RESUMO
Recent advances in high-resolution mass spectrometry (HRMS) have enabled the detection of thousands of chemicals from a single sample, while computational methods have improved the identification and quantification of these chemicals in the absence of reference standards typically required in targeted analysis. However, to determine the presence of chemicals of interest that may pose an overall impact on ecological and human health, prioritization strategies must be used to effectively and efficiently highlight chemicals for further investigation. Prioritization can be based on a chemical's physicochemical properties, structure, exposure, and toxicity, in addition to its regulatory status. This Perspective aims to provide a framework for the strategies used for chemical prioritization that can be implemented to facilitate high-quality research and communication of results. These strategies are categorized as either "online" or "offline" prioritization techniques. Online prioritization techniques trigger the isolation and fragmentation of ions from the low-energy mass spectra in real time, with user-defined parameters. Offline prioritization techniques, in contrast, highlight chemicals of interest after the data has been acquired; detected features can be filtered and ranked based on the relative abundance or the predicted structure, toxicity, and concentration imputed from the tandem mass spectrum (MS2). Here we provide an overview of these prioritization techniques and how they have been successfully implemented and reported in the literature to find chemicals of elevated risk to human and ecological environments. A complete list of software and tools is available from https://nontargetedanalysis.org/.
Assuntos
Meio Ambiente , Espectrometria de Massas em Tandem , HumanosRESUMO
Identification and determination of leachable components are essential for the safety assessment of implantable medical devices. The safety concern threshold (SCT) for leachable components is 0.15 µg/day for genotoxic or carcinogenic compounds and 1.5 µg/day for others. Regulatory agencies require extraction of a whole medical device using an extraction media that simulates in vitro conditions. Large-sized medical devices therefore require large volumes of aqueous media, leading to extracts of very low concentrations of the targeted analytes. Analysis of these dilute solutions is often challenging, and pre-concentration steps are time consuming and can cause significant sample loss. Stir bar sorptive extraction (SBSE) has proven to be a very useful sample preparation technique that is simple and uses no (or minimal (<1 ml)) aqueous or organic solvents. When combined with a highly selective and sensitive GC-MS/MS analysis, volatile and semi-volatile leachable components can be determined at levels below the SCT of 150 ng/device. An SBSE-GC-MS/MS method using multiple reaction monitoring detection was validated for determination of antioxidant related leachable breakdown products from orthopedic knee-inserts made from ultra high molecular weight polyethylene.
Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Prótese do Joelho , Espectrometria de Massas em Tandem/métodos , Fracionamento Químico/métodos , Química Farmacêutica/métodos , Química Farmacêutica/normas , Cromatografia Gasosa-Espectrometria de Massas/normas , Prótese do Joelho/normas , Peso Molecular , Polietileno/análise , Polietileno/química , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/normasRESUMO
Recently, haloanisoles and halophenols are associated with multiple product recall situations in the pharmaceutical industry. The majority of the recalls are associated with consumer complaints due to the presence of 2,4,6-tribromoanisole, as extremely low levels of this component can be easily detected by the human nose. As part of the root cause analysis to address the cause of the consumer complaints, a GC-MS/MS based analytical method combined with stir bar sorptive extraction (SBSE) sample preparation was developed for determination of halophenols and haloanisoles from various drug product formulations. The method also applies to the analysis of 2,4,6-tribromoanisole analysis in various packaging materials. The optimized MS/MS method is based on component-specific MRM transitions. The detection limit is component dependent and in the range of 1-100 pg/tablet for solid dosage formulations and 0.04-4 ng/L for water based solutions. Deuterated tribromoanisole was used as internal standard for quantitation. The paper also may provide guidance for performing trace level method validation in the regulated Pharmaceutical Industry.
Assuntos
Anisóis/análise , Fracionamento Químico/métodos , Clorofenóis/análise , Cromatografia Gasosa-Espectrometria de Massas/métodos , Fenóis/análise , Anisóis/isolamento & purificação , Clorofenóis/isolamento & purificação , Limite de Detecção , Modelos Lineares , Fenóis/isolamento & purificação , Reprodutibilidade dos Testes , Comprimidos/química , Espectrometria de Massas em Tandem/métodosRESUMO
A molecular imaging application was developed to characterize the drug distribution on CYPHER® and NEVO™ Drug-eluting Stents using MALDI Qq-ToF analytical methodology. The coating matrix, laser energy, laser frequency, spatial resolution (related to rastering speed) and mass spectrometer parameters were optimized to analyze drug distribution in both durable and biodegradable polymer matrices. The developed method was extended to generate data from stents explanted from porcine coronary arteries. Due to the method's intrinsic specificity, it offers a significant advantage over other techniques in that it allows low-level detection of the target molecule without biological interferences from the blood or tissue. The method is also capable of detecting drug-related degradation products both from the finished stent product and from explanted stents.
Assuntos
Stents Farmacológicos , Imagem Molecular/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Vasos Coronários/química , Vasos Coronários/cirurgia , Polímeros/química , Sirolimo/administração & dosagem , SuínosRESUMO
Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1-/- and Taldo1+/- mice spontaneously developed HCC, and Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1-/- livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress. Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.
Assuntos
Acetilcisteína/farmacologia , Carcinoma Hepatocelular/enzimologia , Carcinoma Hepatocelular/prevenção & controle , Transformação Celular Neoplásica/metabolismo , Falência Hepática/induzido quimicamente , Neoplasias Hepáticas/enzimologia , Transaldolase/deficiência , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/prevenção & controle , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Fosforilação , Transaldolase/metabolismo , alfa-Fetoproteínas/metabolismo , beta Catenina/metabolismo , Receptor fas/metabolismoRESUMO
Paclitaxel eluting coronary stents were sterilized by e-beam in a closed system, to investigate sterilization related mass-balance issues and evaluate potential volatile paclitaxel degradation products. A solid-phase microextraction (SPME) method utilizing a polydimethyl-siloxane/divinyl-benzene (PDMS/DVB) fiber was optimized for extracting the volatiles from the head-space of the sterilized stents. GC-MS was used for separation, identification, and quantitation of the components. Benzaldehyde and benzoic acid were identified as paclitaxel related volatile degradation products. Three groups of stents were included in the study, a control group (not exposed to e-beam), a group sterilized at 25 kGy, and a final group sterilized at 75 kGy. The stents sterilized by e-beam at 75 kGy contained significantly higher levels of benzoic acid relative to the controls and the stents at 25 kGy contained intermediate levels of benzoic acid. The benzaldehyde levels increased in the 25 kGy e-beam sterilized stents relative to the control but remained fairly constant in the 75 kGy e-beam sterilized stents relative to the 25 kGy e-beam results. Mechanism for the formation of benzoic acid and benzaldehyde from paclitaxel was proposed. The levels of benzoic acid and benzaldehyde observed on the stents did not resolve the original mass-balance issue, but most likely contribute to the lack of mass balance observed for paclitaxel.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Stents Farmacológicos , Elétrons , Cromatografia Gasosa-Espectrometria de Massas/métodos , Paclitaxel/administração & dosagem , Microextração em Fase Sólida/métodos , Antineoplásicos Fitogênicos/química , Doença das Coronárias/patologia , Estrutura Molecular , Peso Molecular , Paclitaxel/química , Esterilização , VolatilizaçãoRESUMO
Transaldolase (TAL) is a key enzyme of the pentose phosphate pathway (PPP). TAL deficiency is a newly recognized cause of liver cirrhosis. We have developed an ion-pair LC separation combined with negative ion electrospray MS/MS detection method to assess PPP metabolites in urine samples from TAL-deficient mice. Sedoheptulose 7-phosphate (S7P), C5-polyols D-arabitol and D-ribitol, and 6-phosphogluconate (6PG) levels were markedly increased in urine of TAL-deficient mice with respect to those of wild-type and heterozygote littermates. The detection limits of S7P, D-arabitol, and 6PG were 0.15 +/- 0.015 pmol, 3.5 +/- 0.41 pmol, and 0.61 +/- 0.055 pmol, respectively. The limit of quantitation was 0.4 +/- 0.024 nmol/ml for S7P, 1.6 +/- 0.11 nmol/ml for 6PG and 10 +/- 0.7 nmol/ml for D-arabitol. Additional metabolites, hexose 6-phosphates (m/z 259), D-ribose 5-phosphate and D-xylulose 5-phosphate (m/z 229), D-fructose 1,6-diphosphate (m/z 339), C6-polyols (m/z 181) and GSSG (m/z 611), that have been positively identified in mouse urine, showed similar levels in control and TAL-deficient mice.
Assuntos
Eletrocromatografia Capilar/métodos , Espectrometria de Massas/métodos , Via de Pentose Fosfato , Fosfatos Açúcares/urina , Transaldolase/química , Transaldolase/metabolismo , Urinálise/métodos , Animais , CamundongosRESUMO
The diastereoisomeric 2-methyltetrols, 2-methylthreitol and 2-methylerythritol, were recently reported as major secondary aerosol components in natural forest aerosols and proposed as molecular markers for the photooxidation of isoprene. In this study, we examine the complex electron and methane chemical ionization behaviors of their trimethylsilyl ethers. In order to gain insight into their fragmentation behaviors, threitol and erythritol were studied as model compounds, and deuterium labeling of the trimethylsilyl groups and ion trap MS2 experiments were performed.
Assuntos
Butadienos/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Hemiterpenos/química , Metanol/análogos & derivados , Metanol/química , Pentanos/química , Compostos de Trimetilsilil/química , Metanol/síntese química , Oxirredução , EstereoisomerismoRESUMO
Sample preparation is an essential step in analysis, greatly influencing the reliability and accuracy of resulted the time and cost of analysis. Solid-Phase Microextraction (SPME) is a very simple and efficient, solventless sample preparation method, invented by Pawliszyn in 1989. SPME has been widely used in different fields of analytical chemistry since its first applications to environmental and food analysis and is ideally suited for coupling with mass spectrometry (MS). All steps of the conventional liquid-liquid extraction (LLE) such as extraction, concentration, (derivatization) and transfer to the chromatograph are integrated into one step and one device, considerably simplifying the sample preparation procedure. It uses a fused-silica fibre that is coated on the outside with an appropriate stationary phase. The analytes in the sample are directly extracted to the fibre coating. The SPME technique can be routinely used in combination with gas chromatography, high-performance liquid chromatography and capillary electrophoresis and places no restriction on MS. SPME reduces the time necessary for sample preparation, decreases purchase and disposal costs of solvents and can improve detection limits. The SPME technique is ideally suited for MS applications, combining a simple and efficient sample preparation with versatile and sensitive detection. This review summarizes analytical characteristics and variants of the SPME technique and its applications in combination with MS.
Assuntos
Testes Respiratórios/métodos , Análise de Alimentos/métodos , Cabelo/química , Espectrometria de Massas , Manejo de Espécimes/métodos , Animais , Saúde Ambiental , HumanosRESUMO
Detailed organic analysis of natural aerosols from the Amazonian rain forest showed considerable quantities of previously unobserved polar organic compounds, which were identified as a mixture of two diastereoisomeric 2-methyltetrols: 2-methylthreitol and 2-methylerythritol. These polyols, which have the isoprene skeleton, can be explained by OH radical-initiated photooxidation of isoprene. They have low vapor pressure, allowing them to condense onto preexisting particles. It is estimated that photooxidation of isoprene results in an annual global production of about 2 teragrams of the polyols, a substantial fraction of the Intergovernmental Panel on Climate Change estimate of between 8 and 40 teragrams per year of secondary organic aerosol from biogenic sources.
RESUMO
We developed and validated a gas chromatographic/ion trap mass spectrometric method for the determination of levoglucosan and the related monosaccharide anhydrides, mannosan, galactosan and 1,6-anhydro-beta-D-glucofuranose in urban atmospheric aerosols collected on quartz fiber filters. The method is based on extraction with dichloromethane-methanol (80 : 20, v/v), trimethylsilylation, multiple reaction monitoring in the tandem mass spectrometric mode using the ion at m/z 217, and the use of an internal standard calibration procedure with the structurally related compound methyl beta-L-arabinopyranoside. In addition, the method allows the quantification of other saccharidic compounds, arabitol, mannitol, glucose, fructose, inositol and sucrose, which were found to be important in summer aerosols. The recovery of levoglucosan was estimated by spiking blank filters and was better than 90%. The precision evaluated by analyzing parts of the same filters was about 2% for the monosaccharide anhydrides and 7% for the other saccharidic compounds in the case of a winter aerosol sample, and the corresponding values for a summer aerosol sample were 5% and 8%. The method was applied to urban PM(10) (particulate matter of <10 microm aerodynamic diameter) aerosols collected at Ghent, Belgium, during a 2000-2001 winter and a 2001 summer episode and revealed interesting seasonal variations. While monosaccharide anhydrides were relatively more important during the winter season owing to wood burning, the other saccharidic compounds were more prevalent during the summer season, with some of them, if not all, originating from the vegetation.