Elsevier

Science of The Total Environment

Volume 443, 15 January 2013, Pages 870-876
Science of The Total Environment

Ecotoxicity of carbamazepine and its UV photolysis transformation products

https://doi.org/10.1016/j.scitotenv.2012.11.059Get rights and content

Abstract

Carbamazepine, an anti-epileptic pharmaceutical agent commonly found in wastewater, is highly recalcitrant to standard wastewater treatment practices. This study investigated the mixture toxicity of carbamazepine transformation products formed during ultraviolet (UV) photolysis using three standard ecotoxicity assays (representing bacteria, algae and crustaceans). UV-treatment of 6 mg L 1 carbamazepine solution was carried out over a 120 min period and samples were removed periodically over the course of the experiment. Quantification results confirmed the degradation of carbamazepine throughout the treatment period, together with concurrent increases in acridine and acridone concentrations. Ecotoxicity was shown to increase in parallel with carbamazepine degradation indicating that the mixture of degradation products formed was more toxic than the parent compound, and all three ecotoxicity endpoints were still inhibited > 60% relative to control populations upon dosing with 90 + min UV-treated carbamazepine solution. Single compound toxicity testing also confirmed the higher toxicity of measured degradation products relative to the parent compound. These results show that transformation products considerably more toxic than carbamazepine itself may be produced during UV-treatment of wastewater effluents and/or photo-induced degradation of carbamazepine in natural waters. This study highlights the need to consider mixture toxicity and the formation and persistence of toxicologically relevant transformation products when assessing the environmental risks posed by pharmaceutical compounds.

Highlights

► Carbamazepine is highly recalcitrant to standard wastewater treatment practices. ► This study investigated the ecotoxicity of carbamazepine UV-photolysis degradation products. ► Carbamazepine was less toxic to three standard test organisms than the tested degradation products. ► Recalcitrant mixture toxicity of the UV-treated solution was still observed at the end of treatment. ► UV-photolysis of carbamazepine may form toxicologically relevant transformation products.

Introduction

There are large knowledge gaps concerning the environmental fate and effects of most active pharmaceutical ingredients (APIs). For regulators, this translates to a high degree of uncertainty about the risks associated with pharmaceutically derived contaminants in the environment (Kümmerer, 2009a, Kümmerer, 2009b). The quantities of APIs released to the environment may be relatively low in comparison with other types of pollutants such as pesticides and industrial pollutants, but there is a tendency for their environmental release to be continuous (via wastewater effluents) and the potential for environmental accumulation and/or chronic ecotoxicity has thus been noted (e.g. Besse and Garric, 2008, Fent et al., 2006, Ferrari et al., 2003, Hernando et al., 2006, Escher et al., 2011).

Carbamazepine, an antiepileptic pharmaceutical compound and mood stabilising drug, has attracted particular attention in recent years due to its widespread detection in municipal wastewaters (e.g. Ternes, 1998, Ollers et al., 2001, Falås et al., 2012), surface waters (e.g. Ternes, 1998, Metcalfe et al., 2003, Andreozzi et al., 2003), and drinking waters (e.g. Heberer et al., 2004, Stackelberg et al., 2004, Stackelberg et al., 2007, Togola and Budzinski, 2008). It is also noted to be highly resistant to biodegradation and thus highly recalcitrant under standard biological wastewater treatment conditions (Clara et al., 2005, Kosjek et al., 2009, Falås et al., 2012). Under these circumstances, advanced oxidation processes (AOPs) may offer additional treatment value (von Gunten, 2003, Huber et al., 2005, Macova et al., 2010, Kosjek et al., 2011, Hey et al., 2012, Keen et al., 2012), however complete oxidation and mineralisation is not always achievable and stable transformation products formed during AOPs may also pose environmental risks (Agüera et al., 2005). The stability and ecotoxicity of transformation products formed during treatment and environmental transport are of major importance when assessing the suitability of water treatment options and in determining environmental risks associated with APIs in the environment.

This paper presents the results of research investigating the ecotoxicity of carbamazepine and two of its UV transformation products (Kosjek et al., 2009), acridine and 9(10H)-acridone. Kosjek et al. (2009) have also identified several other compounds which may form via UV photolysis of carbamazepine, however authentic standard compounds are not commercially available for these other degradation products. Thus, in addition to single compound testing of carbamazepine, acridine and acridone with three different standard test organisms (bacteria, algae, and crustacean), an experiment was also conducted to investigate the changes in ecotoxicity occurring during UV-treatment of water spiked with 6 mg L 1 carbamazepine. This experiment, conducted by using a bench-top circulating flow UV-reactor system, was designed to compare the ecotoxicity of the initial carbamazepine-spiked solution with that of samples collected during the treatment process. These samples contained mixtures of carbamazepine and its UV-transformation products (including, but not limited to, acridine and acridone).

This study provides an example of the ‘effect-driven approach’ for determining the risks associated with pollutant transformation products. The ‘effect driven approach’, described by Escher and Fenner (2011) in their paper on advances in environmental risk assessment of transformation products, focuses on ecotoxicity testing of reaction mixtures in which a parent compound is undergoing degradation (e.g. during UV-treatment). This approach facilitates prioritisation of APIs and their transformation products for risk assessment purposes without requiring the prior identification and quantification of individual transformation products and is thus ideal for situations such as this one in which standard compounds are not available for all relevant transformation products. In ‘effect driven’ assessments, compounds are prioritised for transformation product isolation, purification, and further study if the reaction mixture increases in toxicity in parallel with decreasing parent compound concentration.

This investigation into the relative toxicity of carbamazepine and its phototransformation products is relevant to future discussions regarding the treatment, control and fate of carbamazepine and carbamazepine-derived contaminants in the environment. Knowledge about carbamazepine's UV-induced degradation pathway is also of interest from the perspective of sunlight-induced photochemical oxidation, as this may be a significant process controlling the gradual ongoing breakdown of carbamazepine released to receiving waters and natural aquatic environments. Indeed, for non-biodegradable, non-sorbing APIs such as carbamazepine, sun-induced photodegradation may be one of the most important long-term process affecting persistence and toxicity in the environment (Doll and Frimmel, 2003, Agüera et al., 2005).

Section snippets

Standards, solvents, and other chemicals

Carbamazepine (99%, CAS 298-46-4) and N-Methyl-N- [tert-butyldimethyl-silyl]trifluoroacetimide (MTBSTFA) were purchased from Acros Organics (New Jersey, USA). Acridine (97%, CAS 260-94-6) and 9(10H)-acridone (99%, CAS 578-95-0) were obtained from Sigma-Aldrich (St. Louis, USA). Stock solutions were freshly made prior to use and the volumetric flasks were covered in aluminium foil to prevent photodegradation.

Chemical analyses

Solid phase extraction (SPE) was used for sample preparation for all chemical analyses.

Ecotoxicity of carbamazepine, acridine and acridone

Acute toxicity data for the individual compounds, expressed either as median effective concentrations (EC10/EC50) or NOECs and LOECs are presented in Table 2. The results of all three acute toxicity assays showed the parent compound, carbamazepine, to be significantly less toxic than either acridine or acridone. Furthermore, of the two transformation products tested, acridone was consistently less toxic than acridine across all three assays. Table 3 presents a comprehensive list of published

Discussion

The presented results clearly indicate that the photodegradation products, acridine and acridone, are considerably more toxic than the parent compound carbamazepine across multiple trophic levels. Although the sensitivities of the different test organisms differed, all species showed greater toxicity of the tested photodegradation products compared with the parent compound carbamazepine and this result was further reflected in the increasing toxicity of the carbamazepine spiked water throughout

Conclusion

The results of this study indicate that degradation products considerably more toxic than carbamazepine itself may be produced as a result of UV-treatment of wastewater effluents and/or photo-induced degradation of carbamazepine in natural waters. These findings are clearly relevant to ongoing debates regarding the potential environmental effects of pharmaceutically-derived compounds in the environment, highlighting the need to consider mixture toxicity and the formation and persistence of

Acknowledgements

We thank COST Action 636, Xenobiotics in the Urban Water Cycle for funding E. Donner and T. Kosjek to undertake Short Term Scientific Missions (STSMs) to the Department of Environmental Engineering at the Technical University of Denmark (DTU) where this work was undertaken. This work was also supported by the Swedish MISTRA foundation through the MISTRAPHARMA project. The authors would like to thank Susanne Kruse and Karina Bomholt Henriksen for their technical advice and support.

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