing distancefrom the water treatment plant, indicating that their rate offormation was greater than their rate of decomposition in thedistribution system. In another study, Charrois et al. used GC/positive ion-CI-MS to measure NDMA and 7 other nitrosaminesin 20 drinking water distribution systems from Alberta, Canada(114). NDMA was found up to 100 ng/L, and two other nitro-samines were found: N-nitrosopyrrolidine and N-nitrosomorpho-


line. Chen and Valentine investigated the formation of NDMA fromvarious NOM fractions (115). GC/MS with isotope dilution wasused for analysis. Generally, the hydrophilic fractions formed moreNDMA than the hydrophobic ones, and basic fractions tended toform more NDMA than acidic fractions when normalized to acarbon basis. Finally, a new ESI-high-field asymmetric waveformion mobility spectrometry (FAIMS)-MS method was created formeasuring four nitrosamines in drinking water (N-nitrosodibuty-lamine, N-nitrosodipropylamine, N-nitrosopiperidine, and N-ni-trosodiethylamine) (116). FAIMS was able to significantly reducethe chemical noise and improve the detection limits by as muchas 10× (e.g., 1-5 ng/mL), as compared to conventional ESI-MS.However, the method was not able to detect other nitrosamines,including NDMA.

Other Methods. Epoxides, which are suspected DBPs fromdrinking water ozonation, were the focus of a new method by Khanet al. (117). This method uses aqueous-phase aminolysis, SPE,silylation, and GC/MS analysis to determine these small water-soluble epoxides in water. With this method, 1,2-epoxybutane,epichlorohydrin, and epifluorohydrin could be measured at 5-10ng/L detection limits. The increased resolution capabilities of GC/Fourier transform ion cyclotron resonance (FTICR)-MS are nowbeing used by researchers to identify new DBPs. For example,Solouki’s group at the University of Maine used GC/FTICR-MSto identify six DBPs and solvent artifacts in chlorinated drinkingwater (118). The use of SPME instead of liquid-liquid extractionwas found to reduce the interferences from the solvent stabilizers.Carboxylic acids were the focus of another method by Ford etal., who utilized in situ aqueous derivatization with an ioniccarbodiimide and 2,2,2-trifluoroethylamine (119). Derivatives wereidentified with either GC/EI-MS or GC/ECD. The amidizationreaction was complete within 10 min, and recoveries were >85%with this method.

New Human Exposure Studies. Researchers have beeninvestigating other routes of exposure, besides ingestion, in newhuman exposure studies of drinking water DBPs. And, in manycases, inhalation and dermal exposures that would result frombathing or showering offer greater exposures to particular DBPsthan ingesting 2 L of water per day. Exhaled breath is often aconvenient, noninvasive way to assess a person’s exposure, eitherdermally or through inhalation. Once a DBP has been absorbedeither through the lungs or through the skin, it is transported tothe blood stream, where it can be released in exhaled breath fromthe lungs. Blood measurements are more invasive but can be moreprecise measures of exposure. It is of particular interest toepidemiologic studies to know the entire dose of specific DBPsbeing investigated for effects. Gordon et al. carried out a humanexposure study that investigated breath and blood THM levelsfrom 12 common household water-use activities (120). Water,indoor air, blood, and exhaled breath samples were collectedduring each exposure activity. Water samples were analyzed usingSPME-GC/MS with isotope dilution, air samples were collectedin stainless steel canisters and analyzed by GC/MS, and biologicalsamples were analyzed by SPME-GC/high-resolution-MS withisotope dilution. Although showering (10 min), bathing (14 min),machine washing of clothes, and opening dishwashers at the endof the cycle resulted in significant increases in indoor airchloroform levels, only showering and bathing caused significant

increases in breath chloroform levels. For bromodichloromethane,only bathing produced significantly higher concentrations. Chlo-roform exposure through showering showed strong correlationswith indoor air and exhaled breath, blood and exhaled breath,indoor air and blood, and tap water and blood. In a follow-up study,Backer et al. assessed the importance of personal characteristics,previous exposures, genetic polymorphisms, and environmentalexposures in determining THMs in blood after showering (121).Environmental THM concentrations were found to be importantpredictors of blood THM levels immediately after showering, andthe other factors were significant predictors of baseline andpostshowering blood THM levels.

Researchers from the CDC created a new SPME-GC/high-resolution-MS method for measuring two iodo-THMs (dichlor-oiodomethane and bromochloroiodomethane) in human blood(122). Isotope dilution was used, and 2 ng/L detection limits wereobtained. This method is being used in a current U.S. EPA studyof iodo-DBPs from chloramination plants. In another study, Schultzand Shangraw investigated the effect of short-term drinking waterexposure of dichloroacetic acid (DCAA) to its pharmacokineticsand oral availability (123). Human volunteers consumed DCAA-free bottled water for 2 weeks prior to the study to wash outbackground effects of DCAA (a prominent DBP in chlorinatedtap water), and then each subject consumed 12C-DCAA (2 mg/kg) in 500 mL of water for 3 min. Five minutes later, 13C-labeledDCAA was administered intravenously for 20 s, and plasma 12C/13C DCAA concentrations were measured over 4 h. GC/MSanalysis (with diazomethane derivatization) was used to measureDCAA in the plasma. Volunteers then consumed lower levels ofDCAA (0.02 µg/kg/day) in 500 mL of water for 14 consecutivedays to simulate low-level chronic intake (as with chlorinated tapwater). Afterward, 12C/13C DCAA administrations were repeated.DCAA bioavailability showed a large interindividual variation,ranging from 27 to 100%. However, there were no differencesbetween male and female volunteers in any pharmacokineticparameters, although women adsorbed DCAA more rapidly andcleared DCAA more slowly than men.

A method for measuring bromate and bromide in blood wasdeveloped by Quinones et al. (124). Their method used acetoni-trile to precipitate proteins and lipids, followed by analysis usingion chromatography (IC)/ICPMS. Method detection limits of 1.3and 1.6 µg/L were achieved for bromate and bromide, respec-tively, and excellent recoveries were achieved (88-109%). Anothermethod for measuring cyanuric acid in urine was developed byPatel and Jones (125). Cyanuric acid is a degradation product ofsodium dichloroisocyanurate, which is a stabilized form of chlorineused in swimming pools and other household cleaners. Diatoma-ceous earth columns were used for extraction, and quantificationwas achieved using LC/ESI-MS with a cyano LC column. Detec-tion limits of 0.1 mg/L were achieved.

Evidence of the importance of dermal and inhalation routesfor DBPs, a new epidemiologic study by Villanueva et al., revealeda higher risk of bladder cancer from showering, bathing, andswimming in pools (126). Long-term THM exposure was associ-ated with a 2-fold bladder cancer risk (odds ratio of 2.10) foraverage household THM levels of >49 µg/L. The odds ratio foringestion was 1.35 (compared to people who did not drink tapwater), and the odds ratio from showering and bathing was 1.83.


New Swimming Pool Research. Related to other researchinvolving alternate exposures to ingesting drinking water, swim-ming pool studies have shown a marked increase in the last 2years. The Villanueva et al. epidemiologic study mentioned earliershowed an odds ratio of 1.57 for swimming in pools and developingbladder cancer (126). Zwiener et al. published an article onswimming pool waters, detailing the adverse health effects(including asthma, bladder cancer, and endocrine effects) and theformation of DBPs in swimming pool water, including DBPscomprehensively identified in actual swimming pools and bromi-nated DBPs formed by the reaction of chlorine, bromide, andsunscreens (127). Caro reported a new headspace SPME-GC/MS method for measuring THMs in urine and used this methodto measure THMs in swimmers and nonswimmers at indoor poolsettings (128). Detection limits were 3-10 ng/L for 12 mL ofurine. Results of the study showed that chloroform and bromod-ichloromethane increased 3× in urine following swimming activity.THMs were excreted within 2-3 h following exposure.

Two other important swimming pool DBP occurrence studieshave recently been published. Li and Blatchley used MIMS tomeasure volatile DBPs in a controlled laboratory study with fourmodel compounds (creatinine, urea, L-histidine, and L-arginine),which are found in human sweat and urine and in actual poolwater. Trichloramine, dichloromethylamine, and dichloroaceto-nitrile were found in actual swimming pool waters; this is the firstreport of dichloromethylamine as a DBP in swimming pool water(129). In addition, trichloramine was formed by the chlorinationof all four model compounds; dichloromethylamine was formedby the chlorination of creatinine, and cyanogen chloride anddichloroacetonitrile were formed by the chlorination of L-histidine.Walse and Mitch published an excellent paper entitled, “Nitro-samine carcinogens also swim in chlorinated pools”, which detailsa study of nitrosamines in pools, hot tubs, and aquaria (130).NDMA and seven additional nitrosamines were measured usingGC/NCI-MS/MS (EPA Method 521). NDMA was found inchlorinated swimming pools and hot tubs at levels up to 500×greater than the level (0.7 ng/L) associated with a one in a millionlifetime cancer risk. NDMA levels in indoor pools (32 ng/Lmedian, 44 ng/L maximum) were 6× greater than in outdoor pools(5.3 ng/L median, 6.9 ng/L maximum), and NDMA levels in hottubs at ∼41 °C (313 ng/L median, 429 ng/L maximum) wereapproximately 10× greater than those in indoor swimming pools.N-Nitrosodibutylamine and N-nitrosopiperidine were also detectedbut together represented <5% of the total nitrosamines. Thepresence of N-nitrodimethylamine at levels comparable to NDMAsuggests a competition between nitration and nitrosation of aminesin chlorinated recreational waters. It was also suggested thatbecause dimethylamine is a constituent of urine and sweat, it islikely an important precursor in pools. Previous research ondrinking water and wastewater has shown than NDMA can formfrom the reaction of dimethylamine and chlorine. Because nitro-samines can cause bladder cancer, these results are significantregarding increased bladder cancer that has been recentlyassociated with exposure at indoor pools (126).

Other Occurrence Studies. DBPs were also found in otherlarge occurrence studies. For example, in a survey of 1208domestic well water samples in the United States, researchers atthe U.S. Geological Survey found that chloroform was the most

frequently detected volatile organic compound (VOC) (131). Itwas found in 26% of the wells sampled. The remaining THMs,bromodichloromethane, dibromochloromethane, and bromoform,were also detected frequently, within the top 25 VOCs detected.Purge-and-trap-GC/MS was used for analysis. In another study,Leivadara et al. measured THMs, HAAs, haloacetonitriles, andhalopropanones in several bottled waters from Greece (132).DBPs were measured immediately after purchase and after 3months of storage, either at room temperature or in outdoorconditions, exposed to sun and temperatures up to 30 °C. Levelsof THMs ranged from nondetect to 21.7 µg/L (chloroform). Levelsof HAAs ranged from nondetect to 4.0 µg/L (DCAA). Interestingtrends were observed: chloroform, bromodichloromethane, bro-mochloroacetic acid, dibromoacetic acid, and 1,1,1-trichloropro-panone were not initially detected in the bottled waters sampledimmediately after purchase but were detected in later samplingsof the same water that had been exposed to outdoor conditions(increased temperature and after storing for 3 months). Incontrast, DCAA and trichloroacetic acid levels declined afterstorage, suggesting that they may decompose to other DBPs. Ithad been reported previously that trichloroacetic acid can decom-pose to chloroform. The haloacetonitriles also decreased overstorage, indicating their decomposition over time. In an innovativestudy of DBP formation during cooking, Becalski et al. investi-gated the potential formation of iodoacetic acids (133). In thisstudy, municipal chlorinated tap water (containing NOM) wasallowed to react with iodized table salt (containing potassiumiodide) and with potassium iodide itself in boiling water. Sampleswere extracted with tert-amyl methyl ether and were methylatedprior to analysis with GC/MS. Iodoacetic acid and chloroiodoaceticacid were identified as byproducts, and iodoacetic acid was formedat 1.5 µg/L levels when the water was boiled with 2 g/L of iodizedtable salt. The concentration of chloroiodoacetic acid was esti-mated to be 3-5 times lower.

Discovery Research for High Molecular Weight DBPs.More than 50% of the TOX formed in chlorinated drinking waterremains unidentified, and much higher percentages of TOX areunaccounted for when alternative disinfectants are used (ozone,chloramine, or chlorine dioxide). Earlier ultrafiltration studiesindicate that >50% of the TOX in chlorinated drinking water is>500 Da in molecular weight, which would be missed withtraditional GC/MS approaches. ESI-MS/MS is allowing research-ers to investigate these high molecular weight DBPs. Most of thiswork is very preliminary, because of the complexity of the massspectra obtained (“a peak at every mass” situation). RogerMinear’s group at the University of Illinois has carried out muchof the pioneering work in this area. In a follow-up study to theirearlier work, Zhang and Minear used radiolabeled chlorine (36Cl)to further probe high-molecular weight DBPs formed uponchlorination of drinking water (134). Results of this study showedthat oxidation was the dominant reaction compared to halogena-tion and that high molecular weight DBPs decreased when thechlorine contact time was increased. High molecular weight DBPscould not be separated into discrete LC peaks.

DBPs of Pollutants. DBPs are going beyond the “classic”DBPs formed by the reaction of NOM with disinfectants, suchthat reactions of pollutant material with disinfectants are now beingstudied. Contaminant DBPs have been recently reported from


pharmaceuticals, personal care products, estrogens, pesticides,textile dyes, alkylphenol surfactants, UV filters, and diesel fuel.Much of this research has been conducted in order to find waysto degrade and remove these contaminants from wastewatereffluents and drinking water sources, but some of this researchis being conducted to determine the fate of these contaminantsin drinking water treatment. It is not surprising that DBPs canform from these contaminants, as many of them have activatedaromatic rings that can readily react with oxidants like chlorineand ozone. However, until recently, these types of DBPs have notbeen investigated. Because of the growth in this area and thepotential toxicological significance of these new types of byprod-ucts (by increasing or decreasing the toxicity/biological effectrelative to the parent compound), this research area is includedin this review. GC/MS and LC/MS/MS have been used to identifythese byproducts.

In disinfectant reactions with pharmaceuticals, DBPs have beenrecently reported for the chlorination of acetaminophen, trime-thoprim, and cimetidine (135–137). For example, Bedner andMacCrehan reported DBPs from the chlorination of acetami-nophen (135). DBPs included 1,4-benzoquinone and N-acetyl-p-benzoquinone imine, as well as two other ring chlorinationproducts (chloro-4-acetamidophenol and dichloro-4-acetamidophe-nol). In another study, trimethoprim, an antibacterial agent,reacted with chlorine to form a wide variety of (multi)chlorinatedand hydroxylated products (136). At acidic pH, the 3,4,5-tri-methoxybenzyl group of trimethoprim reacted with chlorine, andat neutral or alkaline pH, the 2,4-diaminopyrimidinyl group reactedwith chlorine. Cimetidine, an over-the-counter antacid, reacted withchlorine to form four major byproducts: cimetidine sulfoxide,4-hydroxylmethyl-5-methyl-1H-imidazole, 4-chloro-5-methyl-1H-imi-dazole, and a product proposed to be either a �- or δ-sulfam (137).The last three products were formed by unexpected reactions thatinvolved more substantial structural changes than is typicallyobserved with chlorine reactions. Triclosan (5-chloro-2-(2,4-dichlo-rophenoxy)phenol), which is an antimicrobial agent used in manyhand soaps and other products, was found to produce chloroformand three chlorinated phenols when reacted with chloramines(138). However, reactions were much slower than in chlorinatedwater, such that it took 1 week before chloroform was detected.Parabens, which are used as bactericides and preservative agentsin antiperspirants, sunscreens, bath gels, shampoos, and tooth-paste reacted with chlorine (and natural bromide in tap water) toform bromo- and bromochloro-parabens (139). Parabens areesters of p-hydroxybenzoic acid and have activated benzene ringssimilar to those found in natural humic acid material, and chlorinereacted with them in the same way by chlorination of the aromaticring at carbons that are ortho to the hydroxyl group. Estrogens,E1, E2, estriol (E3), and EE2, were found to form chlorinatedderivatives when reacted with chlorine (140). The structures ofthese DBPs were determined using fast atom bombardment(FAB)-MS and NMR spectroscopy. DBPs included 4-chloroestroneand 10-chloro-1,4-estradiene-3,17-dione, which had estrogenicactivities similar to E1, and 2-chloroestrone and 2,4-dichlo-roestrone, which had estrogenic activity somewhat lower than E1.Brominated derivatives showed slightly weaker estrogenic activitythan the corresponding chlorinated analogues.

Pesticide DBPs were the focus of other research. Duirk andCollette investigated the reaction of the organophosphate pesticidechlorpyrifos with chlorine (141). Under drinking water treatmentconditions, chlorpyrifos rapidly oxidized to chlorpyrifos oxon byHOCl. The oxon reaction product is of concern because it is moretoxic than the parent pesticide. At elevated pH, both chlorpyrifosand chlorpyrifos oxon were susceptible to alkaline hydrolysis andchlorine-assisted (OCl-) hydrolysis, resulting in the formation of3,5,6-trichloro-2-pyridinol, which is not as toxic. Isoxaflutole, oneof the new isoxazole herbicides, has a very short half-life in soiland rapidly degrades to a stable and phytotoxic degradate,diketonitrile (142). Diketonitrile, in turn, can react readily withchlorine (hypochlorite) to form benzoic acid, cyclopropanecar-boxylic acid, and dichloroacetonitrile. Reaction pathways wereproposed in which a two-step nucleophilic attack occurs, alongwith oxidation of the diketone group.

Oliveira et al. investigated DBPs formed by the chlorinationof disperse azo dyes (143). This study was carried out becausethe local water treatment plant in Sao Paulo, Brazil, had repeateddetections of mutagenic materials that could not be explained bytraditional DBPs, and source waters had been contaminated by adye processing plant. In this study, solutions of a commercial blackdye, which contained Disperse Blue 373, Disperse Orange 37,Disperse Violet 93, and chemically reduced dye, were chlorinatedin a manner similar to the drinking water treatment plant, andthis chlorinated solution was compared to a drinking water samplecollected from the local water treatment plant. LC/MS was usedto identify the byproducts. A reduced chlorinated byproduct wasdetected, along with the parent dye components, in both samples,and the mutagenicity of these products suggested that thebyproduct and dye components accounted for much of themutagenic activity in the drinking water.

Thurman used LC/TOF-MS to identify chlorinated and bro-minated byproducts of 4-nonylphenol, nonylphenolethoxylates, andnonylphenolcarboxylate (144). Exact mass data from TOF-MS wasimportant to their identification. The purpose of this study was tomimic industrial cleaning procedures where 4-nonylphenol, non-ylphenolethoxylate (NPEO-1 and 2), and nonylphenol carboxylate(NPEC-1) were in contact with sodium hypochlorite solutions(with and without bromide) of various strengths at neutral pH.Of the compounds investigated, 4-nonylphenol was the mostreactive, producing chlorinated and dichlorinated nonylphenolsand nonylphenol dimers, and brominated byproducts whenbromide was added. Nonylphenol ethoxylates also formed chlo-rinated and brominated byproducts but only monochloro andmonobromo-substituted ones. Nonylphenol carboxylate was theleast reactive. Negreira et al. identified chlorinated and brominatedDBPs from the reaction of UV filters with chlorine (145). GC/EI-MS was used for their identification. 2-Ethylhexyl-4-(dimethy-lamine)benzoate (EHPABA) and 2-hydroxy-4-methoxybenzophe-none (BP-3) reacted rapidly with chlorine at levels typically foundin tap water to form 10 different DBPs. BP-3 was the most reactive,forming eight mono- and dichlorinated and brominated byprod-ucts. Trichloromethoxyphenol was the most abundant of theDBPs. Finally, Lebedev investigated DBPs resulting from thereaction of chlorine with components found in light diesel fuel(146). With the use of GC × GC with TOF-MS, more than 1500individual compounds could be identified in the unreacted diesel


fuel, which included mostly alkanes and naphthalenes. More than30 substances found in diesel fuel, which contained a variety ofdifferent functional groups, were reacted with chlorine in acontrolled laboratory study. Many chlorinated and brominatedDBPs were identified, including chlorohexanols, bromo- andchloroanisoles, chloro- and bromonapthalenes, and several non-halogenated oxidation products, such as benzyl alcohol, benzal-dehyde, and benzoic acid. It is interesting to note that several ofthese diesel DBPs have also been identified in real drinkingwaters.

SUNSCREENS/UV FILTERSUV filters used in sunscreens, cosmetics, and other personal

care products have increased in interest due to their presence inenvironmental waters and their potential for endocrine anddevelopmental toxicity. A few UV filters have been shown to haveestrogenic effects similar to 17�-estradiol (E2) (a natural estrogen)(147). Levels observed in environmental waters are not far belowthe doses that cause toxic effects in animals. There are two typesof UV filters, organic UV filters, which work by absorbing UVlight, and inorganic UV filters (TiO2, ZnO), which work byreflecting and scattering UV light. Organic UV filters are increas-ingly used in personal care products, such as sunscreens,cosmetics, beauty creams, skin lotions, lipsticks, hair sprays, hairdyes, and shampoos. Examples include benzophenone-3 (BP-3),4-hydroxybenzophenone (HBP), 2-hydroxy-4-methoxylbenzophe-none (HMB), 2,4-dihydroxybenzophenone (DHB), 2,2′-dihydroxy-4-methoxybenzophenone (DHMB), 2,3,4-trihydroxybenzophenone(THB), octyl-dimethyl-p-aminobenzoic acid (ODPABA), 4-meth-ylbenzylidene camphor (4-MBC), ethylhexyl methoxycinnamate(EHMC), octyl methoxycinnamate (OMC), octocrylene (OC),butyl methoxydibenzoylmethane (BM-DBM), terephthalylidinedicamphor sulfonic acid (TDSA), ethylhexyl triazone (EHT),phenylbenzimidazole sulfonic acid (PBSA), ethylhexyl salicylate(EHS), benzhydrol (BH), and 1-(4-tert-butylphenyl)-3-(4-methox-yphenyl)-1,3-propanedione (BPMP). The majority of these arelipophilic compounds (low water solubility) with conjugatedaromatic systems that absorb UV light in the wavelength rangeof 280-315 nm (UVB) and/or 315-400 nm (UVA). Most sun-screen products contain several UV filters, often in combinationwith inorganic micropigments. Because of their use in a widevariety of personal care products, these compounds can enter theaquatic environment indirectly from showering, washing off,washing clothes, etc., via wastewater treatment plants and alsodirectly from recreational activities, such as swimming andsunbathing in lakes and rivers. Giokas et al. published a nicereview on UV filters, detailing their chemical properties, humanabsorption, accumulation, and excretion, occurrence in theenvironment, and analytical methods for measuring them inenvironmental and biological samples (147).

UV filter compounds have been measured mostly using GC/MS or LC-UV. In 2006, Meinerling and Daniels reported a newLC/MS/MS method for measuring the four most commonly usedUV filter compounds, BP-3, 4-MBC, EMHC, and OC, in fish (148).The fish fillets were homogenized and extracted using Soxhletextraction, were cleaned up using gel permeation chromatographyand SPE, and were analyzed using LC/ESI-MS/MS. Special carewas taken to avoid cross contamination of samples: new, pre-washed extraction thimbles were used, care was taken to ensure

that the adapter on the rotary evaporator did not becomecontaminated, and solvent blanks were analyzed to check forcarryover in the LC. Detection limits were 8 ng/g, and recoverieswere 86-108%. Rodil et al. expanded on this by developing a newLC/MS/MS method for the simultaneous analysis of nine UV filtercompounds in river water, seawater, and wastewater (149). BP-3,4-MBC, OC, PBSA, ODPABA, BM-DBM, phenyldibenzimidazo-letetrasulfonic acid (PDT), benzophenone-4 (BP-4), and isoamyl-methoxycinnamate (IAMC) could be determined at detectionlimits of 7-46 ng/L. With this method, BP-4 was identified in anenvironmental sample for the first time, where it was found to beone of the more prevalent UV filters in wastewaters from a regionin Spain, with levels up to 1.5 µg/L in a wastewater influent and1.4 µg/L in the effluent. PBSA was also found at high levels at awastewater treatment plant, up to 2.5 µg/L in wastewater influentand 2.7 µg/L in the effluent.

New GC/MS methods continue to be reported for UV filters.For example, Cuderman and Heath reported a GC/MS methodfor measuring six UV filters and two antimicrobial agents inenvironmental waters (150). Derivatization with MSTFA was used,and detection limits of 13-266 ng/L were achieved. Stir barsorptive extraction with GC/MS continues to be a popular meansof measuring UV filters, as only very small water samples arerequired and low detection limits can be obtained (150, 151).Kawaguchi et al. developed a method using stir bar sorptiveextraction-thermal desorption-GC/MS for analyzing three UVfilter compounds in river water (151). A 10 mL water sample wasextracted, and 0.5-1 ng/L detection limits were obtained. Rodiland Moeder developed a stir bar extraction-thermal desorption-GC/MS method for measuring nine UV filters in environmentalwaters and treated wastewater (152). Detection limits ranged from0.2 to 63 ng/L, and only 20 mL of water was required. This methodwas then used to measure these UV filters in lake water, riverwater, and treated wastewater from Germany. The highestconcentrations were found in lake water, and there were pro-nounced seasonal trends, with much higher concentrations duringthe summer (swimming season). Up to 250 and 148 ng/L wasfound for OC and 4-MBC, respectively. Jeon et al. developed anew GC/MS method for seven UV filters that used derivatizationwith MSTFA (153). BP-3, BH, HBP, HMB, DHB, DHMB, andTHB could be measured in 23 min with detection limits rangingfrom 5 to 100 ng/L. With the use of this method, water samplesfrom Korea were measured and were found to contain 27-204ng/L.

In an interesting human and animal exposure study, Schaueret al. used LC/MS/MS to investigate the toxicokinetics of 4-MBCafter dermal application (154). 4-MBC and its metabolites weremeasured in plasma and urine after topical application of acommercial sunscreen containing 4% 4-MBC on human volunteersand rats. In humans, plasma levels of 4-MBC reached 200 pmol/mL in males and 100 pmol/mL in females, 6 h after application,and then decreased to the limit of detection after 24 h (females)or 36 h (males). In contrast, in the rats, the levels of 4-MBCremained constant (at 200 and 1200 pmol/mL for male and femalerats, respectively) for up to 24-48 h after dermal application. Inhumans, only a small percentage of the dermally applied 4-MBCwas recovered in metabolites (e.g., glucuronides) in the urine.


The results suggest a complex biotransformation of 4-MBC inhumans.

BROMINATED FLAME RETARDANTSBrominated flame retardants have been used for many years

in a variety of commercial products including children’s sleepwear,foam cushions in chairs, computers, plastics, textile coatings, andelectronics. Of the 175 different types of flame retardants, thebrominated ones dominate the market due to their low cost andhigh performance (1). Brominated flame retardants work byreleasing bromine free radicals when heated, and these freeradicals scavenge other free radicals that are part of the flamepropagation process (2). The use of these flame retardants isbelieved to have successfully reduced fire-related deaths, injuries,and property damage. However, there is recent concern becauseof their widespread presence in the environment and in humanand wildlife samples, as well as their presence in locations farfrom where they were produced or used. There is also strongevidence that levels of some of these flame retardants areincreasing, doubling every 3-5 years (2). Worldwide, more than200 000 t of brominated flame retardants are produced each year.PBDEs have been a popular ingredient in flame retardants sincethe polybrominated biphenyls were banned about 30 years ago.Approximately 70 000 t of PBDEs are produced per year, withmost being used in the United States and Canada. This explainsthe higher levels observed in humans and wildlife from NorthAmerica (2). Penta-, octa-, and deca-BDEs (and congeners ofthese) are commercially available. The most commonly observedisomer is the 2,2′,4,4′tetrabromodiphenylether (BDE-47). Thegreatest health concern comes from recent reports of develop-mental neurotoxicity in mice, but there are also concerns regard-ing the potential for hormonal disruption and, in some cases,cancer. As a result, a European Union Directive was establishedto control emissions of these compounds in Europe. Four PBDEs(BDE-47, BDE-99, BDE-153, and BDE-100) and another bromi-nated flame retardant (2,2′,4,4′,5,5′hexbromobiphenyl) are on theUCMR-2 in the U.S., where national drinking water occurrencedata are being collected. In 2004, the major U.S. manufacturer ofPBDE-based flame retardants (Great Lakes Chemical) voluntarilystopped producing the penta- and octa-brominated diphenyl ethers.However, the deca-BDE is still being manufactured.

Covaci et al. published a review on recent GC/MS and LC/MS developments for analyzing brominated flame retardants,including PBDEs and their metabolites, as well as naturalbrominated compounds (155). This review provides a criticalcomparison of different mass spectral techniques used for theiranalysis, including NCI-MS, EI-MS, EI-high-resolution-MS, iontrap-MS/MS, and quadrupole ion trap-MS/MS. GC × GC tech-niques are also discussed (with Q-TOF-MS detection). Stapletonalso reviewed instrumental methods for measuring PBDEs inenvironmental samples and discussed advantages and disadvan-tages in choosing an injection technique, GC column, and detector,as well as challenges in measuring PBDEs (156).

Previous PBDE studies have focused on their measurementin biological samples, including human blood, milk, and tissues,as well as marine mammals and other wildlife. More recently,measurements in environmental waters are increasing. Overall,there is a huge growth in research of PBDEs, with many morecountries beginning to measure them, and also many more human

exposure studies. Because PBDEs are hydrophobic, GC/MS tendsto be used for their measurement. In an extensive study ofdifferent analytical techniques, Cariou et al. compared GC/NCI-MS, GC with positive and negative ion-EI-MS(/MS), and LC/MS/MS with ESI, APCI, or APPI for measuring 49 PBDEs (157). Thetesting of negative ion-EI-MS was particularly innovative, as thisis not generally done, as was the testing of APPI, which has beenshown to be better than ESI and APCI for ionizing nonpolarcompounds (like PBDEs). Of the techniques tested, GC withpositive ion-EI-MS/MS and positive ion-EI-high-resolution-MSwere the best for resolving all of the PBDE congeners andproviding the best compromise between sensitivity and specificity.Detection limits for the GC/positive ion-EI/MS(MS) techniqueswere much lower than negative ion-EI-MS and LC/MS. While GC/NCI-MS is commonly used to measure PBDEs, it was not to befound as specific as EI-MS, due to the primary formation of Br-

ions, which can also arise from interfering compounds in complexbiological matrixes. Neither ESI nor APCI was able to efficientlyionize these nonpolar PBDEs, but APPI did show promise(although detection limits were still much higher than with GC/MS).

Human Exposure Studies. Qu et al. used GC/NCI-MS tomeasure PBDEs in serum of residents from an electronic wastedismantling region in China and also from residents living within50 km of the dismantling region (158). PBDE congeners werehighest in the serum of residents from the electronic dismantlingregion and were 11-20 times higher (3436 ng/g lipid) in thosewith occupational exposures. BDE-209 was the dominant conge-ner; BDE-197, BDE-207, and BDE-208 were also found at elevatedlevels. Human milk was the subject of another human exposurestudy in Australia (159). In this study, human milk samples werepooled from mothers in 12 regions of Australia and were analyzedusing GC/high-resolution-MS for 18 PBDE congeners. PBDEswere detected in all samples, with a mean concentration of 11.0ng/g lipid, and a range of 6.1-18.7 ng/g lipid. Overall, these levelsare lower than those reported in North America but higher thanobserved in Europe and Asia. Congener profiles were dominatedby BDE-47, followed by BDE-99, 100, 153, 154, and 183. Nosignificant differences were observed among the different regionssampled.

Gomara et al. measured PBDEs in human umbilical cordserum, paternal serum, maternal serum, placentas, and breast milkfrom Madrid (160). SPE (with clean up) and GC/NCI-MS wereused for analysis. Median concentrations for total PBDEs were17, 12, 12, and 6.1 ng/g lipid for umbilical cord serum, paternalserum, maternal serum, placentas, and breast milk, respectively.BDE-47 was the predominant congener in serum samples, whileBDE-209 was predominant in placenta and breast milk samples.BDE-196 and 197 were also detected in most placenta and breastmilk samples. These data show that PBDEs can cross the placentalbarrier and that there can be continued exposure after birththrough the breast milk. In another study, Wu et al. collectedbreast milk samples from first-time mothers, sampled house dust,and surveyed mothers regarding various environmental anddietary exposures (161). GC/high-resolution-MS was used foranalysis of PBDEs. Statistically significant, positive associationswere found between PBDE concentrations in breast milk andhouse dust, as well as with reported dietary habits (particularly


the consumption of dairy products and meat). These resultssuggest that the indoor environment and diet both play prominentroles in human exposures to PBDEs. Finally, Xiao et al. developeda new hollow fiber-liquid phase microextraction-GC/ICPMSmethod for measuring PBDEs (BDE-28, 47, 99, and 100) in humanserum, soil, dust, and water (162). Detection limits ranged from15.2 to 40.5 ng/L, and this method provided advantages over othermethods, in that it requires only microliters of solvent and thecost of the fibers is cheap, such that they can be disposable,eliminating issues with carryover that can occur with SPME orcoated stir bars. This method was then tested on a pooled humanserum sample from a hospital in China, as well as lake water, soilfrom a local landfill, and dust from a used computer. No PBDEswere found in the human serum sample or the lake water sample,but PBDEs were found in the soil and computer dust, up to 172ng/g (BDE-47) and 1.5 µg/g (BDE-99), respectively.

Several other interesting biological studies have also beenconducted on a variety of animals. The fate of higher brominatedPBDEs in lactating cows was the subject of one such study byKierkegaard et al. (163). GC/high-resolution-MS and GC/NCI-MS were used to measure the fate of hepta- to deca-BDEs. BDE-209 was the dominant congener in feed, organs, adipose tissues,and feces but not in milk. Concentrations of hepta- to deca-BDEsin adipose tissue were 9-80× higher than in milk fat, and thedifference increased with degree of bromination and log Kow. BDE-207, 196, 197, and 182 accumulated to a surprisingly greater extentin the fat compared to other isomers, suggesting metabolicdebromination of BDE-209 to these BDEs. These results indicatethat meat, rather than dairy product consumption, may be a moreimportant human exposure route to higher brominated BDEs. vonder Recke and Vetter used GC/MS and NMR spectroscopy toidentify an unknown compound previously found in seal blubber(164). This compound was identified as 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE). DPTE is the main component ofa brominated flame retardant called Bromkal 73-5 PE, and astandard was synthesized to confirm its identity. DPTE was thedominant organobromine compound found in blubber and brainsamples from hooded seals and harp seals from the Barents andGreenland Seas, with concentrations up to 470 and 340 µg/kgwet weight, respectively. In addition, another brominated ether(2-bromoallyl-2,4,6-tribromophenyl ether, BATE) was found for thefirst time in environmental samples. Results indicated that DPTE,BATE, and allyl-2,4,6-tribromophenyl ether (ATE) are able topenetrate the blood-brain barrier and that BATE and ATE arelikely biotransformation products of DPTE.

In another study, 27 PBDEs, hexabromocyclododecane (HBCD),and 14 methoxylated PBDEs were measured in the blubber ofCalifornia sea lions stranded between 1993 and 2003 (165). TotalPBDEs ranged from 450 to 4740 ng/g wet mass, and total HBCDranged from <0.3 to 12 ng/g wet mass. From 1993 to 2003, levelsof HBCD increased (from 0.7 to 12.0 ng/g), but a similar trendwas not observed for other brominated compounds. Voorspoelset al. investigated the biomagnification of PBDEs in three smallterrestrial food chains by measuring eight PBDEs in small birds,wood mice, and bank voles (small rodents) (166). These data werecombined with previous data in buzzards, sparrow hawks, andred fox, which enabled estimation of the biomagnification potentialof PBDEs in this food chain. Levels of BDE-209 were below

detection, but all other congeners (BDE-47, 99, 100, 153, 154, 183)except BDE-28 were found to be biomagnified in both predatorybird species. Biomagnification factors ranged from 2 to 34 for thesum of the PBDEs in the predatory bird food chain. No biomag-nification was observed in the rodent-fox food chain, suggestingthat the high metabolic capacity of the fox may be responsibleand that not all top predators will give a representative reflectionof the pollution of their habitat. Antarctic penguins were the focusof another PBDE study by Corsolini et al. (167). Blood samplesof three species of penguin were obtained, and GC/MS was usedto measure several PBDEs, polychlorinated dibenzodioxins,-furans, and -biphenyls. PBDEs ranged from 107 to 291 pg/g inthe penguins, with BDE-47 the most abundant congener in Adelieand Chinstrap penguins and BDE-17 the most abundant in theGentoo penguins. These levels are lower than found in seabirdspecies from other parts of the world. Finally, Hajslova et al.measured PBDEs in fish from the two main rivers in the CzechRepublic, the River Elbe and its main tributary, the River Vltava(168). Eighty samples were collected, representing the mostabundant fresh water fish species, and both GC/NCI-MS and GC× GC-TOF-MS were used to measure the congeners. BDE-47 wasthe dominant congener in the fish, with median and maximumlevels of 7.1 and 16.1 µg/kg wet weight. These levels are similarto those found in fish from other European countries, and levelswere higher from fish located downstream of industrial areas. GC× GC-EI-TOF-MS provided comprehensive information on thePBDEs, but detection limits were higher than with NCI-MS, suchthat minor PBDE species were below detection.

Other PBDE Studies. Water and fish from Lake Michiganwere the focus of another study by Streets et al. (169). GC/NCI-MS was used for analysis. PBDE congeners ranged from 0.2 to10 pg/L and were similar to dissolved-phase PCB congenerconcentrations. Partitioning between the particulate and dissolvedphases were also similar. Su et al. investigated the deposition ofPBDEs, polychlorinated biphenyls, and polycyclic aromatic hy-drocarbons in a boreal deciduous forest in Canada (170). Forestscan play an important role in trapping airborne organic compoundsand transferring them to terrestrial ecosystems through fallingleaves. This study reports the first deposition velocity to a forestin North America. In this study, air (gas and particle phase) andbulk deposition (obtained from extracting rainwater, leaves, andfiltered particles) were analyzed using GC/NCI-MS. Resultsconfirmed the extraordinarily high gaseous deposition velocitiesof the PBDEs and other contaminants to the forest, and the drydeposition velocities from Canada were similar to those previouslyreported in Germany, suggesting that high deposition velocitiesmay be common throughout boreal and temperate deciduousforests. Finally, a new LC/ESI-MS/MS method was developedby Mas et al. for simultaneously measuring eight hydroxylatedPBDE metabolites in environmental samples (soil, fish, sludge,and particulate matter) (171). MRM was used, and quantificationlimits of 45-475 pg/g (dry weight) were obtained in the differentmatrixes. This method provided an advantage over GC/MSmethods, through increased specificity (through the use of MRM)and less sample preparation (no derivatization required).

BENZOTRIAZOLESBenzotriazoles are complexing agents that are widely used as

anticorrosives (e.g., in engine coolants, aircraft deicers, or


antifreeze liquids) and for silver protection in dish washing liquids.The two common forms, benzotriazole and tolyltriazole, aresoluble in water, resistant to biodegradation, and are only partiallyremoved in wastewater treatment. Because of their water solubil-ity, LC/MS and LC/MS/MS methods have been recently devel-oped for their measurement in environmental waters. Whilereports of benzotriazoles in environmental samples have justoccurred in the last 3-4 years, early studies indicate that theyare likely ubiquitous environmental contaminants.

Recent studies have included the measurement of benzotria-zoles in surface waters and wastewater. Reemtsma et al. carriedout a large multicountry study in Europe of benzotriazole,4-tolytriazole, and 5-tolyltriazole in wastewater influents, effluents,and rivers (172). Samples were collected from seven differentcities in four European countries (Austria, Belgium, Germany, andSpain), and SPE-LC/MS/MS was used for their measurement.Benzotriazole and 4/5-tolyltriazole (the two isomers were notseparated chromatographically but were measured as a sum)occurred at mean levels 7.3 and 2.2 µg/L, respectively, inwastewater effluents and were only partially removed by waste-water treatment (approximately 18% and 10%, respectively). Gigeret al. measured benzotriazole and tolyltriazole in rivers andwastewaters in Switzerland using a SPE-LC/MS/MS method(173). Benzotriazole was found at a maximum of 6.3 µg/L in theGlatt River, and a mass flow of 277 kg per week was observed inthe Rhine River. Tolyltriazole was generally found at 5-10× lowerconcentrations. During the winter of 2003-2004, benzotriazolemass flows indicated input from the Zurich airport, wherebenzotriazole was used in airplane deicing fluids. Lake waterscontained 0.1-1.2 µg/L levels. Corsi et al. measured aircraft deicerand anti-icer compounds in airport snowbanks and snowmeltrunoff (174). 4-Methyl-1H-benzotriazole and 5-methyl-1H-benzo-triazole were found in the snowbank and airport snowmeltsamples. Toxicity (as measured in the Microtox assay) remainedin the snowbanks for a long time, after most glycol had beenremoved during melt periods. The benzotriazoles (and alsoalkylphenol ethoxylates) found in the aircraft deicing solutionswere likely the source of the toxicity. Weiss et al. investigatedthe discharge of three benzotriazoles in municipal wastewater(175). Mean concentrations of 12, 2.1, and 1.3 µg/L were observedfor benzotriazole, 4-tolyltriazole, and 5-tolyltriazole, respectively,and they were removed differently in wastewater treatment andwith biodegradation. Removal in sludge was 37% for benzotriazole,but almost no removal of 4-tolyltriazole was observed. In controlledlaboratory biodegradation experiments, 5-tolyltriazole was mineral-ized completely, but 4-tolyltriazole was only mineralized to 25%.A membrane bioreactor was found to improve their removals inwastewater treatment, and the use of ozonation provided almostcomplete removal at a dose of 1 mg of O3 per mg of dissolvedorganic carbon.

DIOXANEInterest is increasing in 1,4-dioxane, which has been discovered

to be a widespread contaminant in groundwater (often exceedingwater quality criteria and guidelines), and is a probable humancarcinogen (176). As a result, it is included in this review for thefirst time. Dioxane is a high production chemical and is used asa solvent stabilizer in the manufacture and processing of paper,cotton, textile products, automotive coolants, cosmetics, and

shampoos, as well as for 1,1,1-trichloroethane (TCA), which is apopular vapor degreasing solvent. In 2002, more than 500 t ofdioxane were produced or imported to the United States (150).The U.S. EPA has identified dioxane as a high priority contami-nant, and it is currently listed on the new proposed CCL-3(www.epa.gov/safewater/ccl/ccl3.html#ccl3). Dioxane is prob-lematic to extract and measure because it is highly water soluble.

Isaacson et al. developed a SPE method based on activatedcarbon disks and used GC/MS for the analysis of dioxane ingroundwater (176). Recovery was 98%, with quantification limitsof 0.31 µg/L for a 80 mL water sample. This method was used tomeasure dioxane at a TCA-impacted site. Dioxane levels rangedfrom below detection to 2800 µg/L and were higher than TCAlevels observed (maximum of 980 µg/L). Jochmann et al.developed a headspace solid phase dynamic extraction (SPDE)-GC/MS method to measure dioxane and other contaminants inwater (177). SPDE is a SPME technique where the inside of asyringe needle is coated with an extraction phase, and the needleis moved up and down in the sample or headspace (as in thisstudy) several times, after which the needle is injected into theGC injection port, and the analytes are thermally desorbed. SPDEtypically has 4-6× larger extraction phase volumes than 100 µmSPME fibers. With this method, detection limits of 0.8 µg/L wereachieved. Finally, Shirey and Linton reported a SPME-GC/MSmethod for measuring dioxane in water (178). A carboxen-polydimethylsiloxane fiber was used, and a quantification limit of0.5 µg/L was achieved. Samples could be extracted using eitherheated headspace with agitation or direct immersion with agitation.

NAPHTHENIC ACIDSNaphthenic acids (NAs) are a complex mixture of alkyl-

substituted acyclic and cycloaliphatic carboxylic acids that dissolvein water at neutral or alkaline pH and have surfactant-likeproperties. They occur naturally in crude oil deposits across theworld and are toxic to aquatic organisms, including phytoplankton,daphnia, fish, and mammals, and are also endocrine disrupting(2). Most research has focused on NAs in the oil-sands region inAlberta, Canada, which is one of the highest producers of crudeoil in the world. Caustic hot water is used in the extraction ofcrude oil from oil-sands, which results in a residual tailing water(0.1-0.2 m3 of tailings per ton of oil-sands processed) that containshigh levels of NAs (80-120 mg/L levels are common) and ishighly toxic. The total volume of tailing ponds is projected toexceed 109 m by the year 2020 (2). Little is known about theenvironmental fate of NAs.

NAs are challenging to measure because they are present asa complex mixture of isomers and homologues. GC × GC-TOF-MS was used to enable better separations of the complex mixtureof NAs (through greater chromatographic peak capacity and fastscanning of the TOF-MS instrument) and to identify the individualcompounds (through the use of exact mass data provided by TOF-MS). Lo et al. tested a new APCI-MS method and analyzedfractions of NAs collected from tailing ponds (179). When theAPCI-MS analysis is compared to to previously published ESI-MS analyses, APCI-MS had a wider range of quantification butwith higher detection limits. Headley et al. developed a surrogatemethod using ESI-FTICR-MS to predict which NAs would bebioavailable (and potentially more toxic) by testing their solubili-ties by ESI in 1-octanol, which is a common surrogate for


bioavailability (through the octanol-water partition coefficient)(180). This approach is a simplification of complex processesinvolved in uptake and toxicity but could be used as a tool to guideresearchers in the isolation of principal toxic components.Bataineh et al. developed a new dilute-and-shoot LC/Q-TOF-MSmethod that allows high specificity and sensitivity and also theability to detect new transformation products and new structuralinformation within each naphthenic acid class (181). This methodwas used to measure NAs in tailing waters from Alberta, and theuse of Q-TOF-MS enabled the detection of oxidized products inthe same chromatographic run; van Krevelen diagrams were usedto visualize the complex data. These results also revealed thatprevious research using GC/low-resolution-MS had likely mis-classified some of the oxidized naphthenic acids. The tailingwaters were dominated by highly persistent alkyl-substitutedisomers, and a biodegradation study revealed that microorganismspreferentially depleted the least alkyl-substituted fraction and maybe responsible for the profiles found in aged tailing waters.

Understanding why NAs persist in tailing waters may help indeveloping techniques to remediate them. To this end, Han et al.conducted a study to determine quantitative structure-persistencerelationships and kinetics for commercial NAs and NAs found inoil sands (182). The commercial mixture showed rapid degrada-tion of one fraction and a recalcitrant fraction composed of highlybranched compounds. In the tailing waters, recalcitrant NAs wereprimarily present, which degraded slowly by first-order kinetics.Carbon number had little effect on the rate of biodegradation, butthere was a general structure-persistence relationship, indicatingthat increased cyclization decreased the biodegradation rate inboth mixtures. Half-lives in the tailing waters ranged from 44 to240 days.

Young et al. developed the first method for measuring NAs infish and used this method to study the uptake of NAs in fishexposed under controlled conditions (183). The fish were ho-mogenized and extracted using solvent extraction, NAs wereisolated using strong anion exchange, and the extracts analyzedusing GC/MS. Detection limits of 1 µg/g were obtained. NAs werefound in all exposed trout (including exposure through feed pelletscontaining NAs, tap water containing NAs, and oil sands tailingwater containing 15 mg/L NAs). Finally, crude oil from Brazilwas the focus of another study by de Campos et al., who usedderivatization and GC/MS (184). Results revealed NAs with one,two, three, and four rings in the molecules.

CHIRAL CONTAMINANTSThe last 2 years has continued to see growth in the use of

chiral chromatography with MS. Chiral chromatography is usedto analyze individual chiral isomers, which are very similarchemically but can behave differently in the environment and inbiological systems. New research on chiral pesticides, PCBs, andnaturally occurring terpenes is reported in this review. For chiralpesticides, typically, one form is active against the insects, weeds,or other pests that the pesticide is designed to attack and theother form is inactive. Likewise, in the environment, one formcan be actively degraded by microbes and the other form canaccumulate. It was not until recent developments allowed theseparation and low-level detection of these isomers that theirenvironmental behavior could be studied. However, early researchis showing that the environmental behavior of chiral compounds

is not straightforward, it is not always possible to predictenantiospecific transformations. Microbial populations in environ-mental matrixes can change, and even reverse, the enantiomericratios (so microbial processes may not always show selectivedegradation of the same enantiomer). Some environmentalprocesses are not enantioselective toward a particular chemical,even if microorganisms are involved. Sometimes microbial deg-radation rates are sufficiently rapid for both enantiomers, suchthat enantioselective degradation is not important. Some com-pounds are degraded much faster chemically (abiotically) thanmicrobially, such that enantioselective degradation is not impor-tant, and sometimes enantiomerization can occur, where oneenantiomer is microbially converted to the other (1).

The ability to separate enantiomers and produce a singleenantiomeric isomer has not been lost on pesticide manufacturers.This ability has allowed manufacturers to sell a new, patentedenantiomeric form of a pesticide, creating new markets for theirproducts. The development of enantiomerically enriched pesticidesmay actually benefit the environment, as less material couldpotentially be applied to crops, less may be accumulated in theenvironment, and there may be fewer unintended side-effects onnontarget species. However, more research is needed to makethis determination.

Most research to-date has investigated chiral profiles in surfacewaters, soil, vegetation, and fish. The most commonly usedanalytical techniques to separate and measure chiral isomersinclude the use of chiral columns with GC and LC (often includingthe use of mass spectrometry). CE and CE/MS are also oftenused. Chiral selectors now include cyclodextrins, proteins, crownethers, polysaccharides, polyacrylamides, polymeric chiral sur-factants, macrocyclic antibiotics, and ergot alkaloids. Cyclodextrinsstill remain the most popular chiral selectors for environmentalapplications. In a recent review, Wong summarized the analyticalchemistry, environmental occurrence, and environmental fate ofemerging chiral organic pollutants (185). GC, LC, and CE havebeen used to separate individual enantiomers, with MS(/MS)typically used for detection. This review includes discussions ofchiral herbicides, pesticides, PCBs, musks, hexabromocyclodode-cane, and pharmaceuticals in the environment.

The measurement of natural enantiomeric monoterpene emis-sions was one of the more unusual studies published in the last2 years. Yassaa and Williams used headspace-SPME with enan-tioselective GC/MS to measure monoterpene enantiomers inemissions from detached needles from natural and damaged Scotspine trees, as well as ambient air around the same trees in a borealconiferous forest (186). A portable dynamic air sampler was usedto collect the ambient air samples. With this method, 17 iso-prenoids were identified, which included several chiral monoter-penes. Two chemotypes of Scots pine could be differentiatedthrough their emission of (+)-delta-3-carene, and significantdifferences in enantiomeric ratios of monoterpenes were observedin natural emissions and in those from damaged leaves.

Fidalgo-Used et al. used SPME with enantioselective GC/ECDand ICPMS to measure chiral speciation of the pesticide ruelenein environmental samples (187). ICPMS was more selective andsensitive than ECD, providing detection limits of 27 ng/L for eachenantiomer. This method could be applied to measurements inriver water, red wine, and orange and tomato juices. Buerge et


al. used enantioselective GC/MS (with a γ-cyclodextrin phase)to measure the degradation of the fungicides epoxiconazole andcyproconazole in soils (188). The degradation of epoxiconazolewas enantioselective in alkaline and slightly acidic soils. Cypro-conazole stereoisomers also degraded at different rates, but onlystereoselectivities between epimers showed a correlation with pHof the soil. Both fungicides were configurationally stable in thesoils, such that no enantiomerization or epimerization occurred.It was assumed that different microorganisms and enzymes wereinvolved in their primary degradation, but how soil pH influencesthis remains to be understood.

Finally, human and animal samples were the subject of a newstudy. Karasek et al. used enantioselective-GC/MS to measuremethylsulfonyl PCB and DDE metabolites in human adiposetissues, seal blubber, and pelican muscle (189). The chiralmetabolites were not found in human tissues but were found inthe pelican and seal samples, where an enantiomeric excess ofthe R-conformation was observed.

ALGAL TOXINSAlgal toxins (mostly cyanobacterial toxins produced from blue-

green algae) continue to be of increasing interest in the UnitedStates and in other countries around the world. Increaseddischarges of nutrients (from agricultural runoff and from waste-water discharges) have led to increased algal blooms and anaccompanying increased incidence of shellfish poisoning, largefish kills, and deaths of livestock and wildlife, as well as illnessand death in humans. Toxins produced by these algae have beenimplicated in these adverse effects. The most commonly occurringalgal toxins are microcystins, nodularins, anatoxins, cylindrosper-mopsin, and saxitoxins. “Red tide” toxins are also often found incoastal waters. Microcystins and nodularins have high-molecularweight, cyclic peptide structures and are hepatotoxic. Anatoxins,cylindrospermopsin, and saxitoxins have heterocyclic alkaloidstructures; anatoxins and saxitoxins are neurotoxic, and cylin-drospermopsin is hepatotoxic. “Red tide” toxins include brevetox-ins, which have heterocyclic polyether structures and are neuro-toxic. Microcystins (of which, more than 70 different variants havebeen isolated and characterized) are the most frequently reportedof the algal toxins. The most common microcystins are cyclicheptapeptides that contain the amino acids leucine and argininein their structures. Nearly every part of the world that uses surfacewater as a drinking water source has encountered problems withcyanobacteria and their toxins. Algal toxins have been on the U.S.EPA’s previous CCLs (CCL-1 and CCL-2) in a general way(“cyanobacteria (blue-green algae, other freshwater algae, andtheir toxins)”), and now the proposed CCL-3 has specificallynamed three cyanobacterial toxins: anatoxin-a, microcystin-LR, andcylindrospermopsin to be included on the new list (www.epa.gov/safewater/ccl/ccl3.html#ccl3). Several countries, including Aus-tralia, Brazil, Canada, France, and New Zealand, have guidelinevalues for microcystins, anatoxin-a, and cylindrospermopsin (from1.0 to 1.5 µg/L) (2). The World Health Organization (WHO) alsohas issued a provisional guideline of 1.0 µg for microcystin-LR indrinking water (www.who.int/water_sanitation_health/dwq/en/gdwq3_12.pdf); the European Drinking Water Directive has aguideline of 0.1 µg/L. Many of these toxins have relatively highmolecular weights and are highly polar. Methods for algal toxinsinclude LC/MS(/MS), MALDI-MS, ESI-FAIMS-MS, LC, and

ELISAs. With these methods, detection limits range from lownanogram per liter to low microgram per liter.

Several reviews have been published in the last 2 years onalgal toxins. van Apeldoorn et al. published a thorough, indepthreview of the different types of algal toxins, including theirchemical structures and properties, analytical methods for theirdetection, their source organisms, habitat, occurrence, potentialfor accumulating in the environment, and their toxicity (190).Toxins included in this review include microcystins, nodularins,anatoxin-a, anatoxin-a(S), cylindrospermopsin, saxitoxins, aply-siatoxins, and lyngbyatoxin. Analytical methods for measuringmicrocystins were the focus of another review by Sangolkar etal., which included a discussion of popular LC/MS and MALDI-MS methods (191). Msagati et al. reviewed extraction methods(including ELISAs) and detection methods (including LC and LC/MS) for measuring microcystins and nodularins (192). Osswaldet al. reviewed the toxicology and detection methods for anatoxin-a(193).

New methods have also been reported in the last 2 years. Zhaoet al. developed a SPME-microbore-LC/Q-TOF-MS method formeasuring microcystins in water (194). Detection limits of 0.6and 1.6 pg were possible for microcystin-RR and microcystin-LR,respectively. Recoveries were >86% and >70%, respectively. Thistechnique also required small sample volumes (12 mL) andprovides sensitive and information-rich analysis of unknown toxins.A new, rapid method for measuring microcystins and nodularinin tap water and in lake water was developed by Allis et al. (195).No preconcentration was needed in this LC/ESI-MS/MS method,and quantification limits of 0.25-0.90 µg/L were achieved, witha short run time of 10 min. This method was used to measuremicrocystins and nodularin in tap waters and lake waters inIreland. No microcystins or nodularin were found in tap waters,but microcystin-LR was found at >20 µg/L in lake water samplescollected at the center of a lake and at >3900 µg/L in cyanobac-terial blooms collected near the shoreline.

A new UPLC/MS/MS method was reported by Wang et al.for measuring microcystins in water (196). SPE allowed 1000×concentration, and limits of quantification for the four microcystins(microcystin-LR, -RR, -LW, and -LF) were 2.5, 6.0, 2.5, and 1.3 ng/L, respectively. This method was used to measure microcystinsin drinking water reservoirs, river water, and lake water in China.Microcystin contamination in the drinking water reservoirs wasthe highest (up to 2.73 µg/L), with microcystin-LR and -RR thepredominant ones found. Howard and Boyer developed a newmethod for simplifying adduct patterns observed with MALDI-TOF-MS for microcystins (197). The addition of zinc sulfateheptahydrate to samples, prior to spotting on the target, signifi-cantly enhanced the detection of the protonated molecule, whilesuppressing competing adducts. This produced a highly simplifiedmass spectrum, with potential to improve quantitative analysis,particularly for complex samples.

New occurrence studies include interesting studies of biologi-cal samples. For example, Sipia et al. used LC/MS and ELISA tomeasure nodularins in feathers and livers from birds (eiders)caught from the western Gulf of Finland (198). Breast featherscontained 8-43 µg/kg nodularin-R, and liver samples contained3-48 µg/kg. Mussels from the same area contained 12-80 µg/kg nodularin-R. Analyzing bird feathers offered an easy and


noninvasive way of assessing their exposure. Kankaanpaa et al.used LC/MS to investigate the accumulation and effects ofnodularin on mussels exposed in a controlled laboratory study(199). Blue mussels were exposed to a natural cyanobacterialmixture containing the toxic cyanobacterium Nodularia spumigena(with 70-110 µg/L nodularin). Nodularin concentrations in-creased from 400 to 1100 mg/kg after 24 h of exposure.Biomarkers indicating neurotoxic effects and oxidative stress weremeasured, and a gradual but incomplete elimination of thenodularin was observed (from 1100 to 600 mg/kg) after exposure.Yuan et al. developed improved GC/MS and LC/MS methods toreanalyze human serum and liver samples from the first confirmedacute lethal human poisoning from microcystins (through thecontamination of tap water used for hemodialysis patients in Brazilin 1996) (200). Human tissues had been stored for nearly 10 yearsat -70 °C, and the microcystins were found to be quite stable inthe reanalyzed tissues. GC/MS with derivatization of the Addagroup proved to be more sensitive than LC/MS for measuringthe covalently bound form of microcystins in human liver tissue.In an interesting study involving the poisoning of five dogs in 2005in New Zealand, LC/MS was used to confirm the presence ofanatoxin-a and homoanatoxin-a, as well as their degradationproducts, dihydro-anatoxin-a and dihydro-homoanatoxin-a (201).This is the first report of homoanatoxin-a and its degradationproduct in New Zealand. The dogs had died rapidly after contactwith water from the Hutt River (lower North Island, New Zealand),and a necropsy on one of the dogs confirmed the presence oflarge quantities of algal material in the dog’s stomach that hadcome from the river.

In a large occurrence study in New Zealand, Wood et al. usedELISAs, LC/MS, LC, and neuroblastoma assays to measuremicrocystins and nodularins in 227 different bodies of waterbetween 2001 and 2004 (202). Microcystins were identified in 54different water bodies; concentrations as high as 36.5 mg/L werefound in the algal mass. Anatoxin-a was found in three bodies ofwater, and saxitoxins were found in 41 bodies of water but at lowerlevels than the other algal toxins. The detection of anatoxin-a wasthe first definitive report for New Zealand. Bogialli et al. developeda SPE-LC/MS/MS method to measure five microcystins (micro-cystin-RR, -YR, -LR, -LA, and -LW) and cylindrospermopsin in water(203). Limits of quantification of 2-9 and 300 ng/L were achieved,respectively. With the use of this method, a lake in Italy wasmonitored in different regions and depths for 4 months. Cylin-drospermopsin was the most abundant algal toxin found, reachingas high as 16.0 µg/L. Of the five microcystins measured,microcystin-YR reached the highest level at 9.2 µg/L. In addition,two desmethyl-microcystin-RR isomers were found in the lakewater, and their levels reached 2.2 µg/L. Demethylated micro-cystin-RR variants are characteristic toxic markers of the algalspecies Planktothrix rubescens.

Fate studies have also been conducted on algal toxins. Mazur-Marzec et al. reported the degradation of nodularin by UVradiation (204). LC/MS/MS was used to characterize the pho-todegradation products. In exposures conducted over 48 h, visiblelight did not degrade nodularin significantly (3.8-4.6% of theoriginal sample degraded), but UV-B was effective for degradingnodularin (up to 0.77 µg/mL/day). Three photodegradationproducts were observed, all having the same molecular ion and

MS/MS fragmentation, indicating that they were geometricisomers of nodularin. The major photodegradation product wasactive biochemically. Finally, Kato et al. investigated the microbialdegradation of cyanobacterial cyclic peptides other than micro-cystins and nodularins (205). Bacterial strain B-9, which wasisolated from a eutrophied lake and had been previously shownto be able to hydrolyze microcystins and nodularins with itsintracellular enzymes, was used for the microbial degradationstudy. The toxins evaluated included nostophycin, microcyclamide,aeruginopeptin 95-A, microviridin I, and anabaenopeptin A. LC/ion trap-MS/MS was used to analyze their degradation products.Bacterial strain B-9 was effective for degrading these algal toxinsthrough hydrolysis of their peptide bonds, and several degradationproducts were found. The enzymes in these microorganismsexisting in the natural environment may contribute to environ-mental self-purification, and understanding the mechanismsinvolved may allow new solutions to algal contamination issues.

PERCHLORATEPerchlorate became an important environmental issue follow-

ing its discovery in a number of water supplies in the westernUnited States. It has since been found in water supplies acrossthe United States at microgram per liter levels, and new reportsincluded in this review show that it is also occurs at significantlevels in environmental and milk/food samples from othercountries. Ammonium perchlorate has been used in solid propel-lants used for rockets, missiles, and fireworks, as well as highwayflares, and there is also potential contamination from fertilizers(that contain Chilean nitrate). In addition, some perchloratecontamination can also come from natural sources, arising fromatmospheric processes (1). Perchlorate is an anion that is verywater soluble and environmentally stable. It can accumulate inplants (including lettuce, wheat, and alfalfa), which can contributeto exposure in humans and animals. In addition, perchlorate isnot removed by conventional water treatment processes, so humanexposure could also come through drinking water. Healthconcerns arise from perchlorate’s ability to displace iodide in thethyroid gland, which can affect metabolism, growth, and develop-ment. Perchlorate has also been found in cow’s milk, human breastmilk, and urine. Because of these concerns, the U.S. EPA placedperchlorate on the U.S. EPA’s CCL (CCL-1 and CCL-2, and nowon the proposed CCL-3; www.epa.gov/safewater/ccl/ccl3.html#ccl3),as well as the UCMR-2. The U.S. EPA also established a referencedose of 0.0007 mg/kg/day, which translates to a drinking waterequivalent level (DWEL) of 24.5 µg/L (www.councilonwaterquality.org/issue/regulation.html). In 2004, the state of California becamethe first state to set a drinking water public health goal (6 µg/L), and at least seven other states have issued advisory levelsranging from 1 to 18 µg/L (1). In October 2007, Californiaissued a new regulation for perchlorate in drinking water, withan maximum contaminant level (MCL) of 6 µg/L (www.cdph.ca.gov/certlic/drinkingwater/Pages/Perchlorate.aspx).

Because perchlorate has been listed on the CCL and theUCMR-2, new EPA methods have been developed, including EPAMethod 331.0 (a LC/ESI-MS/MS method; www.epa.gov/safewa-ter/methods/sourcalt.html), which was created to overcomematrix interferences in high ionic strength waters and also to lowerdetection limits to levels that are of human health concern.Wendelken et al. detailed method uncertainties, lowest concentra-


tion minimum reporting levels, and Hubaux-Vos detection limitsin reagent waters and simulated drinking water using EPA Method331 (206). Further, a May 2006 special issue of Analytca ChimicaActa, entitled “Perchlorate: An enigma for the new millennium”provides an excellent source for current information on perchlo-rate. A few of those papers that include the use of massspectrometry are included in this review.

New methods for perchlorate include a new LC/ESI-MS/MSmethod for analyzing perchlorate and other anions in water (207).This method uses an imidazolium-based dicationic regent to forma complex with the anion, which retains the overall positive chargefor analysis by MS. This reagent enabled the detection ofperchlorate and 31 other anions, including PFOA, nitrate, nitrite,dichloroacetate and other haloacetate DBPs, trifluoroacetate,monomethylarsonate, cyanate, and cyanide in the positive ESImode. Limits of detection ranged from femtogram to low-picogramlevels. Li and George reported a new LC/ESI-MS/MS methodfor analyzing perchlorate in water, using O-18-labeled perchlorateas an internal standard (208). The internal standard helped tocompensate for matrix effects, ion suppression, and other instru-mental effects. Method detection limits were 7 ng/L for reagentwater and 14 ng/L for a simulated water matrix with high ionicstrength.

Fate studies continue as researchers try to uncover sourcesof perchlorate. For example, Sturchio et al. investigated stableisotope ratios of oxygen and chlorine in perchlorate underbiodegradation conditions to determine whether isotope ratioanalysis would be useful for determining the source of perchlorate(209). Negligible isotope exchange was observed between per-chlorate and water in these experiments, indicating that isotoperatio analysis could reliably be used to determine the source ofthe perchlorate (from forensic data).

Several interesting biological studies have been published inthe last 2 years, including investigations of human samples, milk,and other foods. For example, Blount and Valentin-Blasinideveloped a method to measure perchlorate, along with thiocy-anate, nitrate, and iodide in human amniotic fluid (210). Potentialhealth effects of perchlorate exposure to the developing fetus areof special concern, and this method would help assess exposureof the developing fetus to low levels of these sodium iodidesymporter inhibitors and their potential to inhibit thyroid function.This method used isotope dilution (with 18O-labeled perchlorate,13C-labeled thiocyanate, and 15N-labeled nitrate) and IC/ESI-MS/MS. Detection limits of 0.020 µg/L were achieved for perchlorate,and excellent precision was found (<5.2% RSD) when amnioticfluid quality control pools were repetitively analyzed. The methodwas used to measure these analytes in 48 amniotic fluid samples.Perchlorate was found in all samples, ranging from 0.057 to 0.71µg/L. In a follow-up paper, Valentin-Blasini et al. developed asimilar IC/ESI-MS/MS method for quantifying these same ana-lytes in human urine (211). The urine was diluted with 900 µL ofdeionized water and analyzed directly by IC/ESI-MS/MS withoutpreconcentration. Detection limits of 0.05 µg/L were achieved forperchlorate. Perchlorate, nitrate, and thiocyanate were thenmeasured in 2818 urine samples from the National Health andNutrition Examination Survey. All samples contained detectablelevels of perchlorate, and nearly all contained the other analytes.

In an extremely comprehensive study of foods from across theworld, El Aribi et al. used IC/ESI-MS/MS to measure perchloratein fresh and canned fruits and vegetables, baby foods and otherfood products, wine, beer, and other beverages that had beenharvested or produced in many parts of the world (representing>50 countries) but were purchased locally in the greater Torontoarea (212). Isotopically-labeled perchlorate was used as an internalstandard, and an increased level of specificity was achieved byusing chlorine isotope ratios (35Cl/37Cl) as a confirmation tool.More than 350 food and beverage samples were analyzed, and allbut four contained measurable levels of perchlorate. Levels rangedfrom 5 ng/L to 464 µg/kg. Produce samples from California andLatin American countries (including Chile, Costa Rica, Guatemala,and Mexico) had the highest levels of perchlorate, with cantaloupefrom Guatemala having the highest levels (464 µg/kg). Foodproducts from Europe showed relatively low levels of perchlorate,however, grape leaves from Turkey (6.2 µg/kg) and mushroomsfrom Poland (5.7 µg/kg) showed significant levels. A comparisonbetween raw (39.9 µg/kg) and cooked (24.3 µg/kg) asparagusshowed that perchlorate can survive cooking. All of the wine andbeer samples from around the world contained perchlorate. NewZealand and Australian wines had the lowest levels, and thosefrom North and South America showed the highest, particularlyin wines from Chile. However, a wine from Portugal had thehighest level measured (50.2 µg/kg). Considerable variation inperchlorate levels was found in wines coming from differentvineyards in the same region. Beer samples also containedperchlorate, and those from Europe and Asia contained the lowestlevels. Most other beverages sampled, including milk, tea, andjuices, also contained measurable perchlorate.

The first measurements of perchlorate in dairy milk from Japanwas the subject of another paper by Dyke et al. (213). Isotopedilution was used with IC/ESI-MS/MS, and 54 milk samples werecollected from 48 different locations around the country. Perchlo-rate was detected in all samples with a range of 5.47-16.40 µg/Land a mean of 9.4 µg/L, which is higher on average than thosefound in U.S. dairy milk samples reported in a 2004 Food andDrug Administration study. Rice et al. carried out a controlledexposure study with 16 Holstein dairy cows to determine thedose-response relationship between perchlorate concentrationsin feed/drinking water and its appearance in milk (214). In thisstudy, the cows were administered perchlorate by ruminal infusionat different doses (0, 0.4, 4.0, or 40 mg of perchlorate per day for9 weeks). The feed given to the cows was also found to contributeto the cows’ overall exposures (42% coming from corn silage, 23%from alfalfa hay, and 12% from Sudan grass). A correlation betweenthe perchlorate consumed and the perchlorate in the milkproduced was evident.

Shi et al. measured perchlorate in milk, rice, bottled water,and sewage sludge from different regions in China (215). IC/ESI-MS/MS results revealed that perchlorate contamination iswidespread in China, with 0.30-9.1 µg/L in milk, 0.16-4.88 µg/kg in rice, 0.037-2.01 µg/L in bottled drinking water, and0.56-579.9 µg/kg in sewage sludge. Snyder et al. measuredperchlorate and chlorate in dietary supplements and flavorenhancing ingredients (216). LC/ESI-MS/MS was used, withdetection limits of 2-15 ng/g (for perchlorate). Perchlorate andchlorate were detected in 20 and 26, respectively, of the 31 dietary


supplements tested, with concentrations ranging from nondetectto levels as high as 2400 and 10 300 ng/g, respectively. On thebasis of the recommended dose provided by each manufacturer,the daily oral dose of perchlorate could be as high as 18 µg/day.The highest level of perchlorate was found in a supplementrecommended for pregnant women as a prenatal nutritionalsupplement. Perchlorate and chlorate were also found in four foodflavoring products. Lettuce and spinach were the focus of anotherstudy by Seyfferth and Parker, who used isotope dilution withIC/ESI-MS to measure perchlorate (217). Lettuce and spinachwere macerated, centrifuged, filtered, and cleaned up by SPE. Thismethod permitted detection limits of 40 ng/L. In the five types oflettuce and spinach purchased locally (in California), perchloratelevels ranged from 0.6 to 6.4 µg/kg.

Drinking water and groundwater were the focus of other newstudies. Kosaka et al. used IC/ESI-MS/MS to measure perchloratein drinking water source waters from the Tone River Basin inJapan (218). Perchlorate was found at high levels in the upperTone River and its tributary, the Usui River, with maximumconcentrations of 340 and 2300 µg/L, respectively. Industrialeffluents were attributed as sources of these high levels, asmeasured directly at their point of discharge into the rivers. Oneof these industries was from a perchlorate and chlorate manu-facturer, but the other was from an industry using electrolysisprocesses for other purposes besides perchlorate production. Inaddition, a fireworks display on a barge in one of the rivers wasfound to cause increased levels of perchlorate in the river (up to79 µg/L just after the fireworks). Perchlorate was also measuredin source waters and finished drinking water. Levels ranged from0.06 to 0.87 µg/L in source waters and >10 µg/L in 13 tap watersamples. Finally, Parker et al. measured perchlorate in 326 groundwaters from across the United States (219). IC/ESI-MS was used,and detection limits were 40 ng/L. Of the 326 samples, 147 (45%)were below the MDL for perchlorate, while 42 (13%) were betweenthe MDL and the minimum reporting level (MRL). Of the 137samples that could be quantified, most contained <1000 ng/Lperchlorate; 28 samples contained from 1000 to 10 400 ng/L.Results support the idea that perchlorate can occur naturally insome ground waters.

PESTICIDE DEGRADATION PRODUCTS AND NEWPESTICIDES

Herbicides and pesticides continue to be studied more thanany other environmental contaminant. Recent studies have focusedmore on their degradation/transformation products because theirdegradation products (e.g., from hydrolysis, oxidation, biodegra-dation, or photolysis) can be present at greater levels in theenvironment than the parent pesticide itself, and sometimes thedegradation product is as toxic or more toxic than the parentpesticide. New pesticides have also come on the market (such asglyphosate and organophosphorus pesticides), and studies arebeing conducted to understand their fate and transport in theenvironment. Several pesticide degradation products are currentlyon the U.S. EPA’s proposed CCL-3: alachlor ethanesulfonic acid(ESA), alachlor oxanilic acid (OA), acetochlor ESA, acetochlorOA, metolachlor ESA, metolachlor OA, 3-hydroxycarbofuran, andterbufos sulfone (www.epa.gov/safewater/ccl/ccl3.html#ccl3), aswell as on the UCMR-2 (alachlor ESA and OA, acetochlor ESAand OA, and metolachlor ESA and OA).

LC/MS and LC/MS/MS are now common-place for measuringpesticide degradates, which are generally more polar than theparent pesticides, making LC/MS ideal for their detection. Inaddition, researchers are increasingly using TOF-MS and Q-TOF-MS to enable the identification of new pesticide degradates.Several reviews published in the last 2 years have focused on theuse of LC/MS(/MS) and Q-TOF-MS for analyzing pesticides andtheir degradates (220–225). One of these reviews compares LC/MS/MS to GC/MS for measuring 500 high priority pesticides(220). For nearly all of the pesticides, LC/MS/MS was a betterchoice, offering better sensitivity (nanogram per liter vs micro-gram per liter) and the ability to analyze a greater number ofpesticides within one run. The ability to measure more pesticidesin a single run by LC/MS/MS stems from the broader peak widthof LC vs GC. Assuming a cycle time in GC/MS of 1 s or shorterand a dwell time of 40 ms, not more than 25 characteristic ionscan be recorded in one time window. Also, assuming 10 timewindows in a typical GC/MS run, 250 ions or 83 pesticides with3 characteristic ions can be analyzed during a single analysis. Incontrast, typical LC/MS/MS measurements would be able tomonitor 625 MRM transitions with one injection. As a result, 312pesticides vs 83 pesticides can be analyzed by LC/MS/MS vs GC/MS. Of the pesticides investigated, GC/MS performance wassuperior for only one class, the organochlorine pesticides.

Another review discussed matrix effects in the analysis ofpesticides with LC/MS (221). Possible mechanisms of thesematrix effects are discussed, as well as ways to eliminate them,including improving sample pretreatment, improving chromatog-raphy (e.g., increasing analysis time by using a less steep solventstrength gradient, use of HILIC, or LC-LC approaches), changingthe ionization mode (e.g., from ESI to APCI or APPI), changingthe mobile phase composition, or using isotopically labeledinternal standards. In one of the reviews on the use of LC/TOF-MS, Sancho et al. present advantages and limitations of using TOFand Q-TOF-MS for screening, quantification, confirmation, andelucidation of polar pesticides and their transformation products(222). Advantages of LC/TOF-MS include the high sensitivityavailable in full-scan acquisitions and high resolution (10 000-12 000) as compared to other MS analyzers, such as triplequadrupole mass spectrometers. LC/TOF-MS also reduces thechance of false positives, but it can be less sensitive than triplequadrupole mass spectrometers in quantification, when specificMRM transitions are monitored.

A nice example of the use of LC/Q-TOF-MS is provided in astudy by Ibanez et al., where LC/Q-TOF-MS was used to identifytransformation products and metabolites of various pesticides(225). In this study, photodegradation products and in vivo andin vitro metabolism products were identified for the insecticidediazinon. Accurate mass measurements and MS/MS were es-sential for identifying these transformation products.

Occurrence Studies. Marin et al. used online SPE-LC/ESI-MS/MS methods for rapidly determining 18 polar pesticides and9 transformation products (mostly from triazine herbicides) inwater (226). Injection of only 2 mL of a water sample produceddetection limits < 5 ng/L. Two MS/MS transitions allowed reliableconfirmation of positive detections. With the use of this method,groundwater and surface waters were analyzed, and severalsamples had transformation products at higher levels than the


parent pesticides. Glyphosate (N-phosphonomethyl glycine) hasbeen the focus of new occurrence studies. Glyphosate is the activeingredient in the broad spectrum herbicide, Roundup, and iscurrently the most widely used herbicide in the world. Becauseglyphosate is highly polar, LC/MS methods are ideal. Kolpin etal. determined urban contributions of glyphosate and its degradate,aminomethyl phosphonic acid (AMPA) in streams in the UnitedStates (227). Precolumn derivatization with 9-fluorenylmethyl-chloroformate was used, followed by LC/MS analysis. Streamsamples collected upstream and downstream of wastewatertreatment plants showed a 2-fold increase in the downstreamsamples, indicating an urban contribution. Overall, AMPA wasdetected much more frequently (67.5%) compared to glyphosate(17.5%).

While LC/MS/MS methods are now predominantly used forpesticides and their degradation products, GC/MS methods areoccasionally still used. For example, Villaverde used a multiresidueGC/MS method to measure 28 priority pesticides of differentchemical families (organochlorine, organophosphorus, triazines,and anilides), together with some of their transformation productsin river sediment (228). Limits of detection ranged from nanogramper liter to low microgram per liter, and this method was used tomeasure these pesticides and degradates in river sediments fromPortugal. Lindane was detected in almost all of the samples,followed by trace levels of simazine, diazinon, fenitrothion, andparathion-methyl. GC/MS was also used by Hildebrandt et al. tomeasure 30 priority pesticides and their transformation productsin agricultural soils and an underlying aquifer in the Ebro RiverBasin in Spain (229). Triazines were the most commonly foundherbicides, but acetanilides and organophosphorus pesticides werealso found, with levels ranging from 0.57 to 5.37 in groundwater.

Measurements in Foods. The occurrence of carbamates andtheir transformation products in fruits is an important issuebecause several of the transformation products are more toxicthan the parent pesticide. Carbosulfan is an example of this, whereone of its degradation products, carbofuran, is more toxic thancarbosulfan and is persistent in the environment. To this end, Soleret al. compared four mass analyzers for determining carbosulfanand its metabolites by LC/MS (230). Of the analyzers investigated,single quadrupole, triple quadrupole, quadrupole ion trap (QIT),and Q-TOF, the triple quadrupole-MS provided the highestsensitivity, with detection limits of 0.04-0.4 µg/kg compared tosingle quadrupole (4-70 µg/kg), QIT (4-25 µg/kg), and Q-TOF(4-23 µg/kg). Repeatabilities were best on the single quadrupoleand the triple quadrupole, and they also offered the highestdynamic range (3 orders of magnitude vs 2 for the Q-TOF andQIT). However, when these methods were applied to the mea-surement of carbosulfan and its metabolites in field-treated orangesamples, all four instruments provided comparable mean values(20 µg/kg). Garcia-Reyes et al. described a methodology for theidentification and structural elucidation of pesticide transformationproducts in foods, based on the exact mass capability of LC/ESI-TOF-MS (231). Examples included the identification of sixdegradation products of amitraz and malathion in different foodextracts, where unknown degradation products were identifiedwithout the a priori use of standards.

Fate Studies. Several nice studies have also been publishedon the fate of pesticides in the environment, including identi-

fication of transformation products. For example, Goncalveset al. investigated the photolysis of an organophosphorusinsecticide, quinalphos, in environmental waters and soils (232).SPME with GC/MS was used to identify the photolysisproducts. Half-lives ranged from 12 to 19 h, and dissolvedorganic matter retarded the reaction rate, while nitrate ionsaccelerated the reactions. Photolysis rates in soils also de-pended on the type of soil matrix.

ARSENICUnlike many other contaminants that are anthropogenic,

arsenic contamination of waters generally comes from naturalsources. Arsenic contamination of drinking water in Bangladeshand India has become a highly recognized problem, but naturalarsenic contamination also affects several regions of the UnitedStates and other parts of the world. In 2002, the U.S. EPA loweredthe MCL for arsenic in drinking water from 50 to 10 µg/L(www.epa.gov/safewater/arsenic). Drinking water systems hadto comply with this new standard by January 23, 2006. The WHOhas this same standard of 10 µg/L in drinking water. Arsenic canalso be present in foods, dust, soil, and air. The general toxicityof arsenic is well-known, but studies have also linked long-termexposure of arsenic (at lower, nontoxic levels) to a variety ofcancers in humans. In addition, there are recent reports of excessrisk of spontaneous abortion, stillbirth, and neonatal death.

Different arsenic species have different toxicities and chemicalbehavior in aquatic systems and in the environment, so it isimportant to be able to identify and quantify them. More than 20arsenic species are present in the natural environment and inbiological systems. These include arsenite, arsenate, monomethy-larsonic acid, monomethylarsonous acid, dimethylarsinic acid,dimethylarsinous acid, trimethylarsine oxide, trimethylarsine,arsenobetaine, arsenocholine, tetramethylarsonium ion, dimethy-larsinoyl ethanol, and arsenosugars (1). Butcher published a nicereview on the environmental chemistry and toxicity of arsenicspecies, along with instrumentation for measuring arsenic species(including LC/ICPMS) (233).

A puzzling observation about arsenic has been the drasticdifference in metabolism, disposition, and carcinogenicity betweenhumans and rats. In particular, rats show a longer retention timein the blood for arsenic, whereas arsenic is rapidly cleared fromhuman blood (half-life of 1 h). These biological differences havenot been understood and can limit the use of animal models forunderstanding human health effects. Lu et al. made an importantnew discovery that may explain these differences (234). Incharacterizing arsenic species in rats that were treated withinorganic arsenate, monomethylarsonic acid, and dimethylarsinicacid, they found that arsenic significantly accumulated in the redblood cells of rats in the form of hemoglobin complexed withdimethylarsinous acid, regardless of the species of arsenic therat was exposed to. This suggests a rapid methylation of arsenicspecies, followed by strong binding of dimethylarsinous acid torat hemoglobin. The binding site was found to be cysteine-13 inthe R chain of rat hemoglobin, with a stoichiometry of 1:1. Morethan 99% of the total arsenic in rat blood cells was bound tohemoglobin. The lack of cysteine-13-R in human hemoglobin maybe responsible for the shorter retention of arsenic in human blood,and these differences in disposition of arsenic species maycontribute to the differences in susceptibility of carcinogenicity.


Pellizzari and Clayton measured total arsenic and arsenicspecies (arsenate, arsenite, dimethylarsinic acid, monomethylar-sonic acid, arsenobetaine, and arsenocholine using IC/ICPMS inarchived samples from the National Human Exposure AssessmentSurvey (NHEXAS) and in a Children’s Study in Minnesota (235).Samples included drinking water, urine, hair, dust, and food.Except for arsenobetaine and arsenic(V), the levels found indrinking water and food were low or nondetect. However,additional arsenic species were present in the samples (likelyorganic forms of arsenic), as judged by total arsenic measure-ments. Exposures to total arsenic in food were about twice as highas in the general population (17.5 vs 7.72 µg/L). The predominantdietary exposure was from an organic form of As, and the majorform of arsenic in drinking water was As(V). Yuan et al. usedLC/ICPMS to measure arsenic species in saliva, with the goal ofusing this for biomonitoring of human exposure and studyingarsenic metabolism (236). Saliva samples were collected from 301people exposed to increased concentrations of arsenic in theirdrinking water and from 32 volunteers exposed to lower, back-ground levels of arsenic. Arsenic levels in the saliva of the highlyexposed individuals correlated with the levels in drinking water,with means of 2.8, 8.1, 0.8, and 0.4 µg/L for arsenite, arsenate,monomethylarsonic acid, and dimethylarsinic acid, respectively.Odds ratios for skin lesions increased with saliva arsenic concen-trations, and the association between saliva arsenic concentrationsand the prevalence of skin lesions was statistically significant.

ACKNOWLEDGMENTI would like to thank Janice Sims for helping in retrieving

journal articles and David Humphries of the Alberta ResearchCouncil for daily inspiration. This paper has been reviewed inaccordance with the U.S. EPA’s peer and administrative reviewpolicies and approved for publication. Mention of trade names orcommercial products does not constitute endorsement or recom-mendation for use by the U.S. EPA.

Susan D. Richardson is a research chemist at the U.S. EnvironmentalProtection Agency’s National Exposure Research Laboratory in Athens,GA. She received her B.S. degree in Chemistry and Mathematics fromGeorgia College in 1984 and her Ph.D. degree in Chemistry from EmoryUniversity in 1989. Her recent research has focused on the identification,characterization, and quantification of new disinfection byproduct (DBPs),with special emphasis on alternative disinfectants and polar byproducts.She led a recent Nationwide DBP Occurrence Study mentioned in thispaper and is particularly interested in promoting new health effectsresearch so that the risks of DBPs can be determined and minimized.

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Environmental Mass Spectrometry: Emerging Contaminants and Current Issues

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