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Ecological Risk Assessment of Pharmaceuticals in the Surface Water Near a Pharmaceutical Manufacturing Complex in Korea

제약단지 인접 지역 지표수의 잔류 의약물질 생태위해성평가

  • Park, Suhyun (Institute of Natural Science, Yongin University) ;
  • Kang, Habyeong (School of Public Health, Seoul National University) ;
  • Shin, Hyesoo (School of Public Health, Seoul National University) ;
  • Ryoo, Ilhan (Department of Health, Environment & Safety, Eulji University) ;
  • Choi, Kyungho (School of Public Health, Seoul National University) ;
  • Kho, Younglim (Department of Health, Environment & Safety, Eulji University) ;
  • Park, Kyunghwa (National Institute of Environmental Research) ;
  • Kim, Kyungtae (National Institute of Environmental Research) ;
  • Ji, Kyunghee (Department of Occupational and Environmental Health, Yongin University)
  • 박수현 (용인대학교 자연과학연구소) ;
  • 강하병 (서울대학교 보건대학원) ;
  • 신혜수 (서울대학교 보건대학원) ;
  • 유일한 (용인대학교 산업환경보건학과) ;
  • 최경호 (서울대학교 보건대학원) ;
  • 고영림 (을지대학교 보건환경안전학과) ;
  • 박경화 (국립환경과학원) ;
  • 김경태 (국립환경과학원) ;
  • 지경희 (용인대학교 산업환경보건학과)
  • Received : 2019.12.09
  • Accepted : 2020.01.23
  • Published : 2020.02.29

Abstract

Objectives: Limited information is available on the presence and associated ecological risks of pharmaceutical residues in aquatic environments near pharmaceutical manufacturing areas in Korea. In this study, we investigated the current state of pharmaceutical contamination and its associated ecological risks in streams near a pharmaceutical manufacturing complex. Methods: Seven pharmaceuticals (acetaminophen, clarithromycin, diclofenac, diphenhydramine, ibuprofen, mefenamic acid and roxithromycin) were measured in water samples collected from the streams near a pharmaceutical manufacturing complex. A predicted no-effect concentration (PNEC) was derived using either the assessment factor method or species sensitivity distribution method. In addition, a hazard quotient for each pharmaceutical was calculated by dividing its measured environmental concentration by its PNEC. Results: Samples collected downstream from the wastewater treatment plant (WWTP) had higher concentrations of pharmaceuticals than those collected from the reference site (upstream). Moreover, pharmaceutical concentrations were greater in ambient water than in the final effluent from the WWTP, which suggested that non-point sources were contributing to the contamination of the ambient water environment. Some of the target pharmaceuticals exhibited a hazard quotient >1, indicating that their potential ecological effects on the aquatic environment near the pharmaceutical industrial area should not be ignored. Conclusion: This study demonstrated that the pharmaceutical manufacturing area was contaminated with residual drugs, and that there was a possible non-point source near the WWTP effluent discharge area. The results of this study will aid in the development of management plans for pharmaceuticals, particularly in hotspots such as pharmaceutical industrial sites and their vicinities.

Keywords

References

  1. Carlsson C, Johansson AK, Alvan G, Bergman K, Kuhler T. Are pharmaceuticals potent environmental pollutants?: Part I: environmental risk assessments of selected active pharmaceutical ingredients. Sci Total Environ. 2006; 364(1-3): 67-87. https://doi.org/10.1016/j.scitotenv.2005.06.035
  2. Daughton CG. Chapter 2-Pharmaceuticals in the environment: sources and their management. Compr Anal Chem. 2013; 62: 37-69. https://doi.org/10.1016/B978-0-444-62657-8.00002-1
  3. Kummerer K. The presence of pharmaceuticals in the environment due to human use-present knowledge and future challenges. J Environ Manage. 2009; 90(8): 2354-2366. https://doi.org/10.1016/j.jenvman.2009.01.023
  4. Ebele AJ, Abdallah MAE, Harrad S. Pharmaceuticals and personal care products (PPCPs) in the freshwater aquatic environment. Emerging Contaminants. 2017; 3(1): 1-16. https://doi.org/10.1016/j.emcon.2016.12.004
  5. Rehman MS, Rashid N, Ashfaq M, Saif A, Ahmad N, Han JI. Global risk of pharmaceutical contamination from highly populated developing countries. Chemosphere. 2015; 138: 1045-1055. https://doi.org/10.1016/j.chemosphere.2013.02.036
  6. National Institute of Environmental Research. Risk Assessment of Major Pharmaceutical Residues in the Environment, and Future Research Directions. NIER-SP2012-169. Seoul National University, Eulji University, Soonchunhyang University, Chungbuk National University. 2012.
  7. Sim WJ, Lee JW, Lee ES, Shin SK, Hwang SR, Oh JE. Occurrence and distribution of pharmaceuticals in wastewater from households, livestock farms, hospitals and pharmaceutical manufactures. Chemosphere. 2011; 82(2): 179-186. https://doi.org/10.1016/j.chemosphere.2010.10.026
  8. Kim B, Ji K, Kim C, Kang H, Lee S, Kwon B, et al. Pharmaceutical residues in streams near concentrated animal feeding operations of Korea-occurrences and associated ecological risks. Sci Total Environ. 2019; 655: 408-413. https://doi.org/10.1016/j.scitotenv.2018.11.233
  9. National Institute of Environmental Research. Monitoring of Hazardous Substances in Environmental Media for Exposure Assessment. NIER-SP2017-307. Changwon University. 2017.
  10. Sanchez W, Sremski W, Piccini B, Palluel O, Maillot-Marechal E, Betoulle S, et al. Adverse effects in wild fish living downstream from pharmaceutical manufacture discharges. Environ Int. 2011; 37(8): 1342-1348. https://doi.org/10.1016/j.envint.2011.06.002
  11. Larsson DGJ. Pollution from drug manufacturing: review and perspectives. Philos Trans R Soc Lond B Biol Sci. 2014; 369(1656): 20130571. https://doi.org/10.1098/rstb.2013.0571
  12. Painter MM, Buerkley MA, Julius ML, Vajda AM, Norris DO, Barber LB, et al. Antidepressants at environmentally relevant concentrations affect predator avoidance behavior of larval fathead minnows (Pimephales promelas). Environ Toxicol Chem. 2009; 28(12): 2677-2684. https://doi.org/10.1897/08-556.1
  13. Kwak K, Ji K, Kho Y, Kim P, Lee J, Ryu J, et al. Chronic toxicity and endocrine disruption of naproxen in freshwater waterfleas and fish, and steroidogenic alteration using H295R cell assay. Chemosphere. 2018; 204: 156-162. https://doi.org/10.1016/j.chemosphere.2018.04.035
  14. Jung Collard HR, Ji K, Lee S, Liu X, Kang S, Kho Y, et al. Toxicity and endocrine disruption in zebrafish (Danio rerio) and two freshwater invertebrates (Daphnia magna and Moina macrocopa) after chronic exposure to mefenamic acid. Ecotoxicol Environ Saf. 2013; 94: 80-86. https://doi.org/10.1016/j.ecoenv.2013.04.027
  15. National Institute of Environmental Research. Research on Risk Assessment of Pharmaceutical in the Environment for Preparing the Future Management Strategies (II). NIER-SP2014-228. Seoul National University of Science & Technology. 2014.
  16. Verlicchi P, Aukidy MA, Galletti A, Petrovic M, Barcelo D. Hospital effluent: investigation of the concentrations and distribution of pharmaceuticals and environmental risk assessment. Sci Total Environ. 2012; 430: 109-118. https://doi.org/10.1016/j.scitotenv.2012.04.055
  17. Frederic O, Yves P. Pharmaceuticals in hospital wastewater: their ecotoxicity and contribution to the environmental hazard of the effluent. Chemosphere. 2014; 115: 31-39. https://doi.org/10.1016/j.chemosphere.2014.01.016
  18. Korea Meteorological Administration. 2019. Weather Information. [Available at: https://www.weather.go.kr/w/index.do].
  19. National Institute of Environmental Research. Risk Assessment of Pharmaceuticals with Potential Ecological Risks. NIER-SP2016-221. Seoul National University. 2016.
  20. Klimisch HJ, Andreae M, Tillmann U. A systematic approach for evaluating the quality of experimental toxicological and ecotoxicological data. Regul. Toxicol. Pharmacol. 1997; 25: 1-5. https://doi.org/10.1006/rtph.1996.1076
  21. European Communities. Common Implementation Strategy for the Water FrameWork Directive (2000/60/EC) Guidance Document No. 27: Technical Guidance for Deriving Environmental Quality Standards. Technical Report-2011-055. 2011.
  22. National Institute of Environmental Research. Notice No. 2014-48. Annex 4. Regulations on Specific Methods of Chemical Risk Assessment. 2014.
  23. National Institute of Environmental Research. Research on Analytic Method of Residual Pharmaceutical and Investigation on Actual Condition (IV). Kongju University. 2011.
  24. National Institute of Environmental Research. Development of Analytical Method and Study of Exposure of Pharmaceuticals and Personal Care Products in Environment. Kyonggi University, Korea Institute of Science and Technology, Interface Info Tech. 2006.
  25. Choi K, Kim Y, Jung J, Kim MH, Kim CS, Kim NH, et al. Occurrences and ecological risks of roxithromycin, trimethoprim, and chloramphenicol in the Han river, Korea. Environ Toxicol Chem. 2008; 27(3): 711-719. https://doi.org/10.1897/07-143.1
  26. National Institute of Environmental Research. Development of Analytical Method and Study of Exposure of Pharmaceuticals and Personal Care Products in Environment (II). Kyonggi University, Korea Institute of Science and Technology, 2007.
  27. Kim JW, Yoon SM, Lee SJ, Narumiya M, Nakada N, Han IS, et al. Occurrence and fate of PPCPs wastewater treatment plants in Korea. 2012 2nd International Conference on Environment and Industrial Innovation. 35: 57-61.
  28. Lee SH, Jung HW, Jung JY, Min HJ, Kim BR, Park CG, et al. Characteristics of occurrence of pharmaceuticals in the Nakdong river. J Kor Soc Environ Eng. 2013; 35(1): 45-56. https://doi.org/10.4491/KSEE.2013.35.1.045
  29. Han GH, Hur HG, Kim SD. Ecotoxicological risk of pharmaceuticals from wastewater treatment plants in Korea: occurrence and toxicity to Daphnia magna. Environ Toxicol Chem. 2006; 25: 265-271. https://doi.org/10.1897/05-193R.1
  30. Ryu J, Yoon Y, Oh J. Occurrence of endocrine disrupting compounds and pharmaceuticals in 11 WWTPs in Seoul, Korea. J Civil Eng. 2011; 15(1): 57-64.
  31. Uhm JH, Chang TS, Hong YM, Park JE, Kim H. Removal of pharmaceutical compounds in conventional wastewater treatment plant. J Korea Soc Environ Anal. 2012; 15(2): 98-106.
  32. National Institute of Environmental Research. Investigation on Residual Drug Analysis Methodology (III). Kongju University. 2010.
  33. Lin AYC, Yu TH, Lin CF. Pharmaceutical contamination in residential, industrial, and agricultural waste streams: risk to aqueous environments in Taiwan. Chemosphere 2008; 74: 131-141. https://doi.org/10.1016/j.chemosphere.2008.08.027
  34. Lin AYC, Tsai YT. Occurrence of pharmaceuticals in Taiwan's surface waters: impact of waste streams from hospitals and pharmaceutical production facilities. Sci Total Environ. 2009; 407: 3793-3802. https://doi.org/10.1016/j.scitotenv.2009.03.009
  35. Bartelt-hunt SL, Snow DD, Damon T, Shockley J, Hoagland K. The occurrence of illicit and therapeutic pharmaceuticals in wastewater effluent and surface waters in Nebraska. Environ Pollut. 2009; 157: 786-791. https://doi.org/10.1016/j.envpol.2008.11.025
  36. Kleywegt S, Pileggi V, Lam YM, Elises A, Puddicomb A, Purba G, et al., The contribution of pharmaceutically active compounds from healthcare facilities to a receiving sewage treatment plant in Canada. Environ Toxicol Chem. 2016; 35(4): 850-862. https://doi.org/10.1002/etc.3124
  37. Khan GA, Berglund B, Khan KM, Lindgren PE, Fick J. Occurrence and abundance of antibiotics and resistance genes in rivers, canal and near drug formulation facilities-a study in Pakistan. PloS one. 2013; 8(6): e62712. https://doi.org/10.1371/journal.pone.0062712
  38. Nunes B, Antunes SC, Santos J, Martins L, Castro BB. Toxic potential of paracetamol to freshwater organisms: a headache to environmental regulators? Ecotoxicol Environ Saf. 2014; 107: 178-185. https://doi.org/10.1016/j.ecoenv.2014.05.027
  39. Henschel KP, Wenzel A, Diedrich M, Fliedner A. Environmental hazard assessment of pharmaceuticals. Regul Toxicol Pharmacol. 1997; 25: 220-225. https://doi.org/10.1006/rtph.1997.1102
  40. Watanabe H, Tamura I, Abe R, Takanobu H, Nakamura A, Suzuki T, et al. Chronic toxicity of an environmentally relevant mixture of pharmaceuticals to three aquatic organisms (alga, daphnid, and fish). Environ Toxicol Chem. 2016; 35(4): 996-1006. https://doi.org/10.1002/etc.3285
  41. Brain RA, Johnson DJ, Richards SM, Sanderson H, Sibley PK, Solomon KR. Effects of 25 pharmaceutical compounds to Lemna gibba using a seven-day static-renewal test. Environ Toxicol Chem. 2004; 23: 371-382. https://doi.org/10.1897/02-576
  42. Li MH. Chronic toxicity of 30 pharmaceutically active compounds to freshwater planarians, Dugesia japonica. Toxicol Environ Chem. 2013; 95: 1157-1170. https://doi.org/10.1080/02772248.2013.857671
  43. Du J, Mei CF, Ying GG, Xu MY. Toxicity thresholds for diclofenac, acetaminophen and ibuprofen in the water flea Daphnia magna. Bull Environ Contam Toxicol. 2016; 97: 84-90. https://doi.org/10.1007/s00128-016-1806-7
  44. Dave G, Herger G. Determination of detoxification to Daphnia magna of four pharmaceuticals and seven surfactants by activated sludge. Chemosphere 2012; 88: 459-466. https://doi.org/10.1016/j.chemosphere.2012.02.070
  45. Kim PG. Ecotoxicological risk assessment for acetaminophen in Kyongahn river. Korean J Environ Health. 2006; 32: 440-445.
  46. Kim P, Park Y, Ji K, Seo J, Lee S, Choi K, et al. Effect of chronic exposure to acetaminophen and lincomycin on Japanese medaka (Oryzias latipes) and freshwater cladocerans Daphnia magna and Moina macrocopa, and potential mechanisms of endocrine disruption. Chemosphere 2012; 89: 10-18. https://doi.org/10.1016/j.chemosphere.2012.04.006
  47. Gheorghe S, Petre J, Lucaciu I, Stoica C, Nita-Lazar M. Risk screening of pharmaceutical compounds in Romanian aquatic environment. Environ Monit Assess. 2016; 188: 1-16. https://doi.org/10.1007/s10661-015-4999-z
  48. Kuhn R, Pattard M, Pernak KD, Winter A. Results of the harmful effects of selected water pollutants (anilines, phenols, aliphatic compounds) to Daphnia magna. Water Res. 1989; 23: 495-499. https://doi.org/10.1016/0043-1354(89)90141-3
  49. Kim J, Park J, Kim PG, Lee C, Choi K, Choi K. Implication of global environmental changes on chemical toxicity-effect of water temperature, pH, and ultraviolet B irradiation on acute toxicity of several pharmaceuticals in Daphnia magna. Ecotoxicology. 2010; 19: 662-669. https://doi.org/10.1007/s10646-009-0440-0
  50. de Oliveira LLD, Antunes SC, Goncalves F, Rocha O, Nunes B. Acute and chronic ecotoxicological effects of four pharmaceuticals drugs on cladoceran Daphnia magna. Drug Chem Toxicol. 2016; 39(1): 1-9. https://doi.org/10.3109/01480545.2014.994217
  51. Brun GL, Bernier M, Losier R, Doe K, Jackman P, Lee HB. Pharmaceutically active compounds in Atlantic Canadian sewage treatment plant effluents and receiving waters, and potential for environmental effects as measured by acute and chronic aquatic toxicity. Environ Toxicol Chem. 2006; 25: 2163-2176. https://doi.org/10.1897/05-426R.1
  52. Kim Y, Choi K, Jung J, Park S, Kim PG, Park J. Aquatic toxicity of acetaminophen, carbamazepine, cimetidine, diltiazem and six major sulfonamides, and their potential ecological risks in Korea. Environ Int. 2007; 33: 370-375. https://doi.org/10.1016/j.envint.2006.11.017
  53. Sung HH, Chiu YW, Wang SY, Chen CM, Huang DJ. Acute toxicity of mixture of acetaminophen and ibuprofen to Green Neon Shrimp, Neocaridina denticulate. Environ Toxicol Pharmacol. 2014; 38(1): 8-13. https://doi.org/10.1016/j.etap.2014.04.014
  54. Folarin OS, Otitoloju AA, Amaeze NH. Comparative Ecotoxicological Assessment of Acetaminophen and Diclofenac using Freshwater African Catfish Clarias gariepinus (Burchell 1822). J Appl Sci Environ Manage. 2018; 22(9): 1519-1525.
  55. Selderslaghs IW, Blust R, Witters HE. Feasibility study of the zebrafish assay as an alternative method to screen for developmental toxicity and embryotoxicity using a training set of 27 compounds. Reprod Toxicol. 2012; 33: 142-154. https://doi.org/10.1016/j.reprotox.2011.08.003
  56. Broderius SJ, Kahl MD, Hoglund MD. Use of joint toxic response to define the primary mode of toxic action for diverse industrial organic chemicals. Environ Toxicol Chem. 1995; 14: 1591-1605. https://doi.org/10.1002/etc.5620140920
  57. David A, Pancharatna K. Effects of acetaminophen (paracetamol) in the embryonic development of zebrafish, Danio rerio. J Appl Toxicol. 2009; 29(7): 597-602. https://doi.org/10.1002/jat.1446
  58. Baumann M, Weiss K, Maletzki D, Schussler W, Schudoma D, Kopf W, et al. Aquatic toxicity of the macrolide antibiotic clarithromycin and its metabolites. Chemosphere. 2015; 120: 192-198. https://doi.org/10.1016/j.chemosphere.2014.05.089
  59. Villain J, Minguez L, Halm-Lemeille MP, Durrieu G, Bureau R. Acute toxicities of pharmaceuticals toward green algae. mode of action, biopharmaceutical drug disposition classification system and quantile regression models. Ecotoxicol Environ Saf. 2016; 124: 337-343. https://doi.org/10.1016/j.ecoenv.2015.11.009
  60. Yang LH, Ying GG, Su HC, Stauber JL, Adams MS, Binet MT. Growth-inhibiting effects of 12 antibacterial agents and their mixtures on the freshwater microalga Pseudokirchneriella subcapitata. Environ Toxicol Chem. 2008; 27(5): 1201-1208. https://doi.org/10.1897/07-471.1
  61. Isidori M, Lavorgna M, Nardelli A, Pascarella L, Parrella A. Toxic and genotoxic evaluation of six antibiotics on non-target organisms. Sci Total Environ. 2005; 346: 87-98. https://doi.org/10.1016/j.scitotenv.2004.11.017
  62. Harada A, Komori K, Nakada N, Kitamura K, Suzuki Y. Biological effects of PPCPs on aquatic lives and evaluation of river waters affected by different wastewater treatment levels. Water Sci Technol. 2008; 58: 1541-1546. https://doi.org/10.2166/wst.2008.742
  63. Watanabe H, Tamura I, Abe R, Takanobu H, Nakamura A, Suzuki T. et al. Chronic toxicity of an environmentally relevant mixture of pharmaceuticals to three aquatic organisms (alga, daphnid, and fish). Environ Toxicol Chem. 2016; 35(4): 996-1006. https://doi.org/10.1002/etc.3285
  64. Aubakirova BN, Boxall ABA, Beisenova RR. Toxicity study of antibiotics to the common duckweed (Lemna minor). 2017.
  65. Kim JW, Ishibashi H, Yamauchi R, Ichikawa N, Takao Y, Hirano M. Acute toxicity of pharmaceutical and personal care products on freshwater crustacean (Thamnocephalus platyurus) and fish (Oryzias latipes). J Toxicol Sci. 2009; 34: 227-232. https://doi.org/10.2131/jts.34.227
  66. Kaza M, Nalecz-Jawecki G, Sawicki J. The toxicity of selected pharmaceuticals to the aquatic plant Lemna minor. Fresen Environ Bull. 2007; 16: 524-531.
  67. Quinn B, Schmidt W, O'Rourke K, Hernan R. Effects of the pharmaceuticals gemfibrozil and diclofenac on biomarker expression in the zebra mussel (Dreissena polymorpha) and their comparison with standardised toxicity tests. Chemosphere. 2011; 84(5): 657-663. https://doi.org/10.1016/j.chemosphere.2011.03.033
  68. Cleuvers M. Aquatic ecotoxicity of pharmaceuticals including the assessment of combination effects. Toxicol lett. 2003; 142: 185-194. https://doi.org/10.1016/S0378-4274(03)00068-7
  69. Schulze T, Weiss S, Schymanski E, von der Ohe PC, Schmitt-Jansen M, Altenburger R, et al. Identification of a phytotoxic photo-transformation product of diclofenac using effect-directed analysis. Environ Pollut. 2010; 158(5): 1461-1466. https://doi.org/10.1016/j.envpol.2009.12.032
  70. Ferrari B, Mons R, Vollat B, Fraysse B, Paxeus N, Lo Giudice R, et al. Environmental risk assessment of six human pharmaceuticals: are the current environmental risk assessment procedures sufficient for the protection of the aquatic environment? Environ Toxicol Chem. 2004; 23: 1344-1354. https://doi.org/10.1897/03-246
  71. Gomez-Olivan LM, Galar-Martinez M, Garcia-Medina S, Valdes-Alanis A, Islas-Flores H, Neri-Cruz N. Genotoxic response and oxidative stress induced by diclofenac, ibuprofen and naproxen in Daphnia magna. Drug Chem Toxicol. 2014; 37: 391-399. https://doi.org/10.3109/01480545.2013.870191
  72. Cleuvers M. Mixture toxicity of the anti-inflammatory drugs diclofenac, ibuprofen, naproxen, and acetylsalicylic acid. Ecotoxicol Environ Saf. 2004; 59: 309-315. https://doi.org/10.1016/S0147-6513(03)00141-6
  73. Lee J, Ji K, Kho YL, Kim P, Choi K. Chronic exposure to diclofenac on two freshwater cladocerans and Japanese medaka. Ecotoxicol Environ Saf. 2011; 74: 1216-1225. https://doi.org/10.1016/j.ecoenv.2011.03.014
  74. Haap T, Triebskorn R, Kohler HR. Acute effects of diclofenac and DMSO to Daphnia magna: immobilisation and hsp70-induction. Chemosphere. 2008; 73: 353-359. https://doi.org/10.1016/j.chemosphere.2008.05.062
  75. Sanchez AC, Pereira J, Goncalves F, Reboleira AS. Comparative acute toxicity of the pharmaceutical compound Diclofenac on groundwater and surface water crustaceans. In ARPHA Conference Abstracts. Pensoft Publishers. 2018; 1: e29822.
  76. Nalecz-Jawecki G, Persoone G. Toxicity of selected pharmaceuticals to the anostracan crustacean Thamnocephalus platyurus-comparison of sublethal and lethal effect levels with the 1h Rapidtoxkit and the 24h Thamnotoxkit microbiotests. Environ Sci Pollut Res Int. 2006; 13: 22-27. https://doi.org/10.1065/espr2006.01.005
  77. van den Brandhof EJ, Montforts M. Fish embryo toxicity of carbamazepine, diclofenac and metoprolol. Ecotoxicol Environ Saf. 2010; 73(8): 1862-1866. https://doi.org/10.1016/j.ecoenv.2010.08.031
  78. Praskova E, Voslarova E, Siroka Z, Plhalova L, Macova S, Marsalek P. Assessment of diclofenac LC50 reference values in juvenile and embryonic stages of the zebrafish (Danio rerio). Polish J Vet Sci. 2011; 14(4): 545-549. https://doi.org/10.2478/v10181-011-0081-0
  79. Nassef M, Matsumoto S, Seki M, Kang IJ, Moroishi J, Shimasaki Y, et al. Pharmaceuticals and personal care products toxicity to Japanese medaka fish (Oryzias latipes). J Fac Agric Kyushu Univ. 2009; 54(2): 407-411. https://doi.org/10.5109/16123
  80. Stepanova S, Praskova E, Chromcova L, Plhalova L, Prokes M, Blahova J, et al. The effects of diclofenac on early life stages of common carp (Cyprinus carpio). Environ Toxicol Pharmacol. 2013; 35(3): 454-460. https://doi.org/10.1016/j.etap.2012.09.011
  81. Memmert U, Peither A, Burri R, Weber K, Schmidt T, Sumpter JP, et al. Diclofenac: new data on chronic toxicity and bioconcentration in fish. Environ Toxicol Chem. 2013; 32: 442-452. https://doi.org/10.1002/etc.2085
  82. Berninger JP, Du B, Connors KA, Eytcheson SA, Kolkmeier MA, Prosser KN, et al. Effects of the antihistamine diphenhydramine on selected aquatic organisms. Environ Toxicol Chem. 2011; 30: 2065-2072. https://doi.org/10.1002/etc.590
  83. Meinertz JR, Schreier TM, Bernardy JA, Franz JL. Chronic toxicity of diphenhydramine hydrochloride and erythromycin thiocyanate to daphnia, Daphnia magna, in a continuous exposure test system. Bull Environ Contam Toxicol. 2010; 85(5): 447-451. https://doi.org/10.1007/s00128-010-0117-7
  84. Kristofco LA, Du B, Chambliss CK, Berninger JP, Brooks BW. Comparative pharmacology and toxicology of pharmaceuticals in the environment: diphenhydramine protection of diazinon toxicity in Danio rerio but not Daphnia magna. AAPS J. 2015; 17: 175-183. https://doi.org/10.1208/s12248-014-9677-5
  85. Berrebaan I, Montassir L, Said B, Mustapha E, Bessi H. Evaluation of Ecotoxicity of Ibuprofen and Paracetamol on the Freshwater Green Microalgae "Pseudokirchneriella Subcapitata", Engin Technol J. 2017; 2(11): 303-309.
  86. Geiger E, Hornek-Gausterer R, Sacan MT. Single and mixture toxicity of pharmaceuticals and chlorophenols to freshwater algae Chlorella vulgaris. Ecotoxicol Environ Saf. 2016; 129: 189-198. https://doi.org/10.1016/j.ecoenv.2016.03.032
  87. Pomati F, Netting AG, Calamari D, Neilan BA. Effects of erythromycin, tetracycline and ibuprofen on the growth of Synechocystis sp. and Lemna minor. Aquat Toxicol. 2004; 67(4): 387-396. https://doi.org/10.1016/j.aquatox.2004.02.001
  88. Han S, Choi K, Kim J, Ji K, Kim S, Ahn B, et al. Endocrine disruption and consequences of chronic exposure to ibuprofen in Japanese medaka (Oryzias latipes) and freshwater cladocerans Daphnia magna and Moina macrocopa. Aquat Toxicol. 2010; 98: 256-264. https://doi.org/10.1016/j.aquatox.2010.02.013
  89. Pounds N, Maclean S, Webley M, Pascoe D, Hutchinson T. Acute and chronic effects of ibuprofen in the mollusc Planorbis carinatus (Gastropoda: Planorbidae). Ecotoxicol Environ Saf. 2008; 70(1): 47-52. https://doi.org/10.1016/j.ecoenv.2007.07.003
  90. Gonzalez-Perez BK, Sarma SSS, Nandini S. Effects of selected pharmaceuticals (ibuprofen and amoxicillin) on the demography of Brachionus calyciflorus and Brachionus havanaensis (Rotifera). Egyptian J Aquat Res. 2016; 42(3): 341-347. https://doi.org/10.1016/j.ejar.2016.09.003
  91. Saravanan M, Devi KU, Malarvizhi A, Ramesh M. Effects of Ibuprofen on hematological, biochemical and enzymological parameters of blood in an Indian major carp, Cirrhinus mrigala. Environ Toxicol Pharmacol. 2012; 34(1): 14-22. https://doi.org/10.1016/j.etap.2012.02.005
  92. Overturf MD, Overturf CL, Baxter D, Hala DN, Constantine L, Venables B, et al. Early life-stage toxicity of eight pharmaceuticals to the fathead minnow, Pimephales promelas. Arch Environ Contam Toxicol. 2012; 62: 455-464. https://doi.org/10.1007/s00244-011-9723-6
  93. Flippin JL, Huggett D, Foran CM, Changes in the timing of reproduction following chronic exposure to ibuprofen in Japanese medaka, Oryzias latipes. Aquat Toxicol. 2007; 81: 73-78. https://doi.org/10.1016/j.aquatox.2006.11.002
  94. National Institute of Environmental Research. Research on Risk Assessment of Pharmaceutical in the Environment for Preparing the Future Management Strategies. NIER-SP2013-146. Seoul National University. 2013.
  95. Jung Collard HR, Ji K, Lee S, Liu X, Kang S, Kho Y, et al. Toxicity and endocrine disruption in zebrafish (Danio rerio) and two freshwater invertebrates (Daphnia magna and Moina macrocopa) after chronic exposure to mefenamic acid. Ecotoxicol Environ Saf. 2013; 94: 80-86. https://doi.org/10.1016/j.ecoenv.2013.04.027
  96. Yang LH, Ying GG, Su HC, Stauber JL, Adams MS, Binet MT. Growth-inhibiting effects of 12 antibacterial agents and their mixtures on the freshwater microalga Pseudokirchneriella subcapitata. Environ Toxicol Chem. 2008; 27(5): 1201-1208. https://doi.org/10.1897/07-471.1
  97. Xiong Q, Hu LX, Liu YS, Wang TT, Ying GG. New insight into the toxic effects of chloramphenicol and roxithromycin to algae using FTIR spectroscopy. Aquat Toxicol. 2019; 207: 197-207. https://doi.org/10.1016/j.aquatox.2018.12.017
  98. Zhang P, Yan Z, Lu G, Ji, Y. Single and combined effects of microplastics and roxithromycin on Daphnia magna. Environ Sci Pollut Res. 2019; 26(17): 17010-17020. https://doi.org/10.1007/s11356-019-05031-2
  99. Posthuma L, van Gils J, Zijp MC, van de Meent D, de Zwart D. Species sensitivity distributions for use in environmental protection, assessment, and management of aquatic ecosystems for 12386 chemicals. Environ Toxicol Chem. 2018; 38(4): 905-917. https://doi.org/10.1002/etc.4373
  100. RIVM. Guidance Document on Deriving Environmental Risk Limits. (RIVM Report 601501 012). National Institute of Public Health an the Environment, Bilthoven, Netherlands. 2001.
  101. Australian and New Zealand Environment and Conservation Council (ANZECC). Australian and New Zealand Guidelines for Fresh and Marine Water Quality. I. 2000; The Guidelines, vol. 1: Department of the Environment, pp. 1-103.
  102. US Food and Drug Administration (US FDA). 21 CFR Part 25-National Environmental Policy Act: Proposed Revision of Policies and Procedures; Proposed Rule. 1996; Federal Register 61(65): pp. 14922-14942.
  103. European Medicines Agency (EMEA)/Commitee for Medicinal Products for Human Use (CHMP). Guidance on the Environmental Risk Assessment of Medicinal Products for Human Use. Doc. Ref. EMEA/CHMP/SWP/4447/00. 2006.
  104. European Commission. Development of the First Watch List under the Environmental Quality Standards Directive. Report EUR 27142 EN. 2015.
  105. Scientific Committee on Health and Environmental Risks. Opinion on Draft Environmental Quality Standards under the Water Framework Directive-diclofenac. 2011.