Ecotoxicological assessment of biomass-derived furan platform chemicals using aquatic and terrestrial bioassays.

An environmental toxicological assessment of fourteen furanic compounds serving as valuable building blocks produced from biomass was performed. The molecules selected included well studied compounds serving as control examples to compare the toxicity exerted against a variety of highly novel furans which have been additionally targeted as potential or current alternatives to biofuels, building blocks and polymer monomers. The impact of the furan platform chemicals targeted on widely applied ecotoxicity model organisms was determined employing the marine bioluminescent bacterium Aliivibrio fischeri and the freshwater green microalgae Raphidocelis subcapitata, while their ecotoxicity effects on plants were assessed using dicotyledonous plants Sinapis alba and Lepidium sativum. Regarding the specific endpoints evaluated, the furans tested were slightly toxic or practically nontoxic for A. fischeri following 5 and 15 min of exposure. Moreover, most of the building blocks did not affect the growth of L. sativum and S. alba at 150 mg L-1 for 72 h of exposure. Specifically, 9 and 11 out of the 14 furan platform chemicals tested were non-effective or stimulant for L. sativum and S. alba respectively. Given that furans comprise common inhibitors in biorefinery fermentations, the growth inhibition of the specific building blocks was studied using the industrial workhorse yeast Saccharomyces cerevisiae, demonstrating insignificant inhibition on eukaryotic cell growth following 6, 12 and 16 h of exposure at a concentration of 500 mg L-1. The study provides baseline information to unravel the ecotoxic effects and to confirm the green aspects of a range of versatile biobased platform molecules.

Assessment of the health risks associated with the consumption of bivalve mollusks potentially contaminated with phycotoxins from the coastal ecosystem of the Ebrié lagoon, Côte d'Ivoire.

This work focused on assessing of the risk associated with the consumption of bivalve mollusks, potentially contaminated with phycotoxins. The studied phycotoxins are saxitoxin (STX), okadaic acid (OA), dinophysistoxins (DTXs), yessotoxins (YTXs), pectenotoxins (PTX), azaspiracids (AZAs), and domoic acid (DA). These toxins were investigated in three species of bivalve mollusks (Anadara senilis, Crassostrea gasar, and Perna perna), originating from the Ebrié lagoon. Chemical analyses were carried out by LC-MS/MS, HPLC-FLD, and HPLC-UV. The level of OA and DTXs, STX, and DA was 10.92 µg OA eq./kg, 9.6 µg STX eq./kg, and 0.17 mg DA eq./kg, respectively. The level of PTXs and AZAs was 3.3 µg PTX-2 eq./kg and 13.86 µg AZA-1 eq./kg; that of YTXs was 0.01 mg YTX eq./kg. The daily exposure dose (DED) was 0.019 µg OA eq./kg bw for OA and DTXs; 0.285 µg DA eq./kg bw for DA; 0.006 µg PTX-2 eq./kg bw for PTXs; 0.016 µg STX eq./kg bw for STX; 0.01 µg YTX eq./kg bw for YTXs; and 0.024 µg AZA-1 eq./kg bw for AZAs for the oyster Crassostrea gasar. These estimated values are lower than the acute reference dose (ARfD) of each phycotoxin recommended by the European Food Safety Agency (EFSA). The risk of harmful effects is acceptable. The absence of risk is valid only for the study period (11 months) and concerns coastal populations living near the sampling points.

Do GC/MS methods available for furan and alkylfurans in food provide comparable results? - An interlaboratory study and safety assessment of 2-pentylfuran in food.

A call for data on the occurrence of alkylfurans in food and feed from EFSA triggered the development of new methods to cover next to furan also 2- and 3-methylfuran, 2,5-dimethyl- and 2-ethylfuran as well as 2-pentylfuran. A significant variability was noticed when comparing analysis of 2-pentylfuran and furans in the same matrix performed by different laboratories. To assess the variability an interlaboratory study including eight laboratories was organised. The highest variabilities were observed when analysing cereals, with measurements of 2-pentylfuran indicating concentrations from 8 mg/kg up to more than 1000 mg/kg in the same sample. This study illustrates that the analysis of 2-pentylfuran requires special attention, and that additional method development would be necessary to ensure reliable and reproducible determination of 2-pentylfuran at contamination level. Moreover, a recent evaluation of the EFSA Panel on Food Additives and Flavourings indicates that concerns for genotoxicity, reason why it was grouped with the shorter alkylfurans, are now ruled out. We question the need and justification to include 2-pentylfuran in the analytical method as requested by EFSA, from both the analytical and the safety perspective.

Polychlorinated biphenyls and polychlorinated dibenzo-p-dioxins and furans in imported canned fish in Nigeria and risk assessment.

Concentrations of polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) were measured in imported canned fish such as mackerel, sardine and tuna to evaluate the risk relating to human consumption of these products. Gas chromatography-mass spectrometry (GC/MS) was used to evaluate the concentrations of PCBs and PCDD/Fs in the samples. The ∑28 PCB concentrations in the canned mackerel, tuna and sardine ranged from 0.33 to 9.48 ng g -1,

Determination of the relative potencies of brominated dioxins for risk assessment in aquatic environments using the early-life stage of Japanese medaka.

World Health Organization toxic equivalency factors (WHO-TEFs) are recommended for risk management of brominated dioxins in aquatic environments because limited information is available on their toxicity to fish. To validate this approach, we obtained the relative potencies of polybrominated dibenzo-p-dioxins and polybrominated dibenzofurans and mixed-halogenated furans (PXDF, X = Cl/Br) against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on their toxicity to the early-life stage of Japanese medaka (Oryzias latipes). 2,3,7,8-substituted brominated dibenzofurans caused typical dioxin exposure effects, such as blue-sac disease. The TCDD-relative potency factors (REPs) of test substances were calculated based on the concentrations in water and eggs that caused 20% lethality on day 28 post-fertilization, and were in the order of: 2-chloro-3,7,8-tribromodibenzofuran (REPwater 3.3, REPegg 4.6) > 2,3,7,8-tetrabromodibenzofuran (0.85, 0.92) > 2,3,4,7,8-pentabromodibenzofuran (0.053, 0.55) > 1,2,3,7,8-pentabromodibenzofuran (0.0091, 0.19). The transfer rate from water to eggs was lower for pentabrominated furans than tetrabrominated congeners, and was expected to decrease with the log Kow of the test substance. Although the REPegg value can be used to compare the toxicity potential of brominated dioxins, REPwater may be more suitable for environmental risk assessment because the uptake potential of these compounds from water should be considered. This study is the first to report higher toxicity of a PXDF congener compared with TCDD in vivo, further investigations of the toxicity of mixed-halogenated dioxins and environmental behavior are necessary for environmental risk assessment.

Gas chromatography-triple quadrupole mass spectrometry as a cost-effective method for the determination of polychlorinated dibenzo-p-dioxins and furans in contaminated soils.

The aim of this study was to evaluate the performance of gas chromatography (GC)-triple quadrupole mass spectrometry (QqQ, MS/MS) as an alternative to the standard GC-high resolution mass spectrometry (GC-HR/MS) for soils contaminated with polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). GC-QqQ (MS/MS) using a dynamic multiple reaction monitoring (dMRM) mode was optimized for the quantitative analysis of 17 PCDD/Fs. A comparative study between GC-QqQ (MS/MS) and GC-HR/MS was carried out to validate the results of actual field soil samples. Although GC-HR/MS has excellent sensitivity and selectivity, the validation parameters obtained by GC-QqQ (MS/MS) also met the recommended criteria of the standard method. The results for total and I-TEQ (international toxic equivalent) value of the PCDD/F concentrations of over 86.0 pg/g and 4.3 pg I-TEQ/g, respectively, in actual field soil samples showed good agreement between the two methods, falling within ±25% relative difference. In consideration of the remediation goal (100 pg I-TEQ/g), GC-QqQ (MS/MS) can be an alternative cost-effective method for use in soil remediation research.

Health risk assessment to polychlorinated naphthalenes dioxin-like compounds in French sea food consumers.

There has been a recent revival of interest in some historical contaminants such as polychlorinated naphthalenes (PCNs). However, occurrence data are still lacking in some countries although industrial production of PCNs has been reported. This observation led to the first ever assessment of their presence in fish and seafood products in France in the present work. Their analysis was integrated in an already validated method applied for polychlorinated dibenzodioxins/furans (PCDD/Fs) and polychlorinated biphenyls (PCBs), based on the structural similarity existing between these POPs. Performances of the method (LODs in the range 0.10-0.28 pg g-1 wet weight (ww), LOQs in the range 0.33-0.93 pg g-1 ww), enabled monitoring 69 di-to octachlorinated congeners in a large representative set of fish and seafood samples collected in 2005 in four coastal areas of the French mainland (n > 30). Their systematic presence was demonstrated in all the investigated seafood products, with levels (ΣPCNs in the range 2-440 pg g-1 wet weight) close to those already reported in other European fish and seafood sampled at a similar period. In addition, the robust measurement of almost all possible PCNs (69/75) allowed a fine interpretation of the observed profiles, highlighting in particular the specificities between species and fishing areas. Compared to the PCDD/Fs, PCBs, and polybrominated diphenylethers levels also measured for this set of samples, PCNs were observed as minor contributors to total concentrations (0.05-3.2%). The specific PCN related dietary dioxin-like exposure could be evaluated at 0.028-0.051 pg of toxic equivalent (TEQ) per kg of body weight per week for an adult, based on fish and seafood consumption only. Overall, this study provides the first baseline data on the occurrence of a large number of PCNs in France, which will allow future evaluation of temporal trends and associated risks.

Exploitation of distillation region diagrams for energy-efficient and cost-effective treatment of a hazardous effluent discharged from semi-conductor industries.

The hazardous nature of certain azeotropic mixtures has urged the researchers to explore the separation techniques which can impart a contamination free environment. Despite of causing environmental concerns, these azeotropic mixtures are responsible for causing serious health issues to humans and animals. More specifically, in this article, we have taken Tetrahydrofuran (THF) - water azeotropic mixture into consideration. It has been reported that it affects the central nervous system, liver, as well as can cause carcinogenicity. To be more precise, in this article, two different entrainers has been evaluated on their merits of exploiting liquid-liquid phase envelope for separating Tetrahydrofuran-water binary azeotropic mixture. The process flow sheet schematic with n-octane as entrainer (having two distillation regions) has a reduced operating energy requirement by 21.11% while comparing with the Residue Curve Map of n-hexane as entrainer having three distillation regions. The total capital cost for THF-water-n-octane case has been found to be 7.1 $/y × 105 and that of THF-water-n-hexane case has been found to be 9 $/y × 105. However, in both of the cases, the product purity of 99.9% has been achieved for THF. Also, the classical trade-off between capital cost and energy cost has been shown in this study. The salient feature of this work is the use of dynamic simulation to understand the effect of recycle flow rate induced process operational in-feasibility due to distillation region shift.

Population Pharmacokinetics of Remdesivir and GS-441524 in Hospitalized COVID-19 Patients.

The objective of this study was to describe the population pharmacokinetics of remdesivir and GS-441524 in hospitalized coronavirus disease 2019 (COVID-19) patients. A prospective observational pharmacokinetic study was performed in non-critically ill hospitalized COVID-19 patients with hypoxemia. For evaluation of the plasma concentrations of remdesivir and its metabolite GS-441524, samples were collected on the first day of therapy. A nonlinear mixed-effects model was developed to describe the pharmacokinetics and identify potential covariates that explain variability. Alternative dosing regimens were evaluated using Monte Carlo simulations. Seventeen patients were included. Remdesivir and GS-441524 pharmacokinetics were best described by a one-compartment model. The estimated glomerular filtration rate (eGFR) on GS-441524 clearance was identified as a clinically relevant covariate. The interindividual variability in clearance and volume of distribution for both remdesivir and GS-441524 was high (remdesivir, 38.9% and 47.9%, respectively; GS-441525, 47.4% and 42.9%, respectively). The estimated elimination half-life for remdesivir was 0.48 h, and that for GS-441524 was 26.6 h. The probability of target attainment (PTA) of the in vitro 50% effective concentration (EC50) for GS-441524 in plasma can be improved by shortening the dose interval of remdesivir and thereby increasing the total daily dose (PTA, 51.4% versus 94.7%). In patients with reduced renal function, the metabolite GS-441524 accumulates. A population pharmacokinetic model for remdesivir and GS-441524 in COVID-19 patients was developed. Remdesivir showed highly variable pharmacokinetics. The elimination half-life of remdesivir in COVID-19 patients is short, and the clearance of GS-441524 is dependent on the eGFR. Alternative dosing regimens aimed at optimizing the remdesivir and GS-441524 concentrations may improve the effectiveness of remdesivir treatment in COVID-19 patients.

Toward Economical and Sustainable Production of Renewable Plastic: Integrative System-Level Analyses.

2,5-Furandicarboxylic acid (FDCA) is one of the promising renewable plastic monomers enabling to address several environmental issues, instead of petroleum-based terephthalic acid (TPA). In this study, an integrative process for the co-production of FDCA and furfural as well as activated carbon was developed, and the economic feasibility and environmental sustainability for the proposed process were evaluated. In the proposed process, there were major four catalytic conversion reactions: (1) hydrolysis of biomass to its derivatives (cellulose, hemicellulose, and lignin), (2) dehydration of hemicellulose to furfural, (3) dehydration of cellulose to 5-hydroxymethylfurfural (HMF), and (4) successive oxidation of HMF to FDCA. Particularly, a heat exchanger network coupled with a heat pump was established to minimize the utility consumption, thereby reducing 72 % of the heating requirement. Techno-economic analysis revealed that the minimum selling price of FDCA was $1380 ton-1 , which is comparable to that of petroleum-based TPA ($1445 ton-1 ). Uncertainty analysis using the Monte Carlo simulation method was employed to quantify the risk associated with the unforeseen market condition. From the life-cycle assessment, we observed that the proposed process is more environmentally sustainable than conventional TPA production in terms of climate change and fossil depletion metrics.

Assessment of Pharmacological Interactions between SIRT2 Inhibitor AGK2 and Paclitaxel in Different Molecular Subtypes of Breast Cancer Cells.

Breast carcinoma (BC) is the most commonly diagnosed type of cancer in women in the world. Although the advances in the treatment of BC patients are significant, numerous side effects, severe toxicity towards normal cells as well as the multidrug resistance (MDR) phenomenon restrict the effectiveness of the therapies used. Therefore, new active compounds which decrease the MDR, extend disease-free survival, thereby ameliorating the effectiveness of the current treatment regimens, are greatly needed. Histone deacetylase inhibitors (HDIs), including sirtuin inhibitors (SIRTi), are the epigenetic antitumor agents which induce a cytotoxic effect in different types of cancer cells, including BC cells. Currently, combined forms of therapy with two or even more chemotherapeutics are promising antineoplastic tools to obtain a better response to therapy and limit adverse effects. Thus, on the one hand, much more effective chemotherapeutics, e.g., sirtuin inhibitors (SIRTi), are in demand; on the other hand, combinations of accepted cytostatics are trialed. Thus, the aim of our research was to examine the combination effects of a renowned cytotoxic drug paclitaxel (PAX) and SIRT2 inhibitor AGK2 on the proliferation and viability of the T47D, MCF7, MDA-MB-231, MDA-MB-468, BT-549 and HCC1937 BC cells. Moreover, cell cycle arrest and apoptosis induction were explored. The type of pharmacological interactions between AGK2 and PAX in different molecular subtypes of BC cells was assessed using the advanced isobolographic method. Our findings demonstrated that the tested active agents singly inhibited viability and proliferation of BC cells as well as induced cell cycle arrest and apoptosis in the cell-dependent context. Additionally, AGK2 increased the antitumor effect of PAX in most BC cell lines. We observed that, depending on the BC cell lines, the combinations of tested drugs showed synergistic, additive or antagonistic pharmacological interaction. In conclusion, our studies demonstrated that the consolidated therapy with the use of AGK2 and PAX can be considered as a potential therapeutic regimen in the personalized cure of BC patients in the future.

Visible light-assisted Ni-/Ir-catalysed atom-economic synthesis of spiro[furan-3,1'-indene] derivatives.

An atom-economic, efficient, and highly convenient construction of spiro[furan-3,1'-indene] skeletons from isocyanides and 1,5-enynes by synergistic nickel- and iridium-photocatalysis is reported. Spirocyclization was developed under practical and mild conditions, which features excellent functional group tolerance, gram-scale synthesis and representative synthetic transformations for the obtained products and broad substrate scope. Primary mechanistic studies demonstrated that the reaction proceeds through energy-transfer-mediated excitation of intermediate catalytic species.

Intermolecular Diels-Alder Cycloadditions of Furfural-Based Chemicals from Renewable Resources: A Focus on the Regio- and Diastereoselectivity in the Reaction with Alkenes.

A recent strong trend toward green and sustainable chemistry has promoted the intensive use of renewable carbon sources for the production of polymers, biofuels, chemicals, monomers and other valuable products. The Diels-Alder reaction is of great importance in the chemistry of renewable resources and provides an atom-economic pathway for fine chemical synthesis and for the production of materials. The biobased furans furfural and 5-(hydroxymethyl)furfural, which can be easily obtained from the carbohydrate part of plant biomass, were recognized as "platform chemicals" that will help to replace the existing oil-based refining to biorefining. Diels-Alder cycloaddition of furanic dienes with various dienophiles represents the ideal example of a "green" process characterized by a 100% atom economy and a reasonable E-factor. In this review, we first summarize the literature data on the regio- and diastereoselectivity of intermolecular Diels-Alder reactions of furfural derivatives with alkenes with the aim of establishing the current progress in the efficient production of practically important low-molecular-weight products. The information provided here will be useful and relevant to scientists in many fields, including medical and pharmaceutical research, polymer development and materials science.

Polychlorinated dioxins, furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) in food from Italy: Estimates of dietaryintake and assessment.

Dietary intake of polychlorinated dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) from various foods (fish and seafood, meat and meat-based products, milk and dairy products, hen eggs, olive oil and fats) was investigated for various sex/age groups of the Italian population. The concentrations of PCDD/Fs and dl-PCBs and their contribution to total TEQ values varied depending on food matrix. Fish (0.50 pg WHO-TEQ/g wet weight) and seafood (0.16 pg WHO-TEQ/g wet weight) showed the highest mean concentrations of PCDD/Fs plus dl-PCBs, followed by meat (1.70 pg WHO-TEQ/g lipid weight), meat based products (1.03 pg WHO-TEQ/g lipid weight), milk and dairy products (0.78 pg WHO-TEQ/g lipid weight), hen eggs (0.71 pg WHO-TEQ/g lipid weight), fats (0.27 pg WHO-TEQ/g lipid weight) and olive oil (0.09 pg WHO-TEQ/g lipid weight). In all samples WHO-TEQ PCDD/F plus dl-PCB concentrations fulfilled the European Union food law, except in pork loin samples (1.39 pg WHO-TEQ/g lipid weight). Differences in exposure depending on the sex/age groups (children > teenagers > adults > elders) and hypotheses considered (lower bound and upper bound) were encountered. Non-cancer risk values showed a low exposure. Carcinogenicity risk results revealed that highly exposed individuals were distributed over all sex/age groups, even though the proportion of individuals exceeding the safe limit was higher in children. These data once again underline the importance of trying to control the levels of these contaminants in fishery products, particularly in fish, who represents one of the main exposure sources for consumers. PRACTICAL APPLICATION: This paper may help the consumer in making food choices to minimize the exposure risk to dioxins, furans and PCBs.