Explore the vast range of titles available.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has become an indispensable analytical technique in clinical and forensic toxicology for detection and identification of potentially toxic or harmful compounds. Particularly, non-target LC-MS/MS assays enable extensive and universal screening requested in systematic toxicological analysis. An integral part of the identification process is the generation of information-rich product ion spectra which can be searched against libraries of reference mass spectra. Usually, ‘data-dependent acquisition’ (DDA) strategies are applied for automated data acquisition. In this study, the ‘data-independent acquisition’ (DIA) method ‘Sequential Windowed Acquisition of All Theoretical Fragment Ion Mass Spectra’ (SWATH) was combined with LC-MS/MS on a quadrupole-quadrupole-time-of-flight (QqTOF) instrument for acquiring informative high-resolution tandem mass spectra. SWATH performs data-independent fragmentation of all precursor ions entering the mass spectrometer in 21 m/z isolation windows. The whole m/z range of interest is covered by continuous stepping of the isolation window. This allows numerous repeat analyses of each window during the elution of a single chromatographic peak and results in a complete fragment ion map of the sample. Compounds and samples typically encountered in forensic casework were used to assess performance characteristics of LC-MS/MS with SWATH. Our experiments clearly revealed that SWATH is a sensitive and specific identification technique. SWATH is capable of identifying more compounds at lower concentration levels than DDA does. The dynamic range of SWATH was estimated to be three orders of magnitude. Furthermore, the >600,000 SWATH spectra matched led to only 408 incorrect calls (false positive rate = 0.06 %). Deconvolution of generated ion maps was found to be essential for unravelling the full identification power of LC-MS/MS with SWATH. With the available software, however, only semi-automated deconvolution was enabled, which rendered data interpretation a laborious and time-consuming process. Graphical Abstract High-resolution LC-MS/MS with SWATH represents a sensitive and specific compound identification tool that has vast potential to become a leading technique in systematic toxicological analysis. SWATH solves the problem of unused precursor ions often encountered with data-dependent acquisition methods by acquiring complete fragment ion maps of a sample

This paper reviews multi-analyte single-stage and tandem liquid chromatography-mass spectrometry (LC-MS) procedures using different mass analyzers (quadrupole, ion trap, time-of-flight) for screening, identification, and/or quantification of drugs, poisons, and/or their metabolites in blood, plasma, serum, or urine published after 2004. Basic information about the biosample assayed, work-up, LC column, mobile phase, ionization type, mass spectral detection mode, and validation data of each procedure is summarized in tables. The following analytes are covered: drugs of abuse, analgesics, opioids, sedative-hypnotics, benzodiazepines, antidepressants including selective-serotonin reuptake inhibitors (SSRIs), herbal phenalkylamines (ephedrines), oral antidiabetics, antiarrhythmics and other cardiovascular drugs, antiretroviral drugs, toxic alkaloids, quaternary ammonium drugs and herbicides, and dialkylphosphate pesticides. The pros and cons of the reviewed procedures are critically discussed, particularly, the need for studies on matrix effects, selectivity, analyte stability, and the use of stable-isotope labeled internal standards instead of unlabeled therapeutic drugs. In conclusion, LC-MS will probably become a gold standard for detection of very low concentrations particularly in alternative matrices and for quantification in clinical and forensic toxicology. However, some drawbacks still need to be addressed and finally overcome. [graphic removed]

Advances in the biological sciences have led to an ongoing paradigm shift in toxicity testing based on expanded application of high-throughput in vitro screening and in silico methods to assess potential health risks of environmental agents. This review examines progress on the vision for toxicity testing elaborated by the US National Research Council (NRC) during the decade that has passed since the 2007 NRC report on Toxicity Testing in the 21st Century (TT21C). Concomitant advances in exposure assessment, including computational approaches and high-throughput exposomics, are also documented. A vision for the next generation of risk science, incorporating risk assessment methodologies suitable for the analysis of new toxicological and exposure data, resulting in human exposure guidelines is described. Case study prototypes indicating how these new approaches to toxicity testing, exposure measurement, and risk assessment are beginning to be applied in practice are presented. Overall, progress on the 20-year transition plan laid out by the US NRC in 2007 has been substantial. Importantly, government agencies within the United States and internationally are beginning to incorporate the new approach methodologies envisaged in the original TT21C vision into regulatory practice. Future perspectives on the continued evolution of toxicity testing to strengthen regulatory risk assessment are provided.

Exposure of cells or organisms to chemicals can trigger a series of effects at the regulatory pathway level, which involve changes of levels, interactions, and feedback loops of biomolecules of different types. A single-omics technique, e.g., transcriptomics, will detect biomolecules of one type and thus can only capture changes in a small subset of the biological cascade. Therefore, although applying single-omics analyses can lead to the identification of biomarkers for certain exposures, they cannot provide a systemic understanding of toxicity pathways or adverse outcome pathways. Integration of multiple omics data sets promises a substantial improvement in detecting this pathway response to a toxicant, by an increase of information as such and especially by a systemic understanding. Here, we report the findings of a thorough evaluation of the prospects and challenges of multi-omics data integration in toxicological research. We review the availability of such data, discuss options for experimental design, evaluate methods for integration and analysis of multi-omics data, discuss best practices, and identify knowledge gaps. Re-analyzing published data, we demonstrate that multi-omics data integration can considerably improve the confidence in detecting a pathway response. Finally, we argue that more data need to be generated from studies with a multi-omics-focused design, to define which omics layers contribute most to the identification of a pathway response to a toxicant.

The co-Editors-in-Chief of Environmental Health respond to an unusual initiative taken by editors of 14 toxicology journals to influence pending decisions by the European Commission to establish a framework for regulating chemicals that pose a hazard to normal function of the endocrine system. This initiative is also the subject of this Commentary in this journal by authors who recently reviewed the subject and who point out inaccuracies in the toxicology editors’ critique. The dispute is about potential public policy development, rather than on science translation and research opportunities and priorities. The toxicology journal editors recommend that chemicals be examined in depth one by one, ignoring modern achievements in biomedical research that would allow new understanding of the effects of classes of toxic substances in complex biological systems. Concerns about policy positions framed as scientific ones are especially important in a time with shrinking public support for biomedical research affects priorities. In such a setting, conflict of interest declarations are important, especially in research publications that address issues of public concern and where financial and other interests may play a role. Science relies on trust, and reasonable disclosure of financial or other potential conflicts is therefore essential. This need has been emphasized by recent discoveries of hidden financial conflicts in publications in toxicology journals, thus misleading readers and the public about the safety of particular industrial products. The transparency provided by Environmental Health includes open access and open peer review, with reader access to reviews, including the identity of reviewers and their statements on possible conflicts of interest. However, the editors of the 14 toxicology journals did not provide any information on potential conflicts of interest, an oversight that needs to be corrected.

The pharmacology and toxicology of a broad variety of therapies and chemicals have significantly improved with the aid of the increasing in vitro models of complex human tissues. Offering versatile and precise control over the cell population, extracellular matrix (ECM) deposition, dynamic microenvironment, and sophisticated microarchitecture, which is desired for the in vitro modeling of complex tissues, 3D bio-printing is a rapidly growing technology to be employed in the field. In this review, we will discuss the recent advancement of printing techniques and bio-ink sources, which have been spurred on by the increasing demand for modeling tactics and have facilitated the development of the refined tissue models as well as the modeling strategies, followed by a state-of-the-art update on the specialized work on cancer, heart, muscle and liver. In the end, the toxicological modeling strategies, substantial challenges, and future perspectives for 3D printed tissue models were explored.

4,4′-Dimethylaminorex is a stimulant novel psychoactive substance (NPS) first detected in Europe in November 2012. It is a derivative of 4-methylaminorex, a substance controlled under Schedule 1 of the 1971 United Nations Convention on Psychotropic Substances. There is currently no information on the availability or cost of these substances from Internet suppliers. An Internet snapshot study was undertaken in English using established European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) methodology to determine the availability of 4-methylaminorex and 4,4′-dimethylaminorex in April 2014. Twenty Internet sites selling 4-methylaminorex were identified, 18 selling in US dollars and two in GB Pound Sterling. Fourteen (70 %) Internet sites had a minimum purchase amount of ≥10 g (compared to user doses of 10–25 mg). For the 18 suppliers selling in US$, 9 quoted a fixed price per gram irrespective of the amount ordered and 11 had a reducing price per gram with increasing purchase quantity (US$30.8 ± 34.2/g for 1 g purchase to US$15.2 ± 20.3/g for 1 kg purchase). Only one Internet site selling 4,4′-dimethylaminorex was identified, selling in Euros. The minimum purchase quantity was 500 mg. The price per gram reduced from €36.08/g for a 500 mg purchase to €2.20/g for a 100 g purchase. This Internet snapshot demonstrated that there was a greater availability from Internet suppliers of products advertised as 4-methylaminorex than 4,4′-dimethylaminorex, despite the 4-methylaminorex being an internationally controlled substance. Whilst this may reflect misunderstanding by suppliers, it has the potential to put those purchasing at risk of contravening border control and/or local law enforcement legislation. The use of methodology such as Internet snapshot surveys is of increasing interest to clinical/medical toxicologists in their understanding of the supply, availability and cost of novel psychoactive substances.

Mammalian models have served as a basis for R&D over the past decades. Nevertheless, these models are expensive, laborious, may yield results that cannot always be translated into the human in vivo situation and, more recently, have reverberated great social and ethical dilemmas. Hence, the prospect of changes in the global scientific scenario and the Three Rs principle ( R eduction, R eplacement and R efinement) have encouraged the development of alternative methods to the use of mammals. Despite the efforts, suitable alternative tests are not available in all areas of biomedical research, as regulatory acceptance requires time, prior validation and robust financial and scientific investment. In this perspective, we aim to shed light on the concepts, challenges and perspectives for implementation of innovative alternative animal and non-animal methods in scientific research. The applicability and meaningfulness of invertebrate animal models, in silico analysis and reverse pharmacology are discussed, among other aspects of relevance in today’s scenario. Overall, the use of alternative models, including Artemia salina (brine shrimp), Caenorhabditis elegans (roundworm), Danio rerio (zebra fish), Drosophila melanogaster (fruit fly), Galleria mellonella (greater waxmoth) and in silico modelling, increased 909% from 1990 to 2015, as compared to 154% of conventional mammals in the same period. Thus, technological and scientific advancements in the fields of toxicology and drug development seem to have diminished the need for mammalian models. Today, however, mammals still remain critically indispensable to provide – in most cases –reliable data subsidizing and validating translation into the clinical setting.