Irgafos 168 and Irganox 1076 as new cocaine cutting agents: A COVID-19 pandemic impact on cocaine profiling and trafficking in Brazil.

BACKGROUNDS: Restrictions in movement and closure of borders imposed by the Sars-Cov- 2 worldwide pandemic have affected the global illicit drug market, including cocaine trafficking. In this scenario, comparing cutting agents added to the cocaine and the drug purity are valuable strategies to understand how the drug trade has been impacted by the pandemic. METHODS: In this work, 204 cocaine salt materials seized in the Brazilian Federal District, before (2019) and during COVID-19 pandemics (2020) were analyzed by two analytical techniques: gas chromatography-mass spectrometry (GC-MS) and Fourier-transform infrared spectroscopy (FTIR). Statistical analyses, including Principal Component Analysis (PCA), were applied to evaluate the COVID-19 pandemic impact in the local market. Bibliometric analysis was performed as a forensic intelligence tool. RESULTS: From 2019-2020, cocaine average purity decreased 26 % while the frequency of cutting agents, as caffeine and anesthetics (lidocaine, tetracaine) increased. The high percentage of unknown were increased. Different cocaine profiling seized in 2020 showed new cutting agents, such as Irganox 1076, and Irgafos 168, indicating a trend on new adulterants/diluents introduced in the local market to mitigate the local drug shortage. Also in 2020, there was an increase in the local cocaine seizures, despite of the cocaine drug purity decreased by 26 % compared to 2019. CONCLUSIONS: Taken together, these data showed that the covid-19 pandemics has impacted cocaine trafficking in the Brazilian Federal District, an increase in cocaine seizures, which may indicate greater demand for the drug and, specially, changes in the cocaine purity and cutting agents profiling showing how traffickers tried to minimize difficulties in crossing the Brazilian border during COVID-19 restrictions. The information is relevant since Brazil is one of the major departure points for traded cocaine to the world. Bibliometric analysis showed that Irgafos 168 and Irganox 1076 were consistently identified as cocaine cutting agents for the first time.

[Interferonogenic activity of the strain BH-3 duck hepatitis virus type I (Picornaviridae: Avihepatovirus: Avihepatovirus A)].

INTRODUCTION: Duck viral hepatitis type I (DVH-I) is a poorly studied contagious disease caused by RNA-containing duck (Anatinae) hepatitis virus type I (Picornaviridae: Avihepatovirus: Avihepatovirus A). This infection is widespread in many countries, including Russia, and causes significant damage to industrial duck breeding. The study of interferonogenic activity of its etiologic agent strains is of great importance in solving the problem of developing effective means to control the disease. MATERIAL AND METHODS: Strain BH-3 of duck hepatitis virus type I isolated from the liver of sick ducklings was used in the study. The strain was adapted to developing 10-12 day old duck embryos, to the cell culture of chicken and duck fibroblasts and deposited in the State Collection of Viruses of the D.I. Ivanovsky Institute of Virology of FSBI «National Research Centre for Epidemiology and Microbiology named after the honorary academician N.F. Gamaleya¼ of the Ministry of Health of Russia. Experiments were performed using the standard tissue culture method. RESULTS AND DISCUSSION: Data on the ability of the viral strain BH-3 to induce interferon (IFN) and its sensitivity to the action of exogenous interferon in the culture of duck fibroblasts are presented. It has been shown that the interferonogenic activity of this strain of the hepatitis virus is in direct proportion to the multiplicity of infection. The maximum induction of IFN (1 : 256 CEPD50) was observed at a dose of 1.0 TCD50/cell in 72-96 hrs after inoculation of the cell culture. Exogenous IFN at a dose of 1 : 128 completely suppressed the cytopathic effect and death of duck embryos infected with hepatitis virus at a dose of 100 TCD50/cell. CONCLUSION: The data obtained allow us to state that the vaccine strain BH-3 of duck hepatitis virus type I has a pronounced interferonogenic activity and sensitivity to the action of exogenous IFN. This may have implications for the development of effective therapeutic agents against DVH-I.

Changes in adhesive ingredients in continuous glucose monitoring systems may induce new contact allergy pattern.

BACKGROUND: Medical devices (MD) in close skin-contact for a prolonged time, such as glucose monitoring (CGM) systems, are a risk factor for contact allergy, and there has been an increase in patients using these. Correct diagnosis demands targetted testing. OBJECTIVES: We report a new allergen in a continuous CGM system in which the adhesive was changed. The allergy pattern of the patients diagnosed is reported. METHODS: The three patients reported were patch tested with an MD series, own material, and possible allergens found through analysis with gas chromatography-mass spectrometry, comparing analysis from the CGM system before and after change. RESULTS: The patients were sensitized to isobornyl acrylate (IBOA), found in previously used devices and the present CGM. Apart from IBOA, the culprit allergen was found to be 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate. CONCLUSION: Allergic contact dermatitis due to CGM systems and insulin pumps are difficult to investigate and require chemical analysis. Because of the lack of information on substances used in the production, and when changes with MDs are initiated, it is difficult to advise patients, especially since they risk sensitization to several allergens. The use of MDs has increased and, thus, the need for collaboration between manufacturers, clinicians, and patient organizations.

Identification of In Vitro Metabolites of Synthetic Phenolic Antioxidants BHT, BHA, and TBHQ by LC-HRMS/MS.

Butylated hydroxytoluene (BHT) and its analogs, butylated hydroxyanisole (BHA) and tert-butyl-hydroquinone (TBHQ), are widely used synthetic preservatives to inhibit lipid oxidation in the food, cosmetic and pharmaceutical industries. Despite their widespread use, little is known about their human exposure and related biotransformation products. The metabolism of these compounds was investigated using in vitro incubations with human and rat liver fractions. Liquid chromatography coupled to high-resolution tandem mass spectrometry was employed to detect and characterize stable and reactive species formed via oxidative metabolism, as well as phase II conjugates. Several oxidative metabolites have been detected, as well as glutathione, glucuronide, and sulfate conjugates, many of which were not previously reported. A combination of accurate mass measurements, MS/MS fragmentation behavior, and isotope-labeling studies were used to elucidate metabolite structures.

Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies.

Leachables from pharmaceutical container closure systems are a subset of impurities that present in drug products and may pose a risk to patients or compromise product quality. Extractable studies can identify potential leachables, and extractables and leachables (E&Ls) should be evaluated during development of the impurity control strategy. Currently, there is a lack of specific regulatory guidance on how to risk assess E&Ls; this may lead to inconsistency across the industry. This manuscript is a cross-industry Extractables and Leachables Safety Information Exchange (ELSIE) consortium collaboration and follow-up to Broschard et al. (2016), which aims to provide further clarity and detail on the conduct of E&L risk assessments. Where sufficient data are available, a health-based exposure limit termed Permitted Daily Exposure (PDE) may be calculated and to exemplify this, case studies of four common E&Ls are described herein, namely bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010. Relevant discussion points are further explored, including the value of extractable data, how to perform route-to-route extrapolations and considerations around degradation products. By presenting PDEs for common E&L substances, the aim is to encourage consistency and harmony in approaches for deriving compound-specific limits.

In-process prepared deep eutectic solvent based homogeneous liquid-liquid microextraction for the determination of irgaphos 168 and irganox 1010 in polypropylene packed drinks.

In situ synthesis of a deep eutectic solvent and homogeneous liquid-liquid microextraction performed in a narrow bore tube was developed for efficient extraction of irgaphos 168 and irganox 1010 in doogh and water samples packed in polypropylene packages. First, pH of the aqueous sample solutions containing the analytes is adjusted at 9. Then a hydrogen bond acceptor (choline chloride) and a hydrogen bond donor (oleic acid) are dissolved in the solution and vortexed to obtain a homogeneous solution. The solution is filled into a narrow bore tube, in which its bottom was clogged by a septum. Then hydrochloric acid solution is injected into the solution by a syringe. The tube is placed in an ultrasonic bath. During this step, the droplets of choline chloride:oleic acid deep eutectic solvent are produced. The method indicated high enrichment factor (435 for irgaphos 168 and 488 for irganox 1010), low limits of detection (0.03 and 0.09 ng/mL for irgaphos 168 and irganox 1010, respectively) and quantification (0.13 and 0.29 ng/mL for irgaphos 168 and irganox 1010), good recovery (74 and 83% for irgaphos 168 and irganox 1010, respectively), and satisfactory repeatabilities (relative standard deviations ≤12%) can be obtained using the developed method.

Application of dispersive liquid-liquid microextraction based on solidification of floating organic drop for the determination of extractables from pharmaceutical packaging materials.

A new method was established for the determination of the extractables from pharmaceutical packaging materials using dispersive liquid-liquid microextraction based on solidification of floating organic drop (DLLME-SFO) coupled with ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). Packaging samples were filled with three kinds of buffer solutions: acid buffer (pH = 3), alkaline buffer (pH = 9) and 0.9% NaCl solution to extract as many extractables as possible, and then the extractables in buffer solutions were enriched by DLLME-SFO technique. Parameters affecting the efficiency of the extraction procedure were evaluated and optimized, including the type and volume of dispersant, extractant volume, pH and vortex-mixing time. After optimization, the values obtained for limits of detection and quantification for three kinds of common antioxidants were 0.3 and 1.0 µg/L respectively, and good linearity (R2 > 0.99) was observed in their respective concentration ranges. The recoveries ranged from 80.61% to 117.87% at three spiked levels with the relative standard deviations (RSDs) between 0.92% and 9.29% (n = 6) in all three buffer solutions. The developed method was successfully applied to the analysis of extractables from pharmaceutical packaging materials. The results indicated that the proposed procedure is a novel, sensitive, fast and repeatable method and has a great significance for evaluation of safety of pharmaceutical packaging materials.

Ion-Mobility Quadrupole Time-of-Flight Mass Spectrometry: A Novel Technique Applied to Migration of Nonintentionally Added Substances from Polyethylene Films Intended for Use as Food Packaging.

Nontarget analysis of nonvolatile substances in complex samples is a very challenging task that requires powerful analytical techniques and experience of analyzing such samples. An extensive study was conducted in order to identify nonintentionally added substances (NIAS) migrating from 18 polyethylene (PE) samples intended to be in contact with food. The migration assays were performed in five simulants and analyzed by ultrahigh-performance liquid chromatography (UPLC) coupled to an ion-mobility separation (IMS) quadrupole-time-of-flight (QTOF) mass spectrometer. This experimental setup provides a novel and powerful tool for this type of nonvolatile and nontargeted analysis. Thirty-five compounds were identified, 17 of which were NIAS. Methyl and ethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propanoate were found to be degradation products of either Irganox 1010 or Irganox 1076. Additionally, breakdown products including hexa-heptadecanamide, N,N'-1,2-ethanediylbis- and 11-eicosenamide were identified together with impurity reaction products, e.g., dibutyl amine or compounds of unknown origin like phosphine oxide, tributyl-. Forty-five percent of the detected compounds are in the positive list contained in Regulation 10/2011/EU, and their migration values were below their specific migration limits. The risk assessment for the rest of the compounds was carried out by comparing their migration values to the maximum concentration recommended by Cramer, e.g., ethyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propanoate and benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, 1,1'-[2,2-bis(hydroxymethyl)-1,3-propanediyl] ester (both class II toxicity), heptadecanamide, N,N'-1,2-ethanediylbis-, and phosphine oxide, tributyl- (both class III toxicity) were above the maximum concentration values for three samples that were migrated to ethanol 95%, and therefore, these samples are not suitable for food contact. The analytical tools and procedures used in this study are presented and discussed in detail.

Chemo-Enzymatic Synthesis of Renewable Sterically-Hindered Phenolic Antioxidants with Tunable Polarity from Lignocellulose and Vegetal Oil Components.

Despite their great antioxidant activities, the use of natural phenols as antioxidant additives for polyolefins is limited owing to their weak thermal stability and hydrophilic character. Herein, we report a sustainable chemo-enzymatic synthesis of renewable lipophilic antioxidants specifically designed to overcome these restrictions using naturally occurring ferulic acid (found in lignocellulose) and vegetal oils (i.e., lauric, palmitic, stearic acids, and glycerol) as starting materials. A predictive Hansen and Hildebrand parameters-based approach was used to tailor the polarity of newly designed structures. A specific affinity of Candida antarctica lipase B (CAL-B) towards glycerol was demonstrated and exploited to efficiently synthesized the target compounds in yields ranging from 81 to 87%. Antiradical activity as well as radical scavenging behavior (H atom-donation, kinetics) of these new fully biobased additives were found superior to that of well-established, commercially available fossil-based antioxidants such as Irganox 1010® and Irganox 1076®. Finally, their greater thermal stabilities (302 < Td5% < 311 °C), established using thermal gravimetric analysis, combined with their high solubilities and antioxidant activities, make these novel sustainable phenolics a very attractive alternative to current fossil-based antioxidant additives in polyolefins.

Migration Study of Butylated Hydroxytoluene and Irganox 1010 from Polypropylene Treated with Severe Processing Conditions.

Safety concerns have emerged over the increased use of polypropylene (PP) in food-packaging markets. Some antioxidants in PP can migrate to foods and cause undesirable effects in humans. In this study, migration behaviors of butylated hydroxytoluene (BHT) and Irganox 1010 (I-1010) in PP sheets were determined according to the US FDA migration test conditions. In particular, we tested the effects of severe conditions of food processing and storage, such as autoclave heating (sterilization at about 121 °C), microwave radiation (700 W), and deep freezing (-30 °C) on migration of antioxidants. Migrant concentrations were higher in 95% ethanol as lipid food simulant, because of the hydrophobic nature of both PP and antioxidants. Autoclave heating treatment increased migrant concentrations compared with other processing conditions. Moreover, increased migrant concentrations by deep freezing condition were attributed to the brittleness of PP at freezing temperature. Regardless of processing conditions, BHT which has a lower molecular weight, migrated faster than I-1010. PRACTICAL APPLICATION: The antioxidants with hydrophobic nature such as butylated hydroxytoluene (BHT) and Irganox 1010 (I-1010) in polypropylene sheets would be migrated to foods, which is an important issue for industrial production food packaging materials. Migration behavior was promoted by severe processing conditions such as autoclave heating, microwave radiation, freezing, and especially autoclave heating treatment led the highest migration among them. Therefore, control of chemical additive migration from polypropylene food packaging is needed for safe food processing.

Identification of leachable impurities in an ophthalmic drug product originating from a polymer additive Irganox 1010 using mass spectroscopy.

Pharmaceutical packaging employs a wide variety of polymers owing to their desirable features, but the compounds that could leach from the polymers into the drug products can pose serious health risks. Therefore, it is extremely important to identify such compounds so that they can be adequately quantified and evaluated for toxicological impact/safety assessments. Not only the polymer components and the additives should be considered as sources for leachable impurities, their reaction/degradation products should also be evaluated. Irganox 1010 is a common commercial antioxidant (polymer additive) used in the manufacturing of polyolefin materials for container closure systems. In our study, we identified two Irganox1010 related leachable impurities in an ophthalmic drug product using rapid and straightforward orthogonal mass spectroscopy (LC-MS and GC-MS) methods The identified impurities were 7,9-Di-tert-butyl-1 oxaspiro[4.5]deca-6,9-diene-2,8-dione and 3-[3,5-bis(tert-butyl)-1-hydroxy-4-oxocyclohexa-2,5-dienyl]propanoic acid which leached into the ophthalmic drug solution during storage. The analytical methods employed could potentially be used to identify the similar class of compounds as is or in drug products.

Chemical stabilization of polymers: Implications for dermal exposure to additives.

Technical benefits of additives in polymers stand in marked contrast to their associated health risks. Here, a multi-analyte method based on gas chromatography coupled to tandem mass spectrometry (GC-MS/MS) was developed to quantify polymer additives in complex matrices such as low-density polyethylene (LDPE) and isolated human skin layers after dermal exposure ex vivo. That way both technical aspects and dermal exposure were investigated. The effects of polymer additivation on the material were studied using the example of LDPE. To this end, a tailor-made polymer was applied in aging studies that had been furnished with two different mixtures of phenol- and diarylamine-based antioxidants, plasticizers and processing aids. Upon accelerated thermo-oxidative aging of the material, the formation of LDPE degradation products was monitored with attenuated total reflectance-Fourier transformed infrared (ATR-FTIR) spectroscopy. Compared to pure LDPE, a protective effect of added antioxidants could be observed on the integrity of the polymer. Further, thermo-oxidative degradation of the additives and its kinetics were investigated using LDPE or squalane as matrix. The half-lives of additives in both matrices revealed significant differences between the tested additives as well as between LDPE and squalane. For instance, 2-tert-butyl-6-[(3-tert-butyl-2-hydroxy-5-methylphenyl)methyl]-4-methylphenol (Antioxidant 2246) showed a half-life 12 times lower when incorporated in LDPE as compared to squalane. As a model for dermal exposure of consumers, human skin was brought into contact with the tailor-made LDPE containing additives ex vivo in static Franz diffusion cells. The skin was then analyzed for additives and decomposition products. This study proved 10 polymer additives of diverse pysicochemical properties and functionalities to migrate out of the polymer and eventually overcome the intact human skin barrier during contact. Moreover, their individual distribution within distinct skin layers was demonstrated. This is exemplified by the penetration of the procarcinogenic antioxidant N-phenylnaphthalen-2-amine (Neozon D) into the viable epidermis and the permeation through the skin of the neurotoxic plasticizer N-butylbenzenesulfonamide (NBBS). In addition, the analyses of additive degradation products in the isolated skin layers revealed the presence of 2-tert-butyl-4-methylphenol in all layers after contact to a polymer with substances of origin like Antioxidant 2246. Thus, attention needs to be paid to absorption of polymer additives together with their degradation products when it comes to dermal exposure assessment.

STAT3 gain-of-function mutations associated with autoimmune lymphoproliferative syndrome like disease deregulate lymphocyte apoptosis and can be targeted by BH3 mimetic compounds.

Autoimmune lymphoproliferative syndrome (ALPS) is typically caused by mutations in genes of the extrinsic FAS mediated apoptotic pathway, but for about 30% of ALPS-like patients the genetic diagnosis is lacking. We analyzed 30 children with ALPS-like disease of unknown cause and identified two dominant gain-of-function mutations of the Signal Transducer And Activator Of Transcription 3 (STAT3, p.R278H, p.M394T) leading to increased transcriptional activity. Hyperactivity of STAT3, a known repressor of FAS, was associated with decreased FAS-mediated apoptosis, mimicking ALPS caused by FAS mutations. Expression of BCL2 family proteins, further targets of STAT3 and regulators of the intrinsic apoptotic pathway, was disturbed. Cells with hyperactive STAT3 were consequently more resistant to intrinsic apoptotic stimuli and STAT3 inhibition alleviated this effect. Importantly, STAT3-mutant cells were more sensitive to death induced by the BCL2-inhibitor ABT-737 indicating a dependence on anti-apoptotic BCL2 proteins and potential novel therapeutic options.

Benzotriazole-type ultraviolet stabilizers and antioxidants in plastic marine debris and their new products.

Ultraviolet stabilizers (UVSs) and antioxidants are the most widely used additives in plastics to enhance the lifetime of polymeric materials. There is growing interest in the roles of plastic marine debris and microplastics as source or vector of toxic substances to marine environment and organisms. However, there is limited information available on plastic associated chemicals, particularly additive chemicals. Therefore, to evaluate their extent of exposure from plastics to the marine environment, we determined UVSs and antioxidants in plastic debris (n=29) collected from beaches along with their corresponding new plastic products in markets (n=27) belonging to food, fisheries, and general use. Antioxidants were present at higher concentrations than UVSs in both plastic debris and new plastics, indicative of their high use over UVSs. Irganox 1076 and Irganox 1010 were more commonly used than other chemicals investigated. The irregular use with high concentration of additive chemicals was observed in short-term use plastic products. Except for Irganox 1076 and UV 326, most antioxidants and UVSs were relatively high in new plastics compared to corresponding plastic marine debris, implying their potential leaching or degradation during use or after disposal. The present study provides quantitative information about additive chemicals contained in plastic marine debris and their new products. These results could be useful for better understanding of environmental exposure to hazardous chemicals through plastic pollution.

Occurrence of synthetic phenolic antioxidants and transformation products in urban and rural indoor dust.

In this study, seven synthetic phenolic antioxidant (SPA) analogues were positively found in urban and rural indoor dust samples collected from Shandong province in China, among which the novel 2,4,6-tri-tert-butylphenol (AO 246), 2,6-di-tert-butyl-4-sec-butylphenol (DTBSBP), 2,4-di-tert-butylphenol (DBP) and 4,4'-butylidenebis (2-(1,1-dimethylethyl)-5- methyl-phenol) (AO 44B25) analogues accounted for 29% of total SPA concentrations (∑SPAs). Urban dust showed significantly higher ∑SPA levels (range: 1.56e3 - 2.03e4 ng/g) compared with those in rural indoor dust (668-4.39e3 ng/g, p < 0.05). 2,6-Di-tert-butyl-4-methylphenol (BHT) was the dominate analogue in the urban indoor dust, which constituted of 74% in ΣSPAs. While, varied composition profiles of SPAs were noticed in rural indoor dust, for instance, AO 246 (46%) and BHT (43%) had similar contributions to ∑SPAs. Three BHT transformation products (TPs) were also detected in most of the urban and rural dust samples (>97%), with individual residue level in the same order: 2,6-di-tert-butyl-1,4-benzoquinone (BHT-Q) > 2,6-di-tert-butyl-4-hydroxy- 4-methyl-2,5-cyclo-hexadienone (BHT-quinol) > 3,5-di-tert-butyl-4-hydroxybenzal-dehyde (BHT-CHO). Geometric mean values of total TP concentrations were 555 ng/g and 131 ng/g for urban and rural indoor dust samples, respectively. A preliminary estimated daily intake calculation at dust ingestion scenario suggested additional concerns might be paid to simultaneous exposure of several SPA analogues and TPs besides current focus on BHT exposure risks.

Research on degradation product and reaction kinetics of membrane electro-bioreactor (MEBR) with catalytic electrodes for high concentration phenol wastewater treatment.

The membrane electro-bioreactor (MEBR) is a novel technology, it treats wastewater by combining membrane filtration, electrokinetic phenomena, and biological processes in one reactor. This paper aims to deal with hard biodegradation and high concentration phenol wastewater. Investigating the influence factors such as initial concentration, voltage, pH value, temperature and mixed liquor suspended solids (MLSS) toward phenol degradation process in electrocatalytic process and membrane bioreactor (MBR), and then apply the optimum conditions in the MEBR system. Results of continuous flow experiments demonstrated that MEBR increased the quality of the treated wastewater than conventional MBR. The above technics followed the zero-order reaction kinetics. The removal efficiency of MEBR was about 11.1% higher for phenol than the sum of the two individual processes. With the help of gas chromatography/mass spectrometry (GC-MS), this qualitative analysis looks at the degradation products of phenol generated in MEBR, through which 2,6-di-tert-butyl-p-benzoquinone was confirmed as the main degradation product.

Synthetic Phenolic Antioxidants and Their Metabolites in Indoor Dust from Homes and Microenvironments.

Synthetic phenolic antioxidants (SPAs), including 2,6-di-tert-butyl-4-hydroxytoluene (BHT), are extensively used in food, cosmetic and plastic industries. Nevertheless, limited information is available on human exposures, other than the dietary sources, to SPAs. In this study, occurrence of 9 SPAs and their metabolites/degradation products was determined in 339 indoor dust collected from 12 countries. BHT was found in 99.5% of indoor dust samples from homes and microenvironments at concentrations that ranged from < LOQ to 118 µg/g and 0.10 to 3460 µg/g, respectively. This is the first study to measure BHT metabolites in house dust (0.01-35.1 µg/g) and their concentrations accounted for 9.2-58% of the sum concentrations (∑SPAs). 3,5-di-tert-butyl-4-hydroxybenzaldehyde (BHT-CHO), 2,6-di-tert-butyl-4-(hydroxymethyl)phenol (BHT-OH), 2,6-di-tert-butyl-1,4-benzoquinone (BHT-Q) were the major derivatives of BHT found in dust samples. The concentrations of gallic acid esters (gallates) in dust from homes and microenvironments ranged from < LOQ to 18.2 and < LOQ to 684 µg/g, respectively. The concentrations and profiles of SPAs varied among countries and microenvironments. Significantly elevated concentrations of SPAs were found in dust from an e-waste workshop (1530 µg/g). The estimated daily intake (EDI) of BHT via house dust ingestion ranged from 0.40 to 222 ng/kg/d (95th percentile).

Boosting effect of ortho-propenyl substituent on the antioxidant activity of natural phenols.

Seven new antioxidants derived from natural or synthetic phenols have been designed as alternatives to BHT and BHA antioxidants. Influence of various substituents at the ortho, meta and para positions of the aromatic core of phenols on the bond dissociation enthalpy of the ArO-H bond was evaluated using a DFT method B3LYP/6-311++G(2d,2p)//B3LYP/6-311G(d,p). This prediction highlighted the ortho-propenyl group as the best substituent to decrease the bond dissociation enthalpy (BDE) value. The rate constants of hydrogen transfer from these phenols to DPPH radical in a non-polar and non-protic solvent have been measured and were found to be in agreement with the BDE calculations. For o-propenyl derivatives from 2-tert-butyl-4-methylphenol, BHA, creosol, isoeugenol and di-o-propenyl p-cresol, fewer radicals were trapped by a single phenol molecule, i.e. a lower stoichiometric number. Reaction mechanisms involving the evolution of the primary phenoxyl radical ArO are proposed to rationalise these effects.

Knockdown of BAG3 sensitizes bladder cancer cells to treatment with the BH3 mimetic ABT-737.

PURPOSE: BAG3 is overexpressed in several malignancies and mediates a non-canonical, selective form of (macro)autophagy. By stabilizing pro-survival Bcl-2 proteins in complex with HSP70, BAG3 can also exert an apoptosis-antagonizing function. ABT-737 is a high affinity Bcl-2 inhibitor that fails to target Mcl-1. This failure may confer resistance in various cancers. METHODS: Urothelial cancer cells were treated with the BH3 mimetics ABT-737 and (-)-gossypol, a pan-Bcl-2 inhibitor which inhibits also Mcl-1. To clarify the importance of the core autophagy regulator ATG5 and BAG3 in ABT-737 treatment, cell lines carrying a stable lentiviral knockdown of ATG5 and BAG3 were created. The synergistic effect of ABT-737 and pharmaceutical inhibition of BAG3 with the HSF1 inhibitor KRIBB11 or sorafenib was also evaluated. Total cell death and apoptosis were quantified by FACS analysis of propidium iodide, annexin. Target protein analysis was conducted by Western blotting. RESULTS: Knockdown of BAG3 significantly downregulated Mcl-1 protein levels and sensitized urothelial cancer cells to apoptotic cell death induced by ABT-737, while inhibition of bulk autophagy through depletion of ATG5 had no discernible effect on cell death. Similar to knockdown of BAG3, pharmacological targeting of the BAG3/Mcl-1 pathway with KRIBB11 was capable to sensitize both cell lines to treatment with ABT-737. CONCLUSION: Our results show that BAG3, but not bulk autophagy has a major role in the response of bladder cancer cells to BH3 mimetics. They also suggest that BAG3 is a suitable target for combined therapies aimed at synergistically inducing apoptosis in bladder cancer.