III. LA NOCION DE UTILIDAD PUBLICA E INTERES COMUN EN ROMA:
III.1. UTILIDAD PUBLICA E INTERES COMUN EN LA PROPIEDAD ROMANA
543
The exposure to the most common NSAIDs found in the aquatic ecosystems, namely acetylsalicylic 544
acid, diclofenac, ibuprofen, naproxen, paracetamol, as well as to their mixtures, might represent a 545
risk for non-target, freshwater invertebrates. Although data from standardized tests, in terms of 546
EC50 or LC50 from acute or chronic toxicity tests, are comparable, it is not simple to draw a scale of 547
toxicity of NSAIDs because of some contrasting results among studies testing the toxicity of the 548
same drug towards the same model species or the lack of information for specific drugs. However, 549
according to EC50 values obtained on D. magna, which was the model species on which all the 550
NSAIDs were tested, DCF and IBU can be identified as the more toxic drugs, followed by PCM, 551
NPX and ASA. Simultaneously, although different responses occurred within phylogenetic-related 552
species, cladocerans can be indicated as the more sensitive organisms to NSAID exposure.
553
Although acute toxicity of NSAIDs occurs only at high, unrealistic concentrations, much higher 554
than those currently measured in freshwaters worldwide, sub-lethal effects due to long-term 555
exposures cannot be neglected. A growing number of studies performed on diverse invertebrate 556
species belonging to different levels of the ecological hierarchy showed that the exposure to low, 557
environmentally relevant concentrations of NSAIDs, both independently and in mixture, can cause 558
a variety of adverse effects at molecular, biochemical and cellular level, while effects at individual 559
level (e.g., growth, survival, reproduction) seem to be less probable, although they cannot be 560
underestimated considering that are used for risk assessment. For instance, concentrations of PCM 561
similar to those measured in environments worldwide induced ecologically relevant effects on two 562
species belonging to Cnidaria and Mollusca taxa (i.e., Hydra vulgaris and Corbicula fluminea, 563
respectively). Despite these alarming findings, it is important to bearing in mind that chronic 564
toxicity data, in term of sub-lethal effects at individual or sub-individual levels, come from two 565
different approaches, the first one performed on whole animals exposed in vivo and the second one 566
25 on single cells isolated or collected by animals and then exposed in vitro to NSAIDs. These 567
approaches result in different outcomes, which can lead to different considerations concerning the 568
toxicity of NSAIDs towards aquatic organisms. For instance, EC50 or IC50 from whole animal 569
experiments support the conclusion that NSAIDs in the environment are at much lower 570
concentrations than those causing toxicity, while biochemical or molecular investigations from both 571
in vitro and in vivo studies pointed out a potential hazard of these drugs also at environmentally 572
relevant concentrations. However, some caveats need to be considered, mainly related to the 573
uncertainty of the real amount of xenobiotic reaching the cells, the realism of exposures and the 574
lack of cells mechanisms owned by cells to mitigate the effects of xenobiotics, as instead the whole 575
organism have, that might result in a potential overestimation of the effect. In addition, although 576
NSAIDs-induced molecular or biochemical effects were induced in whole body or tissues/organs 577
isolated after in vivo exposures, they are early, and often specific, responses that the organism 578
activate as a consequence of an exposure to these drugs. To date, there is a dearth of information 579
concerning the effects at cellular and tissue levels induced by NSAIDs in freshwater species, 580
including invertebrates, as well as on the propagation of the effects from the lowest levels of the 581
biological organization to the highest ones. Moreover, sub-lethal effects highlighted by short- and 582
mid-term exposures might be also more worrisome considering that in natural ecosystems, 583
invertebrates are exposed to measurable NSAID concentrations for their whole lifespan. For all the 584
reasons mentioned above, the assessment of the risk of NSAIDs towards aquatic species comparing 585
acute or sub-lethal effects only could not be accurate. Thus, an approach using measured 586
environmental concentrations (MECs) combined with predicted no effect concentrations (PNECs) 587
was proposed by European commission (2003) to screen compounds with potential environmental 588
risks and it was recently refined to properly identify the priority pollutants that should be regularly 589
monitored in surface waters (Zhou et al., 2019). According to this approach, DCF and IBU were 590
prioritized as high risk pharmaceuticals, PCM as moderate risk one (Zhou et al., 2019; Palma et al., 591
26 2020), while ASA as a negligible risk compound (Gómez-Canela et al., 2019). To date, the 592
environmental risk of NPX and NSAID mixture was not assessed. This approach is crucial 593
considering that the increasing production and use of NSAIDs worldwide might result in a notable 594
increase in their environmental levels occurring in aquatic ecosystems, with a consequent 595
enhancement of the risk related to the exposure to these pharmaceuticals towards non-target, 596
freshwater invertebrates. For these reasons, further studies should be needed to enlarge the 597
knowledge on NSAID toxicity towards aquatic organisms, not only invertebrates but also 598
vertebrates, considering long-term exposures and the use of alternative and innovative assays to 599
shed light on the mechanism(s) of action of these pharmaceutical compounds. Moreover, as the 600
most of the studies on NSAID toxicity were performed on native, parental compounds, exploring 601
the toxicity of NSAID metabolites, which might results also more toxic than the parental ones (e.g., 602
Marques et al., 2004b; Isidori et al., 2005), should contribute to understand the hazard of these 603
drugs. Lastly, considering that NSAIDs occur in aquatic ecosystems in complex ‘cocktails’ and few 604
previous studies demonstrated that NSAID mixtures induced higher effects than the single 605
compounds, further studies aimed at investigating the toxicity of binary or complex NSAID 606
mixtures should be a priority to shed light on adverse effects, mechanism(s) of action and ecological 607
risk of these therapeutics towards freshwater communities.
608
609
610
611
612
613
27
7. References
614
Acuña, V., Ginebreda, A., Mor, J. R., Petrovic, M., Sabater, S., Sumpter, J., Barceló, D., 2015.
615
Balancing the health benefits and environmental risks of pharmaceuticals: Diclofenac as an 616
example. Environment international 85, 327-333.
617
Aguirre-Martínez, G.V., DelValls, A.T., Martín-Díaz, M.L., 2015. Yes, caffeine, ibuprofen, 618
carbamazepine, novobiocin and tamoxifen have an effect on Corbicula fluminea (Müller, 1774).
619
Ecotoxicology and Environmental Safety,120, 142-154.
620
Al Aukidy, M., Verlicchi, P., Voulvoulis, N., 2014. A framework for the assessment of the 621
environmental risk posed by pharmaceuticals originating from hospital effluents. Science of the 622
Total Environment 493, 54-64.
623
Ashton, D., Hilton, M., Thomas, K.V., 2004. Investigating the environmental transport of human 624
pharmaceuticals to streams in the United Kingdom. Science of the Total Environment 333(1-3), 625
167-184.
626
aus der Beek, T., Weber, F. A., Bergmann, A., Hickmann, S., Ebert, I., Hein, A., Küster, A., 2016.
627
Pharmaceuticals in the environment—Global occurrences and perspectives. Environmental 628
Toxicology and Chemistry 35(4), 823-835.
629
Bagnis, S., Fitzsimons, M. F., Snape, J., Tappin, A., Comber, S., 2018. Processes of distribution of 630
pharmaceuticals in surface freshwaters: implications for risk assessment. Environmental 631
Chemistry Letters 16(4), 1193-1216.
632
Berlioz-Barbier, A., Buleté, A., Faburé, J., Garric, J., Cren-Olivé, C., Vulliet, E., 2014. Multi-633
residue analysis of emerging pollutants in benthic invertebrates by modified micro-quick-easy-634
28 cheap-efficient-rugged-safe extraction and nanoliquid chromatography–nanospray–tandem mass 635
spectrometry analysis. Journal of Chromatography A 1367, 16-32.
636
Blanco, G., Martínez, C., García-Martín, E. Agúndez, J.A., 2005. Cytochrome P450 gene 637
polymorphisms and variability in response to NSAIDs. Clinical Research and Regulatory Affairs 638
22(2), 57-81.
639
Boisseaux, P., Noury, P., Thomas, H., Garric, J., 2017. Immune responses in the aquatic gastropod 640
Lymnaea stagnalis under short-term exposure to pharmaceuticals of concern for immune 641
systems: Diclofenac, cyclophosphamide and cyclosporine A. Ecotoxicology and Environmental 642
Safety 139, 358-366.
643
Boelsterli, U.A., 2007. Mechanistic toxicology: the molecular basis of how chemicals disrupt 644
biological targets. CRC press.
645
Bound, J.P., Voulvoulis, N., 2006. Predicted and measured concentrations for selected 646
pharmaceuticals in UK rivers: implications for risk assessment. Water Research 40(15), 2885-647
2892.
648
Boxall, A.B., Rudd, M.A., Brooks, B.W., Caldwell, D.J., Choi, K., Hickmann, S., Innes, E., 649
Ostapyk, K., Staveley, J.P., Verslycke, T. and Ankley, G.T., 2012. Pharmaceuticals and personal 650
care products in the environment: what are the big questions?. Environmental Health 651
Perspectives 120(9), pp.1221-1229.
652
Brandão, F.P., Pereira, J.L., Gonçalves, F. and Nunes, B., 2014. The impact of paracetamol on 653
selected biomarkers of the mollusc species Corbicula fluminea. Environmental Toxicology 654
29(1), 74-83.
655
29 Brun, G.L., Bernier, M., Losier, R., Doe, K., Jackman, P., Lee, H.B., 2006. Pharmaceutically active 656
compounds in Atlantic Canadian sewage treatment plant effluents and receiving waters, and 657
potential for environmental effects as measured by acute and chronic aquatic toxicity.
658
Environmental Toxicology and Chemistry: An International Journal 25(8), 2163-2176.
659
Buser, H.R., Poiger, T. and Müller, M.D., 1999. Occurrence and environmental behavior of the 660
chiral pharmaceutical drug ibuprofen in surface waters and in wastewater. Environmental 661
Science & Technology 33(15), 2529-2535.
662
Cleuvers, M., 2004. Mixture toxicity of the anti-inflammatory drugs diclofenac, ibuprofen, 663
naproxen, and acetylsalicylic acid. Ecotoxicology and Environmental Safety 59(3), 309-315.
664
Collen, B., Böhm, M., Kemp, R., Baillie, J.E., 2012. Spineless: status and trends of the world's 665
invertebrates. Zoological Society of London.
666
Contardo-Jara, V., Lorenz, C., Pflugmacher, S., Nützmann, G., Kloas, W., Wiegand, C., 2011.
667
Exposure to human pharmaceuticals Carbamazepine, Ibuprofen and Bezafibrate causes 668
molecular effects in Dreissena polymorpha. Aquatic Toxicology 105(3-4), 428-437.
669
de Oliveira, L.L.D., Antunes, S.C., Gonçalves, F., Rocha, O. and Nunes, B., 2016. Acute and 670
chronic ecotoxicological effects of four pharmaceuticals drugs on cladoceran Daphnia magna.
671
Drug and Chemical Toxicology 39(1), 13-21.
672
Du, J., Mei, C.F., Ying, G.G., Xu, M.Y., 2016. Toxicity thresholds for diclofenac, acetaminophen 673
and ibuprofen in the water flea Daphnia magna. Bulletin of Environmental Contamination and 674
Toxicology 97(1), 84-90.
675
30 Du, B., Haddad, S. P., Scott, W. C., Chambliss, C. K., Brooks, B. W., 2015. Pharmaceutical 676
bioaccumulation by periphyton and snails in an effluent-dependent stream during an extreme 677
drought. Chemosphere 119, 927-934.
678
Fekadu, S., Alemayehu, E., Dewil, R., Van der Bruggen, B., 2019. Pharmaceuticals in freshwater 679
aquatic environments: A comparison of the African and European challenge. Science of the 680
Total Environment 654, 324-337.
681
Fent, K., Weston, A.A., Caminada, D., 2006. Ecotoxicology of human pharmaceuticals. Aquatic 682
Toxicology 76(2), 122-159.
683
Gagné, F., Blaise, C., Fournier, M., Hansen, P.D., 2006. Effects of selected pharmaceutical products 684
on phagocytic activity in Elliptio complanata mussels. Comparative Biochemistry and 685
Physiology Part C: Toxicology & Pharmacology 143(2), 179-186.
686
Gheorghe, S., Petre, J., Lucaciu, I., Stoica, C., Nita-Lazar, M., 2016. Risk screening of 687
pharmaceutical compounds in Romanian aquatic environment. Environmental Monitoring and 688
Assessment 188(6), 379.
689
Gierse, J.K., Hauser, S.D., Creely, D.P., Koboldt, C., Rangwala, S.H., Isakson, P.C., Seibert, K., 690
1995. Expression and selective inhibition of the constitutive and inducible forms of human 691
cyclo-oxygenase. Biochemical Journal 305(2), 479-484.
692
Gómez, M.J., Bueno, M.M., Lacorte, S., Fernández-Alba, A.R. and Agüera, A., 2007. Pilot survey 693
monitoring pharmaceuticals and related compounds in a sewage treatment plant located on the 694
Mediterranean coast. Chemosphere 66(6), 993-1002.
695
31 Gómez-Canela, C., Pueyo, V., Barata, C., Lacorte, S., Marcé, R.M., 2019. Development of 696
predicted environmental concentrations to prioritize the occurrence of pharmaceuticals in rivers 697
from Catalonia. Science of the Total Environment 666, 57-67.
698
Gómez-Oliván, L. M., Galar-Martínez, M., García-Medina, S., Valdés-Alanís, A., Islas-Flores, H., 699
Neri-Cruz, N., 2014. Genotoxic response and oxidative stress induced by diclofenac, ibuprofen 700
and naproxen in Daphnia magna. Drug and Chemical Toxicology 37(4), 391-399.
701
Gottardi, M., Kretschmann, A., Cedergreen, N., 2016. Measuring cytochrome P450 activity in 702
aquatic invertebrates: a critical evaluation of in vitro and in vivo methods. Ecotoxicology 25, 703
419–430.
704
Gros, M., Petrović, M., Barceló, D., 2006. Multi-residue analytical methods using LC-tandem MS 705
for the determination of pharmaceuticals in environmental and wastewater samples: a review.
706
Analytical and Bioanalytical Chemistry 386(4), 941-952.
707
Haap, T., Triebskorn, R., Köhler, H.R., 2008. Acute effects of diclofenac and DMSO to Daphnia 708
magna: immobilisation and hsp70-induction. Chemosphere 73(3), 353-359.
709
Han, G.H., Hur, H.G. and Kim, S.D., 2006. Ecotoxicological risk of pharmaceuticals from 710
wastewater treatment plants in Korea: occurrence and toxicity to Daphnia magna.
711
Environmental Toxicology and Chemistry: An International Journal 25(1), 265-271.
712
Hayashi, Y., Heckmann, L.H., Callaghan, A., Sibly, R.M., 2008. Reproduction recovery of the 713
crustacean Daphnia magna after chronic exposure to ibuprofen. Ecotoxicology 17(4), 246-251.
714
Heckmann, L.H., Callaghan, A., Hooper, H.L., Connon, R., Hutchinson, T.H., Maund, S.J., Sibly, 715
R.M., 2007. Chronic toxicity of ibuprofen to Daphnia magna: effects on life history traits and 716
population dynamics. Toxicology letters 172(3), 137-145.
717
32 Heckmann, L.-H., Connon, R., Hooper, H.L., Maund, S.J., Hutchinson, T.H., Sibly, R.M., 718
Callaghan, A., 2005. Molecular and population stress responses of Daphnia magna exposed to 719
ibuprofen. In: SETAC Europe 15th Annual Meeting, Lille, France, 22–26 May 2005, 308–309.
720
Huerta, B., Jakimska, A., Llorca, M., Ruhí, A., Margoutidis, G., Acuña, V., et al., 2015.
721
Development of an extraction and purification method for the determination of multi-class 722
pharmaceuticals and endocrine disruptors in freshwater invertebrates. Talanta 132, 373-381.
723
Huq, F., 2006. Molecular modeling analysis of the metabolism of naproxen. Journal of 724
Pharmacology and Toxicology 1(4), 346-353.
725
Isidori, M., Lavorgna, M., Nardelli, A., Parrella, A., Previtera, L., Rubino, M., 2005. Ecotoxicity of 726
naproxen and its phototransformation products. Science of the Total Environment 348(1-3), 93-727
101.
728
Katzung, B. G., and Trevor, A. J. (Eds.), 2015. Basic & clinical pharmacology (pp. 619-20). New 729
York: McGraw-Hill Education.
730
Kolpin, D.W., Furlong, E.T., Meyer, M.T., Thurman, E.M., Zaugg, S.D., Barber, L.B., Buxton, 731
H.T., 2002. Pharmaceuticals, hormones, and other organic wastewater contaminants in US 732
streams, 1999− 2000: A national reconnaissance. Environmental Science & Technology 36(6), 733
1202-1211.
734
Komori, K., Suzuki, Y., Minamiyama, M., Harada, A., 2013. Occurrence of selected 735
pharmaceuticals in river water in Japan and assessment of their environmental risk.
736
Environmental Monitoring and Assessment 185(6), 4529-4536.
737
33 Kwak, K., Ji, K., Kho, Y., Kim, P., Lee, J., Ryu, J., Choi, K., 2018. Chronic toxicity and endocrine 738
disruption of naproxen in freshwater waterfleas and fish, and steroidogenic alteration using 739
H295R cell assay. Chemosphere 204, 156-162.
740
Liu, Y., Wang, L., Pan, B., Wang, C., Bao, S., Nie, X., 2017. Toxic effects of diclofenac on life 741
history parameters and the expression of detoxification-related genes in Daphnia magna.
742
Aquatic Toxicology 183, 104-113.
743
Lonappan, L., Brar, S. K., Das, R. K., Verma, M., Surampalli, R. Y., 2016. Diclofenac and its 744
transformation products: environmental occurrence and toxicity-a review. Environment 745
International 96, 127-138.
746
Macadam, C. R. and Stockan, J. A., 2015. More than just fish food: ecosystem services provided by 747
freshwater insects. Ecological Entomology 40, 113-123.
748
Marques, C. R., Abrantes, N., Gonçalves, F., 2004a. Life‐history traits of standard and 749
autochthonous cladocerans: I. Acute and chronic effects of acetylsalicylic acid. Environmental 750
Toxicology: An International Journal 19(5), 518-526.
751
Marques, C. R., Abrantes, N., Gonçalves, F., 2004b. Life‐history traits of standard and 752
autochthonous cladocerans: II. Acute and chronic effects of acetylsalicylic acid metabolites.
753
Environmental Toxicology: An International Journal 19(5), 527-540.
754
Metcalfe, C., Miao, X.S., Hua, W., Letcher, R., Servos, M., 2004. Pharmaceuticals in the Canadian 755
environment. In Pharmaceuticals in the Environment (pp. 67-90). Springer, Berlin, Heidelberg.
756
Misra, R., Pandey, H., Chandra, M., Agarwal, P.K., Pandeya, S.N., 1990. Effects of commonly used 757
non steroidal anti-inflammatory drugs on gastric mucosa. A clinical, endoscopic and 758
histopathological study. The Journal of the Association of Physicians of India 38(9), 636-638.
759
34 Nieto, E., Corada-Fernández, C., Hampel, M., Lara-Martín, P.A., Sánchez-Argüello, P., Blasco, J., 760
2017. Effects of exposure to pharmaceuticals (diclofenac and carbamazepine) spiked sediments 761
in the midge, Chironomus riparius (Diptera, Chironomidae). Science of the Total Environment 762
609, 715-723.
763
Nunes, B., Antunes, S.C., Santos, J., Martins, L., Castro, B.B., 2014. Toxic potential of paracetamol 764
to freshwater organisms: a headache to environmental regulators? Ecotoxicology and 765
Environmental Safety 107, 178-185.
766
Ohoro, C. R., Adeniji, A. O., Okoh, A. I., Okoh, O. O., 2019. Distribution and Chemical Analysis 767
of Pharmaceuticals and Personal Care Products (PPCPs) in the Environmental Systems: A 768
Review. International Journal of Environmental Research and Public Health 16(17), 3026.
769
Palma, P., Fialho, S., Lima, A., Novais, M.H., Costa, M.J., Montemurro, N., Pérez, S., de Alda, 770
M.L., 2020. Pharmaceuticals in a Mediterranean Basin: The influence of temporal and 771
hydrological patterns in environmental risk assessment. Science of The Total Environment 709, 772
136205.
773
Parolini, M., Binelli, A., Provini, A., 2011b. Assessment of the potential cyto–genotoxicity of the 774
nonsteroidal anti-inflammatory drug (NSAID) diclofenac on the zebra mussel (Dreissena 775
polymorpha). Water, Air, & Soil Pollution 217(1-4), 589-601.
776
Parolini, M., Binelli, A., Provini, A., 2011c. Chronic effects induced by ibuprofen on the freshwater 777
bivalve Dreissena polymorpha. Ecotoxicology and environmental safety 74(6), 1586-1594.
778
Parolini, M., Binelli, A., Cogni, D., Provini, A., 2010. Multi-biomarker approach for the evaluation 779
of the cyto-genotoxicity of paracetamol on the zebra mussel (Dreissena polymorpha).
780
Chemosphere 79(5), 489-498.
781
35 Parolini, M., Pedriali, A., Binelli, A., 2013. Application of a biomarker response index for ranking 782
the toxicity of five pharmaceutical and personal care products (PPCPs) to the bivalve Dreissena 783
polymorpha. Archives of environmental contamination and toxicology 64(3), 439-447.
784
Parolini, M., Binelli, A., Cogni, D., Riva, C. and Provini, A., 2009. An in vitro biomarker approach 785
for the evaluation of the ecotoxicity of non-steroidal anti-inflammatory drugs (NSAIDs).
786
Toxicology in vitro 23(5), 935-942.
787
Parolini, M., Quinn, B., Binelli, A. and Provini, A., 2011a. Cytotoxicity assessment of four 788
pharmaceutical compounds on the zebra mussel (Dreissena polymorpha) haemocytes, gill and 789
digestive gland primary cell cultures. Chemosphere, 84(1), pp.91-100.
790
Pascoe, D., Karntanut, W., Müller, C.T., 2003. Do pharmaceuticals affect freshwater invertebrates?
791
A study with the cnidarian Hydra vulgaris. Chemosphere 51(6), 521-528.
792
Pingram, M. A., Collier, K. J., Hamilton, D. P., Hicks, B. J., David, B. O., 2014. Spatial and 793
temporal patterns of carbon flow in a temperate, large river food web. Hydrobiologia 729(1), 794
107-131.
795
Pounds, N., Maclean, S., Webley, M., Pascoe, D. and Hutchinson, T., 2008. Acute and chronic 796
effects of ibuprofen in the mollusc Planorbis carinatus (Gastropoda: Planorbidae).
797
Ecotoxicology and environmental Safety, 70(1), pp.47-52.
798
Pritchard, J.B., 1993. Aquatic toxicology: past, present, and prospects. Environmental health 799
perspectives 100, 249-257.
800
Puckowski, A., Mioduszewska, K., Łukaszewicz, P., Borecka, M., Caban, M., Maszkowska, J., 801
Stepnowski, P., 2016. Bioaccumulation and analytics of pharmaceutical residues in the 802
environment: A review. Journal of Pharmaceutical and Biomedical Analysis 127, 232-255.
803
36 Quinn, B., Gagné, F., Blaise, C., 2009. Evaluation of the acute, chronic and teratogenic effects of a 804
mixture of eleven pharmaceuticals on the cnidarian, Hydra attenuata. Science of the Total 805
Environment 407(3), 1072-1079.
806
Quinn, B., Gagné, F., Blaise, C., 2008. The effects of pharmaceuticals on the regeneration of the 807
cnidarian, Hydra attenuata. Science of the Total Environment 402(1), 62-69.
808
Rewitz, K. F., Styrishave, B., Løbner-Olesen, A., Andersen, O., 2006. Marine invertebrate 809
cytochrome P450: emerging insights from vertebrate and insect analogies. Comparative 810
Biochemistry and Physiology Part C: Toxicology & Pharmacology 143(4), 363-381.
811
Roberts, P.H. and Thomas, K.V., 2006. The occurrence of selected pharmaceuticals in wastewater 812
effluent and surface waters of the lower Tyne catchment. Science of the Total Environment, 813
356(1-3), 143-153.
814
Santos, L.H., Araújo, A.N., Fachini, A., Pena, A., Delerue-Matos, C., Montenegro, M.C.B.S.M., 815
2010. Ecotoxicological aspects related to the presence of pharmaceuticals in the aquatic 816
environment. Journal of Hazardous Materials 175(1-3), 45-95.
817
Sarma, S.S.S., González-Pérez, B.K., Moreno-Gutiérrez, R.M., Nandini, S., 2014. Effect of 818
paracetamol and diclofenac on population growth of Plationus patulus and Moina macrocopa.
819
Journal of Environmental Biology 35(1), 119.
820
Schulman, L. J., Sargent, E. V., Naumann, B. D., Faria, E. C., Dolan, D. G., Wargo, J. P., 2002. A 821
human health risk assessment of pharmaceuticals in the aquatic environment. Human and 822
Ecological Risk Assessment 8(4), 657-680.
823
Snyder, M.J., 2000. Cytochrome P450 enzymes in aquatic invertebrates: recent advances and future 824
directions. Aquatic Toxicology 48, 529–547.
825
37 Stegeman, J.J., Livingstone, D.R., 1998. Forms and functions of cytochrome P450. Comparative 826
Biochemistry and Physiology C: Pharmacology Toxicology and Endocrinology 121, 1–3.
827
Strayer, D. L., Eviner, V.T., Jeschke, J. M., Pace, M.L., 2006. Understanding the long-term effects 828
of species invasions. Trends in Ecology & Evolution 21(11), 645-651.
829
Ternes, T.A., 1998. Occurrence of drugs in German sewage treatment plants and rivers. Water 830
Research 32(11), 3245-3260.
831
Todd, P.A. and Sorkin, E.M., 1988. Diclofenac sodium. Drugs, 35(3),244-285.
832
Wang, L., Peng, Y., Nie, X., Pan, B., Ku, P., Bao, S., 2016. Gene response of CYP360A, CYP314, 833
and GST and whole-organism changes in Daphnia magna exposed to ibuprofen. Comparative 834
Biochemistry and Physiology Part C: Toxicology & Pharmacology 179, 49-56.
835
Wiegand, T.J. and Vernetti, C.M. Nonsteroidal anti-inflammatory drug (NSAID) toxicity.
836
https://emedicine.medscape.com/article/816117-overview. Updated December 20, 2017.
837
Accessed November 14th 2019.
838
Yamindago, A., Lee, N., Woo, S., Yum, S., 2019. Transcriptomic profiling of Hydra magnipapillata 839
after exposure to naproxen. Environmental Toxicology and Pharmacology, 71, 103215.
840
Zanger, U.M., Turpeinen, M., Klein, K., Schwab, M., 2008. Functional pharmacogenetics/genomics 841
of human cytochromes P450 involved in drug biotransformation. Analytical and bioanalytical 842
chemistry 392(6), 1093-1108.
843
Zhang, S., Hagstrom, D., Hayes, P., Graham, A., Collins, E.M.S., 2019. Multi-behavioral endpoint 844
testing of an 87-chemical compound library in freshwater planarians. Toxicological Sciences 845
167(1), 26-44.
846
38 Zhao, J. L., Ying, G. G., Liu, Y. S., Chen, F., Yang, J. F., Wang, L., et al., 2010. Occurrence and a 847
screening‐level risk assessment of human pharmaceuticals in the Pearl River system, South 848
China. Environmental Toxicology and Chemistry 29(6), 1377-1384.
849
Zhou, S., Di Paolo, C., Wu, X., Shao, Y., Seiler, T.-B., Hollert, H., 2019. Optimization of 850
screening-level risk assessment and priority selection of emerging pollutants – the case of 851
pharmaceuticals in European surface waters. Environment International 128, 1–10.
852
853
Author contribution
: Marco Parolini, conceptualization and writing of the manuscript.854
Conflict of interest
: the author declares to have no conflict of interest.855
Funding
: no funding was received for this paper.856
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