Estimation of the cancer risk to humans resulting from the presence of cyclophosphamide and ifosfamide in surface water

Background, aim, and scope  

Anti-tumour agents and their metabolites are largely excreted into effluent, along with other pharmaceuticals. In the past, investigations have focused on the input and analysis of pharmaceuticals in surface and ground water. The two oxazaphosphorine compounds, cyclophosphamide and ifosfamide are important cytostatic drugs used in the chemotherapy of cancer and in the treatment of autoimmune diseases. Their mechanism of action, involving metabolic activation and unspecific alkylation of nucleophilic compounds, accounts for genotoxic and carcinogenic effects described in the literature and is reason for environmental concern. The anti-tumour agents cyclophosphamide (CP) and ifosfamide (IF) were not biodegraded in biodegradation tests. They were not eliminated in municipal sewage treatment plants. Degradation by photochemically formed HO radicals may be of some relevance only in shallow, clear, and nitrate-rich water bodies but could be further exploited for elimination of these compounds by advanced oxidation processes, i.e. in a treatment of hospital waste water. Therefore, CP and IF are assumed to persist in the aquatic environment and to enter drinking water via surface water. The risk to humans from input of CP and IF into surface water is not known.     

Biodegradation potential of ofloxacin and its resulting transformation products during photolytic and photocatalytic treatment

The release of pharmaceuticals in the environment, as parent compounds, metabolites and transformation products, and the consequent risks posed to living organisms due to the unintended exposure of the latter to these chemicals are nowadays of increasing scientific concern. The development of advanced oxidation processes able to degrade these substances is in the core of the current research objectives, the main target being the removal of these compounds from wastewaters. Often the focus is on the removal of the parent compound only. However, these processes can form transformation products. Knowledge on the risk related to such transformation products is scarce. Among others, knowledge on their toxic effects and their biodegradability is of importance not only when they are present in the environment but also for the assessment of the advanced oxidation processes’ efficiency applied for their degradation. Photolytic (UV irradiation) and photocatalytic treatment (UV irradiation in the presence of TiO₂) of the fluoroquinolone ofloxacin were applied, and the biodegradability of the formed products was investigated using the Closed Bottle test (OECD 301 D). Various transformation products, formed both during the photo(cata)lytic treatment and the Closed Bottle test, were identified using chromatographic analysis with an ultra high-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) system. The transformation products formed during the phototreatments were found to be non-readily biodegradable as the biodegradation percentages were close to zero. The persistence of the various photo(cata)lytic transformation products during the Closed Bottle test may be attributed to the fluorine present in all the transformation products formed. The transformation products identified suggest that two transformation routes were present: decarboxylation and opening of the piperazinyl ring. Interestingly, it was observed that in the presence of a readily biodegradable carbon source (sodium acetate), the biodegradation percentage increased drastically for some of the photolytically treated samples. This was not the case for the photocatalytically treated samples, in which also mineralization of the parent compound was achieved faster. Further research is needed, however, in order to increase the understanding of the conditions that may lead to less potent and persistent substances during the application of such engineered or natural processes.     

Biodegradability of organic nanoparticles in the aqueous environment

Synthetic nanoparticles have already been detected in the aquatic environment. Therefore, knowledge on their biodegradability is of utmost importance for risk assessment but such information is currently not available. Therefore, the biodegradability of fullerenes, single, double, multi-walled as well as COOH functionalized carbon nanotubes and cellulose and starch nanocrystals in aqueous environment has been investigated according to OECD standards. The biodegradability of starch and cellulose nanoparticles was also compared with the biodegradability of their macroscopic counterparts. Fullerenes and all carbon nanotubes did not biodegrade at all, while starch and cellulose nanoparticles biodegrade to similar levels as their macroscopic counterparts. However, neither comfortably met the criterion for ready biodegradability (60% after 28 days). The cellulose and starch nanoparticles were also found to degrade faster than their macroscopic counterparts due to their higher surface area. These findings are the first report of biodegradability of organic nanoparticles in the aquatic environment, an important accumulation environment for manmade compounds.     

Biodegradability of biofilm extracellular polymeric substances

This study discovered that biofilm extracellular polymeric substances (EPS) are biodegradable by their own producers and by other microorganisms when they are starved. The study was performed in a comparative fashion to examine the biodegradability of biofilm EPS by the microorganisms from the original biofilm (its own producers) and from activated sludge (other microorganisms). Four distinctive phases were observed during EPS biodegradation. In the first phase, instantaneous concentration increases of carbohydrate and protein in the test solutions were observed when EPS was added; in the second phase, easily biodegradable EPS from the added EPS was quickly utilized; in the third phase, microorganisms began to produce soluble EPS, using the minimally biodegradable EPS left from the previously added EPS; in the fourth phase, cells consumed the newly produced EPS and microbial activity gradually stopped. This study suggests that EPS can be used as a substrate, and that the EPS carbohydrate can be utilized faster than the EPS protein. The EPS utilization rates (including carbohydrate and protein) in the activated sludge suspension were greater than those in the biofilm suspension. It may take microorganisms longer to get acclimated to a new nutrient environment if they are in a starved state.     

Approach for detecting mutagenicity of biodegraded and ozonated pharmaceuticals, metabolites and transformation products from a drinking water perspective

Many pharmaceuticals and related metabolites are not efficiently removed in sewage treatment plants and enter into surface water. There, they might be subject of drinking water abstraction and treatment by ozonation. In this study, a systematic approach for producing and effect-based testing of transformation products (TPs) during the drinking water ozonation process is proposed. For this, two pharmaceutical parent substances, three metabolites and one environmental degradation product were investigated with respect to their biodegradability and fate during drinking water ozonation. The Ames test (TA98, TA100) was used for the identification of mutagenic activity present in the solutions after testing inherent biodegradability and/or after ozonation of the samples. Suspicious results were complemented with the umu test. Due to the low substrate concentration required for ozonation, all ozonated samples were concentrated via solid phase extraction (SPE) before performing the Ames test. With the exception of piracetam, all substances were only incompletely biodegradable, suggesting the formation of stable TPs. Metformin, piracetam and guanylurea could not be removed completely by the ozonation process. We received some evidence that technical TPs are formed by ozonation of metformin and piracetam, whereas all tested metabolites were not detectable by analytical means after ozonation. In the case of guanylurea, one ozonation TP was identified by LC/MS. None of the experiments showed an increase of mutagenic effects in the Ames test. However, the SPE concentration procedure might lead to false-positive results due to the generation of mutagenic artefacts or might lead to false-negative results by missing adequate recovery efficiency. Thus, these investigations should always be accompanied by process blank controls that are carried out along the whole ozonation and SPE procedure. The study presented here is a first attempt to investigate the significance of transformation products by a systematic approach. However, the adequacy and sensitivity of the methodology need to be further investigated. The approach of combining biodegradation and ozonation with effect-based assays is a promising tool for the early detection of potential hazards from TPs as drinking water contaminants. It can support the strategy for the evaluation of substances and metabolites in drinking water. A multitude of possible factors which influence the results have to be carefully considered, among them the selectivity and sensibility of the mutagenicity test applied, the extraction method for concentrating the relevant compounds and the biocompatibility of the solvent. Therefore, the results have to be carefully interpreted, and possible false-negative and false-positive results should be considered.     

A method for measuring the anoxic biodegradability under denitrifying conditions

A test for assessing the anoxic biodegradability of organic compounds under denitrifying conditions is proposed. The method is based on the recovery and quantification of the CO2 produced, which is evidence of complete biodegradation of the test compound (added as the sole carbon source). The tests were carried out in a mineral medium, with nitrate as electron acceptor. Whole lake sediments, sediment extracts and a commercial inoculum were assayed as a possible inoculum source by means of glucose biodegradability tests. It was found that the sediment extracts constitute a suitable and environmentally-relevant inoculum source, since they add non-significant amounts of carbon to the tests. Two xenobiotic compounds, namely, aniline and phenol, were tested in the aforementioned conditions as well as in a standard aerobic biodegradability test. Both aniline and phenol attained a biodegradation level higher than 60% in a short time period (<28 days) and thus can be considered as readily biodegradable in denitrifying environments. Nevertheless, the kinetics obtained in the anoxic test were slower than in aerobic conditions, and even suggested the accumulation of intermediate metabolites in the case of phenol. The results of this study indicate that the fate of xenobiotic compounds under anoxic conditions differs from that observed in an oxic environment, and therefore it should be considered by standard biodegradability testing procedures.     

Investigation of pharmaceutical metabolites in environmental waters by LC-MS/MS

Pharmaceuticals, once ingested, are commonly metabolized in the body into more polar and soluble forms. These compounds might not be completely removed in the wastewater treatment plants and consequently being discharged into the aquatic ecosystem. In this work, a multi-class sensitive method for the analysis of 21 compounds, including 7 widely consumed pharmaceuticals and 14 relevant metabolites, has been developed based on the use of UHPLC-MS/MS in selected reaction monitoring (SRM) mode. The method was validated in six surface waters (SW) and six effluent wastewaters (EWW) at realistic concentration levels that can be found in waters. The optimized method was applied to the analysis of different types of water samples (rivers, lakes and effluent wastewater), detecting nearly all the parent compounds and metabolites investigated in this work. This fact illustrates that not only pharmaceuticals but also their metabolites are commonly present in these types of waters. Analytical research and monitoring programs should be directed not only towards parent pharmaceuticals but also towards relevant metabolites to have a realistic overview of the impact of pharmaceuticals in the aquatic environment.     

Soy proteins as environmentally friendly sizing agents to replace poly(vinyl alcohol)

An environmentally friendly and inexpensive substitute to the widely used poly(vinyl alcohol) (PVA) has been developed from soy proteins for textile warp sizing. Textile processing is the major source of industrial water pollution across the world, and sizing and desizing operations account for nearly 30 % of the water consumed in a textile plant. PVA is one of the most common sizing agents used for synthetic fibers and their blends due to PVA’s easy water solubility and ability to provide desired sizing performance. However, PVA does not degrade and is a major contributor to pollution in textile effluent treatment plants. Although considerable efforts have been made to replace PVA with biodegradable sizing materials, the performance properties provided by PVA on synthetic fibers and their blends have been unmatched so far. Soy proteins are inexpensive, biodegradable, and have been widely studied for potential use in food packaging, as resins and adhesives. In this research, the potential of using soy proteins as textile sizing agents to replace PVA was studied. Polyester and polyester/cotton rovings, yarns, and fabrics sized with soy protein showed a considerably better improvement in strength and abrasion resistance compared to commercially available PVA-based size. Soy protein size had a 5-day biochemical oxygen demand /chemical oxygen demand ratio of 0.57 compared to 0.01 for PVA indicating that soy protein sizes were easily biodegradable in activated sludge. The total and ammonia nitrogen released from the proteins also did not adversely impact the biodegradability. Good sizing performance and easy biodegradability demonstrate that soy protein-based sizes have potential to replace PVA-based sizes leading to substantial benefits to the textile industry and the environment.     

Prediction for biodegradability of chemicals by an empirical flowchart

A method for predicting aerobic biodegradability of chemicals was developed based on empirical knowledge. A flowchart was derived from rule of thumb relationships between the biodegradability and the number of the functional groups and substructures in a certain skeletal structure of chemicals. The flowchart classified chemicals into readily biodegradable, not readily biodegradable and not predictable. It was validated by using MITI data of 177 mono benzene derivatives and 168 acyclic compounds, resulting in correct prediction at 94% and 88% levels, respectively.     

Direct VUV photodegradation of gaseous α-pinene in a spiral quartz reactor: intermediates, mechanism, and toxicity/biodegradability assessment

Photodegradation of gaseous α-pinene by a vacuum ultraviolet (VUV) in a spiral reactor was investigated under various gaseous reaction media and residence time, and their respective effects on types and biodegradability of the intermediates were studied. Analysis of carbon amounts showed that about 33% and 43% of total carbon were converted to soluble organic carbon in the air medium with a relative humidity (RH) of 35-40% at empty bed residence times (EBRTs) of 18 and 45 s. Based on the identified intermediates by GC/MS and IC, a photodegradation pathway was proposed by the combined roles of photolysis, OH. photooxidation and O? photooxidation. Biodegradability to active sludge, toxicity to Chlorella vulgaris and 96-well microplates showed that α-pinene could be largely converted to more biodegradable and less toxic compounds through photodegradation in the air reaction medium with a RH of 35-40% at an EBRT of 18s, in which the initial concentration was 600 mg m?3. Therefore, VUV photodegradation could be applied as an effective pre-treatment method for detoxification and biodegradability improvement under the optimized photodegradation conditions. Such results supported the potential use of VUV photodegradation to improve the removal capacity of conventional biological treatments for hydrophobic and poorly biodegradable compounds.     

Biodegradation and bio-sorption of antibiotics and non-steroidal anti-inflammatory drugs using immobilized cell process

In the present study, the removal mechanisms of four antibiotics (sulfamethoxazole, sulfadimethoxine, sulfamethazine, and trimethoprim) and four non-steroidal anti-inflammatory drugs (acetaminophen, ibuprofen, ketoprofen, and naproxen) in immobilized cell process were investigated using batch reactors. This work principally explores the individual or collective roles of biodegradation and bio-sorption as removal routes of the target pharmaceuticals and the results were validated by various experimental and analytical tools. Biodegradation and bio-sorption were found as dominant mechanisms for the drug removal, while volatilization and hydrolysis were negligible for all target pharmaceuticals. The target pharmaceuticals responded to the two observed removal mechanisms in different ways, typically: (1) strong biodegradability and bio-sorption by acetaminophen, (2) strong biodegradability and weak bio-sorption by sulfamethoxazole, sulfadimethoxine, ibuprofen and naproxen, (3) low biodegradability and weak bio-sorption by sulfamethazine and ketoprofen, and (4) low biodegradability and medium bio-sorption by trimethoprim. In the sorption/desorption experiment, acetaminophen, sulfamethoxazole and sulfadimethoxine were characterized by strong sorption and weak desorption. A phenomenon of moderate sorption and well desorption was observed for sulfamethazine, trimethoprim and naproxen. Both ibuprofen and ketoprofen were weakly sorbed and strongly desorbed.     

Assessment of degradation of 18 antibiotics in the Closed Bottle Test

Large quantities of antibiotics are used in health care. After administration, they are discharged into the effluent and reach sewage treatment plants (STPs); if they are not degraded, they will eventually enter the environment. Antibiotics can affect bacteria in the environment and thus disturb natural elemental cycles. For this reason, it is necessary to take a closer look at the fate and effects of these substances in the environment. The biodegradability of 18 clinically important antibiotics and their effects on environmental bacteria was studied using the Closed Bottle Test (CBT) (OECD 301 D 1992). In addition, a toxicity control was performed in the CBT and the colony forming units (CFUs) were monitored. Disappearance of some of the 18 antibiotics was monitored by HPLC (high performance liquid chromatography) analysis. The antibiotics were used in two concentrations: (a) according to OECD 301 D in the mg/l-range and (b) on the basis of calculated concentrations in the influent of STPs in the microg/l-range. None of the 18 antibiotics were readily biodegradable. The HPLC analysis showed that some substances were partially or even completely disappeared by a non-biotic mechanism. In the case of some antibiotics, partial biological removal took place in test vessels containing readily biodegradable sodium acetate and the test compound. However, in the toxicity control, toxicity had not been eliminated.     

Captopril and its dimer captopril disulfide: photodegradation, aerobic biodegradation and identification of transformation products by HPLC-UV and LC-ion trap-MS(n)

In some countries effluents from hospitals and households are directly emitted into open ditches without any further treatment and with very little dilution. Under such circumstances photo- and biodegradation in the environment can occur. However, these processes do not necessarily end up with the complete mineralization of a chemical. Therefore, the biodegradability of photoproduct(s) by environmental bacteria is of interest. Cardiovascular diseases are the number one cause of death globally. Captopril (CP) is used in this study as it is widely used in Egypt and stated as one of the essential drugs in Egypt for hypertension. Three tests from the OECD series were used for biodegradation testing: Closed Bottle test (CBT; OECD 301 D), Manometric Respirometry test (MRT; OECD 301 F) and the modified Zahn-Wellens test (ZWT; OECD 302 B). Photodegradation (150 W medium-pressure Hg-lamp) of CP was studied. Also CBT was performed for captopril disulfide (CPDS) and samples received after 64 min and 512 min of photolysis. The primary elimination of CP and CPDS was monitored by LC-UV at 210 nm and structures of photoproducts were assessed by LC-UV-MS/MS (ion trap). Analysis of photodegradation samples by LC-MS/MS revealed CP sulfonic acid as the major photodegradation product of CP. No biodegradation was observed for CP, CPDS and of the mixture resulting from photo-treatment after 64 min in CBT. Partial biodegradation in the CBT and MRT was observed in samples taken after 512 min photolysis and for CP itself in MRT. Complete biodegradation and mineralization of CP occurred in the ZWT.     

Properties of aminotris (methylenephosphonate) affecting its environmental fate: Degradability,sludge adsorption,mobility in soils,and bioconcentration

In spite of its low aerobic and anaerobic biodegradability ATMP was shown to be quantitatively decomposed in a number of natural and synthetic waters. The primary products formed are iminodi (methylenephosphonate) (IDMP) and the biodegradable hydroxymethylenephosphonate (HMP). Furthermore, IDMP is abiotically degraded yielding HMP and aminomethylenephosphonate (AMP). The latter was shown to be biodegradable under certain environmental conditions. A degradation mechanism similar to that of ATMP was indicated for ethylenediaminetetra (methylenephosphonate) (EDTMP). ATMP was characterized by adsorption studies as having moderate to low mobility in soils. A very low bioconcentration potential of ATMP was demonstrated in a dynamic bioaccumulation fish test.     

Diphenylamine and derivatives in the environment: a review

Diphenylamine (DPA) is a compound from the third European Union (EU) list of priority pollutants. It was assigned by the EU to Germany to assess and control its environmental risks. DPA and derivatives are most commonly used as stabilizers in nitrocellulose-containing explosives and propellants, in the perfumery, and as antioxidants in the rubber and elastomer industry. DPA is also widely used to prevent post-harvest deterioration of apple and pear crops. DPA is a parent compound of many derivatives, which are used for the production of dyes, pharmaceuticals, photography chemicals and further small-scale applications. Diphenylamines are still produced worldwide by the chemical industries. First reports showed that DPA was found in soil and groundwater. Some ecotoxicological studies demonstrated the potential hazard of various diphenylamines to the aquatic environment and to bacteria and animals. Studies on the biodegradability of DPA and its derivatives are very sparse. Therefore, further investigation is required to determine the complete dimension of the potential environmental hazard and to introduce possible (bio)remediation techniques for sites that are contaminated with this class of compounds. This is the first detailed review on DPA and some derivatives summarizing their environmental relevance as it is published in the literature so far and this review will recommend conducting further research in the future.     

Biodegradability testing of synthetic ester lubricants--effects of additives and usage

The optimised biodegradability test system "O2/CO2 Headspace Test with GC-TCD" is used for the assessment of synthetic ester lubricants. The effects of both additives and usage on biodegradability are examined and discussed. Ester based cutting fluids and hydraulic fluids with and without additives are used under defined conditions at machine tools and hydraulic and plain bearing test benches. The lubricants are characterised additionally with respect to kinematic viscosity, acidity and elemental composition. Furthermore, a formulated mineral oil is characterised before and after usage at an hydraulic test bench. The results clearly show that the mineral oil is far less biodegradable than the ester oils and that their biodegradability is not affected by usage. Biodegradability of the ester oils is mainly depending on the characteristics of the base fluids and not affected by the additives. Antioxidants are influencing stability respectively biodegradability indirectly, since they prevent oxopolymerisation effects. Other effects of usage on biodegradation are not detected. In this context, the antioxidants ensure ready biodegradability and have a positive effect on the environmental fate of synthetic ester lubricants.     

The occurrence of antihistamines in sewage waters and in recipient rivers

Background, aim and scope  Each year, large quantities of pharmaceuticals are consumed worldwide for the treatment and prevention of human and animal diseases. Although the drugs and the metabolites observed in the wastewaters and in the environment are present at concentrations several orders of magnitude lower than the concentrations required to exert their effects in humans or animals, their long-term impact on the environment is commonly not known. In this study, the occurrence of six antihistamines, which are used for the relief of allergic reactions such as hay fever, was determined in sewage treatment plants wastewaters and in recipient river waters. Materials and methods  The occurrence of the antihistamines cetirizine, acrivastine, fexofenadine, loratadine, desloratadine and ebastine in sewage treatment plants wastewaters and in recipient river waters was studied. The analytical procedure consisted of solid-phase extraction of the water samples followed by liquid chromatography separation and detection by a triple-quadrupole mass spectrometer in the multiple reaction mode. Results  Cetirizine, acrivastine and fexofenadine were detected in both influent and effluent wastewater samples at concentration levels ranging from about 80 to 220 ng/L, while loratadine, desloratadine and ebastine could not be detected in any samples. During sewage treatment, the concentration of the antihistamines dropped by an average of 16–36%. Furthermore, elevated concentrations of antihistamines were observed in samples collected during the season of most intensive plant pollen production, i.e. in May. In the river water samples, the relative pattern of occurrence of cetirizine, acrivastine and fexofenadine was similar to that in the wastewater samples; although the concentration of the compounds was substantially lower (4–11 ng/L). The highest concentrations of the studied drugs were observed near the discharging point of the sewage treatment plant. Discussion  The highest concentrations of antihistamines in STP wastewaters correlate with the outbreak of allergic reaction caused by high amounts of plant pollens in the air. The analysis results of the river water samples show that the antihistamines are carried far away from the effluent discharge points. They may account for a part of the mix of pharmaceuticals and of pharmaceutical metabolites that occur downstream of STPs. Conclusions  Antihistamines are poorly degraded/eliminated under the biological treatment processes applied in the wastewater treatment plants and, consequently, they are continuously being discharged along with other drugs to the aquatic environment. Recommendations and perspectives  As a huge quantity and variety of drugs and their metabolites are continuously discharged to rivers and the sea, the compounds should be considered as contaminants that may possess risks to the aquatic ecosystem. Further studies are urgently needed on the environmental fate of the antihistamines and other pharmaceuticals in the aquatic environment. These studies should be concerned with the stability of the compounds, their transformation reactions and the identity of the transformation products, the distribution of drugs and their uptake and effects in organisms. On the basis of these studies, the possible environmental hazards of pharmaceuticals may be assessed.     

Ozonisation coupled with biological degradation for treatment of phenolic pollutants: a mechanistically based study

Phenolic acids constitute an important group of pollutants which are reluctant to biological treatment. Solutions containing a mixture of cinnamic acid, p-coumaric acid, caffeic acid and ferulic acid were submitted to ozonisation. Then, the changes in biodegradability along the process were studied by means of respirometry. There is an optimum ozone dosage in the interval 3-5 min of treatment which allows to achieve the maximum increase in biodegradability (more than 10 times) and a high efficiency of the ozonisation process (COD decreases to a half of its initial value). Further ozonisation does not help to increase biodegradability and is clearly disadvantageous. Similar results are obtained with actual samples of olive oil wastewaters. This behaviour is explained based on the formation of highly biodegradable benzaldehydes as key ozonisation intermediates, in the early reaction stages.