Characterizing PFAS hazards and risks: a human population-based in vitro cardiotoxicity assessment strategy.

Per- and poly-fluoroalkyl substances (PFAS) are emerging contaminants of concern because of their wide use, persistence, and potential to be hazardous to both humans and the environment. Several PFAS have been designated as substances of concern; however, most PFAS in commerce lack toxicology and exposure data to evaluate their potential hazards and risks. Cardiotoxicity has been identified as a likely human health concern, and cell-based assays are the most sensible approach for screening and prioritization of PFAS. Human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes are a widely used method to test for cardiotoxicity, and recent studies showed that many PFAS affect these cells. Because iPSC-derived cardiomyocytes are available from different donors, they also can be used to quantify human variability in responses to PFAS. The primary objective of this study was to characterize potential human cardiotoxic hazard, risk, and inter-individual variability in responses to PFAS. A total of 56 PFAS from different subclasses were tested in concentration-response using human iPSC-derived cardiomyocytes from 16 donors without known heart disease. Kinetic calcium flux and high-content imaging were used to evaluate biologically-relevant phenotypes such as beat frequency, repolarization, and cytotoxicity. Of the tested PFAS, 46 showed concentration-response effects in at least one phenotype and donor; however, a wide range of sensitivities were observed across donors. Inter-individual variability in the effects could be quantified for 19 PFAS, and risk characterization could be performed for 20 PFAS based on available exposure information. For most tested PFAS, toxicodynamic variability was within a factor of 10 and the margins of exposure were above 100. This study identified PFAS that may pose cardiotoxicity risk and have high inter-individual variability. It also demonstrated the feasibility of using a population-based human in vitro method to quantify population variability and identify cardiotoxicity risks of emerging contaminants.

Combinatorial Separation of Cd and Te from CdTe via Chemical Vapor Transport with Sulfur and Air/Methane Treatment for the Recovery of Critical Resources from Thin Film Solar Cells.

Elemental Te and Cd are successfully recovered from CdTe via a combinatorial process involving chemical vapor transport (CVT) using sulfur as transport agent giving elemental Te being deposited. Separation is successfully enabled by the first process for CVT of Te starting with CdTe. Cd is subsequently recovered by an oxidation of the formed CdS to CdO followed by reduction to Cd metal with natural gas, in which Cd can also be separated via the gas phase. Hereby, the process addresses the main critical elements of the active material in thin film CdTe solar cells regarding both, scarcity and toxicity. Both, closed and open systems were investigated displaying more or less thermodynamic control of the system. Transport rates were determined for the closed system as well as for an open system working with sulfur vapour at moderate temperatures below and close to the boiling point of sulfur. Excellent purity of tellurium was achieved already by the initial transport, leading to low Cd2+ concentrations in the obtained Te being below the quantification limit of microwave plasma-atomic emission spectroscopy (MP-AES) (<< 0.05 wt%).

Thermochemistry of Solid-State Formation, Structure, Optical, and Luminescent Properties of Complex Oxides Eu2MeO6 (Me-Mo, W), Eu2W2O9: A Combined Experimental and DFT Study.

Complex oxides Eu2MeO6 (Me-Mo, W), Eu2W2O9 were obtained by a solid-phase reaction between binary oxides. The thermodynamic and kinetic mechanisms of the reaction processes were established using a variety of physical-chemical methods. All compounds obtained in this work crystallize in the low-symmetry monoclinic system, forming complex framework structures, which determine a set of very valuable physical-chemical properties. Comparison of experimental Kubelka-Munk functions and DFT- calculated absorption spectra shows adequate agreement and reveals the origin of the fundamental absorption. In addition, the deficiency in DFT calculations in the part of mutual contribution of CTBs of Mo-O and W-O, from one side, and Eu-O contributions, from the other side, is reported. Calculations of absorption spectra are shown to be superior to band structure analysis in the determination of optical band gaps. Additionally, luminescent properties of Eu2MeO6 and Eu2W2O9 compounds were investigated. These studies provide a better understanding of the electronic and optical properties of the compounds Eu2MeO6 and Eu2W2O9, along with their potential applications in various areas.

Hazard and risk characterization of 56 structurally diverse PFAS using a targeted battery of broad coverage assays using six human cell types.

Per- and poly-fluoroalkyl substances (PFAS) are extensively used in commerce leading to their prevalence in the environment. Due to their chemical stability, PFAS are considered to be persistent and bioaccumulative; they are frequently detected in both the environment and humans. Because of this, PFAS as a class (composed of hundreds to thousands of chemicals) are contaminants of very high concern. Little information is available for the vast majority of PFAS, and regulatory agencies lack safety data to determine whether exposure limits or restrictions are needed. Cell-based assays are a pragmatic approach to inform decision-makers on potential health hazards; therefore, we hypothesized that a targeted battery of human in vitro assays can be used to determine whether there are structure-bioactivity relationships for PFAS, and to characterize potential risks by comparing bioactivity (points of departure) to exposure estimates. We tested 56 PFAS from 8 structure-based subclasses in concentration response (0.1-100 µM) using six human cell types selected from target organs with suggested adverse effects of PFAS - human induced pluripotent stem cell (iPSC)-derived hepatocytes, neurons, and cardiomyocytes, primary human hepatocytes, endothelial and HepG2 cells. While many compounds were without effect; certain PFAS demonstrated cell-specific activity highlighting the necessity of using a compendium of in vitro models to identify potential hazards. No class-specific groupings were evident except for some chain length- and structure-related trends. In addition, margins of exposure (MOE) were derived using empirical and predicted exposure data. Conservative MOE calculations showed that most tested PFAS had a MOE in the 1-100 range; ∼20% of PFAS had MOE<1, providing tiered priorities for further studies. Overall, we show that a compendium of human cell-based models can be used to derive bioactivity estimates for a range of PFAS, enabling comparisons with human biomonitoring data. Furthermore, we emphasize that establishing structure-bioactivity relationships may be challenging for the tested PFAS.

Synergetic spin singlet-quintet switching and luminescence in mononuclear Fe(II) 1,3,4-oxadiazole tetradentate chelates with NCBH3 co-ligand.

We report the multi-step synthesis of the tetradentate 2-(naphthalen-2-yl)-5-[N,N-bis(2-pyridylmethyl)aminomethyl]-1,3,4-oxadiazole ligand (LTetra-ODA) along with its corresponding [FeII(LTetra-ODA)(NCBH3)2]·1.5CH3OH (C1) complex, which is the first mononuclear 1,3,4-oxadiazole based Fe(II) spin crossover (SCO) complex, and its zinc analogue [ZnII(LTetra-ODA)(NCBH3)2]·0.5H2O (C2). The spin transition is followed by variable temperature (VT-) X-ray crystallography of [Fe(LTetra-ODA)(NCBH3)2]·1.5CH3OH (C1) at 120 and 220 K. The magnetic susceptibility measurements on the bulk sample recorded from 2 to 300 K show that the complex exhibits a complete abrupt reversible spin transition with a T1/2 of 207 K. The loss of the lattice solvent methanol shifts the T1/2 slightly to around 210 K. The spin transition in solution for [Fe(LTetra-ODA)(NCBH3)2]·1.5CH3OH (C1) was followed using the VT-1H-NMR Evans method in CD3CN, with a T1/2 of 357 K. Solid state VT luminescence studies provide some preliminary evidence of interplay of luminescence and spin transition in the [Fe(LTetra-ODA)(NCBH3)2]·1.5CH3OH (C1) complex.

Negative Thermal Expansion in the Polymorphic Modification of Double Sulfate ß-AEu(SO4)2 (A-Rb+, Cs+).

New polymorphic modifications of double sulfates ß-AEu(SO4)2 (A-Rb+, Cs+) were obtained by the hydrothermal method, the structure of which differs significantly from the monoclinic modifications obtained earlier by solid-state methods. According to single-crystal diffraction data, it was found that the compounds crystallize in the orthorhombic system, space group Pnna, with parameters ß-RbEu(SO4)2: a = 9.4667(4) Å, b = 13.0786(5) Å, c = 5.3760(2) Å, V = 665.61(5) Å3; ß-CsEu(SO4)2: a = 9.5278(5) Å, b = 13.8385(7) Å, c = 5.3783(3) Å, V = 709.13(7) Å3. The asymmetric part of the unit cell contains one-half Rb+/Cs+ ion, one-half Eu3+ ion, both in special sites, and one SO42- ion. Both compounds exhibit nonlinear negative thermal expansion. According to the X-ray structural analysis and theoretical calculations, the polarizing effect of the alkali metal ion has a decisive influence on the demonstration of this phenomenon. Experimental indirect band gaps of ß-Rb and ß-Cs are 4.05 and 4.11 eV, respectively, while the direct band gaps are 4.48 and 4.54 eV, respectively. The best agreement with theoretical calculations is obtained using the ABINIT package employing PAW pseudopotentials with hybrid PBE0 functional, while norm-conserving pseudopotentials used in the frame of CASTEP code and LCAO approach in the Crystal package gave worse agreement. The properties of alkali ions also significantly affect the luminescent properties of the compounds, which leads to a strong temperature dependence of the intensity of the 5D0 → 7F4 transition in ß-CsEu(SO4)2 in contrast to much weaker dependence of this kind in ß-RbEu(SO4)2.

3D-Frameworks and 2D-networks of lanthanide coordination polymers with 3-pyridylpyrazole: photophysical and magnetic properties.

A series of 15 lanthanide-containing coordination polymers, both 3D- and 2D-networks, as well as complexes of Ln-trichlorides with 3-(3-pyridyl)pyrazole (3-PyPzH), were synthesized. A large structural diversity is observed depending on the ligand content: 3∞[Ln(3-PyPzH)Cl3], Ln = Eu and Gd, of sra topology, 2∞[Sm(3-PyPzH)Cl3], 2∞[Ln2(3-PyPzH)3Cl6]·2solv, Ln = Eu3+, Tb3+, Dy3+, Ho3+ and Er3+, solv = Tol and MeCN, of sql topology and 2∞[Ln(3-PyPzH2)Cl4], Ln = La and Nd, of hcb topology with salt like complexes of the formula [(3-PyPzH2)][Ln(3-PyPzH)2Cl4], Ln = Eu, Tb, Dy and Ho. The products were characterized by single-crystal and powder X-ray diffraction, high-temperature X-ray diffraction, differential thermal analysis and thermogravimetry (DTA/TG) combined with mass spectrometry, differential scanning calorimetry (DSC), IR-spectroscopy, UV-visible spectrophotometry, photoluminescence spectroscopy, and magnetic susceptibility. Absorption spectroscopy shows ion-specific 4f-4f transitions that can be assigned to Sm3+, Eu3+, Dy3+, Ho3+ and Er3+ in a wide range from the UV-VIS to NIR region. An excellent antenna effect through ligand-metal energy transfer was observed in 2∞[Tb2(3-PyPzH)3Cl6]·2solv, leading to high efficiency of the luminescence indicated by a quantum yield up to 76%. Direct current magnetic susceptibility studies reveal the absence of interatomic interaction for Dy3+ and Er3+ and weak ferromagnetic interaction for Ho3+. Thermal analysis shows good stability up to 365 °C for 2∞[Ho2(3-PyPzH)3Cl6]·2MeCN.

Exploration of the Crystal Structure and Thermal and Spectroscopic Properties of Monoclinic Praseodymium Sulfate Pr2(SO4)3.

Praseodymium sulfate was obtained by the precipitation method and the crystal structure was determined by Rietveld analysis. Pr2(SO4)3 is crystallized in the monoclinic structure, space group C2/c, with cell parameters a = 21.6052 (4), b = 6.7237 (1) and c = 6.9777 (1) Å, ß = 107.9148 (7)°, Z = 4, V = 964.48 (3) Å3 (T = 150 °C). The thermal expansion of Pr2(SO4)3 is strongly anisotropic. As was obtained by XRD measurements, all cell parameters are increased on heating. However, due to a strong increase of the monoclinic angle ß, there is a direction of negative thermal expansion. In the argon atmosphere, Pr2(SO4)3 is stable in the temperature range of T = 30-870 °C. The kinetics of the thermal decomposition process of praseodymium sulfate octahydrate Pr2(SO4)3·8H2O was studied as well. The vibrational properties of Pr2(SO4)3 were examined by Raman and Fourier-transform infrared absorption spectroscopy methods. The band gap structure of Pr2(SO4)3 was evaluated by ab initio calculations, and it was found that the valence band top is dominated by the p electrons of oxygen ions, while the conduction band bottom is formed by the d electrons of Pr3+ ions. The exact position of ZPL is determined via PL and PLE spectra at 77 K to be at 481 nm, and that enabled a correct assignment of luminescent bands. The maximum luminescent band in Pr2(SO4)3 belongs to the 3P0 → 3F2 transition at 640 nm.

Mixtures-Inclusive In Silico Models of Ocular Toxicity Based on United States and International Hazard Categories.

Computational modeling grounded in reliable experimental data can help design effective non-animal approaches to predict the eye irritation and corrosion potential of chemicals. The National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) has compiled and curated a database of in vivo eye irritation studies from the scientific literature and from stakeholder-provided data. The database contains 810 annotated records of 593 unique substances, including mixtures, categorized according to UN GHS and US EPA hazard classifications. This study reports a set of in silico models to predict EPA and GHS hazard classifications for chemicals and mixtures, accounting for purity by setting thresholds of 100% and 10% concentration. We used two approaches to predict classification of mixtures: conventional and mixture-based. Conventional models evaluated substances based on the chemical structure of its major component. These models achieved balanced accuracy in the range of 68-80% and 87-96% for the 100% and 10% test concentration thresholds, respectively. Mixture-based models, which accounted for all known components in the substance by weighted feature averaging, showed similar or slightly higher accuracy of 72-79% and 89-94% for the respective thresholds. We also noted a strong trend between the pH feature metric calculated for each substance and its activity. Across all the models, the calculated pH of inactive substances was within one log10 unit of neutral pH, on average, while for active substances, pH varied from neutral by at least 2 log10 units. This pH dependency is especially important for complex mixtures. Additional evaluation on an external test set of 673 substances obtained from ECHA dossiers achieved balanced accuracies of 64-71%, which suggests that these models can be useful in screening compounds for ocular irritation potential. Negative predictive value was particularly high and indicates the potential application of these models in a bottom-up approach to identify nonirritant substances.

CurveP Method for Rendering High-Throughput Screening Dose-Response Data into Digital Fingerprints.

The nature of high-throughput screening (HTS) puts certain limits on optimal test conditions for each particular sample; therefore, on top of usual data normalization, additional parsing is often needed to account for incomplete read outs or various artifacts that arise from signal interferences.CurveP is a heuristic, user-tunable curve-cleaning algorithm that attempts to find a minimum set of corrections, which would give a monotonic dose-response curve. After applying the corrections, the algorithm proceeds to calculate a set of numeric features, which can be used as a fingerprint characterizing the sample, or as a vector of independent variables (e.g., molecular descriptors in case of chemical substances testing). The resulting output can be a part of HTS data analysis or can be used as input for a broad spectrum of computational applications, such as quantitative structure-activity relationship (QSAR ) modeling, computational toxicology, bioinformatics, and cheminformatics.

Iodine Chemisorption, Interpenetration and Polycatenation: Cationic MOFs and CPs from Group 13 Metal Halides and Dipyridyl Linkers.

Invited for the cover of this issue are Klaus Müller-Buschbaum and co-workers at Giessen University. The image depicts an aluminium-based MOF as a novel material for the capture of iodine radioisotopes from a potential gas atmosphere exposure. Read the full text of the article at 10.1002/chem.202104171.

Iodine-Chemisorption, Interpenetration and Polycatenation: Cationic MOFs and CPs from Group 13 Metal Halides and Di-Pyridyl-Linkers.

Eight cationic, two-dimensional metal-organic frameworks (MOFs) were synthesized in reactions of the group 13 metal halides AlBr3 , AlI3 , GaBr3 , InBr3 and InI3 with the dipyridyl ligands 1,2-di(4-pyridyl)ethylene (bpe), 1,2-di(4-pyridyl)ethane (bpa) and 4,4'-bipyridine (bipy). Seven of them follow the general formula 2 ∞ [MX2 (L)2 ]A, M=Al, In, X=Br, I, A- =[MX4 ]- , I- , I3 - , L=bipy, bpa, bpe. Thereby, the porosity of the cationic frameworks can be utilized to take up the heavy molecule iodine in gas-phase chemisorption vital for the capture of iodine radioisotopes. This is achieved by switching between I- and the polyiodide I3 - in the cavities at room temperature, including single-crystal-to-single-crystal transformation. The MOFs are 2D networks that exhibit (4,4)-topology in general or (6,3)-topology for 2 ∞ [(GaBr2 )2 (bpa)5 ][GaBr4 ]2 ⋅bpa. The two-dimensional networks can either be arranged to an inclined interpenetration of the cationic two-dimensional networks, or to stacked networks without interpenetration. Interpenetration is accompanied by polycatenation. Due to the cationic character, the MOFs require the counter ions [MX4 ]- , I- or I3 - counter ions in their pores. Whereas the [MX4 ]- , ions are immobile, iodide allows for chemisorption. Furthermore, eight additional coordination polymers and complexes were identified and isolated that elaborate the reaction space of the herein reported syntheses.

Variable Luminescence and Chromaticity of Homoleptic Frameworks of the Lanthanides together with Pyridylpyrazolates.

Homoleptic, 3D coordination polymers of the formula 33 ∞ [Ln(3-PyPz)3 ] and 3 ∞ [Ln(4-PyPz)3 ], (3-PyPz)- =3-(3-pyridyl)pyrazolate anion, (4-PyPz)- =3-(4-pyridyl)pyrazolate anion, both C8 H6 N3 - , Ln=Sm, Eu, Gd, Tb, Dy, were obtained as highly luminescent frameworks by reaction of the lanthanide metals (Ln) with the aromatic heterocyclic amine ligands 3-PyPzH and 4-PyPzH. The compounds form two isotypic series of 3D coordination polymers and exhibit fair thermal stability up to 360 °C. The luminescence properties of all ten compounds were determined in the solid state, with an antenna effect through ligand-metal energy transfer leading to high efficiency of the luminescence displayed by good quantum yields of up to 74 %. The emission is mainly based on ion-specific lanthanide-dependent intra 4 f-4 f transitions for Tb3+ : green, Dy3+ : yellow, Sm3+ : orange-red, Eu3+ : red. For the Gd3+ -containing compounds, the yellow emission of ligand triplet-based phosphorescence is observed at room temperature and 77 K. Co doping of the Gd-containing frameworks with Eu3+ and Tb3+ allow further shifting of the chromaticity towards white light emission.

Harnessing In Silico, In Vitro, and In Vivo Data to Understand the Toxicity Landscape of Polycyclic Aromatic Compounds (PACs).

Polycyclic aromatic compounds (PACs) are compounds with a minimum of two six-atom aromatic fused rings. PACs arise from incomplete combustion or thermal decomposition of organic matter and are ubiquitous in the environment. Within PACs, carcinogenicity is generally regarded to be the most important public health concern. However, toxicity in other systems (reproductive and developmental toxicity, immunotoxicity) has also been reported. Despite the large number of PACs identified in the environment, research attention to understand exposure and health effects of PACs has focused on a relatively limited subset, namely polycyclic aromatic hydrocarbons (PAHs), the PACs with only carbon and hydrogen atoms. To triage the rest of the vast number of PACs for more resource-intensive testing, we developed a data-driven approach to contextualize hazard characterization of PACs, by leveraging the available data from various data streams (in silico toxicity, in vitro activity, structural fingerprints, and in vivo data availability). The PACs were clustered on the basis of their in silico toxicity profiles containing predictions from 8 different categories (carcinogenicity, cardiotoxicity, developmental toxicity, genotoxicity, hepatotoxicity, neurotoxicity, reproductive toxicity, and urinary toxicity). We found that PACs with the same parent structure (e.g., fluorene) could have diverse in silico toxicity profiles. In contrast, PACs with similar substituted groups (e.g., alkylated-PAHs) or heterocyclics (e.g., N-PACs) with varying ring sizes could have similar in silico toxicity profiles, suggesting that these groups are better candidates for toxicity read-across analysis. The clusters/regions associated with certain in silico toxicity, in vitro activity, and structural fingerprints were identified. We found that genotoxicity/carcinogenicity (in silico toxicity) and xenobiotic homeostasis and stress response (in vitro activity), respectively, dominate the toxicity/activity variation seen in the PACs. The "hot spots" with enriched toxicity/activity in conjunction with availability of in vivo carcinogenicity data revealed regions of either data-poor (hydroxylated-PAHs) or data-rich (unsubstituted, parent PAHs) PACs. These regions offer potential targets for prioritization of further in vivo assessment and for chemical read-across efforts. The analysis results are searchable through an interactive web application (https://ntp.niehs.nih.gov/go/pacs_tableau), allowing for alternative hypothesis generation.

Saagar-A New, Extensible Set of Molecular Substructures for QSAR/QSPR and Read-Across Predictions.

Molecular structure-based predictive models provide a proven alternative to costly and inefficient animal testing. However, due to a lack of interpretability of predictive models built with abstract molecular descriptors they have earned the notoriety of being black boxes. Interpretable models require interpretable descriptors to provide chemistry-backed predictive reasoning and facilitate intelligent molecular design. We developed a novel set of extensible chemistry-aware substructures, Saagar, to support interpretable predictive models and read-across protocols. Performance of Saagar in chemical characterization and search for structurally similar actives for read-across applications was compared with four publicly available fingerprint sets (MACCS (166), PubChem (881), ECFP4 (1024), ToxPrint (729)) in three benchmark sets (MUV, ULS, and Tox21) spanning ∼145 000 compounds and 78 molecular targets at 1%, 2%, 5%, and 10% false discovery rates. In 18 of the 20 comparisons, interpretable Saagar features performed better than the publicly available, but less interpretable and fixed-bit length, fingerprints. Examples are provided to show the enhanced capability of Saagar in extracting compounds with higher scaffold similarity. Saagar features are interpretable and efficiently characterize diverse chemical collections, thus making them a better choice for building interpretable predictive in silico models and read-across protocols.

Construction of a web-based nanomaterial database by big data curation and modeling friendly nanostructure annotations.

Modern nanotechnology research has generated numerous experimental data for various nanomaterials. However, the few nanomaterial databases available are not suitable for modeling studies due to the way they are curated. Here, we report the construction of a large nanomaterial database containing annotated nanostructures suited for modeling research. The database, which is publicly available through http://www.pubvinas.com/, contains 705 unique nanomaterials covering 11 material types. Each nanomaterial has up to six physicochemical properties and/or bioactivities, resulting in more than ten endpoints in the database. All the nanostructures are annotated and transformed into protein data bank files, which are downloadable by researchers worldwide. Furthermore, the nanostructure annotation procedure generates 2142 nanodescriptors for all nanomaterials for machine learning purposes, which are also available through the portal. This database provides a public resource for data-driven nanoinformatics modeling research aimed at rational nanomaterial design and other areas of modern computational nanotechnology.

Combination of single-molecule magnet behaviour and luminescence properties in a new series of lanthanide complexes with tris(pyrazolyl)borate and oligo(ß-diketonate) ligands.

A series of tris(pyrazolyl)borate mono-, di- and trinuclear complexes, [Tp2Ln]nX (Ln = Eu, Tb, Gd, Dy, Xn- = various mono-, bis- and tris(ß-diketonates) has been prepared. The Tb3+ and Dy3+ complexes are luminescent single molecular magnets (SMM) and exhibit luminescence quantum efficiencies up to 73% for the Tb3+ and 4.4% for the Dy3+ compounds. Similar Eu3+ complexes display bright emission only at lower temperatures. The Dy3+ and Tb3+ complexes possess SMM behavior in a non-zero dc field at low temperatures, while the polynuclear Dy3+ complexes also show slow magnetic relaxation even in zero dc field up to 8 K. Ueff-values determined from dynamic magnetic measurements were up to 31 and 6 cm-1 for the Dy3+ and Tb3+ complexes, respectively. It was found that within a series of Dy3+ and Tb3+ compounds, Ueff and luminescence quantum yields decreased with increasing nuclearity of the compounds and a shortening of the intramolecular Ln-Ln distance. ΔOrbach-values estimated from low-temperature luminescence spectra were significantly higher than those obtained from ac magnetic data, which may be due to involvement of additional processes in the relaxation mechanism (quantum tunneling, Raman, direct) reducing the energy barrier. Some of the Tb3+-compounds also display metal-centred electroluminescence, giving them potential as emitting layers in LEDs.

Sb- and Bi-based coordination polymers with N-donor ligands with and without lone-pair effects and their photoluminescence properties.

Fifteen new sublimable Sb- and Bi-based chlorido, bromido and iodido coordination polymers (CPs) with linear bispyridyl ligands are presented in this work and compared in terms of their crystal structures and photoluminescence properties. The Sb-CPs occur in two structural motifs: 1∞[Sb2X6(L)2] (X: Cl (a), Br (b), I (c); L: 1,2-bis(4-pyridyl)ethylene (bpe) (1), 1,2-bis(4-pyridyl)ethane (bpa) (2), 4,4'-bipyridine (bipy) (X: Br, I; 3)) with two polymorphs showing negligible stereochemical demand of the lone-pair and 1∞[SbCl3(bipy)] (3a) featuring a stereochemically active lone pair with significant 5p-contribution at SbIII. This is accompanied by differences in the coordination polyhedra being octahedral for high s-character, whereas a high p-character of the lone pair results in a square pyramid as the coordination sphere. The Bi-CPs are represented by the general formula 1∞[Bi2X6(L)2] (X: Cl (a), Br (b), I (c); L: 1,2-bis(4-pyridyl)ethylene (bpe) (4), 1,2-bis(4-pyridyl)ethane (bpa) (5)) and thus show no significant 6p-character of the lone pairs. For examining the parallels and differences between the SbIII- and BiIII-CPs, both are compared in terms of structures and luminescence properties, as well as with related literature known CPs. Altogether, this comparison of structures and properties allows for gaining new insights into the photoluminescence mechanisms of the Sb and Bi-containing CPs. For the first time, distinct hints on the participation of inter-valence charge transfer transitions in E3+-pairs (E: Sb, Bi) were observed for the Sb- and Bi-containing coordination polymers constructed from N-donor ligands.

Development of improved QSAR models for predicting the outcome of the in vivo micronucleus genetic toxicity assay.

All drugs entering clinical trials are expected to undergo a series of in vitro and in vivo genotoxicity tests as outlined in the International Council on Harmonization (ICH) S2 (R1) guidance. Among the standard battery of genotoxicity tests used for pharmaceuticals, the in vivo micronucleus assay, which measures the frequency of micronucleated cells mostly from blood or bone marrow, is recommended for detecting clastogens and aneugens. (Quantitative) structure-activity relationship [(Q)SAR] models may be used as early screening tools by pharmaceutical companies to assess genetic toxicity risk during drug candidate selection. Models can also provide decision support information during regulatory review as part of the weight-of-evidence when experimental data are insufficient. In the present study, two commercial (Q)SAR platforms were used to construct in vivo micronucleus models from a recently enhanced in-house database of non-proprietary study findings in mice. Cross-validated performance statistics for the new models showed sensitivity of up to 74% and negative predictivity of up to 86%. In addition, the models demonstrated cross-validated specificity of up to 77% and coverage of up to 94%. These new models will provide more reliable predictions and offer an investigational approach for drug safety assessment with regards to identifying potentially genotoxic compounds.

Analysis of model PM2.5-induced inflammation and cytotoxicity by the combination of a virtual carbon nanoparticle library and computational modeling.

Health risks induced by PM2.5 have become one of the major concerns among living populations, especially in regions facing serious pollution such as China and India. Furthermore, the composition of PM2.5 is complex and it also varies with time and locations. To facilitate our understanding of PM2.5-induced toxicity, a predictive modeling framework was developed in the present study. The core of this study was 1) to construct a virtual carbon nanoparticle library based on the experimental data to simulate the PM2.5 structures; 2) to quantify the nanoparticle structures by novel nanodescriptors; and 3) to perform computational modeling for critical toxicity endpoints. The virtual carbon nanoparticle library was developed to represent the nanostructures of 20 carbon nanoparticles, which were synthesized to simulate PM2.5 structures and tested for potential health risks. Based on the calculated nanodescriptors from virtual carbon nanoparticles, quantitative nanostructure-activity relationship (QNAR) models were developed to predict cytotoxicity and four different inflammatory responses induced by model PM2.5. The high predictability (R2 > 0.65 for leave-one-out validations) of the resulted consensus models indicated that this approach could be a universal tool to predict and analyze the potential toxicity of model PM2.5, ultimately understanding and evaluating the ambient PM2.5-induced toxicity.