Modification of the Lipid Profile of the Initial Oral Biofilm In Situ Using Linseed Oil as Mouthwash

Lipids are of interest for the targeted modification of oral bioadhesion processes. Therefore, the sustainable effects of linseed oil on the composition and ultrastructure of the in situ pellicle were investigated. Unlike saliva, linseed oil contains linolenic acid (18:3), which served as a marker for lipid accumulation. Individual splints with bovine enamel slabs were worn by five subjects. After 1 min of pellicle formation, rinses were performed with linseed oil for 10 min, and the slabs’ oral exposure was continued for up to 2 or 8 h. Gas chromatography coupled with electron impact ionization mass spectrometry (GC-EI/MS) was used to characterize the fatty acid composition of the pellicle samples. Transmission electron microscopy was performed to analyze the ultrastructure. Extensive accumulation of linolenic acid was recorded in the samples of all subjects 2 h after the rinse and considerable amounts persisted after 8 h. The ultrastructure of the 2 h pellicle was less electron-dense and contained lipid vesicles when compared with controls. After 8 h, no apparent ultrastructural effects were visible. Linolenic acid is an excellent marker for the investigation of fatty acid accumulation in the pellicle. New preventive strategies could benefit from the accumulation of lipid components in the pellicle

Recalcitrant Pharmaceuticals in the Aquatic Environment: A Comparative Screening Study of Their Occurrence, Formation of Phototransformation Products and Their in Vitro Toxicity

Data allowing for a complete environmental risk assessment of pharmaceuticals and their photoderatives in the environment are still scarce. In the present study, in vitro toxicity and both bio- and photopersistence of various pharmaceuticals (aciclovir, allopurinol, cetirizine, cimetidine, fluconazole, hydrochlorothiazide, lisinopril, phenytoin, primidone, ranitidine, sotalol, sulpiride, tramadol and valsartane) as well as their phototransformation products were evaluated in order to fill data gaps and to help prioritise them for further testing. Twelve out of the fourteen compounds investigated were found to be neither readily nor inherently biodegradable in the Organisation of Economic Cooperation and Development-biodegradability tests. The study further demonstrates that the photo-induced transformation of the pharmaceuticals was faster upon irradiation with a Hg lamp (UV light) than with a Xe lamp emitting a spectrum that mimics sunlight. Comparing the non-irradiated with the respective irradiated solutions, a higher acute and chronic toxicity against bacteria was found for the irradiated solutions of seven compounds (cetirizine, cimetidine, hydrochlorothiazide, ranitidine, sulpiride, tramadol and valsartane). No cyto- and genotoxic effects were found in human cervical (HeLa) and liver (Hep-G2) cells for any of the investigated compounds or their phototransformation products. This comparative study documents that phototransformation products can arise as a result of UV treatment of wastewater containing these pharmaceuticals. It further demonstrates that some phototransformation products may have a higher environmental risk potential than the respective parent compounds because some phototransformation products exhibited a higher bacterial toxicity

Dialkyl carbonates: scale-up synthesis and application as green solvents for PVDF membranes preparation

Dialkyl carbonates (DACs) are well-known green solvents and reagents that have been extensively investigated as safe alternatives to chlorine-based compounds. In fact, they can replace alkyl halides and dimethyl sulfate in alkylation and carbonylation reactions as well as phosgene and its derivatives in alkoxycarbonylation ones. Recently we have developed a high yielding scale-up synthesis of non-commercially available or expensive DACs via transcarbonylation reactions of an alcohol with dimethyl carbonate (DMC) promoted by the nitrogen-based organocatalyst 1,5,7-triazabicyclo[4.4.0]dec-5-ene TBD. Compared to previously published works, the proposed procedure has been customized for DACs large scale production (up to 100 mL of product obtained). Purification of these compounds has been achieved by fractional distillation and the exceeding reagents have been recovered and recycled. Selected DACs for this study include both symmetrical and unsymmetrical compounds, incorporating several alkyl, alkoxyalkyl, alkylamino and alkylthio functional groups. Chemical-physical properties of the new DACs have been also evaluated, as well as their water solubility. Furthermore, biodegradability and cytotoxicity tests have been carried out to investigate the effects of the different substituents on the greenness of these potential solvents and reagents. DACs application as green solvents for membrane preparation was next investigated, using non-solvent induced phase separation (NIPS) and vapor induced phase separation (VIPS) techniques, achieving both porous and plain membranes [4]. Morphology, additives effect, physical-chemical and mechanical proprieties as well as their performances in terms of water permeability and rejection were evaluated and compared to membranes obtained using commercially available cyclic carbonates (namely ethylene carbonate – EC and propylene carbonate – PC)

Elution of Monomers from Provisional Composite Materials

The aim of this study was to evaluate the elution of substances from different materials used for the manufacturing of temporary indirect restorations, after storage in saliva and ethanol 75%. 10 samples of three chemically cured materials (Protemp 3 Garant, Systemp.c&b, and Trim) and one light-cured material (Clip F) were stored in saliva and ethanol 75% for 24 h, 7, and days 28 days. From the storage media at each time period, samples were prepared and analysed by LC-MS/MS, in order to access the elution of monomers. The results differed among the materials (P ≤ 0.05). No monomers were detected in the samples of Protemp 3 Garant and Clip F. Substances were detected only in ethanol samples of Systemp.c&b and Trim. The amount of BisGMA, TEGDMA, and UDMA 2 released from Systemp.c&b was higher compared to Trim. Storage time affected the release of substances (P ≤ 0.05). The highest release was observed within the first 24 h. It can be concluded that provisional resin composite materials do not show high release of monomers and this release is material dependent. However, the detection of additional peaks during the analysis, suggesting the formation of by-products of the eluted substances, may not be in favour of these materials with respect to their toxicity

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

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.ISSN:0340-5761ISSN:1432-073

Arzneimittelrückstände in Trinkwasser und Gewässern. Endbericht zum TA-Projekt

Vor dem Hintergrund eines stetig steigenden Verbrauchs von Arzneimitteln gibt der Bericht einen Überblick über den Wissensstand zu Mengen, Qualitäten und Wirkungen der Mikroverunreinigungen auf Mensch und Umwelt. Es werden Vorschläge zur Vermeidung der Verunreinigungen zusammengetragen und Wissenslücken und mögliche Handlungsstrategien zur Verringerung der Risiken durch Arzneimittelrückstände im Wasser aufgezeigt. Geboten wird eine Übersicht dazu, welche Human- und Tierarzneimittel in welchen Quantitäten in Deutschland verwendet werden und nach aktuellem Kenntnisstand ihrer Menge oder ihrer Wirkung nach in human- und ökotoxikologischer Hinsicht relevant sind. Zudem wird der Zielkonflikt zwischen individuellen Ansprüchen auf Heilung durch Medikamente einerseits und den potenziellen Risiken von Arzneimittelrückständen für die allgemeine Gesundheit und Umwelt andererseits analysiert. Weil das Eintreten negativer Effekte unsicher ist, wird diskutiert, welche Anhaltspunkte und Hilfestellung das Vorsorgeprinzip bei der Bewältigung dieser Konflikte leisten kann. Systematisch werden Überlegungen zu technischen Maßnahmen und regulatorischen Strategien zur Verringerung der Risiken von Arzneimittelrückständen in Gewässern vorgestellt, darunter die derzeit intensiv diskutierte vierte Reinigungsstufe von Kläranlagen, die Mikroverunreinigungen zu großen Teilen aus Abwässern entfernen kann. Stärker an der Quelle der Verunreinigung setzen regulatorische Maßnahmen an, z. B. im Zusammenhang mit dem Prozess der Arzneimittelzulassung, oder Informationsmaßnahmen, die bei Verbraucherinnen und Verbrauchern, Ärzteschaft und Apotheken ein Problembewusstsein zu schaffen versuchen. Diskutiert wird, wie die verschiedenen Maßnahmenoptionen sinnvoll miteinander kombiniert und in eine umfassende Strategie eingebettet werden können und welche Rolle bei der Strategiefindung, -entscheidung und -umsetzung den verschiedenen staatlichen und privaten gesellschaftlichen Akteuren zukommt. Inhalt Zusammenfassung 9 1 Einleitung 17 2 Mengenanalyse und Trends von Pharmakarückständen in Gewässern in Deutschland 25 2.1 Verbrauchsmengen von Human- und Tierarzneimitteln 25 2.1.1 Humanarzneimittel 26 2.1.2 Tierarzneimittel 35 2.2 Die Eintragswege der Arzneistoffe in Oberflächengewässer und ins Grundwasser 41 2.2.1 Haupteintragspfade von Arzneimittelrückständen in Gewässer 42 2.2.2 Humanarzneimittel 43 2.2.3 Tierarzneimittel 45 2.3 Nachweise von Arzneimitteln in Trinkwasser und Gewässern 45 2.3.1 Humanarzneimittel 46 2.3.2 Tierarzneimittel 50 2.4 Fazit 51 3 Auswirkungen von Arzneimittelrückständen auf Gesundheit und Umwelt 53 3.1 Methodische Ansätze zur Vorhersage und Bewertung potenziell negativer Auswirkungen 54 3.1.1 Grundbegriffe der Toxikologie 54 3.1.2 Das PEC/PNEC-Risikobewertungskonzept 57 3.1.3 Methoden zur Bewertung von Kombinationswirkungen 60 3.2 Auswirkungen von Arzneimittelrückständen auf die menschliche Gesundheit 63 3.2.1 Akute Gesundheitsgefährdungen durch Trinkwasser 63 3.2.2 Langzeit- und Niedrigdosiswirkungen 65 3.2.3 Antibiotika und Antibiotikaresistenzen 66 3.2.4 Hormonelle Wirkungen 68 3.2.5 Schäden der Erbsubstanz oder von Embryonen durch Zytostatika 70 3.2.6 Neurotoxische Wirkungen 71 3.2.7 Kombinationswirkungen 72 3.3 Auswirkungen von Arzneimittelrückständen auf die Umwelt 73 3.3.1 Akute Wirkungen 74 3.3.2 Langzeit- und Niedrigdosiswirkungen 76 3.3.3 Hormonelle Wirkungen 77 3.3.4 Neurotoxische Wirkungen 78 3.3.5 Umweltwirkungen von Zytostatika 79 3.3.6 Kombinationswirkungen 80 3.4 Fazit 82 4 Das Vorsorgeprinzip: gesellschaftliche Zielkonflikte zwischen Gesundheit, Tierwohl und Umweltschutz 85 4.1 Das Vorsorgeprinzip 86 4.1.1 Handeln unter Unsicherheit und Nichtwissen 86 4.1.2 Vorsorgeprinzip, Nichtwissen und Evidenz 89 4.1.3 Die Verankerung des Vorsorgeprinzips im Recht 90 4.1.4 Schlussfolgerungen für das Problem der Arzneimittelrückstände in Trinkwasser und Gewässern – Strategien zur Beschaffung von Informationen 92 4.2 Relevante Schutzgüter 94 4.2.1 Menschliche Gesundheit 95 4.2.2 Tiergesundheit 95 4.2.3 Umwelt 96 4.2.4 Trinkwasser 97 4.2.5 Konflikte zwischen Schutzgütern 98 4.3 Der rechtliche Rahmen für die Zulassung und das Inverkehrbringen von Medikamenten 99 4.3.1 Bewertung und Berücksichtigung von Umweltrisiken – Humanarzneimittel 99 4.3.2 Bewertung und Berücksichtigung von Umweltrisiken – Tierarzneimittel 102 4.3.3 Regelungen im Gewässer-, Grund- und Trinkwasserschutz 105 4.4 Arzneimittelrückstände im Wasser im medialen Diskurs 107 4.4.1 Entwicklung und Ton der Berichterstattung 109 4.4.2 Inhalte der Berichterstattung 110 4.5 Fazit 114 5 Maßnahmen zur Verringerung der Risiken durch Arzneimittelrückstände im Wasser 117 5.1 Vorgehen bei der Beschreibung und der vergleichenden Bewertung der Maßnahmen 117 5.2 Maßnahmen in der Wasserwirtschaft 120 5.2.1 W1: Verbesserte kommunale Abwasserbehandlung durch eine vierte Reinigungsstufe 121 5.2.2 W2: Dezentrale Behandlung von Abwässern aus Krankenhäusern und anderen Gesundheitseinrichtungen 130 5.2.3 W3: Vermeidung der Einleitung von Rückständen aus der Produktion von Arzneimitteln 133 5.2.4 W4: Regulierungen im Wasserrecht und verstärktes Monitoring von Arzneistoffen in Grundwasser und Gewässern 135 5.3 Maßnahmen im Gesundheitssystem 138 5.3.1 G1: a) Berücksichtigung von Umweltrisiken bei der Zulassung von Humanarzneimitteln und b) Erweiterung des Pharmakovigilanzsystems um ein umfassendes Umweltinformationssystem 138 5.3.2 G2: Green Pharmacy – umweltfreundlichere Arzneimittel 142 5.3.3 G3: Vermeidung von Arzneimittelbedarf durch Gesundheitsförderung und Prävention 144 5.3.4 G4: Sensibilisierung von Ärztinnen und Ärzten sowie Patientinnen und Patienten für die Umweltwirkungen von Arzneimittelrückständen 146 5.3.5 G5: Verschreibung angepasster Verbrauchsmengen 148 5.3.6 G6: Einführung eines Umweltklassifikationssystems für Arzneistoffe und Medikamente 150 5.3.7 G7: Einheitlich geregelte, klar kommunizierte und sichere Entsorgung von Altmedikamenten 153 5.3.8 G8: Sammlung von Röntgenkontrastmitteln in Urinsammelbehältern 155 5.4 Maßnahmen in Landwirtschaft und Tierhaltung 158 5.4.1 L1: Einführung eines Systems zur Bestimmung von Verbrauchsmengen 160 5.4.2 L2: Erweiterung des Pharmakovigilanzsystems für Tierarzneimittel um ein umfassendes Umweltinformationssystem 161 5.4.3 L3: Aus- und Weiterbildungsangebote sowie Informationskampagnen zu Umweltaspekten des Einsatzes von Tierarzneimitteln 162 5.4.4 L4: Weitere Maßnahmen zur Minderung der Einträge von Tierarzneimitteln und zur Entlastung der Umwelt 165 6 Strategien zur Verringerung der Risiken durch Arzneimittelrückstände 169 6.1 Vorsorgeprinzip und Handlungsbedarf – was ist heute schon zu tun? 170 6.2 Der Zusammenhang von Arzneimittelrückständen und weiteren Mikroverunreinigungen 172 6.3 Akteure der Maßnahmenumsetzung 173 6.3.1 Staatliche Akteure 173 6.3.2 Nichtstaatliche Akteure 175 6.4 Maßnahmenkombinationen zur Reduktion und Vorbeugung von Arzneistoffen in Trinkwasser, Grundwasser und Gewässern 175 6.5 Finanzierung einer Strategie gegen Arzneimittelrückstände und andere Mikroverunreinigungen im Wasser 180 6.6 Fazit 185 7 Literatur 187 7.1 In Auftrag gegebene Gutachten 187 7.2 Weitere Literatur 187 8 Anhang 207 8.1 Abbildungen 207 8.2 Tabellen 20

Supported ionic liquids for the efficient removal of acetylsalicylic acid from aqueous solutions

Acetylsalicylic acid, commercially available as aspirin, is one of the most used drugs in the world, being detected in several environmental compartments, including drinking water supplies. Given its environmental impact, the development of a cost‐effective technology capable of removing this pharmaceutical from water samples is of high relevance, for which materials based on silica chemically modified with ionic liquids (SILs) can be foreseen as a promising alternative. In this work, four SILs (with the chloride anion and imidazolium or tetraalkylammonium cations of different alkyl side chain length) were synthesized and characterized, and their potential for the adsorption of acetylsalicylic acid appraised by adsorption kinetics and isotherms. Envisioning their use to treat drinking water, the toxicity of all SILs towards the liver cell line Hep2G was determined. The best identified SIL, comprising the dimethylbutylammonium cation, displays a maximum adsorption capacity of 0.08 mmol/g, being 1 g of this material sufficient to treat ca. 14,500 L of water containing 1 μg/L of acetylsalicylic acid (under ideal conditions). Furthermore, this material has a negligible toxicity towards the liver cell line Hep2G. The results obtained reinforce the potential of SILs as alternative adsorbents to effectively remove a cetylsalicylic acid from aqueous solutions, and may be envisioned as a promising strategy for the treatment of wastewater and drinking water.publishe