Comparison of electrospray ionization, atmospheric pressure chemical ionization, and atmospheric pressure photoionization for the analysis of dinitropyrene and aminonitropyrene LC-MS/MS

The only relevant source for human exposure to dinitropyrenes is diesel engine emissions. Due to this specificity, dinitropyrenes may be used as biomarkers for monitoring human exposure to diesel engine emissions. Only few analytical methods have been described for the quantitation of dinitropyrenes and their metabolites, aminonitropyrenes, and diaminopyrenes. Therefore, for dinitropyrenes, aminonitropyrenes, and diaminopyrenes were selected as model compounds for the development of a sensitive HPLC-MS/MS method (high performance liquid chromatography coupled to triple quadrupole mass spectrometry) was to quantify polyaromatic amines and nitroarenes in biological matrices was developed optimal methods by comparing electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), and atmospheric pressure photoionization (APPI) sources. Dinitropyrene was not effectively ionized and diaminopyrene yielded mainly [M·]+ ions by electrospray ionization. With APCI and APPI, precursor ions of diaminopyrene and aminonitropyrene were [M + H]+ and [M·]− for dinitropyrene. Precursor ions with [M − 30·]− for dinitropyrene and [M − 30 + H]+ for aminonitropyrene were observed. Reversed and normal phase HPLC-MS/MS with ESI, APCI and APPI were optimized separately with respect to unequivocal analyte identification and sensitivity. Normal phase HPLC coupled to APPI-MS/MS gave the highest precision and sensitivity for aminonitropyrene (6%/0.2 pg on column) and dinitropyrene (9%/0.5 pg on column). The limit of detection in spiked rat plasma was 5 pg/100 μL for aminonitropyrene (accuracy 82%) and 10 pg/100 μL for dinitropyrene (accuracy 105%). In plasma of rats treated with dinitropyrene by oral administration, no detectable levels of dinitropyrene but higher aminonitropyrene levels compared with intratracheal instillation were observed. These findings clearly demonstrate that dinitropyrene was absorbed after oral and intratracheal application and that a reduction of nitro groups occurs to a high extent in the reductive environment of the intestine. To our knowledge, this is the first time that aminonitropyrene was observed in plasma after intratracheal or oral administration directly demonstrating the reductive metabolism of dinitropyrene in vivo

The role of hazard- and risk-based approaches in ensuring food safety

AbstractBackgroundFood legislation in the European Union and elsewhere includes both hazard- and risk-based approaches for ensuring safety. In hazard-based approaches, simply the presence of a potentially harmful agent at a detectable level in food is used as a basis for legislation and/or risk management action. Risk-based approaches allow consideration of exposure in assessing whether there may be unacceptable risks to health.Scope and approachThe advantages and disadvantages of hazard- and risk-based approaches for ensuring the safety of food chemicals, allergens, ingredients and microorganisms were explored at an ILSI Europe workshop.Key findings and conclusionsIt was concluded that both types of approach have their place, depending on the context. However, problems can arise when both types of approach are used in regulation by separate agencies that address different aspects of the same agent/substance present in food. This separation of decision-making can result in hazard-based restrictions on marketing and use, whereas risk-based assessments for those exposed show there is reasonable certainty no harm will result. This in turn can lead to contradictory, confusing and ultimately unnecessary actions. Use of hazard-based approaches for foods also means that comparisons with benefits for nutrition and food security cannot be undertaken. This has the potential to lead to bias in the overall conclusions of regulators and risk managers, who may not have been presented with the benefits of particular foods. The value of risk-based approaches is becoming increasingly recognised

Эпидемиологические исследования в сексологии

Представлены результаты эпидемиологического исследования, позволившие автору на примере обследования 1000 человек популяции из западного региона Украины сформулировать основные закономерности изменения отношения к браку и сексуального поведения мужчин и женщин в современном обществе.The findings of epidemiological study, which allowed the author to formulate main regularities of the changes in the attitude to the marriage and sexual behavior of men and women in the contemporary society on the example of the examination of 1000 persons from the western regions of Ukraine, are presented

Application of integrated transcriptomic, proteomic and metabolomic profiling for the delineation of mechanisms of drug induced cell stress

International audience; High content omic techniques in combination with stable human in vitro cell culture systems have the potential to improve on current pre-clinical safety regimes by providing detailed mechanistic information of altered cellular processes. Here we investigated the added benefit of integrating transcriptomics, proteomics and metabolomics together with pharmacokinetics for drug testing regimes. Cultured human renal epithelial cells (RPTEC/TERT1) were exposed to the nephrotoxin Cyclosporine A (CsA) at therapeutic and supratherapeutic concentrations for 14 days. CsA was quantified in supernatants and cellular lysates by LC-MS/MS for kinetic modeling. There was a rapid cellular uptake and accumulation of CsA, with a non-linear relationship between intracellular and applied concentrations. CsA at 15 µM induced mitochondrial disturbances and activation of the Nrf2-oxidative-damage and the unfolded protein-response pathways. All three omic streams provided complementary information, especially pertaining to Nrf2 and ATF4 activation. No stress induction was detected with 5 µM CsA; however, both concentrations resulted in a maximal secretion of cyclophilin B. The study demonstrates for the first time that CsA-induced stress is not directly linked to its primary pharmacology. In addition we demonstrate the power of integrated omics for the elucidation of signaling cascades brought about by compound induced cell stress

Die Notverordnungen des kroatischen Präsidenten aus den Jahren 1991 und 1992

U radu se razmatraju uredbe iz nužde koje je donio predsjednik Republike Franjo Tuđman u drugoj polovici 1991. i početkom 1992. godine u vrijeme otvorene agresije na Republiku Hrvatsku. Glavnina uredbi donesena je 10. rujna 1991., a do kraja 1991. godine donesene su gotovo sve uredbe iz nužde. Uredbama su regulirani klasični državni resori poput pravosuđa, unutarnjih poslova i vojske, no velik dio uredbi regulirao je i javne službe te gospodarstvo.At the beginning, this paper gives a brief notional historical overview of emergency decrees, after which follows a reconstruction of events in 1990 that led to the introduction of articles 17 and 101 of the Constitution of the Republic of Croatia as Constitutional decrees relating to states of emergency. The central part of the paper deals with emergency decrees passed by the Croatian President Franjo Tuđman at the time of the open aggression against the Republic of Croatia in the second half of 1991 and the beginning of 1992. In this section, using sources, especially the minutes of the Commission for Constitutional Matters of the Croatian Partliament and the minutes of the plenary sessions of the Croatian Parliament, and also relevant literature, the paper sheds light on the circumstances under which the decrees were passed and approved by the Croatian Parliament, and thus provides a new interpretation of the decrees. After discussing the circumstances under which the decrees were passed, the author deals with various aspects of the decrees\u27 content, first noting the basic characteristics of the decrees, and then classifying them according to fields, such as: internal affairs, defense and justice, and also those covering public services and the economy. While discussing particular decrees the author sets out only the main provisions of the decrees with a view to presenting their basic characteristics, such as the limitation of constitutional rights and the centralisation of public services and of the economy. In the last part of the paper, the author analyzes the constitutionality of the decrees and their lifting. The question of whether the Parliament could convene is paramount in considering the constitutionality of the decrees, since this is important in establishing whether the President of the Republic had the power to pass decrees limiting constitutional rights. The author also considers the decision of the Constitutional Court to approve the constitutionality of the decrees. The lifting of the decrees is analyzed with special consideration given to the circumstances leading to this.Am Anfang dieser Arbeit wird eine kurze begriffshistorische Übersicht über die Notverordnungen präsentiert, wonach rekonstruiert wird, wie die den Ausnahmezustand regelnden Artikel 17 und 101 der Verfassung der Republik Kroatien von 1990 zustande kamen. Der zentrale Teil dieser Arbeit befasst sich mit den Notverordnungen, die der damalige kroatische Staatspräsident Franjo Tuđman während des offenen Angriffskrieges gegen die Republik Kroatien in der zweiten Hälfte des Jahres 1991 und Anfang 1992 erließ. Dabei wird versucht, anhand des Quellenstudiums, vor allem der Niederschriften zur Arbeit der parlamentarischen Kommission für Verfassungsfragen, der Protokolle zu den Plenarsitzungen des Parlaments der Republik Kroatien (Sabor), aber auch unter Rückgriff auf die entsprechende Literatur die Umstände des Erlasses der Notverordnungen sowie ihrer Bestätigung durch den Sabor zu beleuchten und auf diese Weise einen Beitrag zur Reinterpretation der betreffenden Verordnungen zu leisten. Nach einer dementsprechenden Klärung werden die inhaltlichen Aspekte der Verordnungen dargestellt, indem zunächst deren Hauptmerkmale bestimmt werden und danach eine Zuordnung zum Bereich des Inneren, der Verteidigung und der Justiz beziehungsweise zum Bereich der öffentlichen Aufgaben und der Wirtschaft erfolgt. Innerhalb der Darstellung einzelner Verordnungen versuchen wir, lediglich ihre wesentlichen Bestimmungen zu präsentieren, an denen die wichtigsten Merkmale wie die Beschränkung der Verfassungsrechte und die Zentralisierung der öffentlichen Aufgaben und der Wirtschaft deutlich werden. Im letzten Teil der Arbeit werden die Verfassungskonformität der Verordnungen und das Ende ihrer Gültigkeit analysiert. Die Verfassungsmäßigkeit der Verordnungen wird in erster Linie unter dem Aspekt untersucht, ob das Parlament hätte zusammentreten können, wovon schließlich die Zuständigkeit des Präsidenten der Republik für das Erlassen von verfassungsrechtsbeschränkenden Verordnungen abhing. Ebenfalls wird die Entscheidung des Verfassungsgerichts besprochen, in der es den Verordnungen Verfassungsmäßigkeit bescheinigt. Die Aufhebung der Verordnungen wird hinsichtlich der dafür verantwortlichen Umstände analysiert

Assessment of reproductive and developmental effects of DINP, DnHP and DCHP using quantitative weight of evidence

Quantitative weight of evidence (QWoE) methodology utilizes detailed scoring sheets to assess the quality/reliability of each publication on toxicity of a chemical and gives numerical scores for quality and observed toxicity. This QWoE-methodology was applied to the reproductive toxicity data on diisononylphthalate (DINP), di-n-hexylphthalate (DnHP), and dicyclohexylphthalate (DCHP) to determine if the scientific evidence for adverse effects meets the requirements for classification as reproductive toxicants. The scores for DINP were compared to those when applying the methodology DCHP and DnHP that have harmonized classifications. Based on the quality/reliability scores, application of the QWoE shows that the three databases are of similar quality; but effect scores differ widely. Application of QWoE to DINP studies resulted in an overall score well below the benchmark required to trigger classification. For DCHP, the QWoE also results in low scores. The high scores from the application of the QWoE methodology to the toxicological data for DnHP represent clear evidence for adverse effects and justify a classification of DnHP as category 1B for both development and fertility. The conclusions on classification based on the QWoE are well supported using a narrative assessment of consistency and biological plausibility