Synthetic phenolic antioxidant additives are commonly used to prevent oxidative degradation in various materials, but they present significant challenges due to their non-renewable origins and potential health risks. This study explores the synthesis of novel arylindane diols-specifically diisoeugenol (DiE) and diisoallylsyringol (DiAS)-and evaluates their potential as safer and more sustainable alternatives. Using zeolite catalysis, a highly selective pathway for synthesizing DiE through the dimerization of the lignin-derived monomer isoeugenol (IE) was demonstrated. The synthesis of DiAS and diisoallylphenol (DiAP) enabled further exploration of how structural differences, such as o-methoxy groups, affect the physicochemical and toxicological properties of these arylindanes. The antioxidant activity of the compounds was tested using ABTS and DPPH assays, revealing strong radical-scavenging capabilities. Furthermore, oxidation onset temperature (OOT) measurements in polypropylene (PP) formulations containing these antioxidants showed improved thermal stability, matching or surpassing that of commercial antioxidants. Toxicological evaluations, including cytotoxicity tests on human gingival fibroblasts and an estrogenic activity (EA) screening using the CALUX assay, indicated low levels of EA and cytotoxicity. These results highlight the potential of DiE and DiAS as effective, renewable, and safe lignin-derived antioxidants for industrial applications.

Dental composites remain under scrutiny regarding their (long-term) safety. In spite of numerous studies on the release of monomers both in vitro and in vivo, only limited quantitative data exist on the in vivo leaching of degradation products from monomers and additives. The aim of this observational study was for the first time to quantitatively and qualitatively monitor the release of parent compounds and their degradation products in saliva from patients undergoing multiple restorations. Five patients in need of multiple large composite restorations (minimally 5 up to 28 restorations) due to wear (attrition, abrasion, and erosion) were included in the study, and they received adhesive restorative treatment according to the standard procedures in the university clinic for Restorative Dentistry. Saliva was collected at different time points, starting before the restoration up until 24 h after the treatment with composite restorations. Saliva extracts were analyzed by liquid chromatography–mass spectrometry. Leaching of monomers and degradation products was highest within 30 min after the placement of the restorations. The highest median concentrations of monomers were recorded for UDMA, BisEMA-3, and TEGDMA; yet, besides BisEMA-3 and TEGDMA, no monomers could be detected after 24 h. Mono- and demethacrylated degradation products remained present up to 24 h and concentrations were generally higher than those of monomers. In patients with multiple restorations, degradation products were still present in the sample taken before the next operation, several weeks after the previous operation. Exposure to residual monomers and degradation products occurs in the first hours after restoration. Monomers are present in saliva shortly after restoration, but degradation products can be detected weeks after the restoration confirming a long-term release. Future research should focus more on the release of degradation products from monomers and additives from resin-based materials given their prolonged presence in saliva after restoration.

Bisphenol A (BPA) is an industrial chemical that has been used for the manufacturing of polycarbonate plastics, epoxy resins and other consumer products, including food contact materials and dental resins. However, its petrochemical origin and adverse health effects, such as xeno-oestrogenic activity (EA), pose a challenge for sustainability. Here we show a green synthetic pathway towards genuinely sustainable BPA alternatives from a renewable lignin source. At the heart of this production route is a selective alkylation reaction between bio-based arene (for example, guaiacol) and alkene (for example, isoeugenol) molecules, catalysed by a recyclable zeolite catalyst H-USY. Zeolite catalysis favours regioselectivity and prompts higher reaction rate and chemoselectivity, enabling high yields of bisguaiacols. The synthesized bisguaiacols can be valorized into high-molecular-weight thermoplastic and thermosetting polymers with promising thermophysical properties, showcasing their potential as BPA replacements. This work progresses beyond the state of the art by demonstrating that renewability is not only a goal but also a means for safer chemicals. Bisphenol A (BPA) is an essential building block for manufacturing plastics, but its adverse health effects have become a major concern. Here the authors show a zeolite-catalysed synthetitic route to bio-renewable BPA alternatives that feature excellent safety and preserve efficacy of function.

Introduction: Many natural or synthetic compounds used in foods, dietary supplements, and food contact materials (FCMs) are suspected endocrine disruptors (EDs). Currently, scientific evidence to predict the impacts on biological systems of ED mixtures is lacking. In this study, three classes of substances were considered: i) phytoestrogens, ii) plant protection products (PPP) and iii) substances related to FCMs. Fourteen compounds were selected based on their potential endocrine activity and their presence in food and FCMs.Methods: These compounds were evaluated using an in vitro gene expression assay, the ERα-CALUX, to characterize their responses on the estrogen receptor alpha. Cells were exposed to fixed ratio mixtures and non-equipotent mixtures of full and partial agonists. The concentration-response curves measured for the three classes of compounds were characterized by variable geometric parameters in terms of maximum response (efficacy), sensitivity (slope) and potency (median effective concentration EC50). To account for these variations, a generic response addition (GRA) model was derived from mass action kinetics.Results: Although GRA does not allow us to clearly separate the concentration addition (CA) and independent action (IA) models, it was possible to determine in a statistically robust way whether the combined action of the chemicals in the mixture acted by interaction (synergy and antagonism) or by additive behavior. This distinction is crucial for assessing the risks associated with exposure to xenoestrogens. A benchmark dose approach was used to compare the response of phytoestrogen blends in the presence and absence of the hormone estradiol (E2). At the same time, 12 mixtures of 2–5 constituents including phytoestrogens, phthalates and PPPs in proportions close to those found in food products were tested. In 95% of cases, the response pattern observed showed a joint and independent effect of the chemicals on ER.Discussion: Overall, these results validate a risk assessment approach based on an additive effects model modulated by intrinsic toxicity factors. Here, the CA and IA approaches cannot be distinguished solely based on the shape of the concentration response curves. However, the optimized GRA model is more robust than CA when the efficacy, potency, and sensitivity of individual chemical agonists show large variations.

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 mu g) of eight unpolymerized resinbased 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 x 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.

Objectives: Only little is known about degradation of methacrylate monomers. Therefore, using in vitro chemical and saliva degradation this study aimed to identify the degradation products of organic compounds present in resin-based dental materials. Methods: Ten dental monomers and nine polymerized dental resin-based materials were immersed for 24 h in chemical media (0.1 M HCl, 0.1 M NaOH) and human pooled saliva in order to identify leached monomers and degradation products from chemical and saliva degradation. Samples were analyzed using liquid chromatography coupled to high -resolution mass spectrometry to identify previously unknown degradation products. Results: During in vitro chemical degradation, uncured monomers were rapidly hydrolyzed into monoand demethacrylated degradation products. During chemical degradation in alkaline conditions of polymerized materials, considered the worst-case scenario, only degradation products could be detected. In acidic conditions, monomers and their degradation products were detected. In addition, different additives such as EDMAB, DMPA and HMBP were present in acidic degradation samples. Degradation in human pooled saliva for 24 h to mimic the in vivo situation, resulted in the identification of both monomers and their degradation products.

Abstract Sustainable bisphenol A (BPA) substitutes should be safe and renewable to abolish the environmental burden of BPA’s endocrine disruption and petrochemical origin. Suitable alternatives preferably also retain the rigid and stiff methylenediphenol (MDP) scaffold to emulate the hallmark performance of BPA-based polymers. Here, we report a holistic solution to sustainable BPA substitutes made from abundant lignin-derivable o-methoxyphenols that display low-to-undetectable xeno-estrogenic activity while preserving the MDP scaffold. More specifically, we propose an innovative zeolite-catalyzed synthesis towards the similar albeit safer methylenediguaiacol (MDG) scaffold via Brønsted acid-catalyzed alkylation of guaiacol with different p-alkenylguaiacols yielding various so-called bisguaiacols. Zeolite catalysis favors regioselectivity and prompts higher rate and chemoselectivity for entropic reasons thanks to active site pocket confinement. Exploiting the intrinsic handles present in o-methoxyphenols not only simplifies and ameliorates classic bisphenol chemistry, but also enables to design out xeno-estrogenic activity. Successful direct reaction of a crude lignin oil extract, as produced by reductive catalytic fractionation, highlights the feasibility and robustness of this route as a downstream process for future wood biorefineries. Last but not least, pure p,p’-bisguaiacols are polymerized into high-molecular weight thermoplastic and thermosetting polymers with promising thermo-physical properties. Overall, this work elucidates that renewability should not merely serve as a goal (renewable carbon), but also as a means (safer chemicals), thereby transcending the scope of renewability.

Recently collected dietary exposure data on mineral oil saturated (MOSH) and aromatic (MOAH) hydrocarbons were used to evaluate the risks associated with exposure to mineral oil through food for the Belgian population. For MOSH, the no observed adverse effect level (NOAEL) value of 19 mg kg(-1) bw day(-1) based on the hepatic inflammation-associated granulomas found in a 90-day oral study in F-344 rats was used as point of departure (PoD). Due to existing toxicological uncertainties, the margin of exposure (MOE) approach was applied. In all investigated scenarios, the MOE values were well above 100, indicating that there is no direct health concern related to MOSH exposure for the Belgian population. Nevertheless, more appropriate risk assessment approaches for MOSH based on adequate PoD are needed. For dietary exposure to MOAH, which are potentially genotoxic and carcinogenic, no MOE values could be calculated due to the lack of adequate dose-response carcinogenicity data. In two investigated worst-case scenarios, a health concern related to MOAH exposure could not be excluded, highlighting that more data are needed to perform an adequate risk assessment. The possibility to use in vitro bioassays to collect such additional toxicological information for MOAH present in food samples was also investigated.

Objective. The biocompatibility of resin based dental composites has not yet been fully char-acterized even though certain monomers used in these composites are synthesized from Bisphenol A (BPA), a well-known estrogenic endocrine disruptor. As a result, they show structural relationship to BPA and can contain it as an impurity. Therefore, the estrogenic activity of 9 monomers, 2 photoinitiators, one photostabilizer and leachates of 4 commer-cially available composites was determined. Methods. The ERa-CALUX bioassay was used to determine both agonistic and antagonistic estrogenic activities of the pure compounds (BPA, BisDMA, BisGMA, BisEMA(3), BisEMA(6), BisEMA(10), TEGDMA, TCD-DI-HEA, BADGE, UDMA, HMBP, DMPA, CQ) and the leachates of cured composite disks. The leachates of 4 commercially available composites (Solitaire 2, Ceram.x Spectra ST, G-ae nial Posterior and Filtek Supreme XTE) in water and 0.1 M NaOH (pH = 13, 'worst-case scenario') were tested for estrogenic activity (pooled leachates from 10 cured composite disks). Results. Agonistic estrogenic activity was found for the monomer BisDMA, the photostabi-lizer HMBP and photoinitiator DMPA. All leachates from the 4 tested composites showed significant agonistic estrogenic activity higher than the DMSO control, and the highest activity (potency and efficacy) was found for Solitaire 2, followed by Ceram.x Spectra ST. Furthermore, antagonistic estrogenic activity was found in the leachates from G-ae nial Pos-terior. Significance. These results show that significant estrogenic activity was found in all leachates of the cured composite disks, and that this estrogenicity is most likely due to a mixture effect of multiple estrogenic compounds (including BPA, HMBP and DMPA). This indicates that further research into the endocrine activity of all the compounds that are present these composites (even at low quantities) and their possible mixture effect is warranted guarantee their safe use. (c) 2021 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved.

Objective. There is still much debate about the release of bisphenol-A (BPA) from dental materials. Therefore, this study aimed to quantify BPA present as an impurity in both BPA-based and non-BPA-based monomers and to evaluate whether these monomers may degrade to BPA upon salivary, bacterial, and chemical challenges. Methods. BPA was determined in three different amounts (1, 2, and 3 mu mol) of each monomer (TEGDMA, UDMA, mUDMA, BisGMA, BisEMA-3, -6, -10, -30, BisPMA, EBPADMA urethane, BADGE, and BisDMA). Next, the monomers (3 similar to mol) were immersed in whole human pooled saliva collected from adults, Streptococcus mutans (2 x 10(7) CFU/mL), and acidic (0.1 M HCl), alkaline (0.1 M NaOH), and control media. The amount of BPA was quantified using a specific and highly sensitive UPLC-MS/MS method including derivatization of BPA by pyridine-3-sulfonyl chloride. Results. The monomers BisGMA and BisEMA-3 contained trace amounts (0.0006% and 0.0025%, respectively) of BPA as impurities of their synthesis process. BPA concentrations increased when the monomers BisGMA, BisEMA-3, BisEMA-6, BisEMA-10, BisPMA and BADGE were exposed to saliva and S. mutans, indicating degradation of a small amount of monomer into BPA. In addition, BisPMA and BADGE degraded into BPA under alkaline conditions. The conversion rate of the monomers into BPA ranged between 0.0003% and 0.0025%. Significance. Impurities and degradation of BPA-based monomers may account for the release of BPA from resin-based dental materials. Even though the detected amounts of BPA due to monomer impurity were small, manufacturers of dental materials can reduce the BPA content by using only monomers of the highest purity. Considering the overall current trend towards BPA-free materials, it may be recommendable to investigate whether non-BPA based monomers can be used in dental resin-based materials. (C) 2021 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved.

Exposure to volcanic ash is a long-standing health concern for people living near active volcanoes and in distal urban areas. During transport and deposition, ash is subjected to various physicochemical processes that may change its surface composition and, consequently, bioreactivity. One such process is the interaction with anthropogenic pollutants; however, the potential for adsorbed, deleterious organic compounds to directly impact human health is unknown. We use an in vitro bioanalytical approach to screen for the presence of organic compounds of toxicological concern on ash surfaces and assess their biological potency. These compounds include polycyclic aromatic hydrocarbons (PAHs), polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dlPCBs). Analysis of ash collected in or near urbanised areas at five active volcanoes across the world (Etna, Italy; Fuego, Guatemala; Kelud, Indonesia; Sakurajima, Japan; Tungurahua, Ecuador) using the bioassay inferred the presence of such compounds on all samples. A relatively low response to PCDD/Fs and the absence of a dlPCBs response in the bioassay suggest that the measured activity is dominated by PAHs and PAH-like compounds. This study is the first to demonstrate a biological potency of organic pollutants associated with volcanic ash particles. According to our estimations, they are present in quantities below recommended exposure limits and likely pose a low direct concern for human health.

OBJECTIVES:BPA release from composites on the short term has been reported in several in-vitro and in-vivo studies. However, it remains unclear whether these materials also leach BPA on the long term. Even though composites may release various (BPA-based) methacrylate monomers up to one year, quantitative data about BPA have not been reported due to the lack of a sensitive method to accurately quantify low levels of BPA. In this context, the aim of the study was to quantify the one-year release of BPA with an optimized analytical method. METHODS:Composite disks (n = 6, 6 mm diameter and 2 mm height) from four commercial materials (G-ӕnial Posterior, Venus, Ceram.x mono and Filtek Supreme XTE) were immersed in 1 mL of water or ethanol as extraction solvent and stored in the dark at 37 °C. The extraction solvent was renewed weekly for a period of 52 weeks. Samples were derivatized with pyridine-3-sulfonyl chloride before analysis with ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS/MS). RESULTS:Derivatizing BPA increased the sensitivity of the analytical method and allowed accurate quantification of very low levels of BPA (i.e. 0.78 pmol BPA). BPA eluted continuously in ethanol from all four tested composites over a period of one year. BPA elution was clearly higher when ethanol was used as extraction solution. In water, BPA eluted could be detected up to one year, but levels could not be accurately quantified anymore after several weeks. SIGNIFICANCE:Composites can be considered as a potential long-term source of BPA, and thus should not be neglected when assessing the overall exposure to endocrine disrupting chemicals.

Root canal sealers are commonly used to endodontically treat teeth with periapical infections. Some root canal sealers based on epoxy resin contain bisphenol A diglycidyl ether (BADGE) and bisphenol F diglycidyl ether (BFDGE). The presence of these chemicals is of concern due to the close contact to the blood stream at the apex and the long setting times of up to 24 h. These chemicals, or any of their degradation products or metabolites, can then exert their toxic effects before being excreted. This study aimed to identify the phase I in vitro biotransformation products of BADGE and BFDGE using human liver microsomes. During incubation with microsomal fractions, the epoxides were rapidly hydrolysed in a NADPH independent manner resulting in the formation of BADGE.2H2O and BFDGE.2H2O. Further, oxidative reactions, such as hydroxylation and carboxylation, generated other BADGE metabolites, such as BADGE.2H2O-OH and BADGE.H2O.COOH, respectively. For BFDGE, further oxidation of BFDGE.2H2O led to the newly reported carboxylic acid, BFDGE.H2O.COOH. In total, three specific metabolites have been identified which can serve in future human biomonitoring studies of BADGE and BFDGE.

Polycyclic aromatic hydrocarbons (PAH) are a complex group of organic compounds, consisting of at least three fused aromatic rings, which are formed during combustion of organic matter. While some PAHs have been reported to have carcinogenic and/or mutagenic properties, another possible negative health impact is their endocrine disrupting potential. Therefore, the aim of this study was to determine both the agonistic and antagonistic endocrine activity of 9 environmentally relevant PAHs using three different CALUX bioassays: The AhR-CALUX, The ERα-CALUX and PPARγ-CALUX. For the PPARγ-CALUX anthracene, fluoranthene, pyrene and fluorene showed weak agonistic activity, whilst benzo(a)pyrene (B(a)P) was the only one exhibiting weak antagonistic activity. For the AhR-CALUX, chrysene was the only PAH that showed relatively strong agonist activity (except for B(a)P which was used as a standard). Pyrene, anthracene and fluoranthene showed weak AhR agonist activity. In the ERα-CALUX bioassay, fluoranthene had agonistic activity whilst B(a)P exhibited both agonistic and antagonistic activity (lowering E2 activity by 30%). Phenanthrene and anthracene had weak ERα agonist activities. These results indicate that certain PAHs have multiple modes of action and can activate/inhibit multiple receptor signaling pathways known to play critical roles in mediating endocrine disruption.

Dental resin systems have been in use for several decades. (Meth)acrylic monomers are an important part of the matrix system and are either based on BPA while others lack the BPA core. The degree of conversion during restoration is in general between 50-70 % allowing leaching from unreacted monomers to the oral cavity where they can be taken up through the pulp or gastrointestinal tract after ingestion with subsequent hepatic metabolism. This study identified the in vitro Phase I and Phase II metabolism of the dental resin monomers BisGMA, UDMA, BisPMA and TCD-DI-HEA, using human liver microsomes (HLM) and human liver cytosols. During Phase I incubation with HLM, the (meth)acrylic acid in the monomers was rapidly removed followed by oxidative and hydroxylation pathways. For BisPMA an O-dealkylation pathway occurred resulting in the formation of BPA. The carbamates present in TCD-DI-HEA and UDMA were resistant to biotransformation reactions. Phase II biotransformation products were only observed for BisPMA and included conjugation reactions with sulphate and glucuronic acid. In total 4, 3, 12 and 3 biotransformation products were identified in this study for BisGMA, UDMA, BisPMA and TCD-DI-HEA respectively. Possible human health effects of these biotransformation products remain unclear due to limited data availability.

Paperboard used as packaging, a non-inert material, can transfer chemicals into food. Over the years, endocrine disrupting compounds (EDCs), such as NonylPhenols (NPs), BisPhenol A (BPA) and phthalates have been shown to migrate from packaging materials into food. Due to chronic exposure and mixture effects of these EDCs, they could cause health effects even at very low doses. Many EDCs are still unknown and many more are still unregulated. The ERE-CALUX bioassay was used as a bioanalytical tool to investigate estrogenic activities of paperboard food packaging and its characteristics, including recycling rate and printing ink. A "worst case" scenario with full extraction is compared to a dry food migration experiment. By measuring an overall estrogenic activity, known and unknown estrogenic chemicals and mixture effects are taken into account and the data are compared to molecule specific analysis. Estrogenic activities ranged from 682 ± 66 pg E2 eq./dm2 to 3250 ± 400 pg E2 eq./dm2 for "worst case" extraction and from 347 ± 30 pg E2 eq./dm2 to 1350 ± 70 pg E2 eq./dm2 for migration experiments. A two-factor ANOVA revealed a relationship between estrogenic activity and the recycling rate of the paperboard, but no significant difference with printing ink was observed for these paperboard samples. Bis(2-ethylhexyl)phthalate (DEHP), dibutyl phthalate (DBP), butyl benzyl phthalate (BBP) and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) were determined in all extraction and migrations experiment samples. A Spearman rank correlation analysis showed a relationship between the estrogenic activity and the total phthalates as well as with each compound individually.