Survey of Appearance and temporal concentrations of polar organic pollutants in Saxon waters.

Integrative passive samplers such as the Chemcatcher are often proposed as alternatives for conventional grab sampling of surface waters. So far, their routine application for regulatory monitoring is hampered (among others) by the fact that TWA concentrations may depend significantly on the design and specifics of the samplers employed. The presented study addresses this issue, focusing on the uptake of polar organic pollutants in three different Chemcatcher configurations and polydimethylsiloxane (PDMS) sheets in the field. Covering waste water treatment plant effluents, creeks, and rivers, samplers were deployed for periods of 14-21 days in eight trials over the course of one year. 33 organic pesticides, 14 transformation products and 31 pharmaceuticals could be detected at least once in TWA concentrations ranging from 0.03 ng/L to 16.5 µg/L. We show that through employing generic, i.e. sampler specific, rather than compound specific sampling rates, the variation among results from three integrative passive sampler designs yields linear correlations with an offset of less than 0.1 and correlation coefficients r2 > 0.8. In this way, TWA concentrations enable the identification of low-concentration xenobiotics of concern, which may support regulatory monitoring correspondingly.

Improvement of binding pose prediction of the MR1 covalent ligands by inclusion of simple pharmacophore constraints and structural waters in the docking process.

The major histocompatibility complex (MHC) class I-related molecule, MR1, is a key component of the immune system, presenting antigens to T-cell receptors (TCRs) and modulating the immune response against various antigens. MR1 possesses a compact ligand-binding pocket despite its ability to interact with ligands that can have either agonistic or antagonistic effects on the immune system. Agonistic ligands can stimulate the immune response, while antagonistic ligands do not elicit an immune response. In most cases, ligand binding to MR1 is mediated through a covalent bond with Lys43. However, recent studies have suggested that a variety of small molecules can interact with the MR1-binding site. In this study, we have used several approaches to improve the binding pose prediction of covalent ligands to MR1, including docking in mutated receptors, and imposing simple pharmacophore constraints and structural water molecules. The careful assignment of pharmacophore constraints and inclusion of structural water molecules in the challenging docking process of covalent docking improved the binding pose prediction and virtual screening performance. In a retrospective virtual screening, the proposed approach exhibited EF1% and EF2% values of 7.4 and 5.5, respectively. Conversely, when using the mutated receptor, both EF1% and EF2% were recorded as 0 for the conventional docking method. The performance of the pharmacophore constraints was also evaluated on other covalent docking cases, and compared to previously reported results for common covalent docking methods. The proposed approach achieved an average RMSD of 2.55, while AutoDock4, CovDock, FITTED, GOLD, ICM-Pro, and MOE exhibited average RMSD values of 3.0, 2.93, 3.04, 4.93, 2.44, and 3.36, respectively. Our results demonstrate that the inclusion of simple pharmacophore constraints and structural waters can improve the prediction of binding poses of covalent ligands to MR1, which can aid in the discovery of novel immunotherapeutic agents. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03694-w.

Insight into the Mechanism Underlying Dehalococcoides mccartyi Strain CBDB1-Mediated B12-Dependent Aromatic Reductive Dehalogenation.

Anaerobic bacteria transform aromatic halides through reductive dehalogenation. This dehalorespiration is catalyzed by the supernucleophilic coenzyme vitamin B12, cob(I)alamin, in reductive dehalogenases. So far, the underlying inner-sphere electron transfer (ET) mechanism has been discussed controversially. In the present study, all 36 chloro-, bromo-, and fluorobenzenes and full-size cobalamin are analyzed at the quantum chemical density functional theory level with respect to a wide range of theoretically possible inner-sphere ET mechanisms. The calculated reaction free energies within the framework of CoI···X (X = F, Cl, and Br) attack rule out most of the inner-sphere pathways. The only route with feasible energetics is a proton-coupled two-ET mechanism that involves a B12 side-chain tyrosine (modeled by phenol) as a proton donor. For 12 chlorobenzenes and 9 bromobenzenes with experimental data from Dehalococcoides mccartyi strain CBDB1, the newly proposed PC-TET mechanism successfully discriminates 16 of 17 active from 4 inactive substrates and correctly predicts the observed regiospecificity to 100%. Moreover, fluorobenzenes are predicted to be recalcitrant in agreement with experimental findings. Conceptually, based on the Bell-Evans-Polanyi principle, the computational approach provides novel mechanistic insights and may serve as a tool for predicting the energetic feasibility of reductive aromatic dehalogenation.

New approach methods to improve human health risk assessment of thyroid hormone system disruption-a PARC project.

Current test strategies to identify thyroid hormone (TH) system disruptors are inadequate for conducting robust chemical risk assessment required for regulation. The tests rely heavily on histopathological changes in rodent thyroid glands or measuring changes in systemic TH levels, but they lack specific new approach methodologies (NAMs) that can adequately detect TH-mediated effects. Such alternative test methods are needed to infer a causal relationship between molecular initiating events and adverse outcomes such as perturbed brain development. Although some NAMs that are relevant for TH system disruption are available-and are currently in the process of regulatory validation-there is still a need to develop more extensive alternative test batteries to cover the range of potential key events along the causal pathway between initial chemical disruption and adverse outcomes in humans. This project, funded under the Partnership for the Assessment of Risk from Chemicals (PARC) initiative, aims to facilitate the development of NAMs that are specific for TH system disruption by characterizing in vivo mechanisms of action that can be targeted by in embryo/in vitro/in silico/in chemico testing strategies. We will develop and improve human-relevant in vitro test systems to capture effects on important areas of the TH system. Furthermore, we will elaborate on important species differences in TH system disruption by incorporating non-mammalian vertebrate test species alongside classical laboratory rat species and human-derived in vitro assays.

Amino Chemoassay Profiling of Aromatic Aldehydes-Unraveling Drivers of Their Skin Sensitization Potency.

Aromatic aldehydes are ubiquitous in humans' everyday life. As aldehydes, they can form imines (Schiff bases) with amino groups of skin proteins, leading to immune response-triggered allergic contact dermatitis. Many known aromatic aldehydes are considered as weak or nonsensitizers, but others like atranol and chloratranol, two components of the fragrance oak moss absolute, show strong sensitization potency. This large discrepancy in potency and, in particular, the underlying reaction mechanisms are only little understood so far. To reduce this knowledge gap, our chemoassay employing glycine-para-nitroanilide (Gly-pNA) as an amino model nucleophile was applied to 23 aromatic aldehydes. The determined Gly-pNA second-order rate constants for imine formation (k1 ≤ 2.85 L·mol-1·min-1) and the imine stability constant (K ≤ 333 L·mol-1) are on the lower end of the known amino reactivity scale for aldehydes, confirming many aromatic aldehydes as less potent sensitizers in line with animal and human data. The substantially higher sensitization potency of atranol and chloratranol, in turn, is reflected by their unique reaction chemistry profiles, inter alia, identifying them as cross-linkers able to form thermodynamically more stable epitopes with skin proteins (despite low formation kinetics, k1). The discussion further includes a comparison of experimentally determined k1 values with computed reactivity data (Taft σ*), the impact of the substitution pattern of the aryl ring on the reactivity with Gly-pNA, and analytically determined adduct patterns. Overall, this work provides new insights into the reaction of aromatic aldehydes with amino groups under aqueous conditions and fosters a better understanding of the chemistry underlying skin sensitization.

Mechanistic insight into the Dehalococcoides-mediated reductive dechlorination of polychlorinated biphenyls.

Microbial reductive dechlorination provides a green and highly desirable approach to address the pollution raised by the substantial legacies of polychlorinated biphenyls (PCBs) in soil, sediment, and underground water. It has been shown that the reaction event is catalyzed by supernucleophilic cob(I)alamin housed in reductive dehalogenases (RDases). However, the mechanism still remains elusive. Herein, we unravel the mechanism via quantum chemical calculations, considering a general model of RDase and the dechlorination regioselectivity of two representative PCB congeners, 234-236-CB and 2345-236-CB. The B12-catalzyed reductive dechlorination of PCBs starts with the formation of a reactant complex, followed by a proton-coupled two-electron transfer (PC-TET) and a subsequent single-electron transfer (SET). The PC-TET yields a cob(III)alamin-featured intermediate, which is quickly reduced by the latter SET fueled by significant energetic benefits (∼100 kcal mol-1). It rationalizes the exclusive detection and characterization of cob(I/II)alamins in RDase-mediated dehalogenation experiments. The determined mechanism successfully reproduces the experimental dechlorination regioselectivity and reactivity, as observed with Dehalococcoides mccartyi strain CG1.

Calibration of the Chemcatcher® passive sampler and derivation of generic sampling rates for a broad application in monitoring of surface waters.

We determined sampling rates for 34 pesticides, five pesticide transformation products, and 34 pharmaceutical compounds with the Chemcatcher (CC) passive sampler in a laboratory-based continuous-flow system at 40 cm/s and ambient temperature. Three different sampling phases were used: styrene divinylbenzene disks (SDB-XC), styrene divinylbenzene reversed phase sulfonate disks (SDB-RPS), and hydrophilic lipophilic balance disks (HLB), in all cases covered with a diffusion-limiting polyethersulfone membrane. The measured sampling rates range from 0.007 L/d to 0.193 L/d for CC with SDB-XC (CC-XC), from 0.055 L/d to 0.796 L/d for CC with SDB-RPS (CC-RPS), and from 0.018 L/d to 0.073 L/d for CC equipped with HLB (CC-HLB). Comparison with sampling rates from literature enabled to derive generic sampling rates that can be used for compounds with unknown uptake kinetics such as transformations products and new compounds of interest. Field trial results demonstrate that the presently derived generic sampling rates are suitable for estimating time-weighted average concentrations within reasonable uncertainty limits. In this way, Chemcatcher passive sampling can be applied approximately to a broad range of solutes without the need for deriving compound-specific sampling rates, which enable compliance checks against environmental quality standards and further risk assessment.

Bottom-Up Synthesis of De-Functionalized and Dispersible Carbon Spheres as Colloidal Adsorbent.

Recent innovative adsorption technologies for water purification rely on micrometer-sized activated carbon (AC) for ultrafast adsorption or in situ remediation. In this study, the bottom-up synthesis of tailored activated carbon spheres (aCS) from sucrose as renewable feedstock is demonstrated. The synthesis is based on a hydrothermal carbonization step followed by a targeted thermal activation of the raw material. This preserves its excellent colloid properties, i.e., narrow particle size distribution around 1 µm, ideal spherical shape and excellent aqueous dispersibility. We investigated the ageing of the freshly synthesized, highly de-functionalized AC surface in air and aqueous media under conditions relevant to the practice. A slow but significant ageing due to hydrolysis and oxidation reactions was observed for all carbon samples, leading to an increase of the oxygen contents with storage time. In this study, a tailored aCS product was generated within a single pyrolysis step with 3 vol.-% H2O in N2 in order to obtain the desired pore diameters and surface properties. Adsorption characteristics, including sorption isotherms and kinetics, were investigated with monochlorobenzene (MCB) and perfluorooctanoic acid (PFOA) as adsorbates. The product showed high sorption affinities up to log (KD/[L/kg]) of 7.3 ± 0.1 for MCB and 6.2 ± 0.1 for PFOA, respectively.

Baseline Narcosis for the Glass-Vial 96-h Growth Inhibition of the Nematode C. elegans and Its Use for Identifying Electrophilic and Pro-Electrophilic Toxicity.

The nematode Caenorhabditis elegans has been widely used as a model organism for assessing chemical toxicity. So far, however, a respective baseline narcosis reference has been lacking to predict narcosis-level toxicity and to identify excess-toxic compounds and associated mechanisms of action. Employing 22 organic narcotics that cover 7.2 units of their log Kow (octanol/water partition coefficient) from -1.20 to 6.03, a baseline narcosis model has been derived for a glass-vial 96-h growth inhibition test with C. elegans, both without and with correction for compound loss through volatilization and sorption. The resultant effective concentrations yielding 50% growth inhibition, EC50, vary by 6.4 log units from 5.04 · 10-1 to 1.90 · 10-7 mol/L (exposure-corrected). Application of the new model is illustrated through sensing the toxicity enhancement (Te) of four Michael-acceptor carbonyls driven by their reactive mode of action. Moreover, narcosis-level predicted vs experimental EC50 of two α,ß-unsaturated alcohols demonstrate the biotransformation capability of C. elegans regarding ADH (alcohol dehydrogenase). The discussion includes narcosis-level and excess-toxicity doses (critical body burdens) as well as chemical activities A50 (at the EC50) as compared to fish, daphnids, ciliates, bacteria, zebrafish embryo, and cell lines. Overall, the presently introduced model for predicting C. elegans baseline narcosis enables generating respective pre-test expectations, enriches experimental results by mechanistic information, and may complement 3Rs (reduce, refine, replace) test batteries through its ADH metabolic capacity.

Octanol/Air Partition Coefficient─A General-Purpose Fragment Model to Predict Log Koa from Molecular Structure.

The octanol/air partition coefficient Koa is important for assessing the bioconcentration of airborne xenobiotics in foliage and in air-breathing organisms. Moreover, Koa informs about compound partitioning to aerosols and indoor dust, and complements the octanol/water partition coefficient Kow and the air/water partition coefficient Kaw for multimedia fate modeling. Experimental log Koa at 25 °C has been collected from literature for 2161 compounds with molecular weights from 16 to 959 Da. The curated data set covers 18.2 log units (from -1.0 to 17.2). A newly developed fragment model for predicting log Koa from molecular structure outperforms COSMOtherm, EPI-Suite KOAWIN, OPERA, and linear solvation energy relationships (LSERs) regarding the root-mean-squared error (rms) and the maximum negative and positive errors (mne and mpe) (rms: 0.57 vs 0.86 vs 1.09 vs 1.19 vs 1.05-1.53, mne: -2.55 vs -3.95 vs -7.51 vs -7.54 vs (-5.63) - (-7.34), mpe: 2.91 vs 5.97 vs 7.54 vs 4.24 vs 6.89-10.2 log units). The prediction capability, statistical robustness, and sound mechanistic basis are demonstrated through initial separation into a training and prediction set (80:20%), mutual leave-50%-out validation, and target value scrambling in terms of temporarily wrong compound-Koa allocations. The new general-purpose model is implemented in a fully automatized form in the ChemProp software available to the public. Regarding Koa indirectly determined through Kow and Kaw, a new approach is developed to convert from wet to dry octanol, enabling higher consistency in experimental (and thus also predicted) Koa.

Henry's Law Constant─A General-Purpose Fragment Model to Predict Log Kaw from Molecular Structure.

Henry's law constant is important for assessing the environmental fate of organic compounds, including polar accumulation, indoor contamination, and the impact of airborne predominance on persistence. Moreover, it can be used in the context of alternative 3R bioassays to inform about the compound loss through volatilization as a confounding factor. For 2636 compounds, curated experimental log Kaw (air/water partition coefficient) data at 25° covering 23.6 orders of magnitude (from -18.6 to 5.0) have been collected from the literature. Subsequently, a new fragment model for predicting log Kaw from molecular structures has been developed. According to the root-mean-squared error (rms) and the maximum negative and positive errors (mne and mpe), this general-purpose model outperforms COSMOtherm, EPISuite HENRYWIN, OPERA, and LSER with calculated input parameters significantly (rms 0.50 vs 0.92 vs 1.25 vs 1.28 vs 1.38, mne -2.74 vs -6.78 vs -9.11 vs -6.24 vs -6.27, mpe 2.25 vs 6.22 vs 8.27 vs 11.5 vs 7.69 log units). Initial separation into a training and prediction set (80%:20%), mutual leave-50%-out validation, and target value scrambling (temporarily wrong compound-Kaw allocations) demonstrate the prediction capability, statistical robustness, and mechanistically sound basis of the fragment scheme. The new model is available to the public in fully computerized form through the ChemProp software, and can be combined with a separate existing model to extend the log Kaw prediction to temperatures different from 25 °C.

The Eco-Exposome Concept: Supporting an Integrated Assessment of Mixtures of Environmental Chemicals.

Organisms are exposed to ever-changing complex mixtures of chemicals over the course of their lifetime. The need to more comprehensively describe this exposure and relate it to adverse health effects has led to formulation of the exposome concept in human toxicology. Whether this concept has utility in the context of environmental hazard and risk assessment has not been discussed in detail. In this Critical Perspective, we propose-by analogy to the human exposome-to define the eco-exposome as the totality of the internal exposure (anthropogenic and natural chemicals, their biotransformation products or adducts, and endogenous signaling molecules that may be sensitive to an anthropogenic chemical exposure) over the lifetime of an ecologically relevant organism. We describe how targeted and nontargeted chemical analyses and bioassays can be employed to characterize this exposure and discuss how the adverse outcome pathway concept could be used to link this exposure to adverse effects. Available methods, their limitations, and/or requirement for improvements for practical application of the eco-exposome concept are discussed. Even though analysis of the eco-exposome can be resource-intensive and challenging, new approaches and technologies make this assessment increasingly feasible. Furthermore, an improved understanding of mechanistic relationships between external chemical exposure(s), internal chemical exposure(s), and biological effects could result in the development of proxies, that is, relatively simple chemical and biological measurements that could be used to complement internal exposure assessment or infer the internal exposure when it is difficult to measure. Environ Toxicol Chem 2022;41:30-45. © 2021 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Outer-sphere electron transfer does not underpin B12-dependent olefinic reductive dehalogenation in anaerobes.

Anaerobic microbial B12-dependent reductive dehalogenation may pave a way to remediate soil, sediment, and underground water contaminated with halogenated olefins. The chemical reaction is initiated by electron transfer (ET) from supernucleophilic cob(I)alamin (B12s). However, the inherent mechanism as outer-sphere or inner-sphere route is still under debate. To clarify the possibility of an outer-sphere pathway, we calculated free energy barriers of the initial steps of all outer-sphere ET routes by Marcus theory employing density functional theory (DFT). For 18 fluorinated, chlorinated, and brominated ethenes as representative olefins, 164 of 165 reactions with free energy barriers larger than 20 kcal mol-1 are not feasible under physiological dehalogenase conditions. Moreover, electronic structure analysis of perbromoethene with an outer-sphere free energy barrier of 18.2 kcal mol-1 reveals no ET initiation down to Co⋯Br and Co⋯C distances of 3.15 Å. The results demonstrate that the B12-catalyzed reductive dechlorination of olefins in microbes should proceed through an inner-sphere ET pathway.

Amino Reactivity of Glutardialdehyde and Monoaldehydes─Chemoassay Profile vs Skin Sensitization Potency.

Chemoassay profiling of organic electrophiles through the direct peptide reactivity assay has become an OECD-accepted nonanimal component in the REACH evaluation of potential skin sensitizers. For aldehydes forming imines (Schiff bases), however, existing chemoassays yielded inconclusive results, indicating issues with their NH2 sensitivity and the reversibility of the reaction. In the present study, a new kinetic chemoassay employing the N terminus of glycine-para-nitroanilide, Gly-pNA, as a model nucleophile for protein NH2 groups is introduced and applied to nine aliphatic monoaldehydes and glutardialdehyde (1,5-pentanedial) that have log Kow (octanol/water partition coefficient) values from 0.63 to 3.99. The Gly-pNA second-order rate constants k1 range from 8.56 to 150 L·mol-1·min-1 for the monoaldehydes. Interestingly, glutardialdehyde with a k1 of 17 731 L·mol-1·min-1 is 170-fold more reactive than its monoaldehyde counterpart pentanal. This can be rationalized by hydration or tautomerization of the dialdehyde to monoaldehydic forms, now facilitating Schiff base formation through an intramolecular H bond. Comparison with murine local lymph node assay data from the literature reveals that adduct stability in terms of reaction thermodynamics (K = k1/k-1pseudo) rather than formation kinetics (k1) governs the skin sensitization potency of Schiff-base-forming aldehydes. The discussion includes analytically determined adduct patterns, and the impact of α- and ß-carbon substitution as well as hydrophobicity on aldehyde reactivity.

Pesticides are the dominant stressors for vulnerable insects in lowland streams.

Despite elaborate regulation of agricultural pesticides, their occurrence in non-target areas has been linked to adverse ecological effects on insects in several field investigations. Their quantitative role in contributing to the biodiversity crisis is, however, still not known. In a large-scale study across 101 sites of small lowland streams in Central Europe, Germany we revealed that 83% of agricultural streams did not meet the pesticide-related ecological targets. For the first time we identified that agricultural nonpoint-source pesticide pollution was the major driver in reducing vulnerable insect populations in aquatic invertebrate communities, exceeding the relevance of other anthropogenic stressors such as poor hydro-morphological structure and nutrients. We identified that the current authorisation of pesticides, which aims to prevent unacceptable adverse effects, underestimates the actual ecological risk as (i) measured pesticide concentrations exceeded current regulatory acceptable concentrations in 81% of the agricultural streams investigated, (ii) for several pesticides the inertia of the authorisation process impedes the incorporation of new scientific knowledge and (iii) existing thresholds of invertebrate toxicity drivers are not protective by a factor of 5.3 to 40. To provide adequate environmental quality objectives, the authorisation process needs to include monitoring-derived information on pesticide effects at the ecosystem level. Here, we derive such thresholds that ensure a protection of the invertebrate stream community.

Calibration and field application of the Atlantic HLB Disk containing Chemcatcher® passive sampler - Quantitative monitoring of herbicides, other pesticides, and transformation products in German streams.

The Chemcatcher® (CC) passive sampler containing an Atlantic HLB-L Disk (AD) was calibrated in a laboratory-based flow-through tank over 21 days under stirring for 38 polar organic pesticides with log Kow ranging from -1.7 to 3.8. The resultant sampling rates Rs range from 0.025 to 0.068 L/d. In 2018, field trials were conducted in the German rivers Mulde and Havel, as well as in 7 agricultural streams in Lower Saxony and Saxony-Anhalt. For 36 detected pesticides, the overall low concentrations were 0.2 to 49.4 ng/L. The determined pesticide profiles reflect agricultural use and were dominated by triazine herbicides including transformation products, by neonicotinoid insecticides, and by the herbicide mecoprop. Additional single hot spots were provided by the herbicides metamitron, isoproturon, and MCPA (showing the overall largest value of 49.4 ng/L). Notably, the detected waterborne pesticides include banned herbicides and associated transformation products in concentration ratios suggesting also recent input. This concerns in particular atrazine and its transformation products 2-OH-atrazine, deethylatrazine and deisopropylatrazine. An extended target screening of AD-CC extracts from the river Havel revealed the additional presence of other organic micropollutants including biocides, surfactants and industrial chemicals, and demonstrated the AD-CC applicability up to log Kow of 4.5.

Dehalococcoides-Mediated B12-Dependent Reductive Dehalogenation of Aromatics Does Not Proceed through Outer-Sphere Electron Transfer.

Several anaerobic bacteria can couple the reduction of aromatic halides to energy conservation. This organohalide respiration is catalyzed by enzymes containing cob(I)alamin, an activated supernucleophilic form of the coenzyme vitamin B12. However, the mechanism underlying the electron transfer (inner-sphere vs outer-sphere ET) still remains elusive. To clarify this issue, we selected 36 fluoro-, chloro-, and bromobenzenes as representative substrates and calculated their free-energy barriers at the quantum chemical density functional theory level, considering a wide range of theoretically possible outer-sphere ET mechanisms. Across all 336 reaction routes addressed, 334 routes involve free-energy barriers larger than 20 kcal/mol. For two reaction routes with highly brominated benzenes, free-energy barriers below 20 kcal/mol imply abiotic reduction as observed in experiments. Thus, microbial B12-dependent aromatic reductive dehalogenation does not proceed through an outer-sphere ET mechanism. Instead, the present study strongly suggests that microbe-catalyzed reductive dehalogenation of aromatic halides is governed by inner-sphere ET.

In Silico Finding of Key Interaction Mediated α3ß4 and α7 Nicotinic Acetylcholine Receptor Ligand Selectivity of Quinuclidine-Triazole Chemotype.

The selective binding of six (S)-quinuclidine-triazoles and their (R)-enantiomers to nicotinic acetylcholine receptor (nAChR) subtypes α3ß4 and α7, respectively, were analyzed by in silico docking to provide the insight into the molecular basis for the observed stereospecific subtype discrimination. Homology modeling followed by molecular docking and molecular dynamics (MD) simulations revealed that unique amino acid residues in the complementary subunits of the nAChR subtypes are involved in subtype-specific selectivity profiles. In the complementary ß4-subunit of the α3ß4 nAChR binding pocket, non-conserved AspB173 through a salt bridge was found to be the key determinant for the α3ß4 selectivity of the quinuclidine-triazole chemotype, explaining the 47-327-fold affinity of the (S)-enantiomers as compared to their (R)-enantiomer counterparts. Regarding the α7 nAChR subtype, the amino acids promoting a however significantly lower preference for the (R)-enantiomers were the conserved TyrA93, TrpA149 and TrpB55 residues. The non-conserved amino acid residue in the complementary subunit of nAChR subtypes appeared to play a significant role for the nAChR subtype-selective binding, particularly at the heteropentameric subtype, whereas the conserved amino acid residues in both principal and complementary subunits are essential for ligand potency and efficacy.

Development of Novel Analogs of the Monocarboxylate Transporter Ligand FACH and Biological Validation of One Potential Radiotracer for Positron Emission Tomography (PET) Imaging.

Monocarboxylate transporters 1-4 (MCT1-4) are involved in several metabolism-related diseases, especially cancer, providing the chance to be considered as relevant targets for diagnosis and therapy. [18F]FACH was recently developed and showed very promising preclinical results as a potential positron emission tomography (PET) radiotracer for imaging of MCTs. Given that [18F]FACH did not show high blood-brain barrier permeability, the current work is aimed to investigate whether more lipophilic analogs of FACH could improve brain uptake for imaging of gliomas, while retaining binding to MCTs. The 2-fluoropyridinyl-substituted analogs 1 and 2 were synthesized and their MCT1 inhibition was estimated by [14C]lactate uptake assay on rat brain endothelial-4 (RBE4) cells. While compounds 1 and 2 showed lower MCT1 inhibitory potencies than FACH (IC50 = 11 nM) by factors of 11 and 25, respectively, 1 (IC50 = 118 nM) could still be a suitable PET candidate. Therefore, 1 was selected for radiosynthesis of [18F]1 and subsequent biological evaluation for imaging of the MCT expression in mouse brain. Regarding lipophilicity, the experimental log D7.4 result for [18F]1 agrees pretty well with its predicted value. In vivo and in vitro studies revealed high uptake of the new radiotracer in kidney and other peripheral MCT-expressing organs together with significant reduction by using specific MCT1 inhibitor α-cyano-4-hydroxycinnamic acid. Despite a higher lipophilicity of [18F]1 compared to [18F]FACH, the in vivo brain uptake of [18F]1 was in a similar range, which is reflected by calculated BBB permeabilities as well through similar transport rates by MCTs on RBE4 cells. Further investigation is needed to clarify the MCT-mediated transport mechanism of these radiotracers in brain.

Computational material flow analysis for thousands of chemicals of emerging concern in European waters.

Knowledge of exposure to a wide range of chemicals, and the spatio-temporal variability thereof, is urgently needed in the context of protecting and restoring aquatic ecosystems. This paper discusses a computational material flow analysis to predict the occurrence of thousands of man-made organic chemicals on a European scale, based on a novel temporally and spatially resolved modelling framework. The goal was to increase understanding of pressures by emerging chemicals and to complement surface water monitoring data. The ambition was to provide a first step towards a "real-life" mixture exposure situation accounting for as many chemicals as possible. Comparison of simulated concentrations and chemical monitoring data for 226 substance/basin combinations showed that the simulated concentrations were accurate on average. For 65% and 90% of substance/basin combinations the error was within one and two orders of magnitude respectively. An analysis of the relative importance of uncertainties revealed that inaccuracies in use volume or use type information contributed most to the error for individual substances. To resolve this, we suggest better registration of use types of industrial chemicals, investigation of presence/absence of industrial chemicals in wastewater and runoff samples and more scientific information exchange.