27 research outputs found
Development and application of LC-MS/MS multi-methods for the quantification of antibiotics and cytostatic drugs for occupational safety and environmental investigations
Beim Umgang mit hochwirksamen Arzneimitteln, wie z. B. Antibiotika und Zytostatika, muss neben dem Patientenwohl auch das gesundheitsschädliche Potential für die damit in Berührung kommenden Personen sowie der Umweltschutz beachtet werden. Für die Anwendung bei Antibiotika - Arbeitsschutzuntersuchungen wurde eine Multimethode zur Bestimmung von acht strukturell unterschiedlichen Wirkstoffen mittels HPLC-UV, -MS und -MS/MS entwickelt. Der Vergleich der verschiedenen Detektionsarten hat gezeigt, dass HPLC-UV und –MS zur Messung von Wischproben mit hohen Konzentrationen, z. B. zur Reinigungsvalidierung oder Untersuchungen nach unbeabsichtigten Substanzfreisetzungen, geeignet sind.
Die Auswertung von ersten Wischproben aus vier europäischen Kliniken zeigte, dass bei der Zubereitung von Cefuroxim 89 % der Arbeitsflächen belastet waren. Zur erstmaligen Erfassung der Arbeitsplatzbelastung sowie der inneren und äußeren Exposition der Mitarbeiter gegenüber Antibiotika wurde die LC-MS/MS-Methode um sieben Wirkstoffe erweitert und ein kombiniertes Umgebungs- und Biomonitoring auf die Substanzen Amoxicillin, Ampicillin, Cefazolin, Cefotaxim, Cefotiam, Cefuroxim, Chloramphenicol, Ciprofloxacin, Ofloxacin, Penicillin G, Penicillin V, Piperacillin, Trimethoprim, Sulfamethoxazol und Vancomycin durchgeführt. Dabei stellte sich heraus, dass 98 % der Arbeitsflächen und 100 % der Arbeitskleidung unter den untersuchten Arbeitsbedingungen mit Antibiotika belastet waren. Eine Korrelation zwischen den gefundenen Belastungen und den Angaben zu Art und Menge der verarbeiteten Substanzen und der Tätigkeit der einzelnen Beschäftigten ist erkennbar. Die im Untersuchungszeitraum zubereiteten bzw. applizierten Substanzen wurden häufig und in vergleichsweise hohen Konzentrationen von bis zu 248 ng/cm2 gefunden. Zusätzlich zu den am gleichen Tag verarbeiteten Substanzen konnten insbesondere auf Flächen und Textilien eine Vielzahl weiterer Antibiotika bestimmt werden. Untersuchungen von Urinproben haben eine innere Exposition im unteren ng/mL-Bereich bei 48 % der Beschäftigten nachgewiesen. Neben der geringeren Anzahl verschiedener Antibiotika konnte im Gegensatz zu den Flächen- und Textilbelastungen beim Biomonitoring keine Belastung mit mehreren Substanzen festgestellt werden.
Für den Einsatz beim Zytostatika – Monitoring wurde als Ersatz für die bisher durchgeführten substanzspezifischen Probenahme- und GC-MS-Einzelstoffanalyse¬methoden im Rahmen dieser Arbeit eine wesentlich einfachere LC-MS/MS-Multimethode zur simultanen Probenahme und Analyse der Zytostatika 5-Fluorouracil, Chlorambucil, Cyclophosphamid, Cytarabin, Etoposid, Ifosfamid und Methotrexat entwickelt. Die Validierungsuntersuchungen haben gezeigt, dass insbesondere die Probenahme auf unterschiedlichen Oberflächen einen großen Einfluss auf die Wiederfindungsrate hat. Die Ergebnisse der im Rahmen dieser Arbeit durchgeführten LC-MS/MS-Analysen zeigen das aus der Literatur bekannte Bild für Zytostatika-Einzelanalysen. Die Belastungssituation an verschiedenen Probenahmestellen innerhalb als auch außerhalb der Apotheke unterscheidet sich über mehrere Dekaden (< 0,001 ng/cm2 bis 796 ng/cm2). Bei der Gesamtbewertung der Analyseergebnisse einer Apotheke, einer onkologischen Ambulanz oder einer Krankenhausstation ist aufgrund der großen Unterschiede zwischen sauberen und belasteten Oberflächen die durch den Flächeneinfluss entstehende Messunsicherheit zu vernachlässigen. Problematisch bei der Bewertung von Einzelergebnissen ist, dass entsprechend der GefStoffV beim Umgang mit CMR-Stoffen die Forderung nach einer Nullexposition besteht und aufgrund fehlender Daten bisher keine Schwellen- oder Richtkonzentration festgesetzt werden kann. Insgesamt kann bei konsequenter Umsetzung des Stands der Technik bei Zubereitung und Umgang mit Zytostatika durch den Einsatz technischer und persönlicher Schutzausrüstung sowie durch intensive Schulung der Mitarbeiter die Exposition minimiert werden, so dass das Risiko beim Umgang mit CMR-Stoffen erheblich gesenkt wird. Sowohl zur Überprüfung der Arbeitsplatzbelastung und des Erfolgs der getroffenen Maßnahmen ist mit dem in dieser Arbeit entwickelte LC-MS/MS-Multianalyseverfahren sehr einfach und kostengünstig möglich. Im Fall von unbeabsichtigten Substanzfreisetzungen ist zur Untersuchung von Substanzaufnahmen bei den betroffenen Mitarbeitern ein Biomonitoring und zur Kontrolle der Reinigungsmaßnahmen ein Umgebungsmonitoring zu empfehlen. Eine substanzunabhängige statistische Betrachtung von insgesamt 2644 Messwerten dieser Arbeit liegt das 90. Percentil bei 0,028 ng/cm2. Zur Bildung eines deutschen Orientierungswertes auf Basis einer statistischen Datenanalyse müssen die in dieser Arbeit gemessenen Werte um weitere Messwerte wie Platinmessungen und GC-MS Daten des IUTA, den Analyseergebnissen der LMU München sowie die im Rahmen der MEWIP-Studie zu erwartenden Messwerte erweitert werden. Auf Grundlage dieser breiten Datenbasis kann durch Diskussion mit den Standesorganisationen und Berufsgenossenschaften die Bildung von Orientierungswerten erfolgen.
Neben dem Arbeitsschutz wurde im Rahmen dieser Arbeit auch der Umweltschutzaspekt beim Umgang mit hochwirksamen Arzneimitteln betrachtet. Über die Patientenausscheidungen gelangen die Wirkstoffe und deren Metaboliten in den Wasserkreislauf. Da viele der Wirkstoffe nicht biologisch abbaubar sind, erfolgt ein Eintrag dieser Substanzen aus den Kläranlagenabläufen in die Oberflächengewässer. Eine möglichst frühzeitige Eliminierung am Eintragsort kann einen Beitrag zur Reduzierung von Umwelteinträgen leisten. Hierzu wurde im Labormaßstab ein erweitertes Oxidationsverfahren (AOP – advanced oxidation process) zur Behandlung von hoch belasteten Abwasserteilströmen in Krankenhäusern entwickelt und im halb¬technischen Maßstab evaluiert. Die substanzspezifische Verfahrensanalytik zur Kontrolle und Optimierung des AOP-Verfahrens erfolgte mit einer neu entwickelten LC-MS/MS-Multimethode. Die Nachweisgrenzen für acht Antibiotika und sieben Zytostatika liegen zwischen 0,1 und 5 µg/L. Zur exakten Quantifizierung ist wie bei der Bestimmung von Urinproben beim Biomonitoring eine gewichtete Matrix-Kalibration notwendig. Neben der direkten Analyse von Krankenhausabwasser-Teilströmen ist durch Ergänzung einer geeigneten Probenvorbereitung (clean-up und Aufkonzentrierung) mittels Festphasenextraktion auch die Analyse von wesentlich niedriger belasteten Kläranlagenabläufen oder Oberflächen¬gewässern möglich.
In den AOP - Laborversuchen wurden für die ausgewählten Zytostatika und Antibiotika die Effektivität des Abbaus in Abhängigkeit von der verwendeten UV-Strahlung, Art und Menge des Oxidationsmittels, Behandlungsdauer und Temperatur sowie der Einfluss verschiedener Reaktionsvolumina untersucht. Die Ergebnisse zeigten, dass ein Abbau (> 99 %) sowie eine effektive Reduktion der ökotoxikologischen Eigenschaften (> 95 %) sowohl mittels Ozonisierung als auch mittels UV-Oxidation erreichbar ist. Je nach Art des eingesetzten Oxidationsmittels (Ozon oder Wasserstoffperoxid) und dem verwendeten UV-Strahler sind Behandlungs¬zeiten zwischen 10 und 90 Minuten erforderlich. Die im Rahmen dieser Arbeit im Labormaßstab durchgeführte Verfahrensentwicklung stellt die Grundlage für den Bau einer Pilotanlage sowie weiterer Untersuchungen in Hinblick auf Effektivität und Wirtschaftlichkeit des Verfahrens dar. Als Fazit der Untersuchungen ist festzuhalten, dass die drei Verfahrensvarianten (Hg-Nd-Strahler + H2O2, Hg-Md-Strahler + H2O2 und Ozonisierung) zum Abbau von Antibiotika und Zytostatika aus Krankenhausabwasser-Teilströmen geeignet sind.Apart from patient’s wellbeing, the potential health risk for persons coming into contact with highly effective drugs such as antibiotics and antineoplastics as well as the environmental protection while handling these drugs must be considered. For analysis of occupational exposure, a multi method was developed for eight structurally different antibiotics by means of HPLC-UV, -MS and -MS/MS. The comparison of different types of detection showed that HPLC-UV and -MS were suitable for measurements of wipe samples with high concentrations, e. g. for validation of cleaning procedures or analysis after unintentional substance release. For environmental and biological monitoring purposes, tandem mass spectrometry should be used due to low concentrations in the ng/mL range and matrix effects from urine samples.
The results of first wipe samples from four European hospitals showed that 89 % of the surfaces were contaminated during the preparation of cefuroxime. In the first investigation of surface contaminations as well as internal and outside human exposure to antibiotics, the developed LC-MS/MS method was further extended to seven active substances. A combined environmental and biological monitoring of amoxicillin, ampicillin, cefazoline, cefotaxime, cefotiame, cefuroxime, chloramphenicol, ciprofloxacin, ofloxacin, penicillin G, penicillin V, piperacillin, trimethoprim, sulfamethoxazole and vancomycin was conducted. It was found that 98 % of the work surfaces and 100 % of the work clothes were contaminated with antibiotics under the examined conditions. A correlation between contaminations and preparation of the antibiotics was observed. During the investigation period, used substances were detected frequently and found in relatively high concentrations of up to 248 ng/cm2. In addition to the prepared compounds, a variety of other antibiotics in particular on surfaces and textiles could also be determined. An internal exposition was detected at 48 % of the total number of employees. However, the detected concentrations were in the lower ng/mL range and thus substantially lower than the surfaces and textile samples. Beside the smaller number of different antibiotics no exposure with several substances could be determined contrary to the surface and textile contaminations when biological monitoring was performed.
As a replacement for the substance specific cytostatic drug sampling and GC-MS single compound analysis methods accomplished so far in the context of this thesis a substantially simpler LC-MS/MS multi method was developed for the simultaneous sampling and analysis of the cytostatic drugs 5-fluorouracil, chlorambucil, cyclophosphamide, cytarabin, etoposide, ifosfamide and methotrexate. The validation data obtained confirmed that sampling on different surfaces had a large influence on the recovery rates. Results obtained from the novel LC-MS/MS multi compound analysis in this thesis were comparable to those of antineoplastic analysis from the literature. Contamination levels at different sampling points within and outside of the pharmacy differ over several orders of magnitude (ranges from < 0.001 ng/cm2 to 796 ng/cm2). During total evaluation of a pharmacy or ward, measurement uncertainty resulting from surface influence can be neglected due to a large difference between clean and contaminated surfaces. During evaluation of single results, however, it is problematic that according to the German regulations for handling hazardous substances (GefStoffV) for CMR compounds it is a requirement for no occupational exposure. Therefore, limit values for handling of these substances do not exist. Due to missing toxicological and statistical data, there are also no threshold values. Altogether exposure can be minimized by consistent application of the state-of-the-art preparation and handling of cytostatic drugs using technical and personal protection equipment, as well as intensive training of the personnel. Therefore, the risk during handling of CMR substances could be substantially lowered. Analysis of the working situation and success of the met measures can be achieved in a simple and economic way by using the LC-MS/MS multi methods developed in this thesis. In case of unintentional substance release or accident, biological monitoring of the affected employee to evaluate the substance uptake and environmental monitoring to control the cleaning procedures are recommended. Substance independent statistic calculations of 2644 measured cytostatic drugs gave a value of 0.028 ng/cm2 for the 90th percentile. For the formation of an orientation value on the basis of a statistic data analysis the values in this thesis must be extended by the other German values like platinum and GC-MS data from IUTA, results from the LMU Munich as well as the expected results from the MEWIP study. On the basis of this broad database, the formation of orientation values can be made possible via discussion between pharmacy associations and government safety organizations.
Next to occupational safety in this thesis, aspects of environmental protection were also considered while handling highly effective medicaments in hospitals. Pharmaceuticals and their metabolites excreted by patients may reach the sewage system and wastewater treatment plants. Since many of these highly effective and toxic compounds are not biologically degradable, these substances are released directly into surface waters. Immediate elimination of these substances at the inlet points could contribute to the reduction of environmental loads of highly active ingredients. Advanced oxidation processes (AOP) were developed for the treatment of highly loaded part streams of hospitals and evaluated in a semiworks. For substance specific process analysis for control and optimisation of the AOP procedure a LC-MS/MS multi method was developed and applied. Limits of detection for eight antibiotics and seven cytostatic drugs were between 0.1 and 5 µg/L. A weighted matrix calibration for accurate quantification was necessary for this purpose as well as for the analysis of urine samples from biological monitoring. In addition to direct analysis of hospital part streams, analysis of substantially lower concentration of sewage treatment plant effluents and surface waters is also possible by adding a suitable sample preparation (clean up and enrichment) by means of solid phase extraction. Elimination efficiency of selected cytostatic drugs and antibiotics were investigated in dependence of UV radiation, type and quantity of the oxidation agent, period of treatment and temperature as well as the influence of different reaction volumes in laboratory experiments. The results showed that degradation of the compounds (> 99 %) as well as a reduction of ecotoxicological characteristics (> 95 %) can be achieved with ozone and also UV oxidation processes. Treatment periods between 10 and 90 minutes per litre for primary compound degradation were necessary depending on the type of oxidation agent (ozone or hydrogen peroxide) and on whether low or medium pressure mercury lamps were used. Therefore, AOPs are possible for direct elimination of antibiotics and cytostatic drugs from part streams of hospital wastewaters. Experiments conducted in this thesis are the basis for the construction of a pilot plant
Zur Praxis des biologisch-dynamischen Weinbaus
Die vorgestellte Erhebung beschreibt erstmals die Praxis des biologisch-dynamischen Weinbaus v.a. im deutschen Sprachraum.
Die gefundene Variabilität beim Einsatz der biologisch-dynamischen Präparate zeigt, dass hierzu noch Forschungsbedarf besteht.
Umstellungsmotiv war bei vielen Winzern die höhere Qualität bei Wein und Trauben
Validation of Arxula Yeast Estrogen Screen assay for detection of estrogenic activity in water samples: Results of an international interlaboratory study
Projet AOPTi dans le cadre du 22ème appel ERA-Net CORNET « Collective Research Networking »
Pharmaceuticals, personal care products, pesticides and other chemicals used for domestic purpose or for industrial production are continuously discharged into wastewater and lead to global contamination of the aquatic environment all over Europe. Removal during conventional wastewater treatment is unsatisfactory knowing that 20 to 50% of micropollutants are removed in current waste water treatment plants (WWTPs). Analytical methods become more and more sensitive so that traces of organic compounds are nowadays detected in waste, surface and ground waters. The Water Framework Directive listed 45 priority substances to be controlled. Two hormones and one painkiller have been added in 2013 in this directive as well as three antibiotics macrolides, one pesticide, one anti-UV and one anti-oxidant in 2015.
The objective of the AOPTi project is to develop and validate an innovative technology to ensure efficient elimination of different types of micropollutants and toxic effects in waste water. Relevance and behaviour of transformation products in the treated water will be investigated as second issue. The process will be a tertiary treatment process, which can be easily integrated into municipal and industrial WWTPs. It is an economical physico-chemical treatment step after the conventional biological treatment. The process is based on oxidation by ozone and an additional photocatalytic subsequent treatment, followed by an adsorption step. The technology is developed for companies involved in the water purification sector and for companies with toxic effluents loaded with micropollutants.
Innovation: The AOPTi project aims to validate the elimination of the non-biodegradable micropollutants by advanced oxidative procedures (ozonation and photocatalysis) combined with a biological active adsorption step as final finishing process in lab and demonstration scales. Process parameters have to be determined depending on the type of waste water in order to lead to almost total degradation of all micropollutants and to ensure absence of toxicity of the resulting water. Treated water will be characterized in term of chemical transformation products (TPs) and toxicity
Projet AOPTi dans le cadre du 22ème appel ERA-Net CORNET « Collective Research Networking »
Pharmaceuticals, personal care products, pesticides and other chemicals used for domestic purpose or for industrial production are continuously discharged into wastewater and lead to global contamination of the aquatic environment all over Europe. Removal during conventional wastewater treatment is unsatisfactory knowing that 20 to 50% of micropollutants are removed in current waste water treatment plants (WWTPs). Analytical methods become more and more sensitive so that traces of organic compounds are nowadays detected in waste, surface and ground waters. The Water Framework Directive listed 45 priority substances to be controlled. Two hormones and one painkiller have been added in 2013 in this directive as well as three antibiotics macrolides, one pesticide, one anti-UV and one anti-oxidant in 2015.
The objective of the AOPTi project is to develop and validate an innovative technology to ensure efficient elimination of different types of micropollutants and toxic effects in waste water. Relevance and behaviour of transformation products in the treated water will be investigated as second issue. The process will be a tertiary treatment process, which can be easily integrated into municipal and industrial WWTPs. It is an economical physico-chemical treatment step after the conventional biological treatment. The process is based on oxidation by ozone and an additional photocatalytic subsequent treatment, followed by an adsorption step. The technology is developed for companies involved in the water purification sector and for companies with toxic effluents loaded with micropollutants.
Innovation: The AOPTi project aims to validate the elimination of the non-biodegradable micropollutants by advanced oxidative procedures (ozonation and photocatalysis) combined with a biological active adsorption step as final finishing process in lab and demonstration scales. Process parameters have to be determined depending on the type of waste water in order to lead to almost total degradation of all micropollutants and to ensure absence of toxicity of the resulting water. Treated water will be characterized in term of chemical transformation products (TPs) and toxicity
Projet AOPTi dans le cadre du 22ème appel ERA-Net CORNET « Collective Research Networking »
Pharmaceuticals, personal care products, pesticides and other chemicals used for domestic purpose or for industrial production are continuously discharged into wastewater and lead to global contamination of the aquatic environment all over Europe. Removal during conventional wastewater treatment is unsatisfactory knowing that 20 to 50% of micropollutants are removed in current waste water treatment plants (WWTPs). Analytical methods become more and more sensitive so that traces of organic compounds are nowadays detected in waste, surface and ground waters. The Water Framework Directive listed 45 priority substances to be controlled. Two hormones and one painkiller have been added in 2013 in this directive as well as three antibiotics macrolides, one pesticide, one anti-UV and one anti-oxidant in 2015.
The objective of the AOPTi project is to develop and validate an innovative technology to ensure efficient elimination of different types of micropollutants and toxic effects in waste water. Relevance and behaviour of transformation products in the treated water will be investigated as second issue. The process will be a tertiary treatment process, which can be easily integrated into municipal and industrial WWTPs. It is an economical physico-chemical treatment step after the conventional biological treatment. The process is based on oxidation by ozone and an additional photocatalytic subsequent treatment, followed by an adsorption step. The technology is developed for companies involved in the water purification sector and for companies with toxic effluents loaded with micropollutants.
Innovation: The AOPTi project aims to validate the elimination of the non-biodegradable micropollutants by advanced oxidative procedures (ozonation and photocatalysis) combined with a biological active adsorption step as final finishing process in lab and demonstration scales. Process parameters have to be determined depending on the type of waste water in order to lead to almost total degradation of all micropollutants and to ensure absence of toxicity of the resulting water. Treated water will be characterized in term of chemical transformation products (TPs) and toxicity
Projet AOPTi dans le cadre du 22ème appel ERA-Net CORNET « Collective Research Networking »
Pharmaceuticals, personal care products, pesticides and other chemicals used for domestic purpose or for industrial production are continuously discharged into wastewater and lead to global contamination of the aquatic environment all over Europe. Removal during conventional wastewater treatment is unsatisfactory knowing that 20 to 50% of micropollutants are removed in current waste water treatment plants (WWTPs). Analytical methods become more and more sensitive so that traces of organic compounds are nowadays detected in waste, surface and ground waters. The Water Framework Directive listed 45 priority substances to be controlled. Two hormones and one painkiller have been added in 2013 in this directive as well as three antibiotics macrolides, one pesticide, one anti-UV and one anti-oxidant in 2015.
The objective of the AOPTi project is to develop and validate an innovative technology to ensure efficient elimination of different types of micropollutants and toxic effects in waste water. Relevance and behaviour of transformation products in the treated water will be investigated as second issue. The process will be a tertiary treatment process, which can be easily integrated into municipal and industrial WWTPs. It is an economical physico-chemical treatment step after the conventional biological treatment. The process is based on oxidation by ozone and an additional photocatalytic subsequent treatment, followed by an adsorption step. The technology is developed for companies involved in the water purification sector and for companies with toxic effluents loaded with micropollutants.
Innovation: The AOPTi project aims to validate the elimination of the non-biodegradable micropollutants by advanced oxidative procedures (ozonation and photocatalysis) combined with a biological active adsorption step as final finishing process in lab and demonstration scales. Process parameters have to be determined depending on the type of waste water in order to lead to almost total degradation of all micropollutants and to ensure absence of toxicity of the resulting water. Treated water will be characterized in term of chemical transformation products (TPs) and toxicity
Removal Efficiencies and Electricity Consumed of Pharmaceuticals by Electrocoagulation and UV Processes
Elimination of Pharmaceutical Residues in Municipal Wastewater Using Advanced UV Irradiation Technology
Projet AOPTi dans le cadre du 22ème appel ERA-Net CORNET « Collective Research Networking »
Pharmaceuticals, personal care products, pesticides and other chemicals used for domestic purpose or for industrial production are continuously discharged into wastewater and lead to global contamination of the aquatic environment all over Europe. Removal during conventional wastewater treatment is unsatisfactory knowing that 20 to 50% of micropollutants are removed in current waste water treatment plants (WWTPs). Analytical methods become more and more sensitive so that traces of organic compounds are nowadays detected in waste, surface and ground waters. The Water Framework Directive listed 45 priority substances to be controlled. Two hormones and one painkiller have been added in 2013 in this directive as well as three antibiotics macrolides, one pesticide, one anti-UV and one anti-oxidant in 2015.
The objective of the AOPTi project is to develop and validate an innovative technology to ensure efficient elimination of different types of micropollutants and toxic effects in waste water. Relevance and behaviour of transformation products in the treated water will be investigated as second issue. The process will be a tertiary treatment process, which can be easily integrated into municipal and industrial WWTPs. It is an economical physico-chemical treatment step after the conventional biological treatment. The process is based on oxidation by ozone and an additional photocatalytic subsequent treatment, followed by an adsorption step. The technology is developed for companies involved in the water purification sector and for companies with toxic effluents loaded with micropollutants.
Innovation: The AOPTi project aims to validate the elimination of the non-biodegradable micropollutants by advanced oxidative procedures (ozonation and photocatalysis) combined with a biological active adsorption step as final finishing process in lab and demonstration scales. Process parameters have to be determined depending on the type of waste water in order to lead to almost total degradation of all micropollutants and to ensure absence of toxicity of the resulting water. Treated water will be characterized in term of chemical transformation products (TPs) and toxicity