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Several thousand intentional and unintentional chemical releases occur annually in the U.S., with the contents of almost 30% being of unknown composition. When targeted methods are unable to identify the chemicals present, alternative approaches, including non-targeted analysis (NTA) methods, can be used to identify unknown analytes. With new and efficient data processing workflows, it is becoming possible to achieve confident chemical identifications via NTA in a timescale useful for rapid response (typically 24-72 h after sample receipt). To demonstrate the potential usefulness of NTA in rapid response situations, we have designed three mock scenarios that mimic real-world events, including a chemical warfare agent attack, the contamination of a home with illicit drugs, and an accidental industrial spill. Using a novel, focused NTA method that utilizes both existing and new data processing/analysis methods, we have identified the most important chemicals of interest in each of these designed mock scenarios in a rapid manner, correctly assigning structures to more than half of the 17 total features investigated. We have also identified four metrics (speed, confidence, hazard information, and transferability) that successful rapid response analytical methods should address and have discussed our performance for each metric. The results reveal the usefulness of NTA in rapid response scenarios, especially when unknown stressors need timely and confident identification.
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Non-targeted analysis (NTA) using high-resolution mass spectrometry has enabled the detection and identification of unknown and unexpected compounds of interest in a wide range of sample matrices. Despite these benefits of NTA methods, standardized procedures do not yet exist for assessing performance, limiting stakeholders' abilities to suitably interpret and utilize NTA results. Herein, we first summarize existing performance assessment metrics for targeted analyses to provide context and clarify terminology that may be shared between targeted and NTA methods (e.g., terms such as accuracy, precision, sensitivity, and selectivity). We then discuss promising approaches for assessing NTA method performance, listing strengths and key caveats for each approach, and highlighting areas in need of further development. To structure the discussion, we define three types of NTA study objectives: sample classification, chemical identification, and chemical quantitation. Qualitative study performance (i.e., focusing on sample classification and/or chemical identification) can be assessed using the traditional confusion matrix, with some challenges and limitations. Quantitative study performance can be assessed using estimation procedures developed for targeted methods with consideration for additional sources of uncontrolled experimental error. This article is intended to stimulate discussion and further efforts to develop and improve procedures for assessing NTA method performance. Ultimately, improved performance assessments will enable accurate communication and effective utilization of NTA results by stakeholders.
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Espectrometría de Masas , Espectrometría de Masas/métodosRESUMEN
Non-targeted analysis (NTA) encompasses a rapidly evolving set of mass spectrometry techniques aimed at characterizing the chemical composition of complex samples, identifying unknown compounds, and/or classifying samples, without prior knowledge regarding the chemical content of the samples. Recent advances in NTA are the result of improved and more accessible instrumentation for data generation and analysis tools for data evaluation and interpretation. As researchers continue to develop NTA approaches in various scientific fields, there is a growing need to identify, disseminate, and adopt community-wide method reporting guidelines. In 2018, NTA researchers formed the Benchmarking and Publications for Non-Targeted Analysis Working Group (BP4NTA) to address this need. Consisting of participants from around the world and representing fields ranging from environmental science and food chemistry to 'omics and toxicology, BP4NTA provides resources addressing a variety of challenges associated with NTA. Thus far, BP4NTA group members have aimed to establish a consensus on NTA-related terms and concepts and to create consistency in reporting practices by providing resources on a public Web site, including consensus definitions, reference content, and lists of available tools. Moving forward, BP4NTA will provide a setting for NTA researchers to continue discussing emerging challenges and contribute to additional harmonization efforts.
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Benchmarking , HumanosRESUMEN
Non-targeted analysis (NTA) methods are being increasingly used to aid in the identification of unknown compounds in the environment, a problem that has challenged environmental chemists for decades. Despite its increased use, quality assurance practices for NTA have not been well established. Furthermore, capabilities and limitations of certain NTA methods have not been thoroughly evaluated. Standard reference material dust (SRM 2585) was used here to evaluate the ability of NTA to identify previously reported compounds, as well as a suite of 365 chemicals that were spiked at various stages of the analytical procedure. Analysis of the unaltered SRM 2585 extracts revealed that several previously reported compounds can be identified by NTA, and that correct identification was dependent on concentration. A manual inspection of unknown features in SRM 2585 revealed the presence of two chlorinated and fluorinated compounds in high abundance, likely precursors to perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS). A retrospective analysis of data from the American Healthy Homes Survey revealed that these compounds were present in 42% of sampled homes. Spiking the dust at various stages of sample preparation revealed losses from extraction, cleanup, and instrumental analysis; the log Kow for individual compounds influenced the overall recovery levels but no pattern could be discerned from the various degrees of interference that the matrix had on the ionization efficiency of the spiked chemicals. Analysis of the matrix-free chemical mixture at low, medium, and high concentrations led to more correct identifications than analysis at one, very high concentration. Varying the spiked amount and identifying reported compounds at known concentrations allowed an estimation of the lower limits of identification (LOIs) for NTA, analogous to limits of detection in targeted analysis. The LOIs were much lower than levels in dust that would be likely to cause bioactivity in humans, indicating that NTA is useful for identifying and monitoring compounds that may be of toxicological concern. Graphical abstract.
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Non-targeted analysis (NTA) methods are increasingly used to discover contaminants of emerging concern (CECs), but the extent to which these methods can support exposure and health studies remains to be determined. EPA's Non-Targeted Analysis Collaborative Trial (ENTACT) was launched in 2016 to address this need. As part of ENTACT, 1269 unique substances from EPA's ToxCast library were combined to make ten synthetic mixtures, with each mixture containing between 95 and 365 substances. As a participant in the trial, we first performed blinded NTA on each mixture using liquid chromatography (LC) coupled with high-resolution mass spectrometry (HRMS). We then performed an unblinded evaluation to identify limitations of our NTA method. Overall, at least 60% of spiked substances could be observed using selected methods. Discounting spiked isomers, true positive rates from the blinded and unblinded analyses reached a maximum of 46% and 65%, respectively. An overall reproducibility rate of 75% was observed for substances spiked into more than one mixture and observed at least once. Considerable discordance in substance identification was observed when comparing a subset of our results derived from two separate reversed-phase chromatography methods. We conclude that a single NTA method, even when optimized, can likely characterize only a subset of ToxCast substances (and, by extension, other CECs). Rigorous quality control and self-evaluation practices should be required of labs generating NTA data to support exposure and health studies. Accurate and transparent communication of performance results will best enable meaningful interpretations and defensible use of NTA data. Graphical abstract á .
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Cromatografía Liquida/métodos , Cromatografía de Fase Inversa/métodos , Mezclas Complejas , Monitoreo del Ambiente/métodos , Contaminantes Ambientales/análisis , Espectrometría de Masas/métodos , Contaminantes Ambientales/toxicidad , Trazadores Radiactivos , Estándares de Referencia , Reproducibilidad de los ResultadosRESUMEN
In August 2015, the US Environmental Protection Agency (EPA) convened a workshop entitled "Advancing non-targeted analyses of xenobiotic chemicals in environmental and biological media." The purpose of the workshop was to bring together the foremost experts in non-targeted analysis (NTA) to discuss the state-of-the-science for generating, interpreting, and exchanging NTA measurement data. During the workshop, participants discussed potential designs for a collaborative project that would use EPA resources, including the ToxCast library of chemical substances, the DSSTox database, and the CompTox Chemicals Dashboard, to evaluate cutting-edge NTA methods. That discussion was the genesis of EPA's Non-Targeted Analysis Collaborative Trial (ENTACT). Nearly 30 laboratories have enrolled in ENTACT and used a variety of chromatography, mass spectrometry, and data processing approaches to characterize ten synthetic chemical mixtures, three standardized media (human serum, house dust, and silicone band) extracts, and thousands of individual substances. Initial results show that nearly all participants have detected and reported more compounds in the mixtures than were intentionally added, with large inter-lab variability in the number of reported compounds. A comparison of gas and liquid chromatography results shows that the majority (45.3%) of correctly identified compounds were detected by only one method and 15.4% of compounds were not identified. Finally, a limited set of true positive identifications indicates substantial differences in observable chemical space when employing disparate separation and ionization techniques as part of NTA workflows. This article describes the genesis of ENTACT, all study methods and materials, and an analysis of results submitted to date. Graphical abstract á .
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Conducta Cooperativa , Contaminantes Ambientales/análisis , Proyectos de Investigación , Xenobióticos/análisis , Cromatografía/métodos , Mezclas Complejas , Recolección de Datos , Polvo , Educación , Exposición a Riesgos Ambientales , Contaminantes Ambientales/normas , Contaminantes Ambientales/toxicidad , Humanos , Laboratorios/organización & administración , Espectrometría de Masas/métodos , Control de Calidad , Estándares de Referencia , Suero , Siliconas/química , Estados Unidos , United States Environmental Protection Agency , Xenobióticos/normas , Xenobióticos/toxicidadRESUMEN
This study is a workflow development for the analysis, identification, and categorization of per- and polyfluoroalkyl substances (PFAS) using gas chromatography-high resolution mass spectrometry (GC-HRMS) with non-targeted analysis (NTA) and suspect screening techniques. The behavior of various PFAS in a GC-HRMS was studied with regards to retention indices, ionization susceptibility, fragmentation patterns, etc. A custom PFAS database was constructed from 141 diverse PFAS. The database contains mass spectra from electron ionization (EI) mode, as well as MS and MS/MS spectra from positive and negative chemical ionization (PCI and NCI, respectively) modes. Common fragments of PFAS were identified across a diverse set of 141 PFAS analyzed. A workflow for suspect screening of PFAS and partially fluorinated products of incomplete combustion/destruction (PICs/PIDs) was developed which utilized both the custom PFAS database and external databases. PFAS and other fluorinated compounds were identified in both a challenge sample (designed to test the identification workflow) and incineration samples suspected to contain PFAS and fluorinated PICs/PIDs. The challenge sample resulted in a 100% true positive rate (TPR) for PFAS which were present in the custom PFAS database. Several fluorinated species were tentatively identified in the incineration samples using the developed workflow.
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Fluorocarburos , Intervención Coronaria Percutánea , Espectrometría de Masas en Tándem , Cromatografía de Gases y Espectrometría de Masas/métodos , Incineración , Fluorocarburos/análisisRESUMEN
Non-targeted analysis (NTA) and suspect screening analysis (SSA) are powerful techniques that rely on high-resolution mass spectrometry (HRMS) and computational tools to detect and identify unknown or suspected chemicals in the exposome. Fully understanding the chemical exposome requires characterization of both environmental media and human specimens. As such, we conducted a review to examine the use of different NTA and SSA methods in various exposure media and human samples, including the results and chemicals detected. The literature review was conducted by searching literature databases, such as PubMed and Web of Science, for keywords, such as "non-targeted analysis", "suspect screening analysis" and the exposure media. Sources of human exposure to environmental chemicals discussed in this review include water, air, soil/sediment, dust, and food and consumer products. The use of NTA for exposure discovery in human biospecimen is also reviewed. The chemical space that has been captured using NTA varies by media analyzed and analytical platform. In each media the chemicals that were frequently detected using NTA were: per- and polyfluoroalkyl substances (PFAS) and pharmaceuticals in water, pesticides and polyaromatic hydrocarbons (PAHs) in soil and sediment, volatile and semi-volatile organic compounds in air, flame retardants in dust, plasticizers in consumer products, and plasticizers, pesticides, and halogenated compounds in human samples. Some studies reviewed herein used both liquid chromatography (LC) and gas chromatography (GC) HRMS to increase the detected chemical space (16%); however, the majority (51%) only used LC-HRMS and fewer used GC-HRMS (32%). Finally, we identify knowledge and technology gaps that must be overcome to fully assess potential chemical exposures using NTA. Understanding the chemical space is essential to identifying and prioritizing gaps in our understanding of exposure sources and prior exposures. IMPACT STATEMENT: This review examines the results and chemicals detected by analyzing exposure media and human samples using high-resolution mass spectrometry based non-targeted analysis (NTA) and suspect screening analysis (SSA).
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Contaminantes Ambientales , Exposoma , Humanos , Contaminantes Ambientales/análisis , Plastificantes/análisis , Suelo , Polvo/análisis , Agua/análisisRESUMEN
Unknown chemical releases constitute a large portion of the rapid response situations to which the US Environmental Protection Agency is called on to respond. Workflows used to address unknown chemical releases currently involve screening for a large array of known compounds using many different targeted methods. When matches are not found, expert analytical chemistry knowledge is used to propose possible candidates from the available data, which generally includes low-resolution mass spectra and situational clues such as the location of the release, nearby industrial operations, and other field-reported facts. The past decade has witnessed dramatic improvements in capabilities for identifying unknown compounds using high-resolution mass spectrometry (HRMS) and nontargeted analysis (NTA) approaches. Complementary developments in cheminformatics tools have further enabled an increase in NTA throughput and identification confidence. Together with the expanding availability of HRMS instrumentation in monitoring laboratories, these advancements make NTA highly relevant to rapid response scenarios. In this article, we introduce the concept of NTA as it relates to rapid response needs and describe how it can be applied to address unknown chemical releases. We advocate for the consideration of HRMS-based NTA approaches to support future rapid response scenarios. Environ Toxicol Chem 2022;41:1117-1130. Published 2021. This article is a U.S. Government work and is in the public domain in the USA.
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Espectrometría de Masas , Espectrometría de Masas/métodos , Estados Unidos , United States Environmental Protection AgencyRESUMEN
The northern cardinal (Cardinalis cardinalis) is a good indicator species for environmental contaminants because it does not migrate and its range covers a diversity of habitats, including metropolitan Atlanta, GA and the geographically isolated Hawaiian Islands. In addition, the cardinal is often found near people's homes, making it likely to be exposed to the same outdoor elements, including soil, groundwater, and air, that surrounding humans experience. In this study, blood serum concentrations of 12 per- and polyfluoroalkyl substances (PFASs) were measured in 40 cardinals from Atlanta and 17 cardinals from the Big Island (Hawaii), HI. We observed significantly higher median concentrations of four PFASs and significantly higher detection frequencies of seven PFASs in the cardinals from Atlanta, relative to the PFAS median concentrations and detection frequencies observed in the cardinals from Hawaii (αâ¯=â¯0.05). Among the PFASs measured, perfluorooctane sulfonate (PFOS) was observed in the highest concentrations. A linear regression model controlling for sex, age, and airport distance did not explain PFOS variation within the Atlanta samples, but a similar model explained 90% of PFOS variation within the Hawaii samples. To our knowledge, these are the first measurements of PFASs in northern cardinals.
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Ácidos Alcanesulfónicos/sangre , Aves/metabolismo , Ecosistema , Fluorocarburos/sangre , Especies Centinela/metabolismo , Animales , Aves/sangre , Contaminantes Ambientales/análisis , Georgia , Hawaii , Humanos , Especies Centinela/sangreRESUMEN
The U.S. Environmental Protection Agency (EPA) is faced with the challenge of efficiently and credibly evaluating chemical safety often with limited or no available toxicity data. The expanding number of chemicals found in commerce and the environment, coupled with time and resource requirements for traditional toxicity testing and exposure characterization, continue to underscore the need for new approaches. In 2005, EPA charted a new course to address this challenge by embracing computational toxicology (CompTox) and investing in the technologies and capabilities to push the field forward. The return on this investment has been demonstrated through results and applications across a range of human and environmental health problems, as well as initial application to regulatory decision-making within programs such as the EPA's Endocrine Disruptor Screening Program. The CompTox initiative at EPA is more than a decade old. This manuscript presents a blueprint to guide the strategic and operational direction over the next 5 years. The primary goal is to obtain broader acceptance of the CompTox approaches for application to higher tier regulatory decisions, such as chemical assessments. To achieve this goal, the blueprint expands and refines the use of high-throughput and computational modeling approaches to transform the components in chemical risk assessment, while systematically addressing key challenges that have hindered progress. In addition, the blueprint outlines additional investments in cross-cutting efforts to characterize uncertainty and variability, develop software and information technology tools, provide outreach and training, and establish scientific confidence for application to different public health and environmental regulatory decisions.
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Biología Computacional/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Toxicología/métodos , Toma de Decisiones , Humanos , Tecnología de la Información , Medición de Riesgo , Toxicocinética , Estados Unidos , United States Environmental Protection AgencyRESUMEN
We investigated the concentrations and temporal variability of organophospate esters (OPEs), halogenated flame retardants (HFRs) and polybrominated diphenyl ethers (PBDEs) in indoor and outdoor urban air in Stockholm, Sweden over one year (2014-2015) period. The median concentrations of the three target chemical groups (OPEs, HFRs, PBDEs) were 1-2 orders of magnitude higher in indoor air than outdoor urban air. OPEs were the most abundant target FRs with median concentrations in indoor (Σ10OPEâ¯=â¯340â¯000â¯pg/m3) and outdoor urban (Σ10OPEsâ¯=â¯3100â¯pg/m3) air, being 3 orders of magnitude greater than for HFRs in indoor (Σ15HFRsâ¯=â¯120â¯pg/m3) and outdoor urban (Σ15HFRsâ¯=â¯1.6â¯pg/m3) air. In indoor air, PBDE concentrations (Σ17PBDEsâ¯=â¯33â¯pg/m3) were lower than for the HFRs, but in outdoor urban air, concentrations (Σ17PBDEsâ¯=â¯1.1â¯pg/m3) were similar to HFRs. The most abundant OPEs in both the indoor and outdoor urban air were tris(2-butoxyethyl)phosphate (TBOEP), tris(chloroisopropyl)phosphate (TCIPP), tris(2-chloroethyl)phosphate (TCEP), tri-n-butyl-phosphate (TnBP), triphenyl phosphate (TPhP) and tris(1,3-dichloroisopropyl)phosphate (TDCIPP). TCIPP in indoor air was found in the highest concentrations and showed the greatest temporal variability, which ranged from 85â¯000 to 1â¯900â¯000â¯pg/m3 during the one-year sampling period. We speculate that activities in the building, e.g. floor cleaning, polishing, construction, introduction of new electronics and changes in ventilation rate could explain its variation. Some OPEs (TnBP, TCEP, TCIPP, TDCIPP and TPhP), HFRs/PBDEs (pentabromotoluene, 2, 3-dibromopropyl 2, 4, 6-tribromophenyl ether, hexabromobenzene, BDE-28, -47, and -99) in outdoor urban air showed seasonality, with increased concentrations during the warm period (pâ¯<â¯0.05, Pearson's r ranged from -0.45 to -0.91). The observed seasonality for OPEs was probably due to changes in primary emission, and those for the HFRs and PBDEs was likely due to re-volatilization from contaminated surfaces.
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Contaminación del Aire Interior/análisis , Monitoreo del Ambiente/métodos , Retardadores de Llama/análisis , Éteres Difenilos Halogenados/análisis , Organofosfatos/análisis , Polvo/análisis , Ésteres , Halogenación , Compuestos Organofosforados/análisis , Bifenilos Polibrominados/análisis , SueciaRESUMEN
High-resolution mass spectrometry (HRMS) data has revolutionized the identification of environmental contaminants through non-targeted analysis (NTA). However, chemical identification remains challenging due to the vast number of unknown molecular features typically observed in environmental samples. Advanced data processing techniques are required to improve chemical identification workflows. The ideal workflow brings together a variety of data and tools to increase the certainty of identification. One such tool is chromatographic retention time (RT) prediction, which can be used to reduce the number of possible suspect chemicals within an observed RT window. This paper compares the relative predictive ability and applicability to NTA workflows of three RT prediction models: (1) a logP (octanol-water partition coefficient)-based model using EPI Suite™ logP predictions; (2) a commercially available ACD/ChromGenius model; and, (3) a newly developed Quantitative Structure Retention Relationship model called OPERA-RT. Models were developed using the same training set of 78 compounds with experimental RT data and evaluated for external predictivity on an identical test set of 19 compounds. Both the ACD/ChromGenius and OPERA-RT models outperformed the EPI Suite™ logP-based RT model (R2 = 0.81-0.92, 0.86-0.83, 0.66-0.69 for training-test sets, respectively). Further, both OPERA-RT and ACD/ChromGenius predicted 95% of RTs within a ± 15% chromatographic time window of experimental RTs. Based on these results, we simulated an NTA workflow with a ten-fold larger list of candidate structures generated for formulae of the known test set chemicals using the U.S. EPA's CompTox Chemistry Dashboard (https://comptox.epa.gov/dashboard), RTs for all candidates were predicted using both ACD/ChromGenius and OPERA-RT, and RT screening windows were assessed for their ability to filter out unlikely candidate chemicals and enhance potential identification. Compared to ACD/ChromGenius, OPERA-RT screened out a greater percentage of candidate structures within a 3-min RT window (60% vs. 40%) but retained fewer of the known chemicals (42% vs. 83%). By several metrics, the OPERA-RT model, generated as a proof-of-concept using a limited set of open source data, performed as well as the commercial tool ACD/ChromGenius when constrained to the same small training and test sets. As the availability of RT data increases, we expect the OPERA-RT model's predictive ability will increase.
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Forest-water reuse (FWR) systems treat municipal, industrial, and agricultural wastewaters via land application to forest soils. Previous studies have shown that both large-scale conventional wastewater treatment plants (WWTPs) and FWR systems do not completely remove many contaminants of emerging concern (CECs) before release of treated wastewater. To better characterize CECs and potential for increased implementation of FWR systems, FWR systems need to be directly compared to conventional WWTPs. In this study, both a quantitative, targeted analysis and a nontargeted analysis were utilized to better understand how CECs release to waterways from an FWR system compared to a conventional treatment system. Quantitatively, greater concentrations and total mass load of CECs was exhibited downstream of the conventional WWTP compared to the FWR. Average summed concentrations of 33 targeted CECs downstream of the conventional system were ~ 1000 ng/L and downstream of the FWR were ~ 30 ng/L. From a nontargeted chemical standpoint, more tentatively identified chemicals were present, and at a greater relative abundance, downstream of the conventional system as well. Frequently occurring contaminants included phthalates, pharmaceuticals, and industrial chemicals. These data indicate that FWR systems represent a sustainable wastewater treatment alternative and that emerging contaminant release to waterways was lower at a FWR system than a conventional WWTP.
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Monitoreo del Ambiente , Agricultura Forestal/métodos , Eliminación de Residuos Líquidos/métodos , Aguas Residuales/análisis , Contaminantes Químicos del Agua/análisis , Riego Agrícola , North CarolinaRESUMEN
Monitored contaminants in drinking water represent a small portion of the total compounds present, many of which may be relevant to human health. To understand the totality of human exposure to compounds in drinking water, broader monitoring methods are imperative. In an effort to more fully characterize the drinking water exposome, point-of-use water filtration devices (Brita® filters) were employed to collect time-integrated drinking water samples in a pilot study of nine North Carolina homes. A suspect screening analysis was performed by matching high resolution mass spectra of unknown features to molecular formulas from EPA's DSSTox database. Candidate compounds with those formulas were retrieved from the EPA's CompTox Chemistry Dashboard, a recently developed data hub for approximately 720,000 compounds. To prioritize compounds into those most relevant for human health, toxicity data from the US federal collaborative Tox21 program and the EPA ToxCast program, as well as exposure estimates from EPA's ExpoCast program, were used in conjunction with sample detection frequency and abundance to calculate a "ToxPi" score for each candidate compound. From â¼15,000 molecular features in the raw data, 91 candidate compounds were ultimately grouped into the highest priority class for follow up study. Fifteen of these compounds were confirmed using analytical standards including the highest priority compound, 1,2-Benzisothiazolin-3-one, which appeared in 7 out of 9 samples. The majority of the other high priority compounds are not targets of routine monitoring, highlighting major gaps in our understanding of drinking water exposures. General product-use categories from EPA's CPCat database revealed that several of the high priority chemicals are used in industrial processes, indicating the drinking water in central North Carolina may be impacted by local industries.
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Agua Potable/análisis , Filtración/instrumentación , Contaminantes Químicos del Agua/análisis , Monitoreo del Ambiente/métodos , Espectrometría de Masas/métodos , North Carolina , Proyectos PilotoRESUMEN
Tens-of-thousands of chemicals are registered in the U.S. for use in countless processes and products. Recent evidence suggests that many of these chemicals are measureable in environmental and/or biological systems, indicating the potential for widespread exposures. Traditional public health research tools, including in vivo studies and targeted analytical chemistry methods, have been unable to meet the needs of screening programs designed to evaluate chemical safety. As such, new tools have been developed to enable rapid assessment of potentially harmful chemical exposures and their attendant biological responses. One group of tools, known as "non-targeted analysis" (NTA) methods, allows the rapid characterization of thousands of never-before-studied compounds in a wide variety of environmental, residential, and biological media. This article discusses current applications of NTA methods, challenges to their effective use in chemical screening studies, and ways in which shared resources (e.g., chemical standards, databases, model predictions, and media measurements) can advance their use in risk-based chemical prioritization. A brief review is provided of resources and projects within EPA's Office of Research and Development (ORD) that provide benefit to, and receive benefits from, NTA research endeavors. A summary of EPA's Non-Targeted Analysis Collaborative Trial (ENTACT) is also given, which makes direct use of ORD resources to benefit the global NTA research community. Finally, a research framework is described that shows how NTA methods will bridge chemical prioritization efforts within ORD. This framework exists as a guide for institutions seeking to understand the complexity of chemical exposures, and the impact of these exposures on living systems.