Abstract
Pathways of photochemical degradation of a cardiovascular drug verapamil under conditions relevant to natural waters and the toxicity of the photoproducts to Daphnia magna were investigated. Photodegradation was shown to proceed via photocatalysed mechanism. Two main photodegradation pathways were recognised: the first leading to hydroxylation at the methylamino position followed by splitting of verapamil molecule into two fragments, and the second providing the main active metabolite of verapamil, norverapamil, and a series of norverapamil isomers, followed again by their splitting at the amino group position. Twenty-two products of photodegradation were identified. Toxicity assays in sublethal concentrations of the parental drug, of the photoproduct mixture, and of norverapamil revealed no direct negative response in Daphnia magna to verapamil. On the other hand, photochemical products significantly lowered the number of juveniles, number of clutches, and body size of Daphnia. The exposition of Daphnia to norverapamil showed the same but even more pronounced effects than its exposition to the mixture of photoproducts, which leads to the conclusion that norverapamil is mainly responsible for the toxicity of photoproduct mixture and represents a noteworthy threat to aquatic invertebrates.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-020-09830-w/MediaObjects/11356_2020_9830_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-020-09830-w/MediaObjects/11356_2020_9830_Fig2_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-020-09830-w/MediaObjects/11356_2020_9830_Fig3_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs11356-020-09830-w/MediaObjects/11356_2020_9830_Fig4_HTML.png)
Similar content being viewed by others
References
Ajima NOM, Pandey PK, Kumar K, Poojary N (2017a) Neurotoxic effects, molecular responses and oxidative stress biomarkers in Nile tilapia, Oreochromis niloticus (Linneaus, 1758). Comp Biochem Physiol C: Toxicol Pharmacol 196:44–52
Ajima MNO, Pandey PK, Kumar K, Poojary N (2017b) Assessment of mutagenic, hematological and oxidative stress biomarkers in liver of Nile tilapia, Oreochromis niloticus (Linnaeus, 1758) in response to sublethal verapamil exposure. Drug Chem Toxicol 40:286–294
Biel-Maeso M, Baena-Nogueras RM, Corada-Fernández C, Lara-Martín PA (2018) Occurrence, distribution and environmental risk of pharmaceutically active compounds (PhACs) in coastal and ocean waters from the Gulf of Cadiz (SW Spain). Sci Total Environ 612:649–659
Boreen AL, Arnold WA, McNeill K (2003) Photodegradation of pharmaceuticals in the aquatic environment: a review. Aquat Sci 65:320–341
Boxall AB, Rudd MA, Brooks BW, Caldwell DJ, Choi K, Hickmann S, Innes E, Ostapyk K, Staveley JP, Verslycke T, Anklex GT, Beazley KF, Belanter SE, Berninger JP, Carriquiriborde P, Coors A, Deleo PC, Dyer SD, Ericson JF, Gagné F, Giesy JP, Gouin T, Hallstrom L, Karlsson MV, Larsson DG, Lazorchak JM, Mastrocco F, McLaughlin A, McMaster ME, Meyerhoff RD, Moore R, Parrott JL, Snape JR, Murray-Smith R, Servos MR, Sibley PK, Straub JO, Szabo ND, Topp E, Tetreault GR, Trudeau VL, Van Der Kraak G (2012) Pharmaceuticals and personal care products in the environment: what are the big questions? Environ Health Perspect 120:1221–1229
Bu Q, Shi X, Yu G, Huang J, Wang B (2016) Assessing the persistence of pharmaceuticals in the aquatic environment: challenges and needs. Emerg Contam 2:154–147
Daughton CG (2004) Non-regulated water contaminants: emerging research. Environ Impact Assess 24:711–732
Fent K, Weston AA, Caminada D (2006) Ecotoxicology of human pharmaceuticals. Aquat Toxicol 76:122–159
Godoy AA, Kummrow F, Pamplin PAZ (2015) Occurrence, ecotoxicological effects and risk assessment of antihypertensive pharmaceutical residues in the aquatic environment - A review. Chemosphere 138:281–291
Grabicová K, Grabic R, Bláha M, Kumar V, Cerveny D, Feredova G, Randak T (2015) Presence of pharmaceuticals in benthic fauna living in a small stream affected by effluent from a municipal sewage treatment plant. Water Res 72:145–153
Isidori M, Lavorgna M, Nardelli A, Pascarella L, Parrella A (2005) Toxic and genotoxic evaluation of six antibiotics on non-target organisms. Sci Total Environ 346:87–98
Khetan SK, Collins TJ (2007) Human pharmaceuticals in the aquatic environment: a challenge to green chemistry. Chem Rev 107:2319–2364
Klementová Š, Wagnerová DM (1994) Photocatalytic effect on Fe(III) on oxidation of two-carbon substrates related to natural waters. Collect Czechoslov Chem Commun 59:1066–1076
Klementová Š, Kahoun D, Doubková L, Frejlachová K, Dušáková M, Zlámal M (2017) Catalytic photodegradation of pharmaceuticals–homogeneous and heterogeneous photocatalysis. Photochem Photobiol Sci 16:67–71
Klementová Š, Hornychová L, Šorf M, Zemanová J, Kahoun D (2019) Toxicity of atrazine and the products of its homogeneous photocatalytic degradation on the aquatic organisms Lemna minor and Daphnia magna. Environ Sci Pollut Res 26:27259–27267
Kostich MS, Flick RW, Batt AL, Mash HE, Boone JS, Furlong ET, Kolpin DW, Glassmeyer ST (2017) Aquatic concentrations of chemical analytes compared to ecotoxicity estimates. Sci Total Environ 579:1649–1657
Krishna S, Maslani A, Izdebski T, Horakova M, Klementova S, Špatenka P (2016) Degradation of verapamil hydrochloride in water by gliding arc discharge. Chemosphere 152:47–54
Le T-H, Lim E-S, Lee S-K, Park J-S, Kim Y-H, Min J (2011) Toxicity evaluation of verapamil and tramadol based on toxicity assay and expression patterns of Dhb, Vtg, Arnt, CYP4, and CYP314 in Daphnia magna. Environ Toxicol 26:515–523
Li WC (2014) Occurrence, sources, and fate of pharmaceuticals in aquatic environmental and soil. Environ Pollut 187:193–201
Mezzelani M, Gorbi S, Regoli F (2018) Pharmaceuticals in the aquatic environments: evidence o emerged threat and future challenges for marine organisms. Mar Environ Res 140:41–60
Minguez L, Pedelucq J, Farcy E, Ballandonne C, Budzinski H, Halm-Lemeille MP (2016) Toxicities of 48 pharmaceuticals and their freshwater and marine environmental assessment in northwestern France. Environ Sci Pollut Res 23:4992–5001
OECD Guidelines for the testing of chemicals, Guideline 211 (2012) Daphnia magna reproduction test. Available from: [oecd-ilibrary.org/environment/test-no-211-daphnia-magna-reproduction-test_9789264185203-en] Accessed: [2020-16-01]
Overturf MD, Overturf CL, Baxter D, Hala DN, Constantine L, Venables B, Huggett DB (2012) Early life-stage toxicity of eight pharmaceuticals to the fathead minnow, Pimephales promelas. Archiv Environ Con Tox 6:455–464
Patel M, Kumar R, Kishor K, Mlsna T, Pittman CU Jr, Mohan D (2019) Pharmaceuticals of emerging concern in aquatic systems: chemistry, occurrence, effects, and removal methods. Chem Rev 119:3510–3673
PubChem Database (2020). National Center for Biotechnology Information. PubChem Database. Verapamil, CID=250
Saari NG, Casan SW, Brooks BW (2017) Global scanning assessment of calcium channel blockers in the environment: review and analysis of occurrence, ecotoxicology and hazards in aquatic systems. Chemosphere 189:466–478
Sangion A, Gramatica P (2016) PBT assessment and prioritization of contaminants of emerging concern: pharmaceuticals. Environ Res 147:297–306
Santos L, Gros M, Rodriguez-Mozaz S, Delerue-Matos C, Pena A, Barceló D, Montenegro M (2013) Contribution of hospital effluents to the load of pharmaceuticals in urban wastewaters: identification of ecologically relevant pharmaceuticals. Sci Total Environ 461-462:302–316
Sawicki W (2002) Pharmacokinetics of verapamil and norverapamil from controlled release floating pellets in humans. Eur J Pharm Biopharm 53:29–35
Steinbach C, Fedorova G, Prokes M, Grabicova K, Machova J, Grabic R, Valentova O, Kocour M, Kroupova H (2013) Toxic effects, bioconcentration and depuration of verapamil in the early life stages of common carp (Cyprinus carpio L.). Sci Total Environ 461-462:198–206
Taylor D, Senac T (2014) Human pharmaceutical products in the environment–the “problem” in perspective. Chemosphere 115:95–99
TIBCO Software Inc (2017) Statistica (data analysis software system), version 13. http://statistica.io
Tixier C, Bogaerts P, Sancelme M, Bonnemoy F, Twagilimana L, Cuer A, Bohatier J, Veschambre H (2000) Fungal biodegradation of a phenylurea herbicide, diuron: structure and toxicity of metabolites. Pest Manag Sci 56:455–462
Tixier C, Sancelme M, Äit-Äissa S, Widehem P, Bonnemoy F, Cuer A, Truffaut N, Veschambre H (2002) Biotransformation of phenylurea herbicides by a soil bacterial strain, Arthrobacter sp. N2: structure, ecotoxicity and fate of diuron metabolite with soil fungi. Chemosphere 46:519–526
Trautwein C, Kümmerer K, Metzger JW (2008) Aerobic biodegradability of the calcium channel antagonist verapamil and identification of a microbial dead-end transformation product studied by LC-MS/MS. Chemosphere 72:442–450
Villegas-Navarroa A, Rosas-L E, Reyes JL (2003) The heart of Daphnia magna: effects of four cardioactive drugs. Comp Biochem Phys C 136:127–134
Yunlong L, Wenshan G, Huu Hao N, Long Duc N, Faisal Ibney H, Zhang J, Shuang L, Wang XC (2014) A review on the occurrence of micropollutants in the aquatic environment and their fate and removal wastewater treatment. Sci Total Environ 473-474:619–641
Zhi-Hua L, ** L, Randak T (2010) Ecotoxicological effects of short-term exposure to a human pharmaceutical verapamil in juvenile rainbow trout (Oncorhyncus mykiss). Comp Biochem Phys C Toxicol Pharmacol 152:385–391
Zhi-Hua L, Velisek J, Zlabek V, Grabic R, Machova J, Kolarova J, ** L, Randak T (2011) Chronic toxicity of verapamil on juvenile rainbow trout (Onkorhynchus mykiss): effects on morphological indices, hematological parameters and antioxidant responses. J Hazard Mater 185:870–880
Zhu B, Zonja B, Gonzalez O, Sans C, Pérez S, Barceló D, Esplugas E, Xu K, Qiang Z (2015) Degradation kinetics and pathways of three calcium channel blockers under UV irradiation. Water Res 86:9–16
Acknowledgements
We thank Kateřina Kocourková for her help with the Daphnia experiments. We also would like to thank anonymous reviewers for their suggestions which improved the manuscript.
Funding
The authors gratefully acknowledge the financial support of the research provided by the Faculty of Science, University of South Bohemia. This study was further supported by the PROFISH CZ.02.1.01/0.0/0.0/16_019/0000869 project, which is financed by the European Regional Development Fund in the operational programme VVV MŠMT.
Author information
Authors and Affiliations
Corresponding author
Additional information
Responsible editor: Lotfi Aleya
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Klementová, Š., Poncarová, M., Kahoun, D. et al. Toxicity assessment of verapamil and its photodegradation products. Environ Sci Pollut Res 27, 35650–35660 (2020). https://doi.org/10.1007/s11356-020-09830-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-020-09830-w