ZZS similarity tool: the online tool for similarity screening to identify chemicals of potential concern

Screening and prioritization of chemicals is essential to ensure that available evaluation capacity is invested in those substances that are of highest concern. We, therefore, recently developed structural similarity models that evaluate the structural similarity of substances with unknown properties to known Substances of Very High Concern (SVHC), which could be an indication of comparable effects. In the current study the performance of these models is improved by (1) separating known SVHCs in more specific subgroups, (2) (re-)optimizing similarity models for the various SVHC-subgroups, and (3) improving interpretability of the predicted outcomes by providing a confidence score. The improvements are directly incorporated in a freely accessible web-based tool, named the ZZS similarity tool: . Accordingly, this tool can be used by risk assessors, academia and industrial partners to screen and prioritize chemicals for further action and evaluation within varying frameworks, and could support the identification of tomorrow's substances of concern.Environmental Biolog

High-salt intake affects retinal vascular tortuosity in healthy males: an exploratory randomized cross-over trial.

The retinal microcirculation is increasingly receiving credit as a relatively easily accessible microcirculatory bed that correlates closely with clinical cardiovascular outcomes. The effect of high salt (NaCl) intake on the retinal microcirculation is currently unknown. Therefore, we performed an exploratory randomized cross-over dietary intervention study in 18 healthy males. All subjects adhered to a two-week high-salt diet and low-salt diet, in randomized order, after which fundus photographs were taken and assessed using a semi-automated computer-assisted program (SIVA, version 4.0). Outcome parameters involved retinal venular and arteriolar tortuosity, vessel diameter, branching angle and fractal dimension. At baseline, participants had a mean (SD) age of 29.8 (4.4) years and blood pressure of 117 (9)/73 (5) mmHg. Overall, high-salt diet significantly increased venular tortuosity (12.2%, p = 0.001). Other retinal parameters were not significantly different between diets. Changes in arteriolar tortuosity correlated with changes in ambulatory systolic blood pressure (r = - 0.513; p = 0.04). In conclusion, high-salt diet increases retinal venular tortuosity, and salt-induced increases in ambulatory systolic blood pressure associate with decreases in retinal arteriolar tortuosity. Besides potential eye-specific consequences, both phenomena have previously been associated with hypertension and other cardiovascular risk factors, underlining the deleterious microcirculatory effects of high salt intake

Predicting estrogen receptor binding of chemicals using a suite of in silico methods – Complementary approaches of (Q)SAR, molecular docking and molecular dynamics

With the aim of obtaining reliable estimates of Estrogen Receptor (ER) binding for diverse classes of compounds, a weight of evidence approach using estimates from a suite of in silico models was assessed. The predictivity of a simple Majority Consensus of (Q)SAR models was assessed using a test set of compounds with experimental Relative Binding Affinity (RBA) data. Molecular docking was also carried out and the binding energies of these compounds to the ER\u3b1 receptor were determined. For a few selected compounds, including a known full agonist and antagonist, the intrinsic activity was determined using low-mode molecular dynamics methods. Individual (Q)SAR model predictivity varied, as expected, with some models showing high sensitivity, others higher specificity. However, the Majority Consensus (Q)SAR prediction showed a high accuracy and reasonably balanced sensitivity and specificity. Molecular docking provided quantitative information on strength of binding to the ER\u3b1 receptor. For the 50 highest binding affinity compounds with positive RBA experimental values, just 5 of them were predicted to be non-binders by the Majority QSAR Consensus. Furthermore, agonist-specific assay experimental values for these 5 compounds were negative, which indicates that they may be ER antagonists. We also showed different scenarios of combining (Q)SAR results with Molecular docking classification of ER binding based on cut-off values of binding energies, providing a rational combined strategy to maximize terms of toxicological interest

Effect of high-salt diet on blood pressure and body fluid composition in patients with type 1 diabetes: randomized controlled intervention trial

INTRODUCTION: Patients with type 1 diabetes are susceptible to hypertension, possibly resulting from increased salt sensitivity and accompanied changes in body fluid composition. We examined the effect of a high-salt diet (HSD) in type 1 diabetes on hemodynamics, including blood pressure (BP) and body fluid composition. RESEARCH DESIGN AND METHODS: We studied eight male patients with type 1 diabetes and 12 matched healthy controls with normal BP, body mass index, and renal function. All subjects adhered to a low-salt diet and HSD for eight days in randomized order. On day 8 of each diet, extracellular fluid volume (ECFV) and plasma volume were calculated with the use of iohexol and 125I-albumin distribution. Hemodynamic measurements included BP, cardiac output (CO), and systemic vascular resistance. RESULTS: After HSD, patients with type 1 diabetes showed a BP increase (mean arterial pressure: 85 (5) mm Hg vs 80 (3) mm Hg; p<0.05), while BP in controls did not rise (78 (5) mm Hg vs 78 (5) mm Hg). Plasma volume increased after HSD in patients with type 1 diabetes (p<0.05) and not in controls (p=0.23). There was no significant difference in ECFV between diets, while HSD significantly increased CO, heart rate (HR) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in type 1 diabetes but not in controls. There were no significant differences in systemic vascular resistance, although there was a trend towards an HSD-induced decrease in controls (p=0.09). CONCLUSIONS: In the present study, patients with type 1 diabetes show a salt-sensitive BP rise to HSD, which is accompanied by significant increases in plasma volume, CO, HR, and NT-proBNP. Underlying mechanisms for these responses need further research in order to unravel the increased susceptibility to hypertension and cardiovascular disease in diabetes. TRIAL REGISTRATION NUMBERS: NTR4095 and NTR4788

Het gebruik van quantum-chemische descriptoren voor het modelleren van de anaerobe dehalogenering van aromatische verbindingen

In this study, quantum-chemically derived parameters are developed for a limited number of halogenated aromatic compounds to model the anaerobic reductive dehalogenation reaction rate constants of these compounds. It is shown that due to the heterogeneity of the set of compounds used, no single descriptor or combination of descriptors was able to adequately model the reaction under investigation. Thus subsets had to be created out of the group of compounds. For these subsets it is shown that the assumed reaction mechanism was correct as indicated by the relatively good correlations established between the reaction rate constants and descriptors that can be explained in terms of the reaction mechanism. The database of reaction rate constants for halogenated heterocyclic aromatic compounds was too small to enable the creation of subsets. Therefore no satisfying relationships could yet be obtained ; it may be anticipated that upon additional data becoming available, similar results will be obtained for these compounds as well.EG/DG 12-D-

Het EU (Q)SAR Experience Project: rapportage formats. Sjablonen voor het documenteren van (Q)SAR resultaten voor REACH

De zojuist in werking getreden Europese wetgeving voor chemische stoffen (REACH) propageert alternatieven om het aantal dierproeven te verminderen. (Q)SAR is zo'n alternatief en staat voor kwalitatieve en kwantitatieve structuur-activiteitsrelatie. (Q)SAR's leggen een verband tussen de chemische structuur van de stof en een toxische eigenschap ervan, bijvoorbeeld huidirritatie. Met behulp van deze theoretische modellen is het mogelijk om schadelijke effecten van chemische stoffen voor mens en dier te voorspellen zonder dierproeven te hoeven doen. Het RIVM draagt bij aan het verminderen van het aantal dierproeven door de resultaten van deze modellen, de zogeheten (Q)SAR's, toepasbaar te maken voor beleid. Het RIVM heeft formats ontwikkeld om de resultaten van (Q)SAR's op drie niveaus te beschrijven: het model, het voorspelde effect van een specifieke stof, en de vertaling van dat effect naar beleid. Deze aanvullende informatie is nodig om de geldigheid en betrouwbaarheid van een voorspelling goed te kunnen beoordelen. De formats blijven in ontwikkeling, maar zijn in concept al opgenomen in de REACH-richtlijnen. Ze kunnen bovendien met enige aanpassingen ingezet worden om resultaten van andere alternatieven voor dierproeven, zoals die genoemd worden in Bijlage XI van de REACH wettekst, transparant te documenteren. Genoemde alternatieven zijn onder andere de "read-across"-aanpak en groepering van stoffen ("category"-aanpak), waarbij de toxiciteit van een nieuwe stof gelijk wordt gesteld aan een of meerdere bekende stoffen. Bovenstaande activiteiten zijn het resultaat van het Europese (Q)SAR Experience Project, een initiatief uit 2004 dat het RIVM vooruitlopend op REACH heeft opgezet. Europese beleidsmakers en stoffenbeoordelaars doen hierin kennis en ervaring op met (Q)SAR's, en geven aanbevelingen voor het gebruik ervan in beleid.The European chemicals regulation REACH, which just entered into force, strongly advocates the use of alternatives for animal testing. (Q)SAR is such an alternative and stands for Quantitative Structure-Activity Relationship. (Q)SARs try to correlate the chemical structure of a substance to a toxicological property of that substance, for example skin irritation. The use of these theoretical models makes it possible to predict toxic effects of chemical substances without performing animal tests. RIVM contributes to reducing the number of animal tests by making the results of these models, so called (Q)SARs, suitable for regulatory use. In a European cooperation RIVM developed formats for reporting (Q)SAR results for REACH on three levels: description of the model, the predicted effect for a specific substance, and the interpretation of that effect for regulatory use. This extensive information is needed to be able to judge the validity and reliability of a prediction. These formats continue to develop, but have already been incorporated into the REACH guidance. Furthermore, with simple adaptations they can also serve as reporting formats for other alternatives for animal testing mentioned in Annex XI of the REACH regulation. Examples of such alternatives are the read-across and category approaches, where the unknown toxicity of a new substance is presumed to be equal to one or several similar compounds with known toxic effects. The above mentioned activities are the result of the European (Q)SAR Experience Project, initiated by RIVM in 2004 as a preparation for new regulations under REACH. In this project European regulators and policy makers increase their knowledge of (Q)SARs, gain experience with existing QSAR models, and give recommendations and guidance on the use of these models.VROM-SA

Voorspellingen van degradatiesnelheden in het milieu voor de High Production Volume Chemicals (HPVC) met behulp van Kwantitatieve Structuur-Aktiviteits Relaties

Estimates of (bio)degradation kinetics for 1073 compounds in various environmental compartments have been made as a part of the EU-project 'Fate and Activity Modelling of Environmental Pollutants using Structure-Activity Relationships' (FAME). These estimates have been made for all single compounds on the High Production Volume Chemicals (HPVC) list of the European Union (as of June 4th 1995). No predictions can be made for the large amount (> 50 %) of mixtures and ill-defined compounds on the HPVC-list. The models that have been applied are Quantitative Structure-Activity Relationships (QSARs), which were selected from literature. An indication of the precision of the estimates is given, either based on available validation studies of the models, and/or based on the statistical quality of the models. Given the large amount of compounds for which no or very few experimental degradation kinetics are available, these estimates can serve as supplementary information for the priority setting and the risk assessment of existing chemicals in the EU that is now being performed as a part of EU Regulation (EEC) 793/93 on existing chemical substances. In the future the estimates, and therefore the selected QSAR models, will be validated using new data on the HPVC that are being collected by the EU at this moment, from the European industries.In het kader van het EU-project 'Fate and Activity Modelling of Environmental Pollutants using Structure-Activity Relationships' (FAME) zijn schattingen gemaakt van de (bio)degradatiesnelheden van 1073 stoffen in verschillende milieucompartimenten. Deze schattingen zijn uitgevoerd voor alle zuivere stoffen op de lijst van High Production Volume Chemicals (HPVC) lijst van de Europese Unie (4 Juni 1995). Met behulp van QSARs zijn geen schattingen te maken voor de grote groep van mengsels of slecht definieerbare substanties (> 50 % van de HPVC). De gebruikte modellen zijn Kwantitatieve (Quantitative) Structuur-Activiteits Relaties (QSARs) die in een eerder EU-project (nr. EV5V-CT92-0211 'QSARs for Predicting Fate and Effects of Chemicals in the Environment') zijn geselecteerd uit in de vakliteratuur gepubliceerde modellen. De nauwkeurigheid van de schattingen wordt in dit rapport gegeven aan de hand van eventuele validatiestudies en de statistische gegevens van de modellen. Gezien de grote hoeveelheid bestaande stoffen waarvoor nog geen of slechts enkele gegevens over de degradatie-kinetiek in het milieu beschikbaar zijn, kunnen deze schattingen dienen als aanvullende informatie voor prioritering van stoffen en voor de risico-evaluatie van bestaande stoffen in de EU die momenteel wordt uitgevoerd in het kader van de Europese 'Regulation (EEC) 793/93 on existing chemical substances'. Deze schattingen en daarmee ook de geselecteerde QSAR modellen zullen in de toekomst worden gevalideerd met behulp van data van de Europese chemische industrie, die op dit moment verzameld worden door de EU

Voorspellingen van degradatiesnelheden in het milieu voor de High Production Volume Chemicals (HPVC) met behulp van Kwantitatieve Structuur-Aktiviteits Relaties

In het kader van het EU-project 'Fate and Activity Modelling of Environmental Pollutants using Structure-Activity Relationships' (FAME) zijn schattingen gemaakt van de (bio)degradatiesnelheden van 1073 stoffen in verschillende milieucompartimenten. Deze schattingen zijn uitgevoerd voor alle zuivere stoffen op de lijst van High Production Volume Chemicals (HPVC) lijst van de Europese Unie (4 Juni 1995). Met behulp van QSARs zijn geen schattingen te maken voor de grote groep van mengsels of slecht definieerbare substanties (> 50 % van de HPVC). De gebruikte modellen zijn Kwantitatieve (Quantitative) Structuur-Activiteits Relaties (QSARs) die in een eerder EU-project (nr. EV5V-CT92-0211 'QSARs for Predicting Fate and Effects of Chemicals in the Environment') zijn geselecteerd uit in de vakliteratuur gepubliceerde modellen. De nauwkeurigheid van de schattingen wordt in dit rapport gegeven aan de hand van eventuele validatiestudies en de statistische gegevens van de modellen. Gezien de grote hoeveelheid bestaande stoffen waarvoor nog geen of slechts enkele gegevens over de degradatie-kinetiek in het milieu beschikbaar zijn, kunnen deze schattingen dienen als aanvullende informatie voor prioritering van stoffen en voor de risico-evaluatie van bestaande stoffen in de EU die momenteel wordt uitgevoerd in het kader van de Europese 'Regulation (EEC) 793/93 on existing chemical substances'. Deze schattingen en daarmee ook de geselecteerde QSAR modellen zullen in de toekomst worden gevalideerd met behulp van data van de Europese chemische industrie, die op dit moment verzameld worden door de EU.Estimates of (bio)degradation kinetics for 1073 compounds in various environmental compartments have been made as a part of the EU-project 'Fate and Activity Modelling of Environmental Pollutants using Structure-Activity Relationships' (FAME). These estimates have been made for all single compounds on the High Production Volume Chemicals (HPVC) list of the European Union (as of June 4th 1995). No predictions can be made for the large amount (> 50 %) of mixtures and ill-defined compounds on the HPVC-list. The models that have been applied are Quantitative Structure-Activity Relationships (QSARs), which were selected from literature. An indication of the precision of the estimates is given, either based on available validation studies of the models, and/or based on the statistical quality of the models. Given the large amount of compounds for which no or very few experimental degradation kinetics are available, these estimates can serve as supplementary information for the priority setting and the risk assessment of existing chemicals in the EU that is now being performed as a part of EU Regulation (EEC) 793/93 on existing chemical substances. In the future the estimates, and therefore the selected QSAR models, will be validated using new data on the HPVC that are being collected by the EU at this moment, from the European industries.E