Synthesis and Evaluation of Ivacaftor Derivatives with Reduced Lipophilicity.

Mutations in the unique ATP-binding cassette anion channel, the cystic fibrosis conductance regulator (CFTR), lead to the inherited fatal disease known as cystic fibrosis (CF). Ivacaftor enhances channel gating of CFTR by stabilizing its open state and has been approved as monotherapy for CF patients with CFTR gating mutations (e.g., G551D) and as part of combination therapy with lumacaftor for CFTR folding mutations (e.g., ΔF508). However, in the latter context, ivacaftor may destabilize folding-rescued ΔF508-CFTR and membrane-associated proteins and attenuate lumacaftor pharmacotherapy. Here, we tested the hypothesis that the high lipophilicity of ivacaftor may contribute to this effect. We describe the synthesis of three glutamic acid ivacaftor derivatives with reduced lipophilicity that bear different charges at neutral pH (compounds 2, 3, 4). In a cellular ion flux assay, all three restored G551D-CFTR channel activity at comparable or better levels than ivacaftor. Furthermore, unlike ivacaftor, compound 3 did not attenuate levels of folding-rescued ΔF508 at the cell surface. Molecular modeling predicts that the increased polarity of compound 3 allows engagement with polar amino acids present in the binding pocket with hydrogen bonding and ionic interactions, which are collectively higher in strength as compared to hydrophobic interactions that stabilize ivacaftor. Overall, the data suggests that reduced lipophilicity may improve the efficacy of this class of CFTR potentiators when used for folding-rescued ΔF508-CFTR.

The unusual suspects: Screening for persistent, mobile, and toxic plastic additives in plastic leachates.

Plastic additives are a diverse group of chemical compounds added to plastic products to give them their unique physical-chemical properties. Persistent, mobile, and toxic (PMT) plastic additives are a highly polar, environmentally stable sub-group of plastic additives with a variety of uses in plastic products. Due to their mobility into water, they can pose a significant long-term risk to the aquatic environment. Despite the potential threat, PMT plastic additives remain largely unregulated and under-studied. Notably, there is a need for dedicated analytical methodology and leaching studies to determine their potential emission from plastic products. Here we present an optimized leaching protocol and novel instrumental analysis method for the screening of 124 PMT plastic additives registered for use in Canada using high performance liquid chromatography with quantitative time-of-flight mass spectrometry (HPLC-QToF-MS). The analytical method covered a log Kow/Dow range between 0.21 and 6.02, which covered 72% of the PMT plastic additives used in Canada. A total of 52 PMT plastic additive suspects were leached in the optimization experiments, 44 of which were unique based on accurate mass and retention time. The conditions that resulted in the greatest numbers of PMT plastic additives leached were lake water, UV light exposure, and a timeframe of approximately 30 days. The analytical and leaching methods presented here offer new tools to study PMT plastic additives and assess their leaching in an environmentally relevant matrix, which can inform monitoring, threat assessment, and regulatory efforts moving forward.

Berlin statement on legacy and emerging contaminants in polar regions.

Polar regions should be given greater consideration with respect to the monitoring, risk assessment, and management of potentially harmful chemicals, consistent with requirements of the precautionary principle. Protecting the vulnerable polar environments requires (i) raising political and public awareness and (ii) restricting and preventing global emissions of harmful chemicals at their sources. The Berlin Statement is the outcome of an international workshop with representatives of the European Commission, the Arctic Council, the Antarctic Treaty Consultative Meeting, the Stockholm Convention on Persistent Organic Pollutants (POPs), environmental specimen banks, and data centers, as well as scientists from various international research institutions. The statement addresses urgent chemical pollution issues in the polar regions and provides recommendations for improving screening, monitoring, risk assessment, research cooperation, and open data sharing to provide environmental policy makers and chemicals management decision-makers with relevant and reliable contaminant data to better protect the polar environments. The consensus reached at the workshop can be summarized in just two words: "Act now!" Specifically, "Act now!" to reduce the presence and impact of anthropogenic chemical pollution in polar regions by. •Establishing participatory co-development frameworks in a permanent multi-disciplinary platform for Arctic-Antarctic collaborations and establishing exchanges between the Arctic Monitoring and Assessment Program (AMAP) of the Arctic Council and the Antarctic Monitoring and Assessment Program (AnMAP) of the Scientific Committee on Antarctic Research (SCAR) to increase the visibility and exchange of contaminant data and to support the development of harmonized monitoring programs. •Integrating environmental specimen banking, innovative screening approaches and archiving systems, to provide opportunities for improved assessment of contaminants to protect polar regions.

Persistent, mobile, and toxic plastic additives in Canada: properties and prioritization.

The hazards of many plastic additives on human and environmental health are well documented. However, little emphasis has been put on plastic additives that are persistent, mobile, and toxic (PMT) rather than persistent, bioaccumulative, and toxic. Due to their high mobility and stability, it is unlikely that wastewater treatment plants will effectively remove PMT plastic additives. Herein, an in silico analysis was performed to (1) assess the retention of PMT plastic additives registered for use in Canada in wastewater treatment plants; and (2) determine whether their physical-chemical properties and structural features can be used as identifiers for PMT plastic additives with particularly low retention. We identified 124 PMT plastic additives of which 52% had less than 20% removal from wastewater treatment based on predictions using the model SimpleTreat. Log Kaw, log Kow/Dow, and log Koc/Doc ranges were defined that are indicative of low retention PMT plastic additives. Furthermore, it was found that non-halogenated PMT plastic additives that contain nitrogen are most likely to be poorly retained in wastewater treatment plants. The results of this study provide screening and prioritization criteria, as well as a suspect list for PMT plastic additives.

Co-contaminants of microplastics in two seabird species from the Canadian Arctic.

Through ingestion and subsequent egestion, Arctic seabirds can bioaccumulate microplastics at and around their colony breeding sites. While microplastics in Arctic seabirds have been well documented, it is not yet understood to what extent these particles can act as transport vehicles for plastic-associated contaminants, including legacy persistent organic pollutants (POPs), trace metals, and organic additives. We investigated the occurrence and pattern of organic and inorganic co-contaminants of microplastics in two seabird species from the Canadian Arctic - northern fulmar (Fulmarus glacialis) and black-legged kittiwake (Rissa tridactyla). We found that fulmars had higher levels of plastic contamination and emerging organic compounds (known to be plastic additives) than kittiwakes, whereas higher concentrations of legacy POPs were found in kittiwakes than the fulmars. Furthermore, fulmars, the species with the much larger foraging range (∼200 km), had higher plastic pollution and overall contaminant burdens, indicating that birds may be acting as long-range transport vectors for plastic-associated pollution. Our results suggest a potential connection between plastic additive contamination and plastic pollution burdens in the bird stomachs, highlighting the importance of treating plastic particles and plastic-associated organic additives as co-contaminants rather than separate pollution issues.

Widespread Occurrence of Non-Extractable Fluorine in Artificial Turfs from Stockholm, Sweden.

Per- and polyfluoroalkyl substances (PFAS) are frequently used in the production of rubber and plastic, but little is known about the identity, concentration, or prevalence of PFAS in these products. In this study, a representative sample of plastic- and rubber-containing artificial turf (AT) fields from Stockholm, Sweden, was subjected to total fluorine (TF), extractable organic fluorine (EOF), and target PFAS analysis. TF was observed in all 51 AT samples (ranges of 16-313, 12-310, and 24-661 µg of F/g in backing, filling, and blades, respectively), while EOF and target PFAS occurred in <42% of all samples (<200 and <1 ng of F/g, respectively). A subset of samples extracted with water confirmed the absence of fluoride. Moreover, application of the total oxidizable precursor assay revealed negligible perfluoroalkyl acid (PFAA) formation across all three sample types, indicating that the fluorinated substances in AT are not low-molecular weight PFAA precursors. Collectively, these results point toward polymeric organofluorine (e.g., fluoroelastomer, polytetrafluoroethylene, and polyvinylidene fluoride), consistent with patent literature. The combination of poor extractability and recalcitrance toward advanced oxidation suggests that the fluorine in AT does not pose an imminent risk to users. However, concerns surrounding the production and end of life of AT, as well as the contribution of filling and blades to environmental microplastic contamination, remain.

Fate-directed risk assessment of chemical mixtures: a case study for cedarwood essential oil.

The environmental risk assessment of UVCBs (i.e., substances of unknown or variable composition, complex reaction products, or biological materials) is challenging due to their inherent complexity. A particular problem is that UVCBs can contain constituents with unidentified chemical structures and/or have variable composition of constituents from batch to batch. Moreover, the composition of a UVCB in the environment is not the same as that of the UVCB in a product, meaning that a risk assessment based on environmental exposure to the UVCB in a product does not represent the actual environmental risk. Here we propose an in silico fate-directed risk assessment framework for UVCBs using cedarwood oil as a case study. The framework uses Monte Carlo simulations and the mass-balance models SimpleTreat and RAIDAR to provide quantitative information on whether unidentified constituents within the physical-chemical property space of a UVCB can be the decisive factor for the environmental risk of the entire UVCB. Thereby the framework provides a robust decision tool to evaluate if a UVCB risk assessment requires additional tests or if the data on known constituents is representative for the risk of the entire UVCB. In the case of cedarwood oil, it could be shown that a risk assessment based on the known constituents (representing around 70% of the overall UVCB by weight) is representative for the environmental risk of the entire UVCB - reducing the need for additional testing and test animals.

Climate change influence on the levels and trends of persistent organic pollutants (POPs) and chemicals of emerging Arctic concern (CEACs) in the Arctic physical environment - a review.

Climate change brings about significant changes in the physical environment in the Arctic. Increasing temperatures, sea ice retreat, slumping permafrost, changing sea ice regimes, glacial loss and changes in precipitation patterns can all affect how contaminants distribute within the Arctic environment and subsequently impact the Arctic ecosystems. In this review, we summarized observed evidence of the influence of climate change on contaminant circulation and transport among various Arctic environment media, including air, ice, snow, permafrost, fresh water and the marine environment. We have also drawn on parallel examples observed in Antarctica and the Tibetan Plateau, to broaden the discussion on how climate change may influence contaminant fate in similar cold-climate ecosystems. Significant knowledge gaps on indirect effects of climate change on contaminants in the Arctic environment, including those of extreme weather events, increase in forests fires, and enhanced human activities leading to new local contaminant emissions, have been identified. Enhanced mobilization of contaminants to marine and freshwater ecosystems has been observed as a result of climate change, but better linkages need to be made between these observed effects with subsequent exposure and accumulation of contaminants in biota. Emerging issues include those of Arctic contamination by microplastics and higher molecular weight halogenated natural products (hHNPs) and the implications of such contamination in a changing Arctic environment is explored.

Pollution in the Arctic Ocean: An overview of multiple pressures and implications for ecosystem services.

The Arctic is undergoing unprecedented change. Observations and models demonstrate significant perturbations to the physical and biological systems. Arctic species and ecosystems, particularly in the marine environment, are subject to a wide range of pressures from human activities, including exposure to a complex mixture of pollutants, climate change and fishing activity. These pressures affect the ecosystem services that the Arctic provides. Current international policies are attempting to support sustainable exploitation of Arctic resources with a view to balancing human wellbeing and environmental protection. However, assessments of the potential combined impacts of human activities are limited by data, particularly related to pollutants, a limited understanding of physical and biological processes, and single policies that are limited to ecosystem-level actions. This manuscript considers how, when combined, a suite of existing tools can be used to assess the impacts of pollutants in combination with other anthropogenic pressures on Arctic ecosystems, and on the services that these ecosystems provide. Recommendations are made for the advancement of targeted Arctic research to inform environmental practices and regulatory decisions.

Combining Headspace Solid-Phase Microextraction with Internal Benchmarking to Determine the Elimination Kinetics of Hydrophobic UVCBs.

Substances classified as unknown or variable composition, complex reaction products or biological origin (UVCB) present a challenge for environmental hazard and risk assessment. Here, we present a novel approach for whole-substance bioconcentration testing applied to cedarwood oil-an essential oil composed of volatile, hydrophobic organic chemicals. The method yields whole-body elimination rate constants for a mixture of constituents. Our approach combines in vivo dietary fish exposure with internal benchmarking and headspace solid-phase microextraction (HS-SPME) equilibrium sampling followed by suspect-screening analysis. We quantified depuration rate constants of 13 individual cedarwood oil constituents based on relative peak areas using gas chromatography (GC) coupled with Orbitrap-mass spectrometry (MS) and GC triple-quadrupole (QqQ)-MS. For seven constituents with available analytical standards, we compared the rate constants to the results obtained from solvent extraction, clean-up, and targeted GC-MS analysis. The HS-SPME sampling approach allowed for automated sample extraction and analyte enrichment while minimizing evaporative losses of the volatile target analytes and reducing matrix interferences from low-volatility organics. The suspect-screening analysis enabled the quantification of constituents without available analytical standards, while the internal benchmarking significantly reduced variability from differences in delivered dose and analytical variability between the samples.

Bioconcentration of cedarwood oil constituents in rainbow trout.

Cedarwood oil is an essential oil used as a fragrance material and insect repellent. Its main constituents are sesquiterpenes which are potentially bioaccumulative according to the REACH screening criteria. Cedarwood oil is a complex mixture of hydrophobic and volatile organic chemicals. The volatility and limited water solubility of its constituents are a challenge for standard bioconcentration factor (BCF) test methods using aqueous exposure. We used an abbreviated dietary exposure in vivo testing protocol with internal benchmark substances as "internal standards" to derive the BCF of cedarwood oil constituents using rainbow trout (Oncorhynchus mykiss). Internal benchmarking proved to be a useful tool to control for inter-individual variability, enabling us to calculate the BCF for all major cedarwood oil constituents as a mixture. We found that the BCF of two out of six analysed cedarwood oil constituents exceed a BCF of 5000 and two others exceed a BCF of 2000 (90% confidence level) even though we found evidence for biotransformation for individual constituents. The results of this study indicate that more work is warranted to study the bioaccumulation of essential oils and highlights the utility of internal benchmarking in in vivo dietary exposure BCF tests to increase robustness and allow for the BCF measurement of complex mixtures.

Organophosphate Esters in the Canadian Arctic Ocean.

Eleven organophosphate esters (OPEs) were detected in surface water and sediment samples from yearly sampling (2013-2018) in the Canadian Arctic. In water samples, ∑chlorinated-OPEs (Cl-OPEs) concentrations exceeded ∑non-chlorinated-OPEs (non-Cl-OPEs) with median concentrations of 10 ng L-1 and 1.3 ng L-1, respectively. In sediment samples, ∑Cl-OPEs and ∑nonchlorinated-OPEs had median concentrations of 4.5 and 2.5 ng g-1, respectively. High concentrations of OPEs in samples from the Mackenzie River plume suggest riverine discharge as an OPE source to the Canadian Arctic. The prevalence of OPEs at other sites is consistent with long-range transport. The OPE inventory of the Canadian Arctic Ocean representative of years 2013-2018 was estimated at 450-16,000 tonnes with a median ∑11OPE mass of 4100 tonnes with >99% of the OPE inventory estimated to be in the water column. These results highlight the importance of OPEs as water-based Arctic contaminants subject to long-range transport and local sources. The high OPE inventory in the water column of the Canadian Arctic Ocean points to the need for international regulatory mechanisms for persistent and mobile organic contaminants (PMOCs) that are not covered by the risk assessment criteria of the Stockholm Convention.

Evaluation of the OECD POV and LRTP screening tool for estimating the long-range transport of organophosphate esters.

Scientists and decision makers need accurate, accessible and fast tools to assess and prioritize the persistence (POV) and environmental long-range transport potential (LRTP) of chemicals. Here we evaluated the Organisation for Economic Co-operation and Development (OECD) POV and LRTP Screening Tool ("the Tool") with respect to the POV and LRTP estimates that the Tool provides for organophosphate esters (OPEs). We found that the use of default parameter values could significantly underestimate POV and LRTP values of OPEs and, potentially, other Persistent Mobile Organic Compounds (PMOCs), by not accounting for episodic atmospheric transport and poleward river-based transport in the northern hemisphere. Specifically, sensitivity and Monte Carlo uncertainty analyses indicate that non-chlorinated OPEs could be subject to LRTP when uncertainties in gas-particle partitioning and its implications for atmospheric degradation are considered, and chlorinated OPEs when river-based transport is considered. Further, the analyses showed strong dependence of results on the accuracy of the environmental half-lives used as input parameters. We suggest that the Tool could be modified to include an optional "Arctic (PMOC) LRTP setting" that incorporates episodic atmospheric and river-based transport as well as decreased environmental half-lives due to cold temperatures.

Regional variations of organophosphorus flame retardants - Fingerprint of large river basin estuaries/deltas in Europe compared with China.

This study reports the occurrence and distribution of organophosphorus flame retardants and plasticizer (OPEs) in sediments of eight large river basin estuaries and deltas across Europe. A robust and sensitive OPE analysis method was developed through the application of an in-cell clean-up in an accelerated solvent extraction and the use of an GC-MSMS System for instrumental analyses. OPEs were detected in all sediment samples with sum concentrations of up to 181 ng g-1 dw. A fingerprinting method was used to identify river specific pattern to compare river systems. The estuaries and deltas were chosen to have a conglomerate print of the whole river. The results are showing very similar OPE patterns across Europe with minor differences driven by local industrial input. The European estuary concentrations and patterns were compared with OPEs detected in the Xiaoquing River in China, as an example for a region with other production, usage and legislative regulations. The Chinese fingerprint differed significant from the overall European pattern.

A user's guide to coping with estuarine management bureaucracy: An Estuarine Planning Support System (EPSS) tool.

Estuaries are amongst the most socio-economically and ecologically important environments however, due to competing and conflicting demands, management is often challenging with a complex legislative framework managed by multiple agencies. To facilitate the understanding of this legislative framework, we have developed a GISbased Estuarine Planning Support System tool. The tool integrates the requirements of the relevant legislation and provides a basis for assessing the current environmental state of an estuary as well as informing and assessing new plans to ensure a healthy estuarine state. The tool ensures that the information is easily accessible for regulators, managers, developers and the public. The tool is intended to be adaptable, but is assessed using the Humber Estuary, United Kingdom as a case study area. The successful application of the tool for complex socio-economic and environmental systems demonstrates that the tool can efficiently guide users through the complex requirements needed to support sustainable development.

Qualification of oil-spill treatment products - Adopting the Baffled Flask Test for testing of dispersant efficacy in the UK.

The UK Marine Management Organisation (MMO) tasked the Centre for Environment, Fisheries & Aquaculture Science (Cefas) with reviewing the current UK dispersant efficacy testing procedures. The aim was to identify possibilities to increase standardisation, improve health and safety performance and explore harmonisation possibilities with international dispersant efficacy testing procedures. The US EPA 'Baffled Flask Test' (BFT) was adopted, implemented and validated as a new standard method in the UK. The outputs from this study suggest that dispersant efficacy results from the adopted BFT test and the currently used protocol are in a similar range and results presented by the US EPA. As a result, the transition to the adopted BFT test will require minimal changes in the assessment of the results or reporting and increase harmonisation between tests used in the UK and North America.

Maternal transfer of dioxin-like compounds in artificially matured European eels.

Several eel species of the genus Anguilla are considered endangered due to a severe decline in recruitment. Up to now, the reasons for this threatening development are not fully understood. The eel's highly specialized biology can lead to explicitly high accumulation of globally distributed organic lipophilic contaminants during its continental life. Because of this and due the particular toxicological sensitivity of early life stages of oviparous organisms towards dioxin-like compounds, it is crucial to improve our understanding concerning toxicokinetics and maternal transfer of organic contaminants in eels. This study presents analytical data on maternal transfer of dioxin-like (dl) compounds in relevant tissue samples taken from artificially matured and non-matured European silver eels (Anguilla anguilla) from German inland waters using gas chromatography coupled with mass spectrometry (GC/MS) and high-resolution mass spectrometry (GC/HRMS). Detected concentrations revealed a lipid-driven transfer of targeted compounds from muscle-fat-reserves to gonads and eggs respectively, with no distinct preferences concerning the chlorination degree of targeted compounds. Dl-PCBs were shown to contribute the major share of toxicity equivalents found in analysed eel tissues. Maternal muscle tissue to egg concentration ratios in wet weight-based samples had a mean of 6.95 ± 1.49 in accordance with the differences in total lipid content in the respective body matrices. Dioxins and furans in analysed samples were (from a toxicological point of view) of less relevance. Furthermore it was shown that muscle concentrations in silver eels could be used in future assessments to make conservative predictions for expected egg concentrations in female eels.

Evidence for High Concentrations and Maternal Transfer of Substituted Diphenylamines in European Eels Analyzed by Two-Dimensional Gas Chromatography-Time-of-Flight Mass Spectrometry and Gas Chromatography-Fourier Transform Ion Cyclotron Resonance Mass Spectrometry.

Chemical pollution is hypothesized to be one of the factors driving the strong decline of the critically endangered European eel population. Specifically, the impact of contaminants on the quality of spawning eels and subsequent embryo survival and development has been discussed as crucial investigation point. However, so far, only very limited information on potential negative effects of contaminants on the reproduction of eels is available. Through the combination of nontargeted ultrahigh-resolution mass spectrometry and multidimensional gas chromatography, combined with more-conventional targeted analytical approaches and multimedia mass-balance modeling, compounds of particular relevance, and their maternal transfer in artificially matured European eels from the German river Ems have been identified. Substituted diphenylamines were, unexpectedly, found to be the primary organic contaminants in the eel samples, with concentrations in the µg g-1 wet weight range. Furthermore, it could be shown that these contaminants, as well as polychlorinated biphenyls (PCBs), organochlorine pesticides, and polyaromatic hydrocarbons (PAHs), are not merely stored in lipid rich tissue of eels but maternally transferred into gonads and eggs. The results of this study provide unique information on both the fate and behavior of substituted diphenylamines in the environment as well as their relevance as contaminants in European eels.

Organophosphate Esters in Canadian Arctic Air: Occurrence, Levels and Trends.

Fourteen organophosphate esters (OPEs) were measured in the filter fraction of 117 active air samples from yearly ship-based sampling campaigns (2007-2013) and two land-based stations in the Canadian Arctic, to assess trends and long-range transport potential of OPEs. Four OPEs were detected in up to 97% of the samples, seven in 50% or less of the samples, and three were not detected. Median concentrations of ∑OPEs were 237 and 50 pg m(-3) for ship- and land-based samples, respectively. Individual median concentrations ranged from below detection to 119 pg m(-3) for ethanol, 2-chloro-, phosphate (3:1) (TCEP). High concentrations of up to 2340 pg m(-3) were observed for Tri-n-butyl phosphate (TnBP) at a land-based sampling location in Resolute Bay from 2012, whereas it was only detected in one ship-based sample at a concentration below 100 pg m(-3). Concentrations of halogenated OPEs seemed to be driven by river discharge from the Nelson and Churchill Rivers (Manitoba) and Churchill River and Lake Melville (Newfoundland and Labrador). In contrast, nonhalogenated OPE concentrations appeared to have diffuse sources or local sources close to the land-based sampling stations. Triphenyl phosphate (TPhP) showed an apparent temporal trend with a doubling-time of 11 months (p = 0.044). The results emphasize the increasing relevance of halogenated and nonhalogenated OPEs as contaminants in the Arctic.