Source identification and human exposure assessment of organophosphate flame retardants and plasticisers in soil and outdoor dust from Nigerian e-waste dismantling and dumpsites.

Electronic waste (e-waste) dismantling and dumpsite processes are major sources of organophosphate flame retardant and plasticiser emissions and may pose potentially adverse effects on environment and human health. In 20 outdoor dust and 49 soil samples collected from four e-waste dismantling and three e-waste dumpsites in two States of Nigeria (Lagos and Ogun), we identified 13 alternative plasticisers (APs), 7 legacy phthalate plasticisers (LPs), and 17 organophosphorus flame retardants (OPFRs) for the first time in African e-waste streams. In the samples from dismantling sites, the range (median) concentrations of ∑13APs, ∑7LPs, and ∑17OPFRs were 11 to 2747 µg/g (144 µg/g), 11 to 396 µg/g (125 µg/g), and 0.2 to 68 µg/g (5.5 µg), in dust respectively and 1.8 to 297 µg/g (55 µg/g), 1.3 to 274 µg/g (48.5 µg/g), and 1.6 to 62 µg/g (1.6 µg/g), in soil respectively. Results for soil samples from e-waste dumpsites were (6.6 to 195 µg/g (23.7 µg/g), 6.0 to 295 µg/g (54.8), and 0.4 to 42.3 µg/g (9.0 µg/g) for ∑13APs, ∑7LPs, and ∑17OPFRs respectively. Overall, concentrations of APs were significantly higher at the dismantling sites (p = 0.005) compared to dumpsites, levels of LPs were higher at dismantling sites but not significant, while OPFR concentrations were significantly higher in dumpsite samples (p = 0.005). Plasticisers were found to be major contributors to pollution at e-waste dismantling sites, while OPFRs were associated with both automobile dismantling and e-waste dumpsite processes. Following particle size fractionation of selected soil samples, higher concentrations of targeted compounds were observed in the smaller mesh (180 µm) soil sieve fraction. For dust, the total median estimated daily intake via ingestion and dermal adsorption (EDIing and EDIderm) ranged from 43 to 74 ng/kg bw/day and 0.4 to 0.7 ng/kg bw/day, respectively. Correspondingly, 4.6 to 45 ng/kg bw/day and 0.015 to 0.57 ng/kg bw/day were the values found for soil, respectively. According to these results, the targeted chemicals do not appear to pose a non-carcinogenic risk to e-waste workers through ingestion or dermal contact of bio-accessible fractions of the chemicals. Human biomonitoring campaigns are recommended in the Nigerian e-waste environment considering the elevated concentration levels found for the majority of targeted compounds and that risk parameters required for exposure assessment were only available for a limited number of compounds.

Exposure to bisphenol A in European women from 2007 to 2014 using human biomonitoring data - The European Joint Programme HBM4EU.

BACKGROUND: Bisphenol A (BPA; or 4,4'-isopropylidenediphenol) is an endocrine disrupting chemical. It was widely used in a variety of plastic-based manufactured products for several years. The European Food Safety Authority (EFSA) recently reduced the Tolerable Daily Intake (TDI) for BPA by 20,000 times due to concerns about immune-toxicity. OBJECTIVE: We used human biomonitoring (HBM) data to investigate the general level of BPA exposure from 2007 to 2014 of European women aged 18-73 years (n = 4,226) and its determinants. METHODS: Fifteen studies from 12 countries (Austria, Belgium, Denmark, France, Germany, Greece, Israel, Luxembourg, Slovenia, Spain, Sweden, and the United Kingdom) were included in the BPA Study protocol developed within the European Joint Programme HBM4EU. Seventy variables related to the BPA exposure were collected through a rigorous post-harmonization process. Linear mixed regression models were used to investigate the determinants of total urine BPA in the combined population. RESULTS: Total BPA was quantified in 85-100 % of women in 14 out of 15 contributing studies. Only the Austrian PBAT study (Western Europe), which had a limit of quantification 2.5 to 25-fold higher than the other studies (LOQ=2.5 µg/L), found total BPA in less than 5 % of the urine samples analyzed. The geometric mean (GM) of total urine BPA ranged from 0.77 to 2.47 µg/L among the contributing studies. The lowest GM of total BPA was observed in France (Western Europe) from the ELFE subset (GM=0.77 µg/L (0.98 µg/g creatinine), n = 1741), and the highest levels were found in Belgium (Western Europe) and Greece (Southern Europe), from DEMOCOPHES (GM=2.47 µg/L (2.26 µg/g creatinine), n = 129) and HELIX-RHEA (GM=2.47 µg/L (2.44 µg/g creatinine), n = 194) subsets, respectively. One hundred percent of women in 14 out of 15 data collections in this study exceeded the health-based human biomonitoring guidance value for the general population (HBM-GVGenPop) of 0.0115 µg total BPA/L urine derived from the updated EFSA's BPA TDI. Variables related to the measurement of total urine BPA and those related to the main socio-demographic characteristics (age, height, weight, education, smoking status) were collected in almost all studies, while several variables related to BPA exposure factors were not gathered in most of the original studies (consumption of beverages contained in plastic bottles, consumption of canned food or beverages, consumption of food in contact with plastic packaging, use of plastic film or plastic containers for food, having a plastic floor covering in the house, use of thermal paper…). No clear determinants of total urine BPA concentrations among European women were found. A broader range of data planned for collection in the original questionnaires of the contributing studies would have resulted in a more thorough investigation of the determinants of BPA exposure in European women. CONCLUSION: This study highlights the urgent need for action to further reduce exposure to BPA to protect the population, as is already the case in the European Union. The study also underscores the importance of pre-harmonizing HBM design and data for producing comparable data and interpretable results at a European-wide level, and to increase HBM uptake by regulatory agencies.

Level of BPA contamination in resin composites determines BPA release.

OBJECTIVES: Resin composites may release bisphenol A (BPA) due to impurities present in the monomers. However, there is a lack of knowledge regarding the leaching characteristics of BPA from resin composites. Therefore, experimental resin composites were prepared with known amounts of BPA. The objective of this study was (1) to determine which amount of BPA initially present in the material leaches out in the short term and, (2) how this release is influenced by the resin composition. METHODS: BPA (0, 0.001, 0.01, or 0.1 wt%) was added to experimental resin composites containing 60 mol% BisGMA, BisEMA(3), or UDMA, respectively, as base monomer and 40 mol% TEGDMA as diluent monomer. Polymerized samples (n = 5) were immersed at 37 °C for 7 days in 1 mL of water, which was collected and refreshed daily. BPA release was quantified with UPLC-MS/MS after derivatization with pyridine-3-sulfonyl chloride. RESULTS: Between 0.47 to 0.67 mol% of the originally added BPA eluted from the resin composites after 7 days. Similar elution trends were observed irrespective of the base monomer. Two-way ANOVA showed a significant effect of the base monomer on BPA release, but the differences were small and not consistent. SIGNIFICANCE: The released amount of BPA was directly proportional to the quantity of BPA present in the resin composite as an impurity. BPA release was mainly diffusion-based, while polymer composition seemed to play a minor role. Our results underscore the importance for manufacturers only to use monomers of the highest purity in dental resin composites to avoid unnecessary BPA exposure in patients.

Endocrine disrupting chemicals in children's and their parents' urine: Is the exposure related to the Chinese and Western lifestyle?

Children are known to be more vulnerable to exposure to endocrine-disrupting chemicals (EDCs) compared to adults, but evaluating the exposure pathways can be challenging. This research employed target and non-target analysis (NTA) to examine the exposure characteristics of EDCs in spot urine samples collected from 46 children's (aged 3-12 years) and their parents in Hong Kong (Chinese/Western lifestyle) and Guangzhou (mainly Chinese lifestyle). The results revealed that the geometric mean concentrations of phthalate esters metabolites (mPAEs) and bisphenols (BPs) in children's urine were 127.3 µg/gcrea and 2.5 µg/gcrea in Guangzhou, and 93.7 µg/gcrea and 2.9 µg/gcrea in Hong Kong, respectively, which were consistent with global levels. NTA identified a total of 1069 compounds, including 106 EDCs, commonly detected in food, cosmetics, and drugs. Notable regional differences were observed between Guangzhou and Hong Kong with potential sources of EDCs including dietary and cosmetic additives, toys, flooring and dust, as well as differences in lifestyles, diet, and living environment. However, age was found to significantly impact EDC exposure. The quantified EDCs (mPAEs and BPs) posed possible health risks to 60% of the children. Moreover, the presence of caffeine in children's urine, which exhibited higher detection rates in children from Hong Kong (95.6%) and Guangzhou (44.4%), warrants further attention. The sources of EDCs exposure in these regions need to be fully confirmed.

Urinary phthalate/DINCH metabolites associations with kisspeptin and reproductive hormones in teenagers: A cross-sectional study from the HBM4EU aligned studies.

BACKGROUND: Exposure to phthalate/DINCH metabolites can induce human reproductive toxicity, however, their endocrine-disrupting mechanisms are not fully elucidated. OBJECTIVE: To investigate the association between concentrations of phthalate/DINCH metabolites, serum kisspeptin, and reproductive hormones among European teenagers from three of the HBM4EU Aligned Studies. METHODS: In 733 Belgian (FLEHS IV study), Slovak (PCB cohort follow-up), and Spanish (BEA study) teenagers, ten phthalate and two DINCH metabolites were measured in urine by high-performance liquid chromatography-tandem mass spectrometry. Serum kisspeptin (kiss54) protein, follicle-stimulating hormone (FSH), total testosterone (TT), estradiol (E2), and sex hormone-binding globulin (SHBG) levels were measured by immunosorbent assays. Free Androgen Index (FAI) was calculated as a proxy of free testosterone. Adjusted sex-stratified linear regression models for individual studies, mixed effect models (LME) accounting for random effects for pooled studies, and g-computation and Bayesian kernel machine regression (BKMR) models for the phthalate/DINCH mixture were performed. RESULTS: The LME suggested that each IQR increase in ln-transformed levels of several phthalates was associated with lower kisspeptin [MnBP: %change (95%CI): -2.8 (-4.2;-0.4); MEHP: -1.4 (-3.4,0.2)] and higher FSH [∑DINP: 11.8 (-0.6;25.1)] levels in females from pooled studies. G-computation showed that the phthalates/DINCH mixture was associated with lower kisspeptin [-4.28 (-8.07;-0.34)] and higher FSH [22.13 (0.5;48.4)] also in females; BKMR showed similar although non-significant pattern. In males, higher phthalates metabolites [MEHP: -12.22 (-21.09;-1.18); oxo-MEHP: -12.73 (-22.34;-1.93)] were associated with lower TT and FAI, although higher DINCH [OH-MINCH: 16.31 (6.23;27.35), cx-MINCH: 16.80 (7.03;27.46), ∑DINCH: 17.37 (7.26;29.74)] were associated with higher TT levels. No mixture associations were found in males. CONCLUSION: We observed sex-specific associations between urinary concentrations of phthalate/DINCH metabolites and the panel of selected effect biomarkers (kisspeptin and reproductive hormones). This suggests that exposure to phthalates would be associated with changes in kisspeptin levels, which would affect the HPG axis and thus influence reproductive health. However, further research is needed, particularly for phthalate replacements such as DINCH.

Assessment of legacy and alternative halogenated organic pollutants in outdoor dust and soil from e-waste sites in Nigeria: Concentrations, patterns, and implications for human exposure.

E-waste is often processed informally, particularly in developing countries, resulting in the release of harmful chemicals into the environment. This study investigated the co-occurrence of selected persistent organic pollutants (POPs), including legacy and alternative halogenated flame retardants (10 polybrominated diphenyl ethers (PBDEs), decabromodiphenyl ethane (DBDPE), syn and anti-dechlorane plus (DP)), 32 polychlorinated biphenyls (PCBs) and 12 organochlorine pesticides (OCPs), in 20 outdoor dust and 49 soil samples from 7 e-waste sites in Nigeria. This study provides the first report on alternative flame retardants (DBDPE and DP) in Nigeria. The total concentration range of the selected classes of compounds was in the order: ∑10PBDEs (44-12300 ng/g) > DBDPE (4.9-3032 ng/g) > ∑2DP (0.7-278 ng/g) > ∑32PCBs (4.9-148 ng/g) > ∑12OCPs (1.9-25 ng/g) for dust, and DBDPE (4.9-9647 ng/g) > ∑10PBDEs (90.3-7548 ng/g) > ∑32PCBs (6.1-5025 ng/g) > ∑12OCPs (1.9-250 ng/g) > ∑2DP (2.1-142 ng/g) for soil. PBDEs were the major contributors to POP pollution at e-waste dismantling sites, while PCBs were the most significant contributors at e-waste dumpsites. DBDPE was found to be significantly associated with pollution at both e-waste dismantling and dumpsites. Estimated daily intake (EDI) via dust and soil ingestion and dermal adsorption routes ranged from 1.3 to 2.8 ng/kg bw/day and 0.2-2.9 ng/kg bw/day, respectively. In the worst-case scenario, EDI ranged from 2.9 to 10 ng/kg bw/day and 0.8-5.8 ng/kg bw/day for dust and soil, respectively. The obtained intake levels posed no non-carcinogenic risk, but could increase the incidence of cancer at some of the studied e-waste sites, with values exceeding the USEPA cancer risk lower limit (1.0 × 10-6). Overall, our results suggest that e-waste sites act as emission point sources of POPs.

Time Patterns in Internal Human Exposure Data to Bisphenols, Phthalates, DINCH, Organophosphate Flame Retardants, Cadmium and Polyaromatic Hydrocarbons in Europe.

Human biomonitoring (HBM) data in Europe are often fragmented and collected in different EU countries and sampling periods. Exposure levels for children and adult women in Europe were evaluated over time. For the period 2000-2010, literature and aggregated data were collected in a harmonized way across studies. Between 2011-2012, biobanked samples from the DEMOCOPHES project were used. For 2014-2021, HBM data were generated within the HBM4EU Aligned Studies. Time patterns on internal exposure were evaluated visually and statistically using the 50th and 90th percentiles (P50/P90) for phthalates/DINCH and organophosphorus flame retardants (OPFRs) in children (5-12 years), and cadmium, bisphenols and polycyclic aromatic hydrocarbons (PAHs) in women (24-52 years). Restricted phthalate metabolites show decreasing patterns for children. Phthalate substitute, DINCH, shows a non-significant increasing pattern. For OPFRs, no trends were statistically significant. For women, BPA shows a clear decreasing pattern, while substitutes BPF and BPS show an increasing pattern coinciding with the BPA restrictions introduced. No clear patterns are observed for PAHs or cadmium. Although the causal relations were not studied as such, exposure levels to chemicals restricted at EU level visually decreased, while the levels for some of their substitutes increased. The results support policy efficacy monitoring and the policy-supportive role played by HBM.

Metabolic signature of HepaRG cells exposed to ethanol and tumor necrosis factor alpha to study alcoholic steatohepatitis by LC-MS-based untargeted metabolomics.

Despite the high prevalence of alcoholic liver disease, its identification and characterization remain poor, especially in early stages such as alcoholic fatty liver disease and alcoholic steatohepatitis. This latter implies diagnostic difficulties, few therapeutic options and unclear mechanisms of action. To elucidate the metabolic alterations and pinpoint affected biochemical pathways, alcoholic steatohepatitis was simulated in vitro by exposing HepaRG cells to ethanol (IC10, 368 mM) and tumor necrosis factor alpha (TNF-α, 50 ng/mL) for 24 h. This combined exposure was compared to solely ethanol-exposed as well as -nonexposed cells. Four different metabolomics platforms were used combining liquid chromatography, high-resolution mass spectrometry and drift tube ion mobility to elucidate both intracellular and extracellular metabolic alterations. Some of the key findings include the influence of TNF-α in the upregulation of hepatic triglycerides and the downregulation of hepatic phosphatidylethanolamines and phosphatidylcholines. S-Adenosylmethionine showed to play a central role in the progression of alcoholic steatohepatitis. In addition, fatty acyl esters of hydroxy fatty acid (FAHFA)-containing triglycerides were detected for the first time in human hepatocytes and their alterations showed a potentially important role during the progression of alcoholic steatohepatitis. Ethoxylated phosphorylcholine was identified as a potential new biomarker of ethanol exposure.

Association of Endocrine-Disrupting Chemicals with All-Cause and Cause-Specific Mortality in the U.S.: A Prospective Cohort Study.

Wide exposure to endocrine-disrupting chemicals (EDCs) poses a great risk on human health. However, few large-scale cohort studies have comprehensively estimated the association between EDCs exposure and mortality risk. This study aimed to investigate the association of urinary EDCs exposure with mortality risk and quantify attributable mortality and economic loss. Multivariable Cox proportional hazards regression models were performed to investigate the association of 38 representative EDCs exposure with mortality risk in the National Health and Nutrition Examination Survey (NHANES). During a median follow-up of 7.7 years, 47,279 individuals were enrolled. All-cause mortality was positively associated with 1-hydroxynaphthalene, 2-hydroxynaphthalene, cadmium, antimony, cobalt, and monobenzyl phthalate. Cancer mortality was positively associated with cadmium. Cardiovascular disease (CVD) mortality was positively associated with 1-hydroxynaphthalene, 2-hydroxynaphthalene, and 2-hydroxyfluorene. Nonlinear U-shaped relationships were found between all-cause mortality and cadmium and cobalt, which was also identified between 2-hydroxyfluorene and CVD mortality. J-shaped association of cadmium exposure with cancer mortality was also determined. EDCs exposure may cause 56.52% of total deaths (1,528,500 deaths) and around 1,897 billion USD in economic costs. Exposure to certain phthalates, polycyclic aromatic hydrocarbons, phytoestrogens, or toxic metals, even at substantially low levels, is significantly associated with mortality and induces high economic costs.

Mass Spectrometry-Based Untargeted Metabolomics and Lipidomics Platforms to Analyze Cell Culture Extracts.

Metabolites represent the most downstream level of the cellular organization. Hence, an in vitro untargeted metabolomics approach is extremely valuable to deepen the understanding of how endogenous metabolites in cells are altered under a given biological condition. This chapter describes a robust liquid chromatography-high-resolution mass spectrometry-based metabolomics and lipidomics platform applied to cell culture extracts. The analytical workflow includes an optimized sample preparation procedure to cover a wide range of metabolites using liquid-liquid extraction and validated instrumental operation procedures with the implementation of comprehensive quality assurance and quality control measures to ensure high reproducibility. The lipidomics platform is based on reversed-phase liquid chromatography for the separation of slightly polar to apolar metabolites and covers a broad range of lipid classes, while the metabolomics platform makes use of two hydrophilic interaction liquid chromatography methods for the separation of polar metabolites, such as organic acids, amino acids, and sugars. The chapter focuses on the analysis of cultured HepaRG cells that are derived from a human hepatocellular carcinoma; however, the sample preparation and analytical platforms can easily be adapted for other types of cells.

Overdose of the HIV Medicine Genvoya® in Two Auto-Intoxications.

Toxicological data on overdose with human immunodeficiency virus inhibitors are scarce. We present a case report of two independent suicide attempts by self-administered overdose with the same antiretroviral medicine Genvoya® (emtricitabine/elvitegravir/tenofovir alafenamide/cobicistat). Both patients were admitted to the hospital and presented with a loss of consciousness, lactic acidosis, elevated hepatic transaminase levels and hemodynamic instability. While one patient survived with advanced supportive measures, the other passed away. Emtricitabine levels were measured in vivo in various consecutive serum samples and postmortem urine, peripheral and cardiac serum samples and confirmed excessive use in both cases. This is the first time that emtricitabine levels following overdose are reported. Although measured concentrations for emtricitabine were quite similar in these cases, metabolic acidosis was more pronounced in the fatal case. The difference in outcomes between the two could be due to a difference in physiological status, susceptibility to accumulation and adverse effects, and perhaps a varying interval between ingestion and the start of supportive measures.

Spatial and temporal assessment of crack cocaine use in 13 European cities through wastewater-based epidemiology.

Already in early 2000s, concerns have been growing in the EU about increasing use of cocaine and it is estimated that below 1 % of the population administer the drug by smoking crack cocaine. New available data suggests an increase in the use of crack cocaine and an increase in the number of crack cocaine users entering treatment has been reported in several European countries. Robust estimations of crack cocaine use are however not available yet. The use of crack cocaine has long been associated with severe adverse socio-economic conditions as well as mental health problems, such as suicide ideation and depression. The aim of this study was to assess spatial trends in population-normalized mass loads of crack cocaine biomarkers (i.e., anhydroecgonine and anhydroecgonine methyl ester) in 13 European cities in six countries (the Netherlands, Belgium, Ireland, Portugal, Spain and Italy). Furthermore, temporal trends over a five-year period were evaluated through the analysis of historic samples collected in the Netherlands. Finally, the stability of the crack cocaine biomarkers in wastewater was investigated through batch experiments. The samples were analyzed with a new developed and validated hydrophilic interaction liquid chromatography coupled to mass spectrometry method. Targeted crack cocaine biomarkers were found in all cities. Also, crack cocaine biomarker was detected in wastewater from 2017 to 2021 in the Netherlands, but no significance between the years were found. With respect to biomarker in-sample stability, AEME was found to be stable in wastewater. This study assessed crack cocaine use for the first time on a broad scale, both temporal and in cities across Europe, with wastewater-based epidemiology and it shows the importance of wastewater analysis to monitor community loads of crack cocaine use.

A simple, rapid and accurate method for the sample preparation and quantification of meso- and microplastics in food and food waste streams.

Plastics are produced and used in large quantities worldwide (e.g. as food packaging). In line with this, plastic particles are found throughout the ecosphere and in various foods. As a result, plastics are also present in energy-rich waste biomass derived from the food industry, supermarkets, restaurants, etc. These waste streams are a valuable source for biogas production but can also be used to feed insects that in turn upcycle it into new high-value biomass. In both applications, the remaining residue can be used as fertilizer. Due to the present plastic particles, these applications could pose a continued threat to the environment, and both human and animal health. Therefore, the need of determining the (micro)plastic content to assess the potential danger is rising. In this research, a closed-vessel microwave-assisted acid digestion method was developed to accurately determine meso- and microplastic contents in food (waste) matrices by solubilising this food matrix. Polyvinyl chloride (PVC) food packaging foil was used to develop the method, using a full factorial design with three parameters (nitric acid concentration (c(HNO3)), temperature (T), and time (t)). According to this model, the best practical conditions were c(HNO3) = 0.50 mol/L, T = 170 °C, and t = 5.00 min. Subsequently, the method was tested on five other plastics, namely high- and low-density polyethylene (HDPE and LDPE), polypropylene (PP), polystyrene (PS), and polyethylene terephthalate (PET), mixed with a food matrix, resulting in a mean plastic recovery of 102.2 ± 4.1%. Additionally, the polymers were not oxidised during the microwave digestion. For PVC and PS hardly any degradation was found, while HDPE, LDPE, and PP showed slight chain degradation, although without recovery loss. In conclusion, the method is an accurate approach to quantify the total meso- and microplastic content in food (waste) matrices with minimal change in their intrinsic characteristics.

Estrogenic and growth inhibitory responses to organophosphorus flame retardant metabolites in zebrafish embryos.

Recent evidence has revealed that organophosphorus flame retardants (OPFRs) elicit a variety of toxic effects, including endocrine disruption. The present study examined estrogenic and growth inhibitory responses to OPFR metabolites in comparison to their parent compounds using zebrafish eleutheroembryos.1 Exposure to 4-hydroxylphenyl diphenyl phosphate (HO-p-TPHP) but not its parent compound triphenyl phosphate (TPHP) elicited upregulation of a marker gene of estrogenic responses, cytochrome P450 19A1b (CYP19A1b), and this upregulation was reversed by co-exposure to an estrogen receptor antagonist. Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), as well as 3-hydroxylphenyl diphenyl phosphate (HO-m-TPHP) and diphenyl phosphate (DPHP), did not elicit significant changes in the CYP19A1b expression. Reduction in body length was induced by TPHP and to a lesser extent by its hydroxylated metabolites. Altered expression of genes involved in the synthesis and action of thyroid hormones, including iodothyronine deiodinases 1 and 2, thyroid hormone receptor alpha, and transthyretin, were commonly observed for TPHP and its hydroxylated metabolites. Reduction in the body length was also seen in embryos exposed to TDCIPP but not BDCIPP. The transcriptional effect of TDCIPP was largely different from that of TPHP, with decreased expression of growth hormone and prolactin observed only in TDCIPP-exposed embryos. Considering the concentration-response relationships for the growth retardation and gene expression changes, together with existing evidence from other researchers, it is likely that prolactin is in part involved in the growth inhibition caused by TDCIPP. The present study showed similarities and differences in the endocrine disruptive effects of OPFRs and their metabolites.

Metabolic Signature of Ethanol-Induced Hepatotoxicity in HepaRG Cells by Liquid Chromatography-Mass Spectrometry-Based Untargeted Metabolomics.

Alcoholic liver disease is highly prevalent but poorly identified and characterized, leading to knowledge gaps, which impairs early diagnosis. Excessive alcohol consumption is known to alter lipid metabolism, followed by progressive intracellular lipid accumulation, resulting in alcoholic fatty liver disease. In this study, HepaRG cells were exposed to ethanol at IC10 and 1/10 IC10 for 24 and 48 h. Metabolic alterations were investigated intra- and extracellularly with liquid chromatography-high-resolution mass spectrometry. Ion mobility was added as an extra separation dimension for untargeted lipidomics to improve annotation confidence. Distinctive patterns between exposed and control cells were consistently observed, with intracellular upregulation of di- and triglycerides, downregulation of phosphatidylcholines and phosphatidylethanolamines, sphingomyelins, and S-adenosylmethionine, among others. Several intracellular metabolic patterns could be related to changes in the extracellular environment, such as increased intracellular hydrolysis of sphingomyelins, leading to increased phosphorylcholine secretion. Carnitines showed alterations depending on the size of their carbon chain, which highlights the interplay between ß-oxidation in mitochondria and peroxisomes. Potential new biomarkers of ethanol-induced hepatotoxicity have been observed, such as ceramides with a sphingadienine backbone, octanoylcarnitine, creatine, acetylcholine, and ethoxylated phosphorylcholine. The combination of the metabolic fingerprint and footprint enabled a comprehensive investigation of the pathophysiology behind ethanol-induced hepatotoxicity.

FLEXiGUT: Rationale for exposomics associations with chronic low-grade gut inflammation.

FLEXiGUT is the first large-scale exposomics study focused on chronic low-grade inflammation. It aims to characterize human life course environmental exposure to assess and validate its impact on gut inflammation and related biological processes and diseases. The cumulative influences of environmental and food contaminants throughout the lifespan on certain biological responses related to chronic gut inflammation will be investigated in two Flemish prospective cohorts, namely the "ENVIRONAGE birth cohort", which provides follow-up from gestation to early childhood, and the "Flemish Gut Flora Project longitudinal cohort", a cohort of adults. The exposome will be characterised through biomonitoring of legacy and emerging contaminants, mycotoxins and markers of air pollution, by analysing the available metadata on nutrition, location and activity, and by applying state-of-the-art -omics techniques, including metagenomics, metabolomics and DNA adductomics, as well as the assessment of telomere length and measurement of inflammatory markers, to encompass both exposure and effect. Associations between exposures and health outcomes will be uncovered using an integrated -omics data analysis framework comprising data exploration, pre-processing, dimensionality reduction and data mining, combined with machine learning-based pathway analysis approaches. This is expected to lead to a more profound insight in mechanisms underlying disease progression (e.g. metabolic disorders, food allergies, gastrointestinal cancers) and/or accelerated biological ageing.

Recycling plastics containing decabromodiphenyl ether into new consumer products including children's toys purchased in Japan and seventeen other countries.

Polybrominated diphenyl ethers (PBDEs) are flame retardants widely used to manufacture several commercial plastic products. The major homologue in commercial PBDE mixtures are listed in the Stockholm Convention on Persistent Organic Pollutants and are scheduled for global elimination. Hence, to understand more about unintentional contamination of plastic recycling stream by restricted PBDEs, we examined 540 small plastic consumer products (1139 components after dismantling), including children's toys, purchased in 18 countries (mainly Japan) between 2015 and 2019. Handheld X-ray fluorescence analysis revealed that 219 plastic components (19% of the total samples) contained bromine at a concentration of ≥30 mg kg-1. Chemical analysis of these bromine-positive components revealed that 109 pieces (9.6% of the total), mainly those made of black-colored plastic, contained PBDEs at concentrations ranging between 35 and 10,000 mg kg-1, with the maximum contribution from decabromodiphenyl ether (decaBDE). These PBDE concentrations were insufficient to impart flame retardancy, suggesting that the recycled plastic used to manufacture these consumer products probably originated from electronic waste, the manufacture of which was the primary use of commercial decaBDE mixtures. PBDEs were also found in secondary raw plastic materials and their final products obtained in India in 2019, demonstrating that plastics containing decaBDE end up in products where they serve no functional purpose. To contribute to the circular economy, the recycling of plastic waste in end-of-life products should be promoted. However, urgent action is needed to prevent plastic additives of concern, including PBDEs, from entering new products used in daily lives, particularly those used by children.

Bisphenol A release from short-term degraded resin-based dental materials.

OBJECTIVES: There is still much debate about the release of bisphenol A (BPA) from resin-based dental materials. Therefore, this study aimed to quantify BPA present as an impurity and to evaluate whether their degradation by salivary, bacterial, and chemical challenges could increase its release. METHODS: BPA was determined in three different amounts (300, 400, and 500 µg) of eight unpolymerized resin-based materials (four composites, one fissure sealant, two adhesives and one root canal sealer). Next, polymerized samples (n = 5) of each material were immersed in 1 mL of whole human pooled saliva collected from adults, Streptococcus mutans (2 × 107 CFU/mL), and acidic (0.1 M HCl), alkaline (0.1 M NaOH), and control media, respectively. The amount of BPA was quantified using an UPLC-MS/MS method including derivatization of BPA by pyridine-3-sulfonyl chloride. RESULTS: Only the composites contained trace amounts of BPA above the limit of quantification (ranging from 301±32 pg PBA/mg to 1534±62 pg BPA/mg), most likely as impurity from the synthesis of the monomers. The amounts of BPA released from polymerized materials upon salivary and bacterial degradation were too low for accurate quantification, but in water, quantifiable amounts of BPA were released from all materials. In alkaline media, the BPA release from two composites was significantly decreased, while the release from one adhesive was significantly increased, compared to water. CONCLUSIONS: BPA already present in unpolymerized resin-based materials may account for the release of BPA after polymerization. There was no clear indication that short-term material degradation leads to increased release of BPA.

Development of an analytical method based on solid-phase extraction and LC-MS/MS for the monitoring of current-use pesticides and their metabolites in human urine.

Pyrethroids, organophosphorus pesticides and fipronil have been listed as priority chemicals in human biomonitoring studies because of their wide use and potential health effects in humans. The determination of 13 pesticides, including pyrethroids (deltamethrin, cypermethrin, permethrin, cyfluthrin, bifenthrin), organophosphorus (chlorpyrifos, chlorpyrifos-methyl, and malathion), fipronil, neonicotinoids (imidacloprid, acetamiprid and thiacloprid) and triazole (prothioconazole), together with 13 corresponding metabolites in human urine samples was achieved by solid-phase extraction and analysis by liquid chromatography coupled to tandem mass spectrometry. All targeted compounds, except malathion dicarboxylic acid, were measured with a mean within-accuracy (n = 5) of 71%-114% (RSD: 1%-14%) and between-run (n = 15) accuracy of 80%-118% (RSD: 2%-14%). Limits of quantitation of the targeted analytes ranged from 0.1 to 16 pg/mL. The detection result of urine samples from 25 volunteers indicated that the detection frequencies of 3,5,6-trichloro-2-pyridinol (median: 448 pg/mL), 6-chloropyridine-3-carboxylic acid (median: 193 pg/mL), 2-methyl-3-phenylbenzoic acid (median: 181 pg/mL), 3-phenoxybenzoic acid (median: 99 pg/mL), 2-isopropyl-6-methyl-4-pyrimidinol (median: 77 pg/mL), cyfluthrin (median: 59 pg/mL), cis-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (cis-DCCA, median: 53 pg/mL), trans-DCCA (median: 25 pg/mL), prothioconazole (median: 21 pg/mL), imidacloprid (median: 7 pg/mL), and prothioconazole-desthio (median: 1 pg/mL) were > 50%. The obtained results show that the validated method is suitable for the human biomonitoring of these current-use pesticides and their metabolites.

Suicide by vaping the synthetic cannabinoid 4F-MDMB-BINACA: cannabinoid receptors and fluoride at the crossroads of toxicity?

A 22-year-old man was hospitalized after stating he would 'commit suicide in a non-detectable way'. He was admitted with a severe necrotizing pancreatitis and acute kidney injury, evolving to multiple organ failure. His condition rapidly deteriorated, and he died 11 days after hospital admission. Postmortem histopathology confirmed fulminant necrotizing pancreatitis, acute tubular necrosis, cerebral edema, pericentral/midzonal hepatocellular necrosis and acute respiratory distress syndrome. Metabolites of 4F-MDMB-BINACA, a synthetic cannabinoid, were detected in urine and serum collected at hospital admission. The same drug was found in a vapor fluid found in the man's apartment. As cannabis use has been etiologically linked to acute pancreatitis, we hypothesize that the more afferent and potent 4F-MDMB-BINACA could induce acute pancreatitis via stimulation of cannabinoid (CB)1-receptors. Alternatively, terminal fluorination could have induced a dose-dependent toxic effect on a wide range of cellular processes, leading to cell dysfunction and death. This is the first clinicopathological description of a lethal intoxication with 4F-MDMB-BINACA, following extensive vaping. Toxic effects could either relate to CB-receptor binding or to direct fluoride toxicity.