Abstract
Chloroquine (CQ) has been widely used for many years against malaria and various viral diseases. Its important use and high potential to being persistent make it of particular concern for ecotoxicological studies. Here, we evaluated the toxicity of CQ alone and in combination with copper (Cu) to the euryhaline rotifer Proales similis. All experiments were carried out using chronic toxicity reproductive five‐day tests and an application factor (AF) of 0.05, 0.1, 0.3, and 0.5 by multiplying the 24-h LC50 values of CQ (4250 µg/L) and Cu (68 µg/L), which were administered in solution. The rate of population increase (r, d−1) ranged from 0.50 to 52 (controls); 0.20 to 0.40 (CQ); 0.09 to 0.43 (Cu); and −0.03 to 0.30 (CQ-Cu) and showed significant decrease as the concentration of both chemicals in the medium increased. Almost all tested mixtures induced synergistic effects, mainly as the AF increased. We found that the presence of Cu intensifies the vulnerability of organisms to CQ and vice versa. These results stress the potential hazard that these combined chemicals may have on the aquatic systems. This research suggests that P. similis is sensitive to CQ as other standardized zooplankton species and may serve as a potential test species in the risk assessment of emerging pollutants in marine environments.
Similar content being viewed by others
References
Ali MB, Hedfi A, Almalki M, Karachle PK, Boufahja F (2021) Toxicity of hydroxychloroquine, a potential treatment for COVID-19, on free-living marine nematodes. Mar Pollut Bull 167:112361. https://doi.org/10.1016/j.marpolbul.2021.112361
Almeida Â, Calisto V, Esteves VI, Schneider RJ, Soares AMVM, Figueira E, Freitas R (2018) Effects of single and combined exposure of pharmaceutical drugs (carbamazepine and cetirizine) and a metal (cadmium) on the biochemical responses of R. philippinarum. Aquat Toxicol 198:10–19. https://doi.org/10.1016/j.aquatox.2018.02.011
Ansari TM, Marr IL, Tariq N (2003) Heavy metals in marine pollution perspective–a mini review. J Appl Sci 4:1–20. https://doi.org/10.3923/jas.2004.1.20
Arnold WR, Diamond RL, Smith DS (2011) Acute and chronic toxicity of copper to the euryhaline rotifer, Brachionus plicatilis (“L” Strain). Arch Environ Contam Toxicol 60:250–260. https://doi.org/10.1007/s00244-010-9556-8
Balistrieri LS, Seal II RR, Piatak NM, Paul B (2007) Assessing the concentration, speciation, and toxicity of dissolved metals during mixing of acid-mine drainage and ambient river water downstream of the Elizabeth Copper Mine, Vermont, USA. App Geochem 22:930–952. https://doi.org/10.1016/j.apgeochem.2007.02.005
Bao VW, Leung KM, Lui GC, Lam MH (2013) Acute and chronic toxicities of Irgarol alone and in combination with copper to the marine copepod Tigriopus japonicus. Chemosphere 90:1140–1148. https://doi.org/10.1016/j.chemosphere.2012.09.022
Bao VW, Lui GC, Leung KM (2014) Acute and chronic toxicities of zinc pyrithione alone and in combination with copper to the marine copepod Tigriopus japonicus. Aquat Toxicol 157:81–93. https://doi.org/10.1016/j.aquatox.2014.09.013
Bechmann RK (1994) Use of life tables and LC50 tests to evaluate chronic and acute toxicity effects of copper on the marine copepod Tisbe furcata (baird). Environ Toxicol Chem 13:1509–1517. https://doi.org/10.1002/etc.5620130913
Broderius SJ, Kahl MD, Elonen GE, Hammermeister DE, Hoglund MD (2005) A comparison of the lethal and sublethal toxicity of organic chemical mixtures to the fathead minnow (Pimephales promelas). Environ Toxicol Chem 24:3117–3127. https://doi.org/10.1897/05-094R.1
Brodin T, Piovano S, Fick J, Klaminder J, Heynen M, Jonsson M (2014) Ecological effects of pharmaceuticals in aquatic systems—impacts through behavioural alterations. Philos Trans R Soc B Biol Sci 369:20130580. https://doi.org/10.1098/rstb.2013.0580
Bunke D, Moritz S, Brack W, Herráez DL, Posthuma L, Nuss M (2019) Developments in society and implications for emerging pollutants in the aquatic environment. Environ Sci Eur 31:32. https://doi.org/10.1186/s12302-019-0213-1
Calleja MC, Persoone G, Geladi P (1994) Comparative acute toxicity of the first 50 multicentre evaluation of in vitro cytotoxicity chemicals to aquatic non-vertebrates. Arch Environ Contam Toxicol 26:69–78. https://doi.org/10.1007/BF00212796
Cedergreen N (2014) Quantifying Synergy: A systematic review of mixture toxicity studies within environmental toxicology. PLoS One 9:e96580. https://doi.org/10.1371/journal.pone.0096580
Debelius B, Forja JM, DelValls Á, Lubián LM (2009) Toxicity and bioaccumulation of copper and lead in five marine microalgae. Ecotoxicol Environ Saf 72:1503–1513. https://doi.org/10.1016/j.ecoenv.2009.04.006
Deblonde T, Cossu-Leguille C, Hartemann P (2011) Emerging pollutants in wastewater: a review of the literature. Intern J Hyg Environ Health 214:442–448. https://doi.org/10.1016/j.ijheh.2011.08.002
Delogu I, de Lamballerie X (2011) Chikungunya disease and chloroquine treatment. J Med Virol 83. https://doi.org/10.1002/jmv.22019
Egbuna C, Amadi CN, Patrick-Iwuanyanwu KC, Ezzat SM, Awuchi CG, Ugonwa PO, Orisakwe OE (2021) Emerging pollutants in Nigeria: A systematic review. Environ Toxicol Pharmacol 85:103638. https://doi.org/10.1016/j.etap.2021.103638
EPA, 2017. Contaminants of Emerging Concern. https://www.epa.gov/fedfac/emerging-contaminants-and-federal-facility-contaminants-concern
Essid N, Allouche M, Lazzem M, Harrath AH, Mansour L, Alwasel S, Mahmoudi E, Beyrem H, Boufahja F (2020) Ecotoxic response of nematodes to ivermectin, a potential anti-COVID-19 drug treatment. Mar Pollut Bull 157:111375. https://doi.org/10.1016/j.marpolbul.2020.111375
Fang TH, Nan FH, Chin TS, Feng HM (2012) The occurrence and distribution of pharmaceutical compounds in the effluents of a major sewage treatment plant in Northern Taiwan and the receiving coastal waters. Mar Pollut Bull 64:1435–1444. https://doi.org/10.1016/j.marpolbul.2012.04.008
Farag AM, Skaar D, Nimik DA, MacConell E, Hogstrand C (2003) Characterizing aquatic health using salmonid mortality, physiology, and biomass estimates of arsenic, cadmium, copper, lead, and zinc in the boulder river watershed, Montana. Trans Amer Fish Soc 132:450–467. https://doi.org/10.1577/1548-8659(2003)132<0450:CAHUSM>2.0.CO;2
Finney DJ (1971) Probit Analysis (3th edn.), Cambridge University Press, Cambridge (1971), 333
Forbes VE, Calow P (1999) Is the per capita rate of increase a good measure of population-level effects in ecotoxicology? Environ Toxicol Chem 18:1544–1556. https://doi.org/10.1002/etc.5620180729
Frías-Espericueta MG, Bautista-Covarrubias JC, Osuna-Martínez CC, Delgado-Alvarez C, Bojórquez C, Aguilar-Juárez M, Roos-Muñoz S, Osuna-López I, Páez-Osuna F (2022) Metals and oxidative stress in aquatic decapod crustaceans: A review with special reference to shrimp and crabs. Aquat Toxicol 242:106024. https://doi.org/10.1016/j.aquatox.2021.106024
Gama-Flores JL, Sarma SSS, Nandini S (2005) Interaction among copper toxicity, temperature and salinity on the population dynamics of Brachionus Rotundiformis (Rotifera). Hydrobiologia 546:559–568. https://doi.org/10.1007/s10750-005-4300-5
Gavrilescu M, Demnerová K, Aamand J, Agathos S, Fava F (2015) Emerging pollutants in the environment: Present and future challenges in biomonitoring, ecological risks and bioremediation. N Biotechnol 32:147–156. https://doi.org/10.1016/j.nbt.2014.01.001
Godoy AA, de Oliveira ÁC, Silva JGM, Azevedo CC, de J, Domingues I, Nogueira AJA, Kummrow F (2019) Single and mixture toxicity of four pharmaceuticals of environmental concern to aquatic organisms, including a behavioral assessment. Chemosphere 235:373–382. https://doi.org/10.1016/j.chemosphere.2019.06.200
González-Pérez BK, Sarma SSS, Castellanos-Páez ME, Nandini S (2018) Multigenerational effects of triclosan on the demography of Plationus patulus and Brachionus havanaensis (Rotifera). Ecotoxicol Environ Saf 147:275–282. https://doi.org/10.1016/j.ecoenv.2017.08.049
González-Pérez BK, Sarma SSS, Nandini S (2016) Effects of selected pharmaceuticals (ibuprofen and amoxicillin) on the demography of Brachionus calyciflorus and Brachionus havanaensis (Rotifera). Egypt J Aquat Res 42:341–347. https://doi.org/10.1016/j.ejar.2016.09.003
Gu JD, Wang YS (2015) Coastal and marine pollution and ecotoxicology. Ecotoxicology 24:1407–1410. https://doi.org/10.1007/s10646-015-1528-3
Hernández-Flores S, Rico-Martínez R (2006) Study of the effects of Pb and Hg toxicity using a chronic toxicity reproductive 5-day test with the freshwater rotifer Lecane quadridentata. Environ Toxicol 21:533–540. https://doi.org/10.1002/tox.20218
Hu J, Hellgeth N, Cabay C, Clark J, Oliaro FJ, Van Bonn W, Hartmann EM (2022) Towards understanding microbial degradation of chloroquine in large saltwater systems. Science Total Environ 807:150532. https://doi.org/10.1016/j.scitotenv.2021.150532
Jia D, Li X, Du S, Xu N, Zhang W, Yang R, Yunhai Z, He Y, Zhang Y (2020) Single and combined effects of carbamazepine and copper on nervous and antioxidant systems of zebrafish (Danio rerio). Environ Toxicol 35:1091–1099. https://doi.org/10.1002/tox.22945
Jonathan MP, Roy PD, Thangadurai N, Srinivasalu S, Rodríguez-Espinosa PF, Sarkar SK, Lakshumanan C, Navarrete-López M, Muñoz-Sevilla NP (2011) Metal concentrations in water and sediments from tourist beaches of Acapulco, Mexico. Mar Pollut Bull 62:845–850. https://doi.org/10.1016/j.marpolbul.2011.02.042
Kuroda K, Li C, Dhangar K, Kumar M (2021) Predicted occurrence, ecotoxicological risk and environmentally acquired resistance of antiviral drugs associated with COVID-19 in environmental waters. Sci Total Environ 776:145740. https://doi.org/10.1016/j.scitotenv.2021.145740
Kwok KWH, Leung KMY, Bao VWW, Lee JS (2008) Copper toxicity in the marine copepod Tigropus japonicus: Low variability and high reproducibility of repeated acute and life-cycle tests. Mar Pollut Bull 57:632–636. https://doi.org/10.1016/j.marpolbul.2008.03.026
Leethochavalit S (2011) Characterization of Cryptocaryon sp. Isolated From Marine Fish in Thailand and In Vitro Treatment. Conference Paper INOC-XI International Symposium Bogor Indonesia.
Liu K, Zhang D, Xiao X, Cui L, Zhang H (2020) Occurrence of quinotone antibiotics and their impacts on aquatic environment in typical river-estuary system of Jiaozhou Bay, China. Ecotoxicol Environ Saf 190:109993. https://doi.org/10.1016/j.ecoenv.2019.109993
Luna-Andrade A, Aguilar-Duran R, Nandini S, Sarma SSS (2002) Combined effects of copper and microalgal (Tetraselmis suecica) concentrations on the population growth of Brachionus plicatilis Müller (Rotifera). Water, Air, Soil Pollut 141:143–153. https://doi.org/10.1023/A:1021346512560
Lynch NR, Hoang TC, O’Brien TE (2016) Acute toxicity of binary‐metal mixtures of copper, zinc, and nickel to Pimephales promelas: Evidence of more‐than‐additive effect. Environ Toxicol Chem 35:446–457. https://doi.org/10.1002/etc.3204
Magdaleno A, Saenz ME, Juárez AB, Moretton J (2015) Effects of six antibiotics and their binary mixtures on growth of Pseudokirchneriella subcapitata. Ecotoxicol Environ Saf 113:72–78. https://doi.org/10.1016/j.ecoenv.2014.11.021
Martínez-Macias MDR, Correa-Murrieta MA, Villegas-Peralta Y, Dévora-Isiordia GE, Álvarez-Sánchez J, Saldivar-Cabrales J, Sánchez-Duarte RG (2019) Uptake of copper from acid mine drainage by the microalgae Nannochloropsis oculata. Environ Sci Pollut Res 26:6311–6318. https://doi.org/10.1007/s11356-018-3963-1
Mendonça-Gomes JM, da Costa Araújo AP, da Luz TM, Charlie-Silva I, Braz HLB, Jorge RJB, Ahmed M, Nóbrega RH, Vogel C, Malafaia G (2021) Environmental impacts of COVID-19 treatment: Toxicological evaluation of azithromycin and hydroxychloroquine in adult zebrafish. Sci Total Environ 790:148129. https://doi.org/10.1016/j.scitotenv.2021.148129
Midassi S, Bedoui A, Bensalah N (2020) Efficient degradation of chloroquine drug by electro-Fenton oxidation: Effects of operating conditions and degradation mechanism. Chemosphere 260:127558. https://doi.org/10.1016/j.chemosphere.2020.127558
Nalecz-Jawecki G, Persoone G (2006) Toxicity of selected pharmaceuticals to the Anostracan crustacean Thamnocephalus platyurus - Comparison of sublethal and lethal effect levels with the 1h Rapidtoxkit and the 24 h thamnotoxkit microbiotests. Environ Sci Pollut Res-Int 13:22–27. https://doi.org/10.1065/espr2006.01.005
Njiro B, Ritah F, Amisa M, Chamani T, Deodatus TM, George S, Bwire M (2022) Molecular surveillance of chloroquine resistant Plasmodium falciparum after withdrawal of chloroquine for treatment of malaria: a systematic review. J Infection Public Health 15:550–557. https://doi.org/10.1016/j.jiph.2022.03.015
Olatunde JO, Chimezie A, Tolulope B, Aminat TT (2014) Determination of pharmaceutical compounds in surface and underground water by solid phase extraction-liquid chromatography. J Environ Chem Ecotoxicol 6:20–26. https://doi.org/10.5897/jece2013.0312
Páez-Osuna F, Osuna-Martínez CC (2015) Bioavailability of cadmium, copper, mercury, lead, and zinc in subtropical coastal lagoons from the Southeast Gulf of California using mangrove oysters (Crassostrea corteziensis and Crassostrea palmula). Arch Environ Contam Toxicol 68:305–316. https://doi.org/10.1007/s00244-014-0118-3
Páez-Osuna F, Sanchez-Cabeza JA, Ruiz-Fernández AC, Alonso-Rodríguez R, Piñón-Gimate A, Cardoso-Mohedano JG, Flores-Verdugo FJ, Carballo JL, Cisneros-Mata MA, Álvarez-Borrego S (2016) Environmental status of the Gulf of California: A review of responses to climate change and climate variability. Earth-Sci Rev 162:253–268. https://doi.org/10.1016/j.earscirev.2016.09.015
Petrie B, Barden R, Kasprzyk-Hordern B (2015) A review on emerging contaminants in wastewaters and the environment: current knowledge, understudied areas and recommendations for future monitoring. Water Res 72:3–27. https://doi.org/10.1016/j.watres.2014.08.053
Plantone D, Koudriavtseva T (2018) Current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neurological diseases: a mini-review. Clin Drug Investig 38:653–671. https://doi.org/10.1007/s40261-018-0656-y
Ramesh M, Anitha S, Poopal RK, Shobana C (2018) Evaluation of acute and sublethal effects of chloroquine (C18H26CIN3) on certain enzymological and histopathological biomarker responses of a freshwater fish Cyprinus carpio. Toxicol Rep 5:18–27. https://doi.org/10.1016/j.toxrep.2017.11.006
Rebolledo UA, Nandini S, Sánchez-Escobar O, Sarma SSS (2018) Combined effects of temperature and salinity on the demographic response of Proales similis (Beauchamp, 1907) and Brachionus plicatilis (Müller, 1786) (Rotifera) to mercury. Chemosphere 202:312–321. https://doi.org/10.1016/j.chemosphere.2018.03.111
Rebolledo UA, Páez-Osuna F, Fernández R (2021) Single and mixture toxicity of As, Cd, Cr, Cu, Fe, Hg, Ni, Pb, and Zn to the rotifer Proales similis under different salinities. Environ Pollut 116357. https://doi.org/10.1016/j.envpol.2020.116357
Rendal C, Kusk KO, Trapp S (2011) The effect of pH on the uptake and toxicity of the bivalent weak base chloroquine tested on Salix viminalis and Daphnia magna. Environ Toxicol Chem 30:354–359. https://doi.org/10.1002/etc.391
Rico-Martínez R, Snell TW, Shearer TL (2013) Synergistic toxicity of Macondo crude oil and dispersant Corexit 9500A® to the Brachionus plicatilis species complex (Rotifera). Environ Pollut 173:5–10. https://doi.org/10.1016/j.envpol.2012.09.024
Schuler LJ, Hoang TC, Rand GM (2008) Aquatic risk assessment of copper in freshwater and saltwater ecosystems of South Florida. Ecotoxicology 17(7):642–659. https://doi.org/10.1007/s10646-008-0236-7
Snell TW, Johnston RK, Matthews AB, Park N, Berry S, Brashear J (2019) Using Proales similis (Rotifera) for toxicity assessment in marine waters. Environ Toxicol 34:634–644. https://doi.org/10.1002/tox.22729
Taylor WRJ, White NJ (2004) Antimalarial drug toxicity. Drug Saf 27(1):25–61. https://doi.org/10.2165/00002018-200427010-00003
Varano V, Fabbri E, Pasteris A (2017) Assessing the environmental hazard of individual and combined pharmaceuticals: acute and chronic toxicity of fluoxetine and propranolol in the crustacean Daphnia magna. Ecotoxicology 26(6):711–728. https://doi.org/10.1007/s10646-017-1803-6
Vazquez GF, Sharma VK, Magallanes VR, Marmolejo AJ (1999) Heavy metals in a coastal lagoon of the Gulf of Mexico. Mar Pollut Bull 38:479–485. https://doi.org/10.1016/S0025-326X(98)00173-8
Walker CH, Sibly RM, Hopkin SP, Peakall DB (2012) Principles of ecotoxicology. CRC press.
Watanabe H, Tamura I, Abe R, Takanobu H, Nakamura A, Suzuki T, Hirose A, Nishimura T, Tatarazako N (2016) Chronic toxicity of an environmentally relevant mixture of pharmaceuticals to three aquatic organisms (alga, daphnid, and fish). Environ Toxicol Chem 35:996–1006. https://doi.org/10.1002/etc.3285. 10.2175/106143010X12756668802292
Yan Y, Zou Z, Sun Y, Li X, Xu KF, Wei Y, Jin N, Jiang C (2013) Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res 23:300–302. https://doi.org/10.1038/cr.2012.165
Zenker A, Cicero MR, Prestinaci F, Bottoni P, Carere M (2014) Bioaccumulation and biomagnification potential of pharmaceuticals with a focus to the aquatic environment. J Environ Manag 133:378–387. https://doi.org/10.1016/j.jenvman.2013.12.017
Zurita JL, Jos Á, Peso A, del Salguero M, López-Artíguez M, Repetto G (2005) Ecotoxicological evaluation of the antimalarial drug chloroquine. Aquat Toxicol 75:97–107. https://doi.org/10.1016/j.aquatox.2005.07.009
Acknowledgements
Uriel Arreguin Rebolledo thanks CONACyT (490764) for the financial support. Thanks to H. Bojórquez-Leyva for the support of the laboratory.
Author contributions
All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version.
Funding
This work was supported by the institutional (ICML, UNAM) project titled “Biogeoquímica de los nutrientes y oligoelementos en sistemas acuáticos: acumulación, distribución, transferencia, efectos y ciclaje” (year 2020).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Consent to participate
All authors consent to participate.
Consent for publication
All authors consent for publication.
Ethical approval
This article does not contain any studies with human participants or protected animals performed by any of the authors.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Rebolledo, U.A., Rico-Martínez, R., Fernández, R. et al. Synergistic effect of chloroquine and copper to the euryhaline rotifer Proales similis. Ecotoxicology 31, 1035–1043 (2022). https://doi.org/10.1007/s10646-022-02570-2
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10646-022-02570-2