Tenofovir disoproxil fumarate is a prodrug, i.e. inative substance converted in vivo , after absorption to the active form deesterified tenofovir, which acts as an inhibitor of viral reverse transcriptase. To better understand the toxic effects of these drugs in the environment, three organisms were tested, the effective concentration (EC 50 ) and inhibitory concentration (IC 50 ) of tenofovir disoproxil that resulted in 50% growth inhibition of Microcystis novacekii , 50% immobilization of Artemia salina , and 50% loss of bioluminescence of Aliivibrio fischeri were evaluated. The EC 50 value after 96 h of treatment for the cyanobacterium was 161.01 (156.81 - 165.21) mg · L -1 ; the IC50 value for A. salina after 24 h of treatment was 111.82 (103.18 - 120.45) mg · L -1 ; and the IC 50 at 15 min for A. fischeri was 14.83 (13.87 - 15.79) mg · L -1 . The test organism most sensitive to the drug was A. fischeri , indicating the importance of using representative models at different trophic levels to assess the potential risk of drugs for environmental toxicity. These results highlight the possible effect of tenofovir disoproxil on decomposer organisms, which may contribute to the environmental persistence of this drug.
López-Doval, J.C., Montagner, C.C., Alburquerque, A.F., Moschini-Carlos, V., Umbuzeiro, G. and Pompêo, M. (2017) Nutrients, Emerging Pollutants and Pesticides in a Tropical Urban Reservoir: Spatial Distributions and Risk Assessment. Science of The Total Environment, 575, 1307-1324. https://doi.org/10.1016/j.scitotenv.2016.09.210
Schaider, L.A., Rudel, R.A., Ackerman, J.M., Dunagan, S.C. and Brody, J.G. (2014) Pharmaceuticals, Perfluorosurfactants, and Other Organic Wastewater Compounds in Public Drinking Water Wells in a Shallow Sand and Gravel Aquifer. Science of The Total Environment, 468-469, 384-393. https://doi.org/10.1016/j.scitotenv.2013.08.067
Rimayi, C., Odusanya, D., Weiss, J.M., Boer, J. and Chimuka, L. (2018) Contaminants of Emerging Concern in the Hartbeespoort Dam Catchment and the Mngeni River Estuary 2016 Pollution Incident, South Africa. Science of The Total Environment, 627, 1008-1017. https://doi.org/10.1016/j.scitotenv.2018.01.263
Godoy, A.A., Kummrow, F. and Pamplin, P.A. (2015) Occurrence, Ecotoxicological Effects and Risk Assessment of Antihypertensive Pharmaceutical Residues in the Aquatic Environment—A Review. Chemosphere, 138, 281-291. https://doi.org/10.1016/j.chemosphere.2015.06.024
Agunbiade, F.O. and Moodley, B. (2016) Occurrence and Distribution Pattern of Acidic Pharmaceuticals in Surface Water, Wastewater, and Sediment of the Msunduzi River, Kwazulu-Natal, South Africa. Environmental Toxicology and Chemistry, 35, 36-46. https://doi.org/10.1002/etc.3144
K'oreje, K.O., Vergeynst, L., Ombaka, D., De Wispelaere, P., Okoth, M., Van Langenhove, H. and Demeestere, K. (2016) Occurrence Patterns of Pharmaceutical Residues in Wastewater, Surface Water and Groundwater of Nairobi and Kisumu City, Kenya. Chemosphere, 149, 238-244. https://doi.org/10.1016/j.chemosphere.2016.01.095
Kearney, B.P., Flaherty, J.F. and Shah, J. (2004) Tenofovir Disoproxil Fumarate: Clinical Pharmacology and Pharmacokinetics. Clinical Pharmacokinetics, 43, 595-612. https://doi.org/10.2165/00003088-200443090-00003
Kim, Y.K., Choi, M.J., Oh, T.Y., Yu, K.-S. and Lee, S. (2017) A Comparative Pharmacokinetic and Tolerability Analysis of the Novel Orotic Acid Salt form of Tenofovir Disoproxil and the Fumaric Acid Salt form in Healthy Subjects. Drug Design, Development and Therapy, 11, 3171-3177. https://doi.org/10.2147/DDDT.S149125
Al-Rajab, A.J., Sabourin, L., Chapman, R., Lapen, D.R. and Topp, E. (2010) Fate of the Antiretroviral Drug Tenofovir in Agricultural Soil. Science of the Total Environment, 408, 5559-5564. https://doi.org/10.1016/j.scitotenv.2010.07.074
Ncube, S., Madikizel, L.M., Chimuka, L. and Nindi, M.M. (2018) Environmental Fate and Ecotoxicological Effects of Antiretrovirals: A Current Global Status and Future Perspectives. Water Research, 145, 231-247. https://doi.org/10.1016/j.watres.2018.08.017
Prasse, C., Schlüsener, M.P., Schulz, R. and Ternes, T.A. (2010) Antiviral Drugs in Wastewater and Surface Waters: A New Pharmaceutical Class of Environmental Relevance? Environmental Science & Technology, 44, 1728-1735. https://doi.org/10.1021/es903216p
Jain, S., Kumar, P. and Vas, R.K. (2013) Occurrence and Removal of Antiviral Drugs in Environment: A Review. Water, Air, & Soil Pollution, 224, 1410-1413. https://doi.org/10.1007/s11270-012-1410-3
Wood, T.P., Duvenage, C.S.J. and Rohwer, E. (2015) The Occurrence of Anti-Retroviral Compounds Used for HIV Treatment in South African Surface Water. Environmental Pollution, 199, 235-243. https://doi.org/10.1016/j.envpol.2015.01.030
Taylor, D. and Senac, T. (2014) Human Pharmaceutical Products in the Environment-the “Problem” in Perspective. Chemosphere, 115, 95-99. https://doi.org/10.1016/j.chemosphere.2014.01.011
Ghosh, P., Thakur, I.S. and Kaushik, A. (2017) Bioassays for Toxicological Risk Assessment of Landfill Leachate: A Review. Ecotoxicology and Environmental Safety, 141, 259-270. https://doi.org/10.1016/j.ecoenv.2017.03.023
El-Bestawy, E.A., Ab Elsalam, A.L. and Mansy, A.E.R. (2007) Potential Use of Environmental Cyanobacterial Species in Bioremediation of Lindane-Contaminated Effluents. International Biodeterioration & Biodegradation, 59, 180-192. https://doi.org/10.1016/j.ibiod.2006.12.005
Bukaveckas, P.A., Franklin, R., Tassone, S., Trache, B. and Egerton, T. (2018) Cyanobacteria and Cyanotoxins at the River-Estuarine Transition. Harmful Algae, 76, 11-21. https://doi.org/10.1016/j.hal.2018.04.012
Bicudo, C. and Menezes, M. (2006) Gêneros de algas continentais do Brasil: chave para identificacao e descricoes. RiMa, Sao Carlos.
Ates, M., Demir, V., Arslan, Z., Camas, M. and Celik, F. (2016) Toxicity of Engineered Nickel Oxide and Cobalt Oxide Nanoparticles to Artemia salina in Seawater. Water, Air, & Soil Pollution, 227, 70-78. https://doi.org/10.1007/s11270-016-2771-9
Rajabi, S., Ramazani, A., Hamid, M. and Naji, T. (2015) Artemia salina as a Model Organism in Toxicity Assessment of Nanoparticles. DARU Journal of Pharmaceutical Sciences, 23, 20. https://doi.org/10.1186/s40199-015-0105-x
Abbas, M., Adil, M., Ehtisham-Ul-Haque, S., Munir, B., Yameen, M., Ghaffar, A., Shar, G.A., Asif Tahir, M. and Iqbal, M. (2018) Vibrio Fischeri Bioluminescence Inhibition Assay for Ecotoxicity Assessment: A Review. Science of the Total Environment, 626, 1295-1309. https://doi.org/10.1016/j.scitotenv.2018.01.066
Fioravante, I.A., Albergaria, B., Teodoro, T.S., Starling, S.M., Barbosa, F. and Augusti, R. (2012) Removal of 17α-Ethinylestradiol from a Sterile WC Medium by the Cyanobacteria Microcystis novacekii. Journal of Environmental Monitoring, 14, 2362-2366. https://doi.org/10.1039/c2em30320e
Gorham, P.R., McLachlan, J., Hammer, U.T. and Kim, W.K. (1964) Isolation and Culture of Toxic Strains of Anabaena Flos-Aquae (Lyngb.) de Bréb. SIL Proceedings, 15, 796-804. https://doi.org/10.1080/03680770.1962.11895606
Ma, J., Lin, F., Qin, W. and Wang, P. (2004) Differential Response of Four Cyanobacterial and Green Algal Species to Triazophos, Fentin Acetate, and Ethephon. Bulletin of Environmental Contamination and Toxicology, 73, 890-897. https://doi.org/10.1007/s00128-004-0510-1
OECD (2006) Freshwater Alga and Cyanobacteria, Growth Inhibition Test. Organization for Economic Cooperation and Development—Guidelines for Testing Chemicals.
Meyer, B.N., Ferrigni, N.R., Putnam, J.E., Jacobsen, L.B., Nichols, D.E. and Mclaughlin, J.L. (1982) Brine Shrimp: A Convenient General Bioassay for Active Plant Constituents. Planta Medica, 45, 31-34. https://doi.org/10.1055/s-2007-971236
Associacao Brasileira de Normas Técnicas (ABNT) (2012) NBR 15411-3: Ecotoxicologia Aquática-Determinacao do efeito inibitório de amostras de água sobre a emissao de luz de Vibrio fischeri (ensaio de bactéria luminescente). Rio de Janeiro, 23 p.
Oller, I., Gernjak, W., Maldonado, M.I., Pérez-Estrada, L.A., Sánchez-Pérez, J.A. and Malato, S. (2006) Solar Photocatalytic Degradation of Some Hazardous Water-Soluble Pesticides at Pilot-Plant Scale. Journal of Hazardous Materials, 138, 507-517. https://doi.org/10.1016/j.jhazmat.2006.05.075
Ritz, C., Baty, F., Streibig, J.C. and Gerhard, D. (2015) Dose-Response Analysis Using R. PLoS ONE, 10, e0146021. https://doi.org/10.1371/journal.pone.0146021
Yuan, L., Dahl, T.C. and Oliyai, R. (2001) Degradation Kinetics of Oxycarbonyloxymethyl Prodrugs of Phosphonates in Solution. Pharmaceutical Research, 18, 234-237. https://doi.org/10.1023/A:1011044804823
Brooks, K.M., Ibrahim, M.E., Castillo-Mancilla, J.R., MaWhinney, S., Alexander, K., Tilden, S., Kerr, B., Ellison, L., McHugh, C., Bushman, L.R., Kiser, J., Hosek, S., Huhn, G.D. and Anderson, P.L. (2019) Pharmacokinetics of Tenofovir Monoester and Association with Intracellular Tenofovir Diphosphate Following Single-Dose Tenofovir Disoproxil Fumarate. Journal of Antimicrobial Chemotherapy, 74, 2352-2359. https://doi.org/10.1093/jac/dkz187
GHS (2017) Globally Harmonized System of Classification and Labelling of Chemicals. United Nations, New York.
Panda, T. and Gowrishankar, B.S. (2005) Production and Applications of Esterases. Applied Microbiology and Biotechnology, 67, 160-169. https://doi.org/10.1007/s00253-004-1840-y
Russo, D., Siciliano, A., Guida, M., Andreozzi, R., Reis, N.M., Li, Puma, G.L. and Marotta, R. (2018) Removal of Antiretroviral Drugs Stavudine and Zidovudine in Water under UV254 and UV254/H2O2 Processes: Quantum Yields, Kinetics and Ecotoxicology Assessment. Journal of Hazardous Materials, 349, 195-204. https://doi.org/10.1016/j.jhazmat.2018.01.052
Gao, J.F., Zhang, Q., Wang, J.H., Wu, X.L., Wang, S.Y. and Peng, Y.Z. (2011) Contributions of Functional Groups and Extracellular Polymeric Substances on the Biosorption of Dyes by Aerobic Granules. Bioresource Technology, 102, 805-813. https://doi.org/10.1016/j.biortech.2010.08.119
Wang, Z., Hessler, C.M., Xue, Z. and Seo, Y. (2012) The Role of Extracellular Polymeric Substances on the Sorption of Natural Organic Matter. Water Research, 46, 1052-1060. https://doi.org/10.1016/j.watres.2011.11.077
Bai, L., Xu, H., Wang, C., Deng, J. and Jiang, H. (2016) Extracellular Polymeric Substances Facilitate the Biosorption of Phenanthrene on Cyanobacteria Microcystis aeruginosa. Chemosphere, 162, 172-180. https://doi.org/10.1016/j.chemosphere.2016.07.063
More, T.T., Yadav, J.S., Yan, S., Tyagi, R.D. and Surampalli, R.Y. (2014) Extracellular Polymeric Substances of Bacteria and Their Potential Environmental Applications. Journal of Environmental Management, 144, 1-25. https://doi.org/10.1016/j.jenvman.2014.05.010
Oliveira-Filho, E.C. and Paumgartten, F.J. (2000) Toxicity of Euphorbia milii Latex and Niclosa-midetosnails and Nontarget Aquatic Species. Ecotoxicology and Environmental Safety, 46, 342-350. https://doi.org/10.1006/eesa.2000.1924
Bhuvaneshwari, M., Thiagarajan, V., Nemade, P., Chandrasekaran, N. and Mukherjee, A. (2018) Toxicity and Trophic Transfer of P25 TiO2 NPs from Dunaliella salina to Artemia salina: Effect of Dietary and Waterborne Exposure. Environmental Research, 160, 39-46. https://doi.org/10.1016/j.envres.2017.09.022
Riisgard, H.U., Jeune, N., Pleissner, D., Zalacáin, D., Lüskow, F. and Wiersma, J.B. (2015) Adaptation of the Brine Shrimp Artemia salina (Branchiopoda: Anostraca) to Filter-Feeding: Effects of Body Size and Temperature on Filtration and Respiration Rates. Journal of Crustacean Biology, 35, 650-658. https://doi.org/10.1163/1937240X-00002362
Fisher, J.A., Baxter-Lowe, L.A. and Hokin, L.E., (1986) Regulation of Na, K-ATPase Biosynthesis in Developing Artemia salina. The Journal of Biological Chemistry, 261, 515-519.
Peterson, G.L., Ewing, R.D. and Conte, F.P. (1978) Membrane Differentiation and de Novo Synthesis of the (Na+ + K+)-Activated Adenosine Triphosphatase during Development of Artemia salina Nauplii. Developmental Biology, 67, 90-98. https://doi.org/10.1016/0012-1606(78)90302-0
Miralles, J., Sebastian, J. and Heredia, C.F. (1978) Independent Temporal Expression of Two N-Substituted Aminoacyl-tRNA Hydrolases during the Development of Artemia salina. Biochimica et Biophysica Acta, 518, 326-333. https://doi.org/10.1016/0005-2787(78)90189-2
Ahmed-Ouameur, A., Neault, J.F., Claveau, S. and Tajmir-Riahi, H.A. (2005) AZT binding to Na, K-ATPase. Cell Biochemistry and Biophysics, 42, 87-94. https://doi.org/10.1385/CBB:42:1:087
Havele, S. and Dhaneshwar, S.R. (2012) Development and Validation of a Stability-Indicating Lc Method for the Determination of Tenofovir Disoproxil Fumarate in Pharmaceutical Formulation. Songklanakarin Journal of Science and Technology, 34, 615-622. https://doi.org/10.1100/2012/894136
Shashi Kumar, B.M. and Rajkamal, B. (2017) A Simple, Selective, Rapid and Rugged Method Development and Validation of Tenofovir and Rilpivirine in Human Plasma Using Liquid Chromatography Coupled with Tandem Mass Spectrometry. European Journal of Pharmaceutical and Medical Research, 4, 605-613.
Agrahari, V., Putty, S., Mathes, C., Murowchick, J.B. and Youan, B.B.C. (2014) Evaluation of Degradation Kinetics and Physicochemical Stability of Tenofovir. Drug Testing and Analysis, 7, 207-213. https://doi.org/10.1002/dta.1656
Mennillo, E., Arukwe, A., Monni G., Meucci, V., Intorre, L. and Pretti, C. (2018) Ecotoxicological Properties of Ketoprofen and the S+-Enantiomer (Dexketoprofen): Bioassays in Freshwater Model Species and Biomarkers in Fish PLHC-1 Cell Line. Environmental Toxicology and Chemistry, 37, 201-212. https://doi.org/10.1002/etc.3943
Maselli, B.S., Luna, L.A., Palmeira, J.O., Tavares, K.P., Barbosa, S., Beijo, L.A., Umbuzeiro, G.A. and Kummrow, F. (2015) Ecotoxicity of Raw and Treated Effluents Generated by a Veterinary Pharmaceutical Company: A Comparison of the Sensitivities of Different Standardized Tests. Ecotoxicology, 24, 795-804. https://doi.org/10.1007/s10646-015-1425-9
Minagh, E., Hernan, R., O’Rourke, K., Lyng, F.M. and Davoren, M. (2009) Aquatic Ecotoxicity of the Selective Serotonin Reuptake Inhibitor Sertraline Hydrochloride in a Battery of Freshwater Test Species. Ecotoxicology and Environmental Safety, 72, 434-444. https://doi.org/10.1016/j.ecoenv.2008.05.002