Repurposing chemical waste: Sustainable chemistry for circularity beyond artificial intelligence.

Generating considerable amounts of industrial waste requires rethinking chemistry for circularity in a broader picture. We discuss the study by Wolos et al. (2022) showing that the critical application of artificial intelligence on chemical reactivity can help us trace an unprecedented number of syntheses to novel responsible uses of waste.

Modernizing persistence-bioaccumulation-toxicity (PBT) assessment with high throughput animal-free methods.

The assessment of persistence (P), bioaccumulation (B), and toxicity (T) of a chemical is a crucial first step at ensuring chemical safety and is a cornerstone of the European Union's chemicals regulation REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals). Existing methods for PBT assessment are overly complex and cumbersome, have produced incorrect conclusions, and rely heavily on animal-intensive testing. We explore how new-approach methodologies (NAMs) can overcome the limitations of current PBT assessment. We propose two innovative hazard indicators, termed cumulative toxicity equivalents (CTE) and persistent toxicity equivalents (PTE). Together they are intended to replace existing PBT indicators and can also accommodate the emerging concept of PMT (where M stands for mobility). The proposed "toxicity equivalents" can be measured with high throughput in vitro bioassays. CTE refers to the toxic effects measured directly in any given sample, including single chemicals, substitution products, or mixtures. PTE is the equivalent measure of cumulative toxicity equivalents measured after simulated environmental degradation of the sample. With an appropriate panel of animal-free or alternative in vitro bioassays, CTE and PTE comprise key environmental and human health hazard indicators. CTE and PTE do not require analytical identification of transformation products and mixture components but instead prompt two key questions: is the chemical or mixture toxic, and is this toxicity persistent or can it be attenuated by environmental degradation? Taken together, the proposed hazard indicators CTE and PTE have the potential to integrate P, B/M and T assessment into one high-throughput experimental workflow that sidesteps the need for analytical measurements and will support the Chemicals Strategy for Sustainability of the European Union.

Status quo on identified transformation products of organic ultraviolet filters and their persistence.

Organic micropollutants of concern-including organic UV filters (UVF)-are getting increasing attention. Personal care products such as sunscreens or cosmetic articles often contain large quantities of UVF. These substances enter the environment either directly (during outdoor activities) or indirectly (via sewages from households). Therefore, the removal or degradation of UVF by natural or technical treatment processes is important to understand. UVF are often incompletely removed and transformed to side products of incomplete mineralization by abiotic and biotic processes. An extensive overview on transformation products (TPs) is essential to systematically identify knowledge gaps and to derive research needs. While there are many reviews on the UVF themselves, the number of reviews which focus on their TPs is limited. Consequently, this review gives an overview on the latest findings regarding TPs of UVF. In this publication, known TPs of UVF, which were formed during abiotic and biotic processes, are reviewed. Target substances were defined and a literature database was reviewed for studies on TPs of the target substances. The first list of studies was shortened stepwise, thus generating a final list of studies which contained only the relevant studies. Since biodegradation is one of the most important pathways for removal of organic compounds from the environment, this review presents an overview on known TPs of organic UVF and their biodegradability, which determines their environmental fate. In this way, all identified TPs of UVF were listed and checked for information on their biodegradability. A total of 2731 records of studies were assessed. Forty-two studies, which assessed 46 processes that lead to the formation of identified TPs, were included in this review. One hundred and seventyseven different TPs resulting from 11 different UVF were identified. Little to no data on the biodegradability was found for TPs. This indicates a severe lack of data on the biodegradability of TPs of organic UVF substances. Since most TPs lack information on biodegradability, further research should provide information on both-identity and biodegradability-of formed TPs to be able to assess their hazardousness for the environment.

Les micropolluants organiques préoccupants, y compris les filtres UV organiques (UVF), font l'objet d'une attention croissante. Les produits de soins personnels tels que les écrans solaires ou les articles cosmétiques contiennent souvent de grandes quantités de filtres UV. Ces substances pénètrent dans l'environnement soit directement (lors d'activités de plein air), soit indirectement (via les eaux usées ménagères). Il est donc important de comprendre l'élimination ou la dégradation des UVF par des processus de traitement naturels ou techniques. Les UVF sont souvent éliminés de manière incomplète et transformés en produits secondaires de minéralisation incomplète par des processus abiotiques et biotiques. Il est essentiel de disposer d'une vue d'ensemble des produits de transformation pour identifier systématiquement les lacunes dans les connaissances et déterminer les besoins en matière de recherche. S'il existe de nombreuses études sur les UVF eux-mêmes, le nombre d'études portant sur leurs produits de transformation est limité. Par conséquent, cette étude donne un aperçu des dernières découvertes concernant les produits de transformation des UVF. Dans cette publication, les TP connus des UVF, qui ont été formés au cours de processus abiotiques et biotiques, sont passés en revue. Des substances cibles ont été définies et une base de données bibliographiques a été examinée pour trouver des études sur les PT des substances cibles. La première liste d'études a été raccourcie progressivement, ce qui a permis d'obtenir une liste finale d'études qui ne contenait que les études pertinentes. La biodégradation étant l'une des voies les plus importantes pour l'élimination des composés organiques de l'environnement, cette étude présente une vue d'ensemble des PT connus des UVF organiques et de leur biodégradabilité, qui détermine leur devenir dans l'environnement. Ainsi, tous les PT identifiés d'UVF ont été répertoriés et des informations sur leur biodégradabilité ont été vérifiées. Au total, 2731 enregistrements d'études ont été évalués. Quarante-deux études, qui ont évalué 46 processus conduisant à la formation des polluants organiques persistants identifiés, ont été incluses dans cette analyse. Cent soixante-dix- sept TP différents résultant de 11 UVF différents ont été identifiés. Peu ou pas de données sur la biodégradabilité ont été trouvées pour les PT. Cela indique un manque important de données sur la biodégradabilité des produits finis des substances UVF organiques. Étant donné que la plupart des PT manquent d'informations sur la biodégradabilité, les recherches futures devraient fournir des informations sur l'identité et la biodégradabilité des PT formés afin de pouvoir évaluer leur dangerosité pour l'environnement.

Genetic toxicology in silico protocol.

In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol. The protocol outlines a hazard assessment framework including key effects/mechanisms and their relationships to endpoints such as gene mutation and clastogenicity. IST models and data are reviewed that support the assessment of these effects/mechanisms along with defined approaches for combining the information and evaluating the confidence in the assessment. This protocol has been developed through a consortium of toxicologists, computational scientists, and regulatory scientists across several industries to support the implementation and acceptance of in silico approaches.

Bioavailability of Antibiotics at Soil-Water Interfaces: A Comparison of Measured Activities and Equilibrium Partitioning Estimates.

There are growing concerns that antibiotic pollution impacts environmental microbiota and facilitates the propagation of antibiotic resistance. However, the prediction or analytical determination of bioavailable concentrations of antibiotics in soil is still subject to great uncertainty. Biological assays are increasingly recognized as valuable complementary tools that allow a more direct determination of the residual antibiotic activity. This study assessed the bioavailability of structurally diverse antibiotics at a soil-water interface applying activity-based analyses in conjunction with equilibrium partitioning (EqP) modeling. The activity against Gram-positive and Gram-negative bacteria of nine antibiotics from different classes was determined in the presence and absence of standard soil (LUFA St. 2.2). The addition of soil affected the activity of different antibiotics to highly varying degrees. Moreover, a highly significant correlation ( p < 0.0001) between the experimentally observed and the EqP-derived log EC50 (half-maximal effective concentration) values was observed. The innovative experimental design of this study provided new insights on the bioavailability of antibiotics at soil-water interfaces. EqP appears to be applicable to a broad range of antibiotics for the purpose of screening-level risk assessment. However, EqP estimates cannot replace soil-specific ecotoxicity testing in higher-tier assessments, since their accuracy is still compromised by a number of factors.

Fragrance allergens in household detergents.

Consumers are confronted with a large number of fragrance allergens from various sources. Until now, the discussion of exposure sources has mainly addressed cosmetic products and neglected other scented products in households. For the first time, fragrance allergens were evaluated in a complete set of detergents in households. In 131 households, we investigated the prevalence of detergents and searched their lists of ingredients for 26 fragrance allergens liable to be indicated on products according to the European Detergents Regulations. On the ingredient lists of 1447 products, these 26 fragrance substances were named almost 2000 times, most often limonene, linalool and hexyl cinnamal. Benzyl salicylate was used frequently in all-purpose cleaners. Linalool and limonene, hexyl cinnamal and butylphenyl methylpropional and citronellol and linalool co-occurred most often together in products. Fragrance allergens co-occurring together most frequently within households were eugenol, coumarin and cinnamyl alcohol. The study shows that detergents could play a relevant role for the exposure of consumers towards fragrance allergens and that they should not be underestimated as an exposure source during the exposure assessment.

In silico toxicology protocols.

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information.

LC-HRMS Data Processing Strategy for Reliable Sample Comparison Exemplified by the Assessment of Water Treatment Processes.

The behavior of micropollutants in water treatment is an important aspect in terms of water quality. Nontarget screening by liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) offers the opportunity to comprehensively assess water treatment processes by comparing the signal heights of all detectable compounds before and after treatment. Without preselection of known target compounds, all accessible information is used to describe changes across processes and thus serves as a measure for the treatment efficiency. In this study, we introduce a novel LC-HRMS data processing strategy for the reliable classification of signals based on the observed fold changes. An approach for filtering detected features was developed and, after parameter adjustment, validated for its recall and precision. As proof of concept, the fate of 411 target compounds in a 0.1 µg/L standard mix was tracked throughout the data processing stages, where 406 targets were successfully recognized and retained during filtering. Potential pitfalls in signal classification were addressed. We found the recursive peak integration to be a key point for the reliable classification of signal changes across a process. For evaluating the repeatability, a combinatorial approach was conducted to verify the consistency of the final outcome using technical replicates of influent and effluent samples taken from an ozonation process during drinking water treatment. The results showed sufficient repeatability and thus emphasized the applicability of nontarget screening for the assessment of water treatment processes. The developed data processing strategies may be transferred to other research fields where sample comparisons are conducted.

Sustainable Chemistry: A Future Guiding Principle.

"… Chemistry is currently faced with one of the biggest challenges in its history. The main reaction to this is a search for how new resources can be utilized in the synthesis of (new) compounds. However, much more is needed to meet this challenge: Sustainable chemistry is simultaneously both a path and a goal. It is not a new subdiscipline of chemistry, but a guiding principle. It uses the knowledge of all chemical subdisciplines along the entire lifecycles of chemical products …" Read more in the Guest Editorial by Klaus Kümmerer.

Re-Designing of Existing Pharmaceuticals for Environmental Biodegradability: A Tiered Approach with ß-Blocker Propranolol as an Example.

Worldwide, contamination of aquatic systems with micropollutants, including pharmaceuticals, is one of the challenges for sustainable management of water resources. Although micropollutants are present at low concentrations, many of them raise considerable toxicological concerns, particularly when present as components of complex mixtures. Recent research has shown that this problem cannot be sustainably solved with advanced effluent treatment. Therefore, an alternative that might overcome these environmental problems is the design of new pharmaceutical molecules or the redesign of existing pharmaceutical molecules that present the functionality needed for their application and have improved environmental biodegradability. Such redesigning can be performed by small molecular changes in the drug molecule with intact drug moiety which could incorporate the additional attribute such as biodegradability while retaining its pharmacological potency. This proof of concept study provides an approach for the rational redesign of a given pharmaceutical (Propranolol as an example). New derivatives with small molecular changes as compared to propranolol molecule were generated by a nontargeted photolysis process. Generated derivatives with intact drug moieties (an aromatic ring and a ß-ethanolamine moiety) were further screened for aerobic biodegradability and pharmacological potency. The feasibility of the approach of redesigning an existing pharmaceutical through nontargeted generation of new derivatives with intact drug moiety and through subsequent screening was demonstrated in this study. Application of such approaches in turn might contribute to the protection of water resources in a truly sustainable manner.

Designing greener active pharmaceutical ingredients: Insights from pharmaceutical industry into drug discovery and development.

Active pharmaceutical ingredients (APIs), their metabolites and transformation products (TPs) are found as pollutants in the environment. They can impact human and environmental health. To address this issue, an efficient, long-term prevention strategy could be the design of APIs that have less impact on the natural environment, i.e. the design of greener APIs, by the implementation of environmental parameters into the drug discovery and development process (also abbreviated R&D for 'research and development'). Our study aimed to evaluate the feasibility of the design of greener APIs based on insights from drug design experts working in large, research-based pharmaceutical companies. The feasibility evaluation also identified needs and incentives for process modification. For this purpose, 30 R&D and environmental experts from seven globally active pharmaceutical companies were interviewed along a structured questionnaire. Main findings are that the interviewed experts saw manifold opportunities to include properties rendering APIs greener in different stages along the R&D process. This implementation would be favoured by the fact that the pharmaceutical R&D process is very flexible and relies on balancing multiple parameters. Furthermore, some API properties that reduce environmental risks were considered compatible with common desirable properties for application. Environmental properties should be considered early during R&D, i.e. when molecules are screened and optimized. It has been found that availability of suitable in silico models and in vitro assays is crucial for this environmental consideration. Their attributes, e.g. throughput and costs, determine at which process stage they can be successfully applied. An intensified exchange between R&D and environmental experts within and outside companies would push the industrial application of the benign by design approach for APIs forward. Collaboration across pharmaceutical companies, authorities, and academia is seen as highly promising in this respect. Financial, social, and regulatory incentives would support future design of greener APIs.

Analysis of environmental biodegradability of cellulose-based pharmaceutical excipients in aqueous media.

Pharmaceutical cellulosic polymers will inevitably reach natural water systems if they are not removed after entering wastewater. Biodegradation of organic chemicals in sewage or in the aquatic environment is an important removal mechanism. In this study, we investigated the environmental biodegradation of 14 cellulose derivatives commonly utilized as pharmaceutical excipients using three different test systems that are based on the closed bottle test (OECD 301D) and the manometric respirometry test (OECD 301F). For the different cellulose derivatives tested, we observed varying degrees of biodegradation ranging from 0 to 20.4 % chemical oxygen demand (COD). However, none met the criteria for classification as 'readily biodegradable'. In addition, 10 out of 14 cellulose derivatives and/or their possible transformation products formed during the experiments, may exhibit possible toxic inhibitory effects on the inoculum. This includes one or several derivatives of hydroxy propyl methyl cellulose, hydroxy propyl cellulose, methyl cellulose, ethyl cellulose, and hydroxy ethyl cellulose. Based on the results obtained, we have developed a graded classification score ('traffic light system') for excipient biodegradation. This could help streamline the assessment and classification of cellulose derivatives concerning risk of persistence and potential adverse environmental effects, thereby assisting in the prioritization of more favorable compounds. In the long term, however, excipients should be designed from the very beginning to be biodegradable and mineralizable in the environment ('benign by design').

How data on transformation products can support the redesign of sulfonamides towards better biodegradability in the environment.

Sulfonamide antibiotics (SUAs) released into the environment can affect environmental und human health, e.g., by accelerating the development and selection of antimicrobial resistant bacteria. Benign by Design (BbD) of SUAs is an effective risk prevention approach. BbD principles aim for fast and complete mineralization or at least deactivation of the SUA after release into the aquatic environment. Main objective was to test if mixtures of transformation products (TPs) generated via photolysis of SUAs can be used as an efficient way to screen for similarly effective but better biodegradable SUA alternatives. Six SUAs were photolyzed (Hg ultraviolet (UV) light), and generated UV-mixtures analysed by high performance liquid chromatography coupled to an UV and tandem mass spectrometry detector. UV-mixtures were screened for antibiotic activity (luminescence bacteria test, LBT, on luminescence and growth inhibition of Aliivibrio Fischeri) and environmental biodegradability (manometric respirometry test, MRT, OECD 301F) using untreated parent SUAs in comparison. Additionally, ready environmental biodegradability of three commercially available hydroxylated sulfanilamide derivatives was investigated. SUA-TPs contributed to acute and chronic bacterial luminescence inhibition by UV-mixtures. LBT's third endpoint, growth inhibition, was not significant for UV-mixtures. However, it cannot be excluded for tested TPs as concentrations were lower than parents' concentrations and inhibition by most parental concentrations tested was also not significant. HPLC analysis of MRT samples revealed that one third of SUA-TPs was reduced during incubation. Three of these TPs, likely OH-SIX, OH-SMX and OH-STZ, were of interest for BbD because the sulfonamide moiety is still present. However, hydroxylated sulfanilamide derivatives, tested to investigate the effect of hydroxylation on biodegradability, were not readily biodegraded. Thus, improving mineralization through hydroxylation as a general rule couldn't be confirmed, and no BbD candidate could be identified. This study fills data gaps on bioactivity and environmental biodegradability of SUAs' TP-mixtures. Findings may support new redesign approaches.

Biodegradation of flavonoids - Influences of structural features.

Flavonoids, a class of natural products with a variety of applications in nutrition, pharmacy and as biopesticides, could substitute more harmful synthetic chemicals that persist in the environment. To gain a better understanding of the biodegradability of flavonoids and the influence of structural features, firstly, the ultimate biodegradation of 19 flavonoids was investigated with the Closed Bottle Test according to the OECD guideline 301 D. Secondly, regarding the fast abiotic degradation reported for several flavonoids with severe concentration decrease within hours and its possible impacts on the processes behind the ultimate biodegradation, primary degradation of 4 selected flavonoids was compared at conditions representing biodegradation, abiotic degradation, and mixed substrates by monitoring the flavonoids' concentrations with HPLC-UV/vis. Our results showed that 17 out of the 19 tested flavonoids were readily biodegradable. Structural features like a hydroxy group at C3, the C2-C3 bond order, a methoxy group in the B ring, and the position of the B ring in regard to the chromene core did not affect biodegradation of the tested flavonoids. Only flavone without any hydroxy groups and morin with an uncommon 2',4' pattern of hydroxy groups were non-readily biodegradable. Monitoring the concentration of 4 selected flavonoids by HPLC-UV/vis revealed that biodegradation occurred faster than abiotic degradation at CBT conditions with no other carbon sources present. The presence of an alternative carbon source tends to increase lag phases and decrease biodegradation rates. At this condition, abiotic degradation contributed to the degradation of unstable flavonoids. Overall, as a first tier to assess the environmental fate, our results indicate low risks for persistence of most flavonoids. Thus, flavonoids could represent benign substitutes for persistent synthetic chemicals.

Learning from Safe-by-Design for Safe-and-Sustainable-by-Design: Mapping the current landscape of Safe-by-Design reviews, case studies, and frameworks.

With the introduction of the European Commission's "Safe and Sustainable-by-Design" (SSbD) framework, the interest in understanding the implications of safety and sustainability assessments of chemicals, materials, and processes at early-innovation stages has skyrocketed. Our study focuses on the "Safe-by-Design" (SbD) approach from the nanomaterials sector, which predates the SSbD framework. In this assessment, SbD studies have been compiled and categorized into reviews, case studies, and frameworks. Reviews of SbD tools have been further classified as quantitative, qualitative, or toolboxes and repositories. We assessed the SbD case studies and classified them into three categories: safe(r)-by-modeling, safe(r)-by-selection, or safe(r)-by-redesign. This classification enabled us to understand past SbD work and subsequently use it to define future SSbD work so as to avoid confusion and possibilities of "SSbD-washing" (similar to greenwashing). Finally, the preexisting SbD frameworks have been studied and contextualized against the SSbD framework. Several key recommendations for SSbD based on our analysis can be made. Knowledge gained from existing approaches such as SbD, green and sustainable chemistry, and benign-by-design approaches needs to be preserved and effectively transferred to SSbD. Better incorporation of chemical and material functionality into the SSbD framework is required. The concept of lifecycle thinking and the stage-gate innovation model need to be reconciled for SSbD. The development of high-throughput screening models is critical for the operationalization of SSbD. We conclude that the rapid pace of both SbD and SSbD development necessitates a regular mapping of the newly published literature that is relevant to this field.

Design of greener drugs: aligning parameters in pharmaceutical R&D and drivers for environmental impact.

Active pharmaceutical ingredients (APIs) in the environment, primarily resulting from patient excretion, are of concern because of potential risks to wildlife. This has led to more restrictive regulatory policies. Here, we discuss the 'benign-by-design' approach, which encourages the development of environmentally friendly APIs that are also safe and efficacious for patients. We explore the challenges and opportunities associated with identifying chemical properties that influence the environmental impact of APIs. Although a straightforward application of greener properties could hinder the development of new drugs, more nuanced approaches could lead to drugs that benefit both patients and the environment. We advocate for an enhanced dialogue between research and development (R&D) and environmental scientists and development of a toolbox to incorporate environmental sustainability in drug development.

Do edible oils reduce bacterial colonization of enamel in situ?

OBJECTIVE: Edible oils are an empiric approach for the prevention of oral diseases. The present in situ study investigated the effect of edible oils on initial bacterial colonization of enamel surfaces. METHODS AND MATERIALS: Initial biofilm formation was performed on enamel specimens mounted on maxillary splints and carried by eight subjects. After 1 min of pellicle formation, rinses with safflower oil, olive oil and linseed oil were performed for 10 min. Application of chlorhexidine for 1 min served as positive control. Afterwards, the slabs were carried for 8 h overnight. Samples carried for 8 h without any rinse served as negative controls. The amount of adherent bacteria was determined by DAPI staining (4',6-diamidino-2-phenylindole) and live-dead staining (BacLight). Additionally, determination of colony forming units was performed after desorption of the bacteria. TEM evaluation was carried out after application of the rinses. RESULTS: The number of adherent bacteria on control samples was 6.1 ± 8.1 × 10(5)/cm(2) after 8 h (DAPI). Fluorescence microscopic data from DAPI staining and live-dead staining as well as from the determination of CFU revealed no significant effects of rinsing with oils on the amount of adherent bacteria compared to the non-rinsed control samples. However, with chlorhexidine a significant reduction in the number of bacteria by more than 85 % was achieved (DAPI, chlorhexidine: 8.2 ± 17.1 × 10(4)/cm(2)). The ratio of viable to dead bacteria was almost equal (1:1) irrespective of the rinse adopted as recorded with BacLight. TEM indicated accumulation of oil micelles at the pellicle's surface and modification of its ultrastructure. CONCLUSION: Rinses with edible oils have no significant impact on the initial pattern and amount of bacterial colonization on enamel over 8 h. CLINICAL RELEVANCE: Rinses with edible oils cannot be recommended for efficient reduction of oral biofilm formation.

Elution of monomers from three different bonding systems and their antibacterial effect.

The aim of the present study was to evaluate the release of monomers from three bonding systems and to correlate it with their antibacterial effect. Three bonding systems (Optibond FL(®), Xeno III(®) and Clearfil™ Protect Bond) were tested after storage in ethanol 75 % and human saliva. Twenty samples (n = 10/medium) of each bonding material were prepared and polymerized according to the manufacturers' instructions. Each sample was stored in 1 ml of the respective storage medium. The medium was renewed after 24 h, 7 days, and 28 days and was analysed by LC-MS/MS for the release of substances. Additionally, the antibacterial effect of the unpolymerized components of each bonding system and their polymerized mixture was tested using agar disc-diffusion test with Streptococcus mutans. Only HEMA was found to be released. The amount of HEMA detected in the ethanol samples was significantly higher compared to the saliva samples (p < 0.0001). The release of HEMA was as follows: Clearfil™ Protect Bond < Optibond FL(®) < Xeno III(®.) According to the agar disc-diffusion test, all materials exhibited certain antibacterial activity. The release of HEMA from all tested materials even after storing in human saliva increases the concerns about their toxicity. Their antibacterial effect seems not be due to the release of substances.

Environmental degradation of human metabolites of cyclophosphamide leads to toxic and non-biodegradable transformation products.

The present study assessed the ready biodegradability of the prodrug cyclophosphamide (CPA) and its stable human metabolites in the closed bottle test (CBT). The results of the CBT showed that only the main human metabolite, carboxyphosphamide (CXP), was biodegradable to a certain extent (23 ± 2.4 % ThODNH3). All other metabolites showed neither biodegradation under these conditions nor were any toxic effects on the inoculum observed. Yet, HRMSn results revealed partial primary elimination of all human metabolites and formation of 25 new transformation products. Abiotic degradation via SNi and SN2 reactions was proposed as the main degradation pathway during the CBT. The main degradation products were assigned as 3-(2-chloroethyl)oxazolidin-2-one (COAZ), cytotoxic N-2-chloroethylaziridine (CEZ) and nor­nitrogen mustard (NNM), an analogue of the chemical warfare agent HN2. While the acute ecotoxicity of the detected products is widely unknown, many have already been reported in medical literature to be either mutagenic, genotoxic, cytotoxic or carcinogenic and may therefore cause a greater risk than their precursors. QSAR models predicted that 16 of them are mutagenic and genotoxic, thus classifying the majority of the chemicals as potential environmental hazards. The central intermediates during the degradation process were proposed as CEZ and its corresponding aziridinium ion. However, other degradation products may occur depending on the type and strength of nucleophiles present in the matrices. Overall, the results demonstrated the importance to include human metabolites in the evaluation of the environmental fate of pharmaceuticals and their risk assessment especially when investigating prodrugs. The results underline the importance of identifying possible degradation products of metabolites, as they can be more toxic than related parent compounds and metabolites and can cause a greater risk to the environment and humans.

Are Si-C bonds cleaved by microorganisms? A critical review on biodegradation of methylsiloxanes.

Methylsiloxanes, compounds that contain H3C-Si-O subunits in their molecular structure, are emerging ubiquitous pollutants now detected in many environmental compartments. These compounds and generally Si-C bonds do not occur in living nature, but are industrially produced worldwide in millions of tons per annum and are widely used, resulting in their release to the environment. It is an open question whether or to what extent microorganisms are able to decompose these compounds. The presence of methylsiloxanes in many biogases adds to the economic relevance of this question. We here review and critically discuss, for the first time, the evidence obtained for and against degradation of methylsiloxanes by microorganisms, and in particular for microbial cleavage of Si-CH3 bonds. As a result, no convincing demonstration of Si-C cleavage by native environmental microorganisms has been found.