background report on pharmaceutical …...2016/09/28 · 1 (88) background report on pharmaceutical...

Background report on pharmaceutical concentrations and effects in the Baltic Sea SWECO ENVIRONMENT AB, Contaminated Land and Chemicals Management, Malmö, Sweden

Pär Hallgren and Petra Wallberg 2015-12-11 Updated by Policy Area Hazards after an external review process of data by HELCOM Contracting Parties 2016-09-01

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Background report on pharmaceutical concentrations and effects in the Baltic Sea This report has been published with financial support from the Interreg Baltic Sea Region Programme 2014 to 2020 via the Swedish Environmental Protection Agency (SEPA) in its capacity as the coordinator of the Policy Area Hazards of the EU Strategy for the Baltic Sea Region. HELCOM Contracting Parties have contributed with data to this background report. The contents of this working paper do not necessarily reflect the views, policies or recommendations of SEPA or HELCOM. The report has not been reviewed by HELCOM Working Groups. The report was written by Pär Hallgren and Petra Wallberg (Sweco Environment AB). Graphic production by Christoph Kircher (Sweco Position AB) and Lisa Sjölund (Sweco Position AB). The project was managed by Jenny Hedman, the Swedish EPA. Data used in this report can be found at: http://maps.helcom.fi/website/mapservice/index.html. Select the following item in the map legend and activate the layers: Pressures and Human activities -> Land-based pollution -> Pharmaceuticals. This report should be cited as: Hallgren P and Wallberg P (2015). Background report on pharmaceutical concentrations and effects in the Baltic Sea. Policy Area Hazards of the EU Strategy for the Baltic Sea Region. Swedish Environmental Protection Agency, Stockholm, Sweden. The report is available at: www.swedishepa.se/hazards Stockholm, September 2016.

http://maps.helcom.fi/website/mapservice/index.html

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Background report on pharmaceutical concentrations and effects in the Baltic Sea SUMMARY This report presents a compilation of concentrations and effects of pharmaceuticals in the Baltic Sea marine environment based on data collected by all Baltic Sea states via working groups of the Helsinki Commission, HELCOM. It contributes to a joint initiative by the Policy Area Hazards of the EU Strategy for the Baltic Sea Region (EUSBSR) and the HELCOM to develop a regional approach on how to reduce pharmaceutical pollution to the Baltic Sea. Data collected between the years 2003 to 2014, from coastal, open sea and transitional areas, was received from Denmark, Estonia, Finland, Germany, Poland and Sweden.

• 4600 individual data posts were included in the complete data set • 167 different pharmaceuticals have been measured and 74 of these were found in at least one

of the sampling matrices (water, sediment, biota) • 51 different pharmaceuticals have been detected in water (of 148 measured) • 9 different pharmaceuticals have been detected in sediment samples (of 25 measured) • 35 different pharmaceuticals have been detected in biota samples (of 116 measured) • Pharmaceuticals from all drug classes were detected

General conclusions regarding monitoring of pharmaceuticals in the Baltic Sea The following pharmaceuticals were found in concentrations above 0.1 µg/l in sea water (HELCOM sub-basin in parenthesis):

Phenazone (Bornholm Basin) Paracetamol (Bothnian Bay) Ibuprofen (Bay of Mecklenburg) Bisopropol (Arkona Basin) Amidotrizoic acid (Arkona Basin)

Among pharmaceuticals detected in concentrations below 0.1 µg/l the most sensitive method quantified 26 pg/l of clofibric acid in sea water using LC-MS/MS1. The following pharmaceuticals were found in concentrations above 10 µg/kg dw in sediment (HELCOM sub-basin in parenthesis):

Sulfamethoxazole (Åland Sea) Paracetamol (Bothnian Bay) Sulfadiazine (Åland Sea) Ibuprofen (Gulf of Riga)

The following pharmaceuticals were found in concentrations above 100 µg/kg ww in biota (blue mussel). All these mussel samples were from Gothenburg and Askeröfjorden, HELCOM sub-basin Kattegat:

Trihexyphenidyl Tramadol Maprotiline Loperamide

1 Liquid chromatography-tandem mass spectrometry

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Dipyridamole Diphenhydramine Felodipine Carbamazepine Trihexyphenidyl Tramadol Mirtazapine Miconazol Bromocriptine Bisoprolol

The European Commission has legally established a “Watch List” under the Water Framework Directive (WFD) that at present includes diclofenac, 17-beta-estradiol (E2), 17-alpha-ethinylestradiol (EE2) and estrone (E1), and three macrolide antibiotic; erythromycin, clarithromycin and azithromycin. This requires that Member States monitor these substances across a wide range of water bodies in order to ascertain the extent of presence in the environment. The WFD assessment criteria for diclofenac (10 ng/l) in coastal waters and transitional waters was exceeded in 6 out of 257 (2.3%) samples. Sub-basins with exceedance were: Bay of Mecklenburg, Arkona and Bornholm Basin. However, it should be noted that in 30% (56 of 187) of the non-detects the reported Limit of Detection (LOD2) was 20 ng/l or higher. The Environmental Quality Standard (EQS) for “Good Status” according to Swedish classification HVMFS (2013:19) is 0.007 ng/ l for the synthetic hormone ethinylestradiol (see Table 3). The monitoring of this compound is problematic since in general the analytical methods are not sensitive enough to detect the substance at levels considered to represent good status . Measurements reported that ethinylestradiol was not detected in 105 of 107 water samples but in 90% of these cases the reported LOD was 0.1 ng/l or higher. For several other pharmaceuticals, more sensitive analytical methods are needed. In addition to diclofenac and hormones commented on above, higher detection frequency could then also be expected for clarithromycin, sulfamethoxazole, trimethoprim and oxazepam. In contrast, primidone, an anti-epileptic drug, was detected in 51 out of 51 analysed water samples. It was noted that, despite the potential to measure very low concentrations of pharmaceutical compounds in open sea water, passive sampling (e.g. POCIS3) was only used in one study (from Finland). General conclusions regarding effects of pharmaceuticals on species from the Baltic Sea All data on pharmaceuticals in biota samples were from Sweden and of totally 839 measurements 77 (9.2%) were over the detection limit. The results indicate that the largest number of pharmaceuticals and the highest concentrations have been found in blue mussels.

In a recent non-target screening conducted in Norway a relatively large number of pharmaceuticals were found in sea birds (Miljødirektoratet, 2013). This suggests that pharmaceuticals may be transferred in aquatic food chains up to seabirds. Together these results from sea birds in Norway and the results presented here on pharmaceuticals in mussel in the Baltic Sea, imply that it should

2 LOD was not reported in all data sets, therefore, in some cases the lowest reported measured concentration is presented as a proxy representing a worst case scenario 3 POCIS = Polar Organic Chemical Integrative Sampler

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be of interest to include sea birds, such as Common eider, that primarily feed on blue mussels, in future monitoring studies for pharmaceuticals. A few studies on the effects of pharmaceutical substances on species from the Baltic Sea were found in the literature survey. Among the reported results were effects of the β-blocker propranolol and the anti-inflammatory drugs diclofenac and ibuprofen on the following littoral organisms: blue mussel (Mytilus edulis trossulus), algae (Fucus vesiculosus or Ceramium tenuicorne) and amphipod crustacean (Gammarus spp) (Ericson et al 2010, Eriksson Wiklund et al 2011, Oskarsson et al 2012, Oskarsson et al 2014, Kumblad et al 2015). Propanolol showed effects on all the tested littoral organisms and the algae Fucus vesiculosus was the most sensitive species. However, in a microcosm study with exposure of propranolol the blue mussel was the most sensitive species (Kumblad et.al. 2015). Ibuprofen and diclofenac only showed effects on the blue mussel.

One study reported behavioural effects of the antidepressant drug citalopram for fish (Gasterosteus aculeatus; Kellner et al 2015).

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TABLE OF CONTENT

1. Introduction ................................................................................................................................................ 6

2. Data overview, compilation and exclusion of data ............................................................................. 7

3. Reading instructions.................................................................................................................................13

4. Methodology for statistical and visual presentations of data .........................................................14

5. Available assessment criteria .................................................................................................................15

6. Anti-inflammatory and analgesics ........................................................................................................17

7. Antimicrobial (antibiotic, antifungal, antiviral, antiparasitic, disinfectant, antiseptic) and antidote........................................................................................................................................................25

8. Cardiovascular agents (blood pressure, diuretics, anticoagulants, antihistamine) ..................29

9. Central nervous system agents (psychotherapeutic, antiepileptic, antiparkinsonian, muscle relaxant) ......................................................................................................................................................34

10. Chemotherapeutic agents and X-ray contrast media ........................................................................39

11. Dermatological agents .............................................................................................................................40

12. Hormones and hormone antagonists ...................................................................................................41

13. Metabolic agents and gastrointestinal agents ....................................................................................44

14. Pharmaceuticals found in biota .............................................................................................................47

15. Effects of pharmaceuticals ......................................................................................................................51

16. Final comments .........................................................................................................................................54

17. References ...................................................................................................................................................55

Appendix 1 Detected pharmaceuticals in water Appendix 2 Detected pharmaceuticals in sediment Appendix 3 Detected pharmaceuticals in biota

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1. Introduction The awareness is growing that while pharmaceuticals are useful and sometimes life-saving for humans and domestic animals, they may be harmful for wildlife in the environment. Several papers have also demonstrated that pharmaceutical substances are frequently detected in the environment (Küster et al 2014). Two well documented examples of pharmaceuticals adversely affecting wildlife are ethinylestradiol and diclofenac (e.g. EEA 2010). Ethinylestradiol has been reported by many countries to be responsible for the feminization of male fish, at concentrations that can be found in surface water downstream sewage treatment plants. For instance, Kidd et al (2007) reported that chronic exposure of fathead minnow (Pimephales promeals) to low concentrations (5-6 ng/l) of 17α-ethynylestradiol led to the feminization of the males and altered oogenesis in females and, ultimately, a near extinction of the species from a lake. In the 1990s, the treatment of cows with diclofenac almost leads to the extinction of vultures in India and Pakistan (Oaks 2004). Furthermore, psychotherapeutic drugs such as, oxazepam (Brodin et al 2013) and citalopram (Kellner et al 2015) have been reported to alter the behaviour of fish. For many pharmaceutical substances (i.e. active pharmaceutical substances, APIs) data concerning e.g. toxicity, persistence and bioaccumulation, is however lacking, which makes it difficult to assess the impact and consequences of the spreading of these substances in the environment (Tema Nord 2012; Andersson et al. 2013). The Baltic Sea has a low salinity, low biodiversity, few trophic levels and a long retention time for persistent substances and this makes it a more sensitive ecosystem to hazardous substances than other marine areas (Magnusson & Norén, 2012). The Helsinki Commission (HELCOM) Ministerial Declaration in May 2010 stated that Ministers of the Environment of the Baltic Coastal Countries and the High Level EU Representative agreed to: Further assess the environmentally negative impacts of pharmaceuticals and other substances that are not monitored regularly, with the aim as a first step to assess in a coordinated manner their occurrence in the Baltic Sea and evaluate their impacts on the Baltic biota.” Also in 2013, the Ministerial Declaration addresses pharmaceuticals: “BEING CONCERNED about the negative impacts of some pharmaceuticals and resistant micro-organisms, WE DECIDE to collect more information and assess the state of contamination with pharmaceuticals and their degradation products of the aquatic environment, which would also contribute to the development of the EU's strategic approach to addressing the pollution of water by pharmaceutical substances, and to develop measures, as appropriate, to prevent pharmaceuticals from reaching the Baltic Sea.” In order to develop a regional approach on how to reduce pharmaceutical pollution to the Baltic Sea, Policy Area Hazards of the EU Strategy for the Baltic Sea Region and HELCOM launched a joint process in May 2015 (HELCOM Pressure 2-2015). The aim is to make a comprehensive assessment of the status of contamination by pharmaceuticals of the Baltic environment. This report provides an input to this process by giving a summary of reported concentrations and effects of pharmaceuticals in the Baltic Sea marine environment. The aim of this report was to present an overview of available data and comment on these. An in depth analysis of the consolidated data or review of published data and methods was beyond the scope of this assignment.

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2. Data overview, compilation and exclusion of data HELCOM Contracting Parties, through the working groups State and Conservation and Pressure, were invited to compile and report available national data on concentrations and effects of pharmaceuticals in the Baltic marine environment of the following type: a. Water (costal, open sea and transitional) b. Sediment c. Biota (concentrations and effects, specifically Baltic biota, not general) Data from national monitoring, screening data, and scientific and commissioned studies relevant for each country were included. Many data have been published in national reports (in national languages) and some are available in national databases. Data on concentrations in water, sediment and biota was received (Table 1). No data on effects was received from the Contracting Parties, however data from scientific studies on effects of pharmaceuticals on Baltic biota was found and included in this study. Only data from sampling points in coastal, open sea and transitional areas are included in this summary. Data from 2003 to 2014 was received from Denmark, Estonia, Finland, Germany, Poland and Sweden (Table 1). Data on pesticides included in the submitted data was excluded.

• 4600 individual data posts were included in the complete data set • 167 different pharmaceuticals have been measured and 74 of these were found in at least one

of the matrices (water, sediment, biota) • 51 different pharmaceuticals have been detected in water (of 148 measured) • 9 different pharmaceuticals have been detected in sediment samples (of 25 measured) • 35 different pharmaceuticals have been detected in biota samples (of 116 measured)

An overview of all data submitted, including references, from the contracting parties is presented in Table 1.

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Table 1 Data overview. The total number of data posts on measurements of pharmaceuticals in the Baltic Sea region that was submitted from HELCOM Contracting Parties. Number of data posts with detected values is presented together with the total number of data posts. Data from approximately 2003 to 2014. References were provided with the data from Contracting Parties and refer to scientific publications as well as national reports. Number of detected / number of submitted data REFERENCES TOTAL WATER SEDIMENT BIOTA

Denmark [13][23][24] 0/54 (0%) 0/54

Estonia [14] 2/75 (3%) 0/40 2/35

Finland [11] [12] 30/51 (59%) 19/27 11/24

Germany [9][25] 435/3148 (14%) 435/3148

Poland [1] [2] [3] [4] [5] [6] [7] [8] 0/18 (0%) 0/18

Sweden [10] [15] [16] [17] [18] [19] [20] [21]

[22] 173/1254 (14%) 78/360 18/55 77/839

Total 640/4600 (14%) 532/3647 31/114 77/839

[1] Migowska, Caban, Stepnowski, and Kumirska. 2012. Sci. Total Environ. 441, pp. 77–88. [2] Caban, Czerwicka, Lukaszewicz, Migowska, Stepnowski, Kwiatkowski, et al. 2013. J. Chromatogr. A. 1301, pp. 215–24. [3] Borecka, Bialk-Bielinska, Siedlewicz, Kornowska, Kumirska, Stepnowski, et al. 2013. J. Chromatogr. A. 1304, pp. 138–146. [4] Kumirska, Migowska, Caban, Plenis, and Stepnowski. 2011. J. Chemom. 25, pp. 636–643. [5] Nödler, Voutsa, and Licha. 2014. Mar. Pollut. Bull. 85 (1), pp. 50–9. [6] Beck, Bruhn, Gandrass, and Ruck. 2005. J. Chromatogr. A. 1090, pp. 98–106. [7] McEneff, G., Barron, L., Kelleher, B., Paull, B., and Quinn, B. 2014. Sci. Total Environ. 476-477, pp. 317–26. [8] Stachel, U. Ehrhorn, O.-P. Heemken, P. Lepom, H. Reincke, G. Sawal, et al. 2003. Environ. Pollut. 124, pp. 497–507. [9] BSH Bundesamt für Seeschifffahrt und Hydrographie [10] Karlsson, M. and Viktor, T. 2014. Miljöstörande ämnen i fisk från Stockholmsregionen 2013. Report B2214 from the Swedish Environmental Research Institute IVL. [11] Muziasari, W. I., Managaki, S., Pärnänen, K., Karkman, A., Lyra, C., Tamminen, M., Suzuki, S., and Virta, M. 2014. Sulphonamide and Trimethoprim Resistance Genes Persist in Sediments at Baltic Sea Aquaculture Farms but Are Not Detected in the Surrounding Environment. [12] Turja R., Lehtonen, K.K., Meierjohann, A., Brozinski, J.-M., Vahtera, E., Soirinsuo, A., Sokolov, A., Snoeijs, P., Budzinski, H., Devier, M.-H., Peluhe,t L., Pääkkönen, J.-P., Viitasalo, M., and Kronberg L. 2015. Marine Pollution Bulletin 97(1-2), pp. 135-49. [13] Miljøministeriet, Naturstyrelsen. 2015. NOVANA-Screeningsundersøgelse for humane lægemidler i vandmiljøet. [14] Estonian Environmental Research Centre. 2012. Euroopa Liidu prioriteetsete ainete nimekirja potentsiaalsete uute ainete esinemise uuring Eesti pinnaveekogudes II. [15] Fick, J., Lindberg, R.H., Kaj, L. and Brorström-Lundén, E. 2011. Results from the Swedish national screening programme 2010. Sub-report 3: Pharmaceuticals. Report B2014 from the Swedish Environmental Research Institute IVL. [16] Löfgren, H. and Gottby, L. 2012. Miljögifter i Gävleborg, resultat från verifieringar 2009 – 2011. Rapport 2012:4, Länsstyrelsen Gävleborg. [17] Johansson, M., Lindberg, R., Wennberg, P. and Tysklind, M. 2003. Redovisning från nationell miljöövervakning 2003. Screening av antibiotika i avloppsvatten, slam och fisk under 2002/2003. Miljökemi, Umeå Universitet, på uppdrag av Naturvårdsverket. [18] Törneman, N., Hallgren, P. and Bjarke M. 2014. Screening Report 2013. Occurrence of additional WFD priority substances in Sweden. Sweco Environment AB, on assignment from the Swedish Environmental Protection Agency. [19] Andersson, J., Woldegiorgis, A., Remberger, M., Kaj, L., Ekheden, Y., Dusan, B., Svenson, A., Brorström-Lundén, E., Dye, C. and Schlabach, M. 2006. Results from the Swedish national screening programme 2005. Subreport 1: Antibiotics, anti-inflammatory. [20] Remberger, M., Wiklund, P., Woldegiorgis, A., Viktor, T., Kaj, L. and Brorström-Lundén, E. 2009. Anti-inflammatory and analgesic drugs in WWTP influent and effluent streams and the occurrence in the aquatic environment. Report B1810 from the Swedish Environmental Research Institute IVL. [21] Woldegiorgis, A., Green, J., Remberger, M., Kaj, L., Brorström-Lundén, E., Dye, C. and Schlabach, M. 2007. Results from the Swedish screening 2006. Sub-report 4: Pharmaceuticals. Report B1751 from the Swedish Environmental Research Institute IVL. [22] Johansson, M., Lindberg, R., Wennberg, P. and Tysklind, M. 2003. Redovisning från nationell miljöövervakning 2003. Screening av antibiotika i avloppsvatten, slam och fisk under 2002/2003. Miljökemi, Umeå Universitet. [23] Naturstyrelsen. 2015. Punktkilder 2014. Miljø- og Fødevareministeriet, Naturstyrelsen. [24] Mogensen, B., Bossi, R., Kjær, J., Juhler, R. and Boutrup, S. 2007. Lægemidler og triclosan i punktkilder og vandmiljøet. Faglig rapport fra DMU nr. 638, 2007. [25] State Agency of Environment, Nature Protection and Geology of Mecklenburg-Vorpommern.

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Pharmaceuticals were grouped according to their general clinical use into the following drug classes:

Anti-inflammatory and analgesics Antimicrobial (antibiotic, antifungal, antiviral, antiparasitic, disinfectant, antiseptic) and

antidote Cardiovascular agents (blood pressure, diuretics, anticoagulants, antihistamine) Central nervous system agents (psychotherapeutic, antiepileptic, antiparkinsonian, muscle

relaxant Chemotherapeutic agents and X-ray contrast media Dermatological agents Hormones and hormone antagonists Metabolic agents and gastrointestinal agents

For regional monitoring and assessment purposes within HELCOM, the Baltic Sea is divided into sub-basins and coastal areas (HELCOM monitoring and assessment strategy 2013). Division according to HELCOM Level 2 refers to the sub-basins listed below.

1. Kattegat 2. Great Belt 3. The Sound 4. Kiel Bay 5. Bay of Mecklenburg 6. Arkona Basin 7. Bornholm Basin 8. Gdansk Basin 9. Eastern Gotland Basin 10. Western Gotland Basin 11. Gulf of Riga 12. Northern Baltic Proper 13. Gulf of Finland 14. Åland Sea 15. Bothnian Sea 16. The Quark 17. Bothnian Bay

Division according to HELCOM Level 3 refers to the division of the Baltic Sea into the 17 sub-basins and further division into 42 coastal areas4. In all subsequent figures (maps), numbers in maps refers to the 17 sub-basins (level 2). Coastal areas (level 3) are also outlined in the maps but for clarity these are not numbered. In Appendices 1-3 all detected data is presented together with the short information on sample location that was provided with the data from contributing parties. Data points have also been related to level 2 and level 3 based on the given coordinates. The geographical distribution of all water, sediment and biota samples is present in Figure 1, Figure 2 and Figure 3 respectively.

4 1 Bothnian Bay Finnish Coastal waters 2 Bothnian Bay Swedish Coastal waters 3 The Quark Finnish Coastal waters 4 The Quark Swedish Coastal waters 5 Bothnian Sea Finnish Coastal waters 6 Bothnian Sea Swedish Coastal waters 7 Åland Sea Finnish Coastal waters 8 Åland Sea Swedish Coastal waters 9 Archipelago Sea Coastal waters 10 Northern Baltic Proper Finnish Coastal waters 11 Northern Baltic Proper Swedish Coastal waters 12 Northern Baltic Proper Estonian Coastal waters 13 Gulf of Finland Finnish Coastal waters 14 Gulf of Finland Estonian Coastal waters 15 Gulf of Finland Russian Coastal waters 16 Gulf of Riga Estonian Coastal waters 17 Gulf of Riga Latvian Coastal waters 18 Western Gotland Basin Swedish Coastal waters 19 Eastern Gotland Basin Estonian Coastal waters 20 Eastern Gotland Basin Latvian Coastal waters 21 Eastern Gotland Basin Lithuanian Coastal waters 22 Eastern Gotland Basin Swedish Coastal waters 23 Eastern Gotland Basin Russian Coastal waters 24 Eastern Gotland Basin Polish Coastal waters 25 Gdansk Basin Russian Coastal waters 26 Gdansk Basin Polish Coastal waters 27 Bornholm Basin Swedish Coastal waters 28 Bornholm Basin Polish Coastal waters 29 Bornholm Basin Danish Coastal waters 30 Bornholm Basin German Coastal waters 31 Arkona Basin Swedish Coastal waters 32 Arkona Basin Danish Coastal waters 33 Arkona Basin German Coastal waters 34 Mecklenburg Bight German Coastal waters 35 Mecklenburg Bight Danish Coastal waters 36 Kiel Bight Danish Coastal waters 37 Kiel Bight German Coastal waters 38 Belts Danish Coastal waters 39 The Sound Swedish Coastal waters 40 The Sound Danish Coastal waters 41 Kattegat Swedish Coastal waters 42 Kattegat Danish Coastal waters, including Limfjorden

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Figure 1 Overview of all 3647 water samples in the compiled data set with data submitted from contracting parties (Denmark, Estonia, Finland, Germany, Poland, Sweden). Numbers refer to the 17 sub-basins (level 2). Coastal areas (level 3) are also outlined but for clarity these are not numbered.

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Figure 2 Overview of all 114 sediment samples in the compiled data set with data submitted from contracting parties (Estonia, Finland, Sweden). Numbers refer to the 17 sub-basins (level 2). Coastal areas (level 3) are also outlined but for clarity these are not numbered.

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Figure 3 Overview of all 839 biota samples in the compiled data set with data submitted from contracting parties (Sweden only). Numbers refer to the 17 sub-basins (level 2). Coastal areas (level 3) are also outlined but for clarity these are not numbered.

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3. Reading instructions Data, by clinical use Results are presented by grouping pharmaceuticals according to their general clinical use. If the reader is interested in a pharmaceutical of a certain drug class, please refer to the corresponding chapter. First, a summary table presents all pharmaceuticals reported measured within this drug class, divided into detected and not detected. Thereafter, graphs and tables present detailed information for selected pharmaceuticals. (Basis for selection of detailed information is presented in chapter 4.) Data, by HELCOM sub-basins If the reader is interested in finding information on measurements conducted in specific sub-basins of the Baltic Sea according to the sub-division set by HELCOM level 2 or level 3, please refer to all presented maps. In Appendix 1 (water), Appendix 2 (sediment) and Appendix 3 (biota) spatial information (level 2 and 3) is presented for measurements with detected pharmaceuticals.

Data, alphabetical All measurements with detected pharmaceuticals are listed in Appendix 1 (water), Appendix 2 (sediment) and Appendix 3 (biota). Pharmaceuticals are sorted in alphabetical order and the highest measured concentration is listed first. These lists also contain the following information:

Name of sampling point (various degree of information, in some cases only codes are provided)

In what sub-basin (1-17), and if applicable, what coastal area (1-42) the sampling point is located. (HELCOM monitoring and assessment strategy 2013).

Country that has provided the data Analytical method (information scarce) Reference

Data, analytical methods with low limit of detection (LOD) The figures, presenting concentrations of individual pharmaceuticals, intend to visualize the variability in the sensitivity of the analytical methods used; referred to as LOD (limit of detection) in the figures. The highest reported limit of detection (High-LOD) in the data set represents the least sensitive analytical method used, while the Low-LOD represents the most sensitive method used. However, LOD was not reported in all data sets. Therefore, in some cases the lowest reported measured concentration is presented as a proxy for the Low-LOD, representing a worst case scenario. The LOD indicator is missing when no sufficient data on LOD were reported. The LODs presented in the figures are thus indicative.

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4. Methodology for statistical and visual presentations of data Maps are presented to give an overview of sampling sites, sampling matrices and, samples above the detection limit. When pharmaceuticals have been detected in water, the median and maximum concentrations are presented in graphs together with the sensitivity of the analytical methods used. For pharmaceuticals detected in water, with an assessment criterion according to the Water Framework Directive (WFD; see Section 5 below), the assessment criterion was included in the graphic presentation. Concentration data from sediment and biota samples are not presented in graphs. This data is less suitable for statistical comparison since sediment and biota data are not as abundant and are highly influenced by choice of sampling method, analytical method, sampled species of biota, age of species, sampled tissue etc. Maps and graphs are presented for pharmaceuticals that:

are on the WFD watch list (table 2) and have been detected are of relevance for monitoring according to the Swedish Medical Products Agency (table 4)

and have been detected are none of the above but have been detected in >5 measurements

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5. Available assessment criteria In cases where international or national assessment criteria are available, the results are compared to these. Within EU and HELCOM, preparatory work to include pharmaceuticals in the environmental regulation is ongoing. In this section we have summarized the present status within the HELCOM Baltic Sea Action Plan (BSAP), EU Marine Strategy Framework Directive (MSFD) and EU Water Framework Directive (WFD). HELCOM BSAP and MSFD The goal of the BSAP is to achieve good environmental status (GES) by 2021 and the status is to be assessed for a set of ecological objectives. The HELCOM strategic goals and objectives are to a large extent comparable to the descriptors and criteria of the MSFD, which stipulates that GES is to be achieved by 2020. HELCOM core indicators are used to follow up on the progress made to reach the goals of both policies within the Baltic Sea. A core indicator measures the progress towards a BSAP objective and/or an MSFD criteria. The agreed core indicators are the outcome of the HELCOM CORESET II project that ended in June 2015. At present (October 2015) diclofenac and estrogenic-effects indicators are so called pre-core indicators. The HELCOM State & Conservation 2-2015 meeting considered them as not yet being ready for core indicator nomination, and recommended for Heads of Delegation 48-2015 to keep them as pre-core. EU Water Framework Directive (WFD) The European Commission has legally established a “Watch List” under the WFD that at present includes pharmaceutical substances.

Commission Implementing Decision 2015/495 lists diclofenac, 17-beta-estradiol (E2), 17-alpha-ethinylestradiol (EE2) and estrone (E1), a breakdown product of E2, and three macrolide antibiotic; erythromycin, clarithromycin and azithromycin, for inclusion on this initial watch list. This requires that Member States monitor these substances across a wide range of water bodies in order to ascertain the extent of presence in the environment. This is a challenge as the proposed levels at which these should be monitored are low (Table 2) and many laboratories cannot meet these requirements. Se discussion related to diclofenac and ethinylestradiol below (Figure 4 and Figure 21 respectively). Table 2 Watch list of pharmaceuticals for Union-wide monitoring as set out in Article 8b of Directive 2008/105/EC Name of the substance CAS number EU number Maximum acceptable

detection limit (ng/l) diclofenac 15307-86-5 239-348-5 10 17-alpha-ethinylestradiol (EE2)

57-63-6 200-342-2 0,035

17-beta-estradiol (E2) 50-28-2 53-16-7

200-023-8 0,5

estrone (E1) 0,4 erythromycin 114-07-8 204-040-1 90 clarithomycin 81103-11-9 90 azithromycin 83905-01-5 617-500-5 90

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(Swedish) National assessment criteria Within the WFD each EU country can have a national list and assessment criteria for particular pollutants. In Sweden three pharmaceuticals are listed as specific pollutants (HVMFS 2013:19, Table 3). Table 3 Swedish assessment criteria for specific pollutants in coastal waters and transitional waters (HVMFS 2013:19) Name of the substance Good status

Annual Average (ng/l) diclofenac 10 17-alpha-ethinylestradiol (EE2) 0.007 17-beta-estradiol (E2) 0.08

Other voluntary initiatives of relevance for monitoring In September 2015, a national working group, coordinated by the Swedish Medical Products Agency (MPA) and consisting of a number of national agencies within the health and medical sector and a representative from the industry, presented a list of substances that were suggested should be monitored in the environment on a regular basis (MPA 2015). In addition to the substances included on the watch list within the WFD, 17 pharmaceuticals were suggested due to the following reasons (Table 4). Table 4 Seventeen pharmaceuticals suggested for monitoring by a Swedish stakeholder working group in addition to the substances on the WFD watch list (MPA 2015). Name Justification by Swedish MPA (2015) Ciprofloxacin Persistent and demonstrated resistance development in the environment Citalopram Has been detected in fish and drinking water. PBT- properties. Relatively large usage. Fluconazol Has been detected in drinking water, surface water and sludge. Ibuprofen Large usage and has been detected in surface water Carbamazepin Has been detected in drinking water and surface water. Cetoconazol Has been detected in sludge Levonorgestrel PBT- properties Losartan Large usage Metoprolol Large usage and has been detected in drinking water, surface water and sludge. Metotrexat Unknown environmental effects and presence. A chemotherapy that is used by the households. Naproxen Has been detected in drinking water and surface water. Increased usage as it is often used as a replacer

for diclofenac. Oxazepam Has been detected in fish, surface water and drinking water. Toxic at environmental relevant

concentration. Sertralin Has been detected in surface water, fish and sludge. Sulfametoxazol Has been detected in surface water, fish and sludge. Tramadol Has been detected in surface water and drinking water. Trimetroprim Large usage. Has been detected in drinking water, surface water and sludge Zolpidem Has been detected in drinking water, surface water and sludge

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6. Anti-inflammatory and analgesics An overview of pharmaceuticals, of drug class: anti-inflammatory and analgesics, for which monitoring data has been received, is presented in Table 5 below.

Table 5 Anti-inflammatory and analgesics. Summary of pharmaceuticals monitored in the Baltic Sea. Pharmaceuticals detected in any sample of water, sediment or biota, are listed in the left column. These compounds are further presented in individual tables and maps below. Pharmaceuticals not detected in any media are listed to the right along with further information on number of samples analysed for each media.

Detected, details in tables and figures below Not detected, number of samples Pharmaceutical Detected,

map Concentration,

graph Detected, statistics Pharmaceutical WATER SEDIMENT BIOTA

Codein Table 10 Acetylsalicylic Acid 8 4 6

Diclofenac Figure 5 Figure 4 Table 6 Azelastine 2 4

Dihydroergotamine Table 10 Beclomethasone 3 1 5

Ibuprofen Figure 6 Figure 4 Table 7 Biperiden 2

Ketoprofen Figure 4 Table 10 Bromocriptine 2

Naproxen Figure 7 Figure 4 Table 8 Budenoside 1

Paracetamol Figure 4 Table 10 Buprenorphine 2 4

Phenazone Figure 8 Figure 4 Table 9 Dextropropoxyphene 2

Pizotifen Table 11 Fenoprofen 1

Tramadol Figure 4 Table 11 Fentanyl 4 6

Trihexyphenidyl Table 11 Indomethacin 1

Norpropoxyphene 2

Propofol 2 2

Propyphenazone 137

Tolfenamic acid 1

Of all monitored pharmaceuticals in this category, 11 out of 26 (42%) were detected in environmental samples (water, sediment or biota). Pharmaceuticals detected in water samples are presented in Figure 4 below. Highest reported limit of detection (High-LOD) in the data set represents the least sensitive analytical method used. A High-LOD, close to the reported detected concentrations, means that the compound might be more frequently present in water bodies than what can be concluded from the number of detected samples. As the reported analytical limit of detection (LOD) in some studies are above the highest reported value in other studies, diclofenac, ketoprofen and naproxene would probably be detected more frequently in water samples if more sensitive analytical methods are used. The WFD assessment criterion for diclofenac in coastal waters and transitional waters is 10 ng/l. In 6 of 257 (2.3%) samples this criterion was exceeded. Sub-basins with exceedance were: Bay of Mecklenburg, Arkona Basin and Bornholm Basin.

18 (88)

Figure 4 Anti-inflammatory and analgesics. Concentrations in Baltic Sea water.

It is very plausible that more cases of exceedance over the WFD assessment criteria would be observed if better analytical methods had been used. For diclofenac the minimum acceptable detection limit for diclofenac, according to Article 8b of Directive 2008/105/EC (Table 2), is 10 ng/l, i.e. the same as the assessment criterion. For 187 water samples the result was reported as <LOD for diclofenac. In 30% of these cases (56 of 187) the reported LOD was 20 ng/l or higher. In 15 cases the limit of detection was not stated. Diclofenac and ibuprofen have been evaluated in toxicity studies using species relevant for the Baltic Sea. For further information on effect studies and comparison with the detected concentrations in this report please refer to chapter 15 below. For detected pharmaceuticals, statistical data is further presented individually in tables. Selected pharmaceuticals, of special interest or with >5 detected, are also presented in maps and bar diagrams.

19 (88)

Figure 5 Sample locations for the compiled data of diclofenac. Each presented data point might conceal several measurements conducted on the exact same location.

Table 6 Overview of submitted data on measurements of diclofenac in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. The WFD assessment criteria for diclofenac in coastal waters and transitional waters is 0.01 µg/l. For more information about sample locations and references for detected, see Appendix 1-3.

Diclofenac Total Denmark Estonia Finland Germany Poland Sweden

WATER

Detected/sampled 70/257 0/2 0/10 2/3 67/212 0/9 1/21

Max (µg/l) 0.054 * 0.054 0.002

MD (µg/l) 0.002

SEDIMENT

Detected/sampled 4/15 0/10 4/5

Max (µg/kg dw) 3.5 3.5

BIOTA

Detected/sampled 5/50 5/50

Max (µg/kg ww) 5.2 5.2 *33 ng/passive sampler (POCIS), not translatable to a concentration per litre

20 (88)

Figure 6 Sample locations for the compiled data of ibuprofen (including ibuprofen-OH and ibuprofen-COOH). Each presented data point might conceal several measurements conducted on the exact same location.

Table 7 Overview of submitted data on measurements of ibuprofen in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1-3.

Ibuprofen** Total Denmark Estonia Finland Germany Poland Sweden

WATER

Detected/ sampled 31/180 0/2 0/10 1/3 6/137 24/28

Max (µg/l) 0.158 * 0.158 0.011

MD (µg/l) 0.0016

SEDIMENT

Detected / sampled 6/18 2/5 4/13

Max (µg/kg dw) 45 45 6

BIOTA

Detected / sampled 1/62 1/62

Max (µg/kg ww) 2.4 2.4

*12 ng/passive sampler (POCIS), not translatable to a concentration per litre **including Ibuprofen-OH and Ibuprofen-COOH

21 (88)

Figure 7 Sample locations for the compiled data of naproxen. Each presented data point might conceal several measurements conducted on the exact same location.

Table 8 Overview of submitted data on measurements of naproxen in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1-3.

Naproxen Total Denmark Estonia Finland Germany Poland Sweden

WATER

Detected / sampled 10/33 0/2 2/3 1/16 7/12

Max (µg/l) 0.014 * 0.014

MD (µg/l) 0.0056

SEDIMENT


Max (µg/kg dw) 0.31 0.31

BIOTA


Max (µg/kg ww)

*39 ng/passive sampler (POCIS), not translatable to a concentration per litre

22 (88)

Figure 8 Sample locations for the compiled data of phenazone. Each presented data point might conceal several measurements conducted on the exact same location.

Table 9 Overview of submitted data on measurements of phenazone in water. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1.

Phenazone Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.504 0.504

MD (µg/l) 0.034

23 (88)

Table 10 Overview of submitted data on measurements of codein, dihydroergotamine, ketoprofen, paracetamol, in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1-3.

Dihydro- ergoatmine Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l)

MD (µg/l)

BIOTA


Max (µg/kg ww) 32 32

Ketoprofen Total Denmark Estonia Finland Germany Poland Sweden

WATER

Detected / sampled 6/17 0/2 1/3 5/12

Max (µg/l) 0.0088 * 0.0088

MD (µg/l) 0.0017

SEDIMENT


Max (µg/kg dw)

BIOTA


Max (µg/kg ww)

Paracetamol Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.36 0.36

MD (µg/l) 0.195

SEDIMENT


Max (µg/kg dw) 69 69

BIOTA


Max (µg/kg ww)

*20 ng/passive sampler (POCIS), not translatable to a concentration per litre

Codein Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l)

MD (µg/l)

BIOTA



24 (88)

Table 11 Overview of submitted data on measurements of pizotifen, tramadol and trehexyphenidyl, in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1-3.

Pizotifen Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l)

MD (µg/l)

BIOTA


Max (µg/kg ww) 0.7 0.7

Tramadol Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.00069 0.0016 0.00069

MD (µg/l)

BIOTA



Trihexy-phenidyl Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l)

MD (µg/l)

BIOTA



25 (88)

7. Antimicrobial (antibiotic, antifungal, antiviral, antiparasitic, disinfectant, antiseptic) and antidote

An overview of pharmaceuticals, of drug class; antimicrobial (antibiotic, antifungal, antiviral, antiparasitic, disinfectant, antiseptic) and antidote, for which monitoring data has been received, is presented in Table 12 below.

Table 12 Antimicrobial (antibiotic, antifungal, antiviral, antiparasitic, disinfectant, antiseptic) and antidote. Summary of pharmaceuticals monitored in the Baltic Sea. Pharmaceuticals detected in any sample of water, sediment or biota, are listed in the left column. These compounds are further presented in individual tables and maps below. Pharmaceuticals not detected in any media are listed to the right along with further information on number of samples analysed for each media.


map Concentration,

graph Detected, statistics

Pharmaceutical WATER SEDIMENT BIOTA Ciprofloxacin

Fel! Hittar inte referenskälla.

9,10-Anthraquinone 9

Clarithromycin Figure 10 Figure 9 Table 13 Amoxicillin 2

Clindamycin Figure 9 Azithromycin 4

4

Clotrimazole Figure 9 Chloramphenicol 1

Erythromycin Figure 10 Table 13 Chlortetracyline 51 1

Ketoconazol Cloxacilline 1

Miconazol Demeclocycline 1 1

1

Norfloxacin Dicloxacilline 1

Sulfadiazine Doxycycline 51 1

Sulfamethoxazole Figure 11 Figure 9 Table 14 Fluconazole 4 3

4

Trimethoprim Figure 9 Lufenuron 9

Nafcilline 1

Naloxone 2

Ofloxacin 2

4

Oxacillin 1

Oxytetracycline 51 1

Phoxim 101

Roxithromycin 4 4

Tetracycline 51 1 4

Of all monitored pharmaceuticals in this category, 11 out of 30 (37%) were detected in environmental samples (water, sediment or biota). Concentrations for pharmaceuticals detected in water samples are presented in Figure 9 below. Highest reported limit of detection (High-LOD) in the data set represents the least sensitive analytical method used. A High-LOD, close to the reported detected concentrations, means that the compound might be more frequently present in water bodies then what can be concluded from the number of detected samples. Clarithromycin, sulfamethoxazole and trimethoprim would probably be detected more frequently in water samples if more sensitive analytical methods were used. In some studies, the reported analytical limit of detection (LOD) is above the highest reported value in other studies. For sulfamethoxazole the reported analytical limit of detection is in many cases close to the median concentration in detected samples.

26 (88)

Figure 9 Antimicrobial (antibiotic, antifungal, antiviral, antiparasitic, disinfectant, antiseptic) and antidote. Concentrations in Baltic Sea water.

27 (88)

Figure 10 Sample locations for the compiled data of erythromycin, clarithromycin and azithromycin. Each presented data point might conceal several measurements conducted on the exact same location.

Table 13 Overview of submitted data on measurements of erythromycin, clarithromycin and azithromycin,, in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1 and 3.

Erythromycin, Clarithomycin, Azithromycin Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.00027 0.00027

MD (µg/l)

BIOTA


Max (µg/kg ww) 12.7 12.7

28 (88)

Figure 11 Sample locations for the compiled data of sulfamethoxazole. Each presented data point might conceal several measurements conducted on the exact same location.

Table 14 Overview of submitted data on measurements of sulfamethoxazole, in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1-3.

Sulfamethoxazole Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.033 0.033

MD (µg/l) 0.016

SEDIMENT


Max (µg/kg dw) 101 101

BIOTA



29 (88)

8. Cardiovascular agents (blood pressure, diuretics, anticoagulants, antihistamine)

An overview of pharmaceuticals, of drug class; cardiovascular agents (blood pressure, diuretics, anticoagulants, antihistamine), for which monitoring data has been received, is presented in Table 15 below.

Table 15 Cardiovascular agents (blood pressure, diuretics, anticoagulants, antihistamine). Summary of pharmaceuticals monitored in the Baltic Sea. Pharmaceuticals detected in any sample of water, sediment or biota, are listed in the left column. These compounds are further presented in individual tables and maps below. Pharmaceuticals not detected in any media are listed to the right along with further information on number of samples analysed for each media.


map Concentration,

graph Detected, statistics Pharmaceutical WATER SEDIMENT BIOTA

Acebutolol Amiloride 2 Alfuzosin Amiodarone 2 2 Atenolol Desloratadine 2 4

Bisoprolol Figure 14 Figure 12 Table 17 Diltiazem 2 4 Cilazapril Fexofenadine 2 4

Clemastine Flecainide 4 Cyproheptadine Isradipine 1

Diphenhydramine Figure 12 Losartan 2 Dipyridamole Meclozine 2 4

Eprosartan Promethazine 2 4 Felodipine Propranolol 139 40 Irbesartan Figure 12 Metoprolol Figure 13 Figure 12 Table 16

Sotalol Figure 15 Figure 12 Table 18

Of all monitored pharmaceuticals in this category, 14 out of 25 (56%) were detected in environmental samples (water, sediment or biota). Concentrations for pharmaceuticals detected in water samples are presented in Figure 12 below. Highest reported limit of detection (High-LOD) in the data set represents the least sensitive analytical method used. A High-LOD, close to the reported detected concentrations, means that the compound might be more frequently present in water bodies then what can be concluded from the number of detected samples. The highest reported limit of detection for non-detects was 0.01 µg/l for most compounds. Given this sensitivity of the analytical method it is reasonable to believe that the number of detected values of metoprolol, bisoprolol and sotalol gives a fair representation of the abundance of these compounds in the environment. Propranolol was measured in 139 water samples but never detected. The reported LOD is between 0.01 and 0.0005 µg/l. It is difficult to conclude if the sensitivity of the analytical methods are sufficient to conclude weather propranolol is spread in the Baltic Sea water. The sensitivity of the methods are however sufficient to conclude that this pharmaceutical is not present in the environment at concentrations comparable to the effect levels for this compound. (see Table 28).

30 (88)

Figure 12 Cardiovascular agents (blood pressure, diuretics, anticoagulants, antihistamine). Concentrations in Baltic Sea water.

31 (88)

Figure 13 Sample locations for the compiled data of metoprolol. Each presented data point might conceal several measurements conducted on the exact same location.

Table 16 Overview of submitted data on measurements of metoprolol, in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1 and 3.

Metoprolol Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.055 * 0.055 0.0016

MD (µg/l) 0.015

BIOTA


Max (µg/kg ww) *40 ng/passive sampler (POCIS), not translatable to a concentration per liter

32 (88)

Figure 14 Sample locations for the compiled data of bisoprolol. Each presented data point might conceal several measurements conducted on the exact same location.

Table 17 Overview of submitted data on measurements of bisoprolol, in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1 and 3.

Bisoprolol Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.128 * 0.128

MD (µg/l) 0.015

BIOTA


Max (µg/kg ww) 102 102 *39 ng/passive sampler (POCIS), not translatable to a concentration per liter

33 (88)

Figure 15 Sample locations for the compiled data of sotalol. Each presented data point might conceal several measurements conducted on the exact same location.

Table 18 Overview of submitted data on measurements of sotalol in water. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1.

Sotalol Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.024 0.024 0.00024

MD (µg/l) 0.0055

34 (88)

9. Central nervous system agents (psychotherapeutic,

antiepileptic, antiparkinsonian, muscle relaxant) An overview of pharmaceuticals, of drug class; central nervous system agents (psychotherapeutic, antiepileptic, antiparkinsonian, muscle relaxant), for which monitoring data has been received, is presented in Table 19 below.

Table 19 Central nervous system agents (psychotherapeutic, antiepileptic, antiparkinsonian, muscle relaxant. Summary of pharmaceuticals monitored in the Baltic Sea. Pharmaceuticals detected in any sample of water, sediment or biota, are listed in the left column. These compounds are further presented in individual tables and maps below. Pharmaceuticals not been detected in any media are listed to the right along with further information on number of samples analysed for each media.


map Concentration,

graph Detected, statistics

Pharmaceutical WATER SEDIMENT BIOTA Alprazolam 7-aminoflunitrazepam 2

Bromocriptine Amitryptiline 2 4 Carbamazepine Figure 17 Figure 16 Table 20 Atracurium besylate 2 4 Chlorpromazine Biperiden 4

Citalopram Figure 16 Bupropion 2 4 Clonazepam Caffeine 2

Donepezil Clomipramine 2 4 Duloxetine Clozapine 2 Fluoxetine Diazepam 16 4

Haloperidol Flunitrazepam 6 Maprotiline Flupentixol 2 4 Memantine Fluphenazine 2 4 Mianserin Hydroxyzine 2 4

Mirtazapine Levomepromazine 2 4 Orphenadrine N-demethylflunitrazepam 2

Oxazepam Figure 18 Figure 16 Table 21 Nefazodone 2 4 Paroxetine Perphenazine 2 4 Primidone Figure 19 Figure 16 Table 22 Risperidone 2 6 Sertraline Figure 16 Temazepam 16

Venlafaxine Figure 16 Thioridazine 2 Zolpidem Zopiclone 2

Zopiclone N-oxide 2 Zuclopenthixol 1

Of all monitored pharmaceuticals in this category, 21 out of 44 (48%) were detected in environmental samples (water, sediment or biota). Concentrations for pharmaceuticals detected in water samples are presented in Figure 16 below. Highest reported limit of detection (High-LOD) in the data set represents the least sensitive analytical method used. A High-LOD, close to the reported detected concentrations, means that the compound might be more frequently present in water bodies then what can be concluded from the number of detected samples. Oxazepam would probably be detected more frequently in water samples if more sensitive analytical methods were used. In some studies, the reported analytical limit of detection (LOD) is above the highest reported value in other studies.

35 (88)

Figure 16 Central nervous system agents (psychotherapeutic, antiepileptic, antiparkinsonian, muscle relaxant. Concentrations in Baltic Sea water.

36 (88)

Figure 17 Sample locations for the compiled data of carbamazepine. Each presented data point might conceal several measurements conducted on the exact same location.

Table 20 Overview of submitted data on measurements of carbamazepine, in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1-3.

Carbamazepine Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.073 * 0.073 0.0031

MD (µg/l) 0.0034

SEDIMENT


Max (µg/kg dw)

BIOTA


Max (µg/kg ww) 141 141 *232 ng/passive sampler (POCIS), not directly translatable to a concentration per liter

37 (88)

Figure 18 Sample locations for the compiled data of oxazepam. Each presented data point might conceal several measurements conducted on the exact same location.

Table 21 Overview of submitted data on measurements of oxazepam in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1 and 3.

Oxazepam Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.0019 0.0019 0.00085

MD (µg/l) 0.0004

BIOTA


Max (µg/kg ww) 6.7 6,7

38 (88)

Figure 19 Sample locations for the compiled data of primidone. Each presented data point might conceal several measurements conducted on the exact same location.

Table 22 Overview of submitted data on measurements of primidone in water. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1.

Primidone Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.0058 0.0058

MD (µg/l) 0.00225

39 (88)

10. Chemotherapeutic agents and X-ray contrast media Three different pharmaceuticals of drug class; chemotherapeutic agents and X-ray contrast media, have been measured in water samples alone. Amidotrizoic acid was detected in 16 of 137 water samples from Germany. The highest recorded concentration of amidotrizoic acid was 0.125 µg/l and the median among the detected samples was 0.047 µg/l. The highest reported limit of detection for non-detects was 0.03 µg/l. Given this sensitivity of the analytical method it is reasonable to believe that the number of detected values of amidotrizoic acid gives a fair representation of the abundancy of this compound in the environment. Iopamidol was detected in 2 of 137 samples from Germany, the highest concentration being 0.09 µg/l. Capecitabine was not detected in two water samples from Denmark.

Figure 20 Sample locations for the compiled data of amidotrizoic acid. Each presented data point might conceal several measurements conducted on the exact same location.

40 (88)

11. Dermatological agents Salicylic acid is used, among other things, as a dermatological agent. Data was available from measurements on water, sediment and biota from Sweden. No other data on dermatological agents was available. Salicylic acid was detected in 4 water samples. In for water samples the reported results were <0.0005 µg/l. Given this sensitivity of the analytical method it is reasonable to believe that the number of detected values of salicylic acid gives a fair representation of the abundance of this compound in the environment Table 23 Overview of submitted data on measurements of salicylic acid in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1-3.

Salicylic acid Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.014 0.014

MD (µg/l) 0.012 0.012

SEDIMENT


Max (µg/kg dw) 3.9 3.9

BIOTA


Max (µg/kg ww)

41 (88)

12. Hormones and hormone antagonists An overview of pharmaceuticals, of drug class; hormones and hormone antagonists, for which monitoring data has been received, is presented in Table 24 below. Measured concentrations of estradiol and ethinylestradiol in comparison with assessment criteria and method sensitivity are presented in Figure 21 below. Table 24 Hormones and hormone antagonists. Summary of pharmaceuticals monitored in the Baltic Sea. Pharmaceuticals detected in any sample of water, sediment or biota, are listed in the left column. These compounds are further presented in individual tables and maps below. Pharmaceuticals not detected in any media are listed to the right along with further information on number of samples analysed for each media.

Detected, details in tables and figures below Not detected, number of samples Pharmaceutical Pharmaceutical WATER SEDIMENT BIOTA

Estradiol Estriol 3 1 Ethinylestradiol Estrone 1

Etonogestrel Finasteride 2 4 Flutamide Fulvestrant 1 Tamoxifen Levonorgestrel 3 1 5

Medroxyprogesterone 2 Mestranol 43 Norethindrone 1 Norethisteron 2 Progesterone 2

Of all monitored hormones and hormone antagonists, 5 of 15 (33%) were detected in environmental samples (water, sediment or biota). Concentrations for estradiol and ethinylestradiol are presented in Figure 21 below. Highest reported limit of detection (High-LOD) in the data set represents the least sensitive analytical method used. A High-LOD, close to the reported detected concentrations, means that the compound might be more frequently present in water bodies then what can be concluded from the number of detected samples. For the synthetic estrogen ethinylestradiol, EQS for “Good Status” according to Swedish classification HVMFS (2013:19) is 0.007 ng/ l (see Table 3) and the minimum acceptable detection limit, according to Article 8b of Directive 2008/105/EC (Table 2), is 0.035 ng. It is obvious that monitoring of these hormones, the synthetic hormone ethinylestradiol and the natural hormone estradiol, is problematic since in general the analytical methods are not sensitive enough to detect the substance at levels considered to represent good status. It is likely that several more cases of exceedance over the assessment criteria would be noted for ethinylestradiol if better analytical methods had been used. For 107 water samples the result was reported as <LOD for 105 samples. In 90% of these cases (95 of 105) the reported LOD was 0.1 ng/l or higher. In 10 cases the limit of detection was not stated. With GC–MS/MS5 or SPME–HPLC6 it is possible to reach detection limits around 0.05 ng/l for ethinylestradiol (Campbell 2006). The least sensitive method used for measurements of ethinylestradiol in water samples has a limit of detection of 0.1 µg/l. The method needs to be 100 or 1000 times more sensitive than this in order to give a meaningful result.

5 Gas chromatography-tandem mass spectrometry 6 Solid Phase Microextraction- high-performance liquid chromatography

42 (88)

Sample locations and statistical data for estradiol, ethinylestradiol and estrone are presented in Figure 22 and Table 25 respectively.

Figure 21 Hormones and hormone antagonists. Concentrations in Baltic Sea water. EQS represents the Environmental Quality Standard for “Good Status” according to Swedish classification HVMFS (2013:19) (see Table 3).

43 (88)

Figure 22 Sample locations for the compiled data of ethinylestradiol, estradiol and estrone. Each presented data point might conceal several measurements conducted on the exact same location.

Table 25 Overview of submitted data on measurements of ethinylestradiol, estradiol and estrone, in different matrices. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1-3.

Ethinylestradiol, Estradiol, Estrone Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.0011 0.0011*

MD (µg/l) 0.00073

SEDIMENT


Max (µg/kg dw)

BIOTA


Max (µg/kg ww) *maximum detected concentration is for estradiol

44 (88)

13. Metabolic agents and gastrointestinal agents An overview of pharmaceuticals, of drug class; metabolic agents and gastrointestinal agents, for which monitoring data has been received, is presented in Table 26 below.

Table 26 Metabolic agents and gastrointestinal agents. Summary of pharmaceuticals monitored in the Baltic Sea. Pharmaceuticals detected in any sample of water, sediment or biota, are listed in the left column. These compounds are further presented in individual tables and maps below. Pharmaceuticals not detected in any media are listed to the right along with further information on number of samples analysed for each media.

Detected, details in tables and figures below

Not detected, number of samples Pharmaceutical Pharmaceutical WATER SEDIMENT BIOTA

Atorvastatin Bezafibrate 139 Clofibric acid (metabolite of Clofibrate) Ezetimibe 2 4

Dicycloverine Fenofibrate 1 Loperamide Gemfibrozil 17 Ranitidine Glibenclamide 4

Rosuvastatin Glimepiride 2 4 Metformin 1 5 Repaglinide 2 4

Of the metabolic agents and gastrointestinal agents only chlofibric acid and rosuvastatin were detected in water and the measured concentrations are presented in Figure 23 below in comparison with method sensitivity. Highest reported limit of detection (High-LOD) in the data set represents the least sensitive analytical method used. A High-LOD, close to the reported detected concentrations, means that the compound might be more frequently present in water bodies then what can be concluded from the number of detected samples. Data on LOD for non-detected samples of these two pharmaceuticals was scarce in the data set and no conclusions can be drawn regarding the detection frequency.

45 (88)

Figure 23 Metabolic agents and gastrointestinal agents. Concentrations in Baltic Sea water.

46 (88)

Figure 24 Sample locations for the compiled data of clofibric acid. Each presented data point might conceal several measurements conducted on the exact same location.

Table 27 Overview of submitted data on measurements of clofibric acid in water. Number of detected values is presented together with the total number of measurements. Max= maximum value, MD= median among detected. For more information about sample locations and references for detected, see Appendix 1.

Clofibric acid Total Denmark Estonia Finland Germany Poland Sweden

WATER


Max (µg/l) 0.0004 0.0004

MD (µg/l) 0.0001

47 (88)

14. Pharmaceuticals found in biota All biota samples have been collected in Sweden and of totally 839 measurements 77 was over the detection limit. All measurements with detected pharmaceuticals in biota are presented in Figure 25, Figure 26, Figure 27, Figure 28 and Figure 29 below. The results are presented grouped by species. Note should be taken that information on what type of tissue (e.g. fish muscle or bile) that has been sampled was sometimes missing in the compiled data set.

Figure 25 Detected pharmaceuticals (ciprofloxacin) in muscle from Atlantic cod (Gadus morhua). Locaition a) Kalmar, Western Gotland Basin (HELCOM sub-basin 10). Location b) Gothenburg, Kattegat (HELCOM sub-basin 1).

0

1

2

3

4

5

6

7

8

9

Ciprofloxacin a) Ciprofloxacin b) Ciprofloxacin b)

µg/

kg w

w

Atlantic cod

48 (88)

Figure 26 Detected pharmaceuticals in Blue mussel7 (Mytilus edulis trossulus). Locaition a) Askeröfjorden, north of Gothenburg, Kattegat (north of HELCOM sub-basin 1). Location b) Älvsborgsfjorden, Gothenburg, Kattegat (HELCOM sub-basin 1).

Figure 27 Detected pharmaceuticals in bile from European perch (Perca fluviatilis). Locaition a) Käppala, Stockholm, Northern Baltic Proper (HELCOM sub-basin 12). Location b) Gällnö, Stockholm, Northern Baltic Proper (HELCOM sub-basin 12.

7 Information on sampled tissue not available, presumably soft body of the mussel.

49 (88)

Figure 28 Detected pharmaceuticals in muscle from Flounder (Platichthys flesus). All samples from location Askeröfjorden, north of Gothenburg, Kattegat (north of HELCOM sub-basin 1).

Figure 29 Detected pharmaceuticals in muscle from Eel (Anguilla Anguilla). All samples from location Askeröfjorden, north of Gothenburg, Kattegat (north of HELCOM sub-basin 1).

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The results indicate that the largest number of pharmaceuticals and the highest concentrations are found in blue mussels. Mussels are widely used in marine pollution monitoring as they filter large amounts of water efficiently and use waterborne particles as food, thus being exposed to extensive amounts of different chemicals, either in dissolved form or bound to particles (Viarengo and Canesi, 1991). Some pharmaceuticals may be transferred in the aquatic food chain from fish and mussel up to seabirds. Since the largest number of pharmaceuticals and the highest concentrations were found in mussel it should be of interest to include sea birds, such as Common eider, that primarily feed on blue mussels in monitoring studies, for instance, in the vicinity of waste water treatment plants. In general sea birds are interesting for monitoring of pharmaceuticals. In a recent non-target screening conducted in Norway a relatively large number of pharmaceuticals were found in sea birds (Common eider 33, Herring Gull 34 and Common Shag 3 pharmaceuticals, respectively; Miljødirektoratet, 2013). In the Norwegian study advanced analytical methods (e.g. two-dimensional gas-chromatography) were used in a wide screening approach whereas the data presented above is from targeted screening.

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15. Effects of pharmaceuticals It is well-known that pharmaceuticals cause effects in the environment. As the Baltic Sea has a low biodiversity with low functional redundancy, this makes the ecosystem particularly sensitive for pollutants. In the tables Table 28, Table 29, Table 30, Table 31 and Table 32 below, the results from studies concerning the effects of pharmaceutical substances on species from the Baltic Sea are summarized concerning the species, test conditions (concentration and duration) and the essential outcome of the studies. It was not within the assignment to assess of the reported results. For more details on the specific effects etc., please refer to the publications. Studies where combined effects of pharmaceuticals and other contaminants in the Baltic Sea are studied have been excluded; e.g. Turja et al (2015). In summary, several publications report on the effects of the β-blocker propranolol and the anti-inflammatory drugs diclofenac and ibuprofen on the littoral organisms blue mussel (Mytilus edulis trossulus), algae (Fucus vesiculosus or Ceramium tenuicorne) and amphipod crustacean (Gammarus spp (Ericson et al. 2010, Eriksson Wiklund et al 2011, Oskarsson et al 2012, Oskarsson et al 2014, Kumblad et al 2015). One study reported the effects of the antidepressant drug citalopram on fish (Gasterosteus aculeatus; Kellner et al 2015). Propanolol showed effects on all the tested littoral organisms and the algae Fucus vesiculosus was the most sensitive species. However, in a microcosm study with exposure of propranolol the blue mussel was the most sensitive species (Kumblad et al 2015). Ibuprofen and diclofenac only showed effects on blue mussel.

Of the data summarized in this report, propranolol has been analysed in 139 water samples and 40 biota samples (bile of European perch from two locations, Käppala and Gällnö, in the Stockholm archipelago), but has not been reported over the detection limit.

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Table 28 Propranolol - effects on species from the Baltic Sea Species Test conditions LOEC* (µg/l) Endpoints Ref Mytilus edulis trossulus

1, 100, 1000, 5000 and 10 000 µg/l (1-3 weeks)

1000 Physiology: Lower byssus strength and lower byssus thread abundance at 10 000 µg/l. Lower SFG*’ after 2 weeks at 1000 µg/l. Mortality 16% > 1000 µg/l (2% in control treatments)

Ericson et.al. (2010)

Gammarus spp 100, 1000 and 5000 µg/l (1 week)

100 Behavioral: Swimming activity decreased and time to find habitat increased with increased concentration. Feeding rates were more than 2 times higher than the control.

Eriksson et.al. (2011)

Fucus vesiculosus 100, 1000 and 5000 µg/l (1 week)

5000 Physiology: Significant dose-/response relationship and the significantly lower GP/R***

Eriksson et.al. (2011)

Fucus vesiculosus 10 – 1000 µg/l (8 weeks)

10 Physiology: Lower GP/R** at 10 µg/l after 4 weeks. Effects increased with increasing concentration and with exposure time. Lower chlorophyll fluorescence after 4 weeks at 1000 µg/l Negative effect on the photosynthesis.

Oskarsson et.al. (2012)

Gammarus spp 10 -1000 µg/l (8 weeks)

100 Physiology: Reduced respiration (4 weeks). Inconsistent results at different concentrations over time.


Microcosm study Ceramium tenuicorne, Mytilus edulis trossulus, Gammarus spp., water and sediment

1000 µg/l 100 µg/l (6 weeks)

1000 µg/l Algae: Higher carbon content at 1000 µg/l. At 1000 µg/l: Mussels: increased mortality Amphipods: Increased reproduction. Algae: Higher carbon content Ecosystem structural change: The effect on the mussel led to a feeding shift from alga to mussel by the amphipods. Better food quality increased reproduction. Less amphipod grazing, and increased nutrient levels in the water was favorable for the alga.


* LOEC Lowest Effect Concentration **(SFG) Scope for growth: the energy available for normal metabolism ***(GP/R): primary production (GP) to respiration (R) ratio

Diclofenac and ibuprofen has been detected in water (highest concentration 0.054 µg/l and 0.158 µg/l, respectively), sediment (highest concentration 3.5 and 45 µg/kg ww, respectively) and biota samples (highest concentration 5.2 µg/kg ww and 2.4 µg/kg ww, respectively, in bile from European perch).

Table 29 Diclofenac - effects on species from the Baltic Sea Species Test conditions LOEC* (µg/l) Endpoints Ref Mytilus edulis trossulus

1, 100, 1000, 5000 and 10 000 µg/l (1-3 weeks)

100 Physiology: Lower byssus strength and lower byssus thread abundance at 10 000 µg/l. Lower SFG** after 2 weeks at 100 µg/l Mortality: 14% >1000 µg/l (2% in control treatments)


Fucus vesiculosus 10, 100, 1000 µg/l (4 weeks)

>1000 No significant effects Oskarsson et.al. (2012)

Gammarus spp 10, 100, 1000 µg/l (4 weeks)

>1000 No significant effects Oskarsson et.al. (2012)

* LOEC Lowest Effect Concentration **(SFG) Scope for growth: the energy available for normal metabolism

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Table 30 Mixture of Diclofenac (D) and Propanolol (P)- effects on species from the Baltic Sea Species Test conditions LOEC* (µg/l) Endpoints Ref Mytilus edulis trossulus

Mixture exposure 2 weeks

P: 250 D: 750 Total:1000

Physiology: lower SFG** Ericson et.al. (2010)

Mytilus edulis trossulus

50/50 mixture of diclofenac and propranolol. Total exposure concentration: 20, 200 and 2000 µg/l. Sampled with increasing distance to a WTP outlet, exposed to the mixture for 3 weeks, and then tested for their physiological response and subsequent recovery from the exposure.

P: 100 D: 100 Total: 200

Physiology: increased effect on SFG (and its components) Mussels collected further from outlet were more affected by the exposure and did not recover to the same extent as mussels closer to the outlet. The authors suggests that the mussels sampled closer to the WTP, have a higher food availability (= improved health status) and/or pre-exposure to natural disturbances, and the test substances, via the WTP effluent.

Kumblad et.al. (2015)


Table 31 Ibuprofen - effects on species from the Baltic Sea Species Test conditions LOEC (ug/l) Endpoints Ref

Mytilus edulis trossulus

1, 100, 1000, 5000 and 10 000 µg/l (1-3 weeks)

1000 Physiology: lower SFG* after 2 weeks at 1000 µg/l Byssus strength = Control treatment Mortality = Control treatments


Gammarus spp

1, 1000 and 10 000 µg/l (1 week)

> 10 000 No significant effects Eriksson et.al. (2011)

Fucus vesiculosus 1, 1000 and 10 000 µg/l (1 week)

> 10 000 No significant effects Eriksson et.al. (2011)

Fucus vesiculosus 10, 100, 1000 µg/l (4 weeks)

> 1000 No significant effects Oskarsson et.al. (2012)

Gammarus spp 10, 100, 1000 µg/l (4 weeks

> 1000 No significant effects Oskarsson et.al. (2012)


Citalopram was only detected in water samples and the highest concentration was 0.00023 µg/l.

Table 32 Citalopram - effects on species from the Baltic Sea Species Test conditions LOEC (µg/l) Endpoint Ref

Gasterosteus aculeatus

0,15 and 1,5 µg/l (3 weeks)

< 0,15 µg/l (based on mode of action)

Behavioural: Decreased food intake within less than 1 week.

Kellner et.al. (2015)

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16. Final comments This report summarizes data of heterogenic origin and it has not been possible to evaluate the analytical methods used or the quality of the data in detail. HELCOM Contracting Parties have contributed with national data. In most cases no information was provided on analytical methods used and sometimes other vital information was missing. Without further evaluation of the quality of this data it is not safe to draw conclusions on e.g. possible differences in concentrations between different regions. However, the sheer volume of data points outweighs some of the deficits regarding heterogenic data, and the data compiled in this report serves as a good starting point for a discussion about what pharmaceuticals have been monitored in the Baltic Sea and what have been found.

Of the total number of pharmaceuticals used only few are monitored (Örtlund et al 2014). In monitoring, a fixed number of substances are analysed in a given matrix. Sometimes neither the analyte, nor the matrix of choice, is the most relevant. Given the environmental concern for pharmaceuticals and the particular sensitivity of the Baltic Sea (see Introduction) it is of high importance that the Baltic countries cooperate and exchange information to improve the knowledge of methods, status and what pharmaceuticals are of most environmental concern.

Regarding methods, it is clear that for many substances analytical challenges remain.

Regarding environmental concern, for the vast majority of pharmaceutical listed in the chapters above, very little is known about possible ecological effects.

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17. References

Andersson H, Magnér J, Wallberg P (2013) Self –declarations of environmental classification in www.fass.se. IVL report B2124.

Brodin T, Fick J, Jonsson M, Klaminder J.(2013) Dilute concentrations of a psychiatric drug alter behaviour of fish from natural populations Science. Vol 339:814-815

Campbell, Chris G., Sharon E Borglin, F Bailey Green, Allen Grayson, Eleanor Wozei, William T. Stringfellow (2006) Biologically directed environmental monitoring, fate, and transport of estrogenic endocrine disrupting compounds in water: A review. Chemosphere 65 1265–1280.

COMMISSION IMPLEMENTING DECISION (EU) 2015/495 of 20 March 2015 establishing a watch list of substances for Union-wide monitoring in the field of water policy pursuant to Directive 2008/105/EC of the European Parliament and of the Council (notified under document C(2015) 1756)

EEA (2010) Pharmaceuticals in the environment. European Environmental Agency EEA Technical report 1/2010

Ericson H, Thorsén G, Kumblad L (2010) Physiological effects of diclofenac, ibuprofen and propranolol on Baltic Sea blue mussels. Aquatic Toxicology 99:223-231¨

Eriksson Wiklund A-K, Oskarsson H, Thorsén G, Kumblad L (2011) Behavioural and physiological responses to pharmaceutical exposure in macroalgae and grazers from a Baltic Sea littoral community Aquatic Biology 14:29-39

HELCOM monitoring and assessment strategy 2013. http://www.helcom.fi/action-areas/monitoring-and-assessment/monitoring-and-assessment-strategy

HELCOM Pressure 2-2015. Preparing a regional status report on pharmaceuticals in the marine environment. Background document for the Second Meeting of the Working Group on Reduction of Pressures from the Baltic Sea Catchment Area Tallinn, Finland, 6-8 May 2015. https://portal.helcom.fi/meetings/PRESSURE%202-2015-240/MeetingDocuments/4-6%20Preparing%20a%20regional%20status%20report%20on%20pharmaceuticals%20in%20the%20marine%20environment.pdf

HVMFS (2013:19) Havs- och vattenmyndighetens föreskrifter om klassificering och miljökvalitetsnormer avseende ytvatten (Swedish Agency for Marine and Water Management regulations (HVMFS 2013: 19) on Classification and quality standards regarding surface water)

Kellner M, Porseryd T, Porsch-Hallström I, Hansen S (2015) Environmentally relevant concentrations of citalopram partially inhibit feeding in the three-spine stickleback (Gasterosteus aculeatus) Aquat Toxicol.;158:165-70.

Kidd KA, Blanchfield PJ, Mills KH, Palace VP, Evand RE, Lazorchak JM, and Flick RW (2007) Collapse of a fish population after exposure to a synthetic extrogen. PNAS 104:887-8901

Kumblad L Oskarsson H, Palmer C, Eriksson Wiklund A-K (2015) Response and recovery of Baltic Sea blue mussels from exposure to pharmaceuticals. Marin Ecol Prog Ser 526: 89–100

Küster A, Adler N. (2014) Pharmaceuticals in the environment: scientific evidence of risks and its regulation. Phil. Trans. R. Soc. B 369: 20130587. http://dx.doi.org/10.1098/rstb.2013.0587

Magnusson, K and Norén K (2012) The sensitivity of the Baltic Sea ecosystems to hazardous substances. Swedish Chemicals Agency Report PM 9/12

Miljødirektoratet (2013) Non-target screening – A powerful tool for selecting environmental pollutants. Rapport M-27

MPA (2015) Miljöindikatorer inom ramen för nationella läkemedelsstrategin (NLS) Rapport från CBL-kansliet, Läkemedelsverket 2015-09-07 (Environmental indicators under the national drugs strategy (NLS) Report of CBL's Office, MPA 2015-09-07 in Swedish)

http://www.fass.se/

http://www.ncbi.nlm.nih.gov/pubmed/?term=Brodin%20T%5BAuthor%5D&cauthor=true&cauthor_uid=23413353

http://www.ncbi.nlm.nih.gov/pubmed/?term=Fick%20J%5BAuthor%5D&cauthor=true&cauthor_uid=23413353

http://www.ncbi.nlm.nih.gov/pubmed/?term=Jonsson%20M%5BAuthor%5D&cauthor=true&cauthor_uid=23413353

http://www.ncbi.nlm.nih.gov/pubmed/?term=Klaminder%20J%5BAuthor%5D&cauthor=true&cauthor_uid=23413353

http://www.ncbi.nlm.nih.gov/pubmed/23413353

http://www.helcom.fi/action-areas/monitoring-and-assessment/monitoring-and-assessment-strategy

http://www.helcom.fi/action-areas/monitoring-and-assessment/monitoring-and-assessment-strategy

https://portal.helcom.fi/meetings/PRESSURE%202-2015-240/MeetingDocuments/4-6%20Preparing%20a%20regional%20status%20report%20on%20pharmaceuticals%20in%20the%20marine%20environment.pdf





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Oaks, J. Lindsay; Gilbert, Martin; Virani, Munir Z.; Watson, Richard T.; Meteyer, Carol U.; Rideout, Bruce A.; Shivaprasad, H. L.; Shakeel Ahmed; Muhammad Jamshed Iqbal Chaudhry; Muhammad Arshad; Shahid Mahmood; Ahmad Ali and Aleem Ahmed Khan (2004) Diclofenac residues as the cause of vulture population decline in Pakistan’; Nature, 427, p. 630

Oskarsson H, Eriksson Wiklund A-K, Lindh K, Kumblad L (2012) Effect studies of human pharmaceuticals on Fucus vesiculosus and Gammarus spp. Marine Environmental Research, Vol. 74:1-8

Oskarsson H, Eriksson Wiklund A-K, Thorsén G, Danielsson G, Kumblad L (2014) Community Interactions Modify the Effects of Pharmaceutical Exposure: A Microcosm Study on Responses to Propranolol in Baltic Sea Coastal Organisms. PLoS ONE 9(4): e93774. doi:10.1371/journal.pone.0093774

Tema Nord (2012) PPCP monitoring in the Nordic Countries – Status report

Turja R, Lehtonen KK, Meierjohann A, Brozinski JM, Vahtera E, Soirinsuo A, Sokolov A, Snoeijs P, Budzinski H, Devier MH, Peluhet L, Pääkkönen JP, Viitasalo M, Kronberg L. (2015) The mussel caging approach in assessing biological effects of wastewater treatment plant discharges in the Gulf of Finland (Baltic Sea). Mar Pollut Bull. 97:135-49. doi: 10.1016/j.marpolbul.2015.06.024.

Viarengo, A., Canesi, L. (1991) Mussels as biological indicators of pollution. Aquaculture 94, 225–243.

Örtlund, L., Magnér, J., Wallberg, P. (2014) Self-declarations of environmental classification in www.fass.seexperiences from the reviewing process during 2013. IVL report.

References Internet http://www.helcom.fi/baltic-sea-trends/indicators 2015-10-23

http://www.ncbi.nlm.nih.gov/pubmed/?term=Turja%20R%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=Lehtonen%20KK%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=Meierjohann%20A%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=Brozinski%20JM%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=Vahtera%20E%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=Soirinsuo%20A%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=Sokolov%20A%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=Snoeijs%20P%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=Budzinski%20H%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=Devier%20MH%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=Peluhet%20L%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=P%C3%A4%C3%A4kk%C3%B6nen%20JP%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

http://www.ncbi.nlm.nih.gov/pubmed/?term=Viitasalo%20M%5BAuthor%5D&cauthor=true&cauthor_uid=26117817

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Appendix 1

Detected pharmaceuticals in the Baltic Sea 2003-2014

WATER

Pharmaceutical Concentration,

µg/l, *ng/passive sampler (not translatable to concentration per liter)

Location, name Location, HELCOM sub-basin, Level 2***

Location, HELCOM coastal area, Level 3

Reporting country

Analytical method

Reference

Acebutolol 8* Helsinki coast, 1000 m from Viikinmäki WWTP discharge pipe

SEA-013 13 FI Passive samplers (POCIS)

2

Acebutolol 4* Helsinki coast, 800 m from Viikinmäki WWTP discharge pipe


2

Amidotrizoic acid

0.125 Saaler Bodden SEA-006 33 DE 7

Amidotrizoic acid

0.079 Unterwarnow SEA-005 34 DE 7

Amidotrizoic acid


Amidotrizoic acid


Amidotrizoic acid


Amidotrizoic acid


Amidotrizoic acid

0.047 Barther Bodden SEA-006 33 DE 7

Amidotrizoic acid

0.047 Wismarbucht SEA-005 34 DE 7

Amidotrizoic acid

0.044 Greifswalder Bodden SEA-006 33 DE 7

Amidotrizoic acid


Amidotrizoic acid


Amidotrizoic acid

0.03 Kleines Haff SEA-007 30 DE 7

Amidotrizoic acid


Amidotrizoic acid

0.013 Pommersche Bucht SEA-007 0 DE 7

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Amidotrizoic acid

0.012 Barther Bodden SEA-006 33 DE 7

Amidotrizoic acid

0.011 Grabow SEA-006 33 DE 7

Atenolol 0.013 Unterwarnow SEA-005 34 DE 7

Atenolol 0.012 Unterwarnow SEA-005 34 DE 7

Atenolol 0.0011 Yttre Fjärden SEA-015 6 SE 3

Atenolol 0.0011 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Bisoprolol 0.128 Greifswalder Bodden SEA-006 33 DE 7

Bisoprolol 0.037 Unterwarnow SEA-005 34 DE 7

Bisoprolol 0.035 Arkonasee SEA-006 0 DE 7


Bisoprolol 0.026 Pommersche Bucht SEA-007 0 DE 7

Bisoprolol 0.025 Kleines Haff SEA-007 30 DE 7


Bisoprolol 0.021 Wismarbucht SEA-005 34 DE 7









Bisoprolol 0.014 Barther Bodden SEA-006 33 DE 7








59 (88)







Bisoprolol 39* Helsinki coast, 1000 m from Viikinmäki WWTP discharge pipe


2

Bisoprolol 19* Helsinki coast, 800 m from Viikinmäki WWTP discharge pipe


2

Bisoprolol 5* Helsinki coast, 4000 m east from Viikinmäki WWTP discharge pipe (reference)


2

Carbamazepine 0.073 Kleines Haff SEA-007 30 DE 7













Carbamazepine 0.037 Greifswalder Bodden SEA-006 33 DE 7



Carbamazepine 0.034 Arkonasee SEA-006 0 DE 7

Carbamazepine 0.033 Unterwarnow SEA-005 34 DE 7

Carbamazepine 0.032 Pommersche Bucht SEA-007 30 DE 7



60 (88)











Carbamazepine 0.018 Andershofer Bucht SEA-006 33 DE 7




Carbamazepine 0.0157 CE1412B_ODER,0005LA SEA-007 0 DE LC-MS/MS 1


Carbamazepine 0.013 Barther Bodden SEA-006 33 DE 7


Carbamazepine 0.013 Saaler Bodden SEA-006 33 DE 7

Carbamazepine 0.0122 AL365_ODER,0005LA SEA-007 0 DE LC-MS/MS 1



Carbamazepine 0.012 Grabow SEA-006 33 DE 7






Carbamazepine 0.01 Wismarbucht SEA-005 34 DE 7


Carbamazepine 0.0075 AL385B_ODER,0004LA SEA-007 0 DE LC-MS/MS 1

Carbamazepine 0.0072 AL430_ODER,0004LA SEA-007 0 DE LC-MS/MS 1


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Carbamazepine 0.0045 AL430_113,0004LA SEA-006 0 DE LC-MS/MS 1

Carbamazepine 0.0038 AL407A_152,0004LA SEA-006 0 DE LC-MS/MS 1


Carbamazepine 0.0037 HE316_152,0004LA SEA-006 0 DE LC-MS/MS 1





Carbamazepine 0.0033 CE1412B_OMBMPK4,0005LA SEA-006 0 DE LC-MS/MS 1


Carbamazepine 0.0031 Yttre Fjärden SEA-015 6 SE 3


Carbamazepine 0.0031 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Carbamazepine 0.003 CE1412B_OMBMPM1,0005LA

SEA-005 0 DE LC-MS/MS 1



Carbamazepine 0.003 CE1412B_OMBMPM2,0005LA


Carbamazepine 0.0029 CE1412B_OMBMPN1,0005LA





Carbamazepine 0.0026 CE1412B_BSH2,0005LA SEA-005 0 DE LC-MS/MS 1




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Carbamazepine 0.0026 AL385B_152,0004LA SEA-006 0 DE LC-MS/MS 1













Carbamazepine 0.0024 CE1412B_OMBMPN3,0005LA


Carbamazepine 0.0023 MM0803_66,0006LA SEA-006 0 DE LC-MS/MS 1





Carbamazepine 0.002 MM0803_65B,0006LA SEA-006 0 DE LC-MS/MS 1


Carbamazepine 0.0019 MM0803_65A,0006LA SEA-007 0 DE LC-MS/MS 1











63 (88)















Carbamazepine 0.0006 MM0803_BB3,0006LA SEA-017 0 DE LC-MS/MS 1


Carbamazepine 232* Helsinki coast, 1000 m from Viikinmäki WWTP discharge pipe


2

Carbamazepine 232* Helsinki coast, 800 m from Viikinmäki WWTP discharge pipe


2

Carbamazepine 147* Helsinki coast, 4000 m east from Viikinmäki WWTP discharge pipe (reference)


2

Citalopram 0.00023 Yttre Fjärden SEA-015 6 SE 3

Citalopram 0.00023 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Clarithromycin 0.00027 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Clarithromycin 0.00027 Yttre Fjärden SEA-015 6 SE 3

Clindamycin 0.00038 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Clindamycin 0.00038 Yttre Fjärden SEA-015 6 SE 3

Clofibric acid (metabolite of

0.0004 GA442_ARKO2,0005LA SEA-006 0 DE LC/MS-MS 1

64 (88)

Clofibrate)

Clofibric acid (metabolite of Clofibrate)

0.0004 GA442_KALKGR,0005LA SEA-002 38 DE LC/MS-MS 1


0.0004 GA442_ARKO3,0005LA SEA-006 0 DE LC/MS-MS 1


0.0004 GA442_DARSS2,0005LA SEA-006 0 DE LC/MS-MS 1


0.0002 MM0803_62,0006LA SEA-010 0 DE LC/MS-MS 1


0.0002 GA439_213/2,0005LA SEA-007 0 DE LC/MS-MS 1


0.0002 GA439_113,0005LA SEA-006 0 DE LC/MS-MS 1


0.0002 AL331_113,0004LA SEA-006 0 DE LC/MS-MS 1




0.0002 GA421_25A,0005LA SEA-006 0 DE LC/MS-MS 1


0.0002 GA439_ODER,0005LA SEA-007 0 DE LC/MS-MS 1














0.0002 AL365_ODER,0005LA SEA-007 0 DE LC/MS-MS 1

65 (88)

Clofibrate)








0.0001 AL385B_30,0004LA SEA-006 0 DE LC/MS-MS 1




0.0001 AL407A_30,0004LA SEA-006 0 DE LC/MS-MS 1




0.0001 HE316_113,0004LA SEA-006 0 DE LC/MS-MS 1



















66 (88)

Clofibrate)


































0.0001 MM0803_65B,0006LA SEA-006 0 DE LC/MS-MS 1

67 (88)

Clofibrate)








0.0001 MM0803_65A,0006LA SEA-007 0 DE LC/MS-MS 1



























68 (88)

Clofibrate)
















0.0001 AL385B_ODER,0004LA SEA-007 0 DE LC/MS-MS 1


0.000047660001

AL407A_360,0004LA SEA-004 0 DE LC/MS-MS 1




0.000041730002





0.000026149999



0.000025969751

MM0803_BB3,0006LA SEA-017 0 DE LC/MS-MS 1

Clotrimazole 0.00042 Yttre Fjärden SEA-015 6 SE 3

Clotrimazole 0.00042 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Diclofenac 0.054 Wismarbucht SEA-005 34 DE 7

69 (88)

Diclofenac 0.04 Arkonasee SEA-006 0 DE 7

Diclofenac 0.0271 AL365_46,0005LA SEA-005 0 DE LC-MS/MS 1

Diclofenac 0.014 Wismarbucht SEA-005 34 DE 7

Diclofenac 0.0134 AL365_ODER,0005LA SEA-007 0 DE LC-MS/MS 1

Diclofenac 0.013 Strelasund SEA-006 33 DE 7

Diclofenac 0.0033 MM0803_57,0006LA SEA-012 0 DE LC-MS/MS 1

Diclofenac 0.0028 HE316_10,0004LA SEA-004 0 DE LC-MS/MS 1

Diclofenac 0.002 AL385B_ODER,0004LA SEA-007 0 DE LC-MS/MS 1

Diclofenac 0.002 Mellanfjärden SEA-012 11 SE 5

Diclofenac 0.0015 AL430_ODER,0004LA SEA-007 0 DE LC-MS/MS 1




Diclofenac 0.0006 AL407A_360,0004LA SEA-004 0 DE LC-MS/MS 1













Diclofenac 0.0002 AL385B_152,0004LA SEA-006 0 DE LC-MS/MS 1







70 (88)




























Diclofenac 0.000045512669

AL385B_109,0004LA SEA-006 0 DE LC-MS/MS 1


MM0803_62,0006LA SEA-010 0 DE LC-MS/MS 1



71 (88)



MM0803_65B,0006LA SEA-006 0 DE LC-MS/MS 1


MM0803_65A,0006LA SEA-007 0 DE LC-MS/MS 1



Diclofenac 33* Helsinki coast, 800 m from Viikinmäki WWTP discharge pipe


2

Diclofenac 25* Helsinki coast, 1000 m from Viikinmäki WWTP discharge pipe


2

Dipyridamole 0.0028 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Dipyridamole 0.0028 Yttre Fjärden SEA-015 6 SE 3

Estradiol 0.0011 Hamnbassängen Oskarshamn

0 SE 14

Ethinylestradiol 0.00036 Göta Älv Hjärtholmen Göteborg

0 SE 14

Ethinylestradiol 0.00012 Edeboviken 1 Hallstavik 0 SE 14

Ibuprofen 0.158 Wismarbucht SEA-005 34 DE 7

Ibuprofen 0.11 Unterwarnow SEA-005 34 DE 7

Ibuprofen 0.089 Kleines Haff SEA-007 30 DE 7

Ibuprofen 0.031 Unterwarnow SEA-005 34 DE 7

Ibuprofen 0.03 Arkonasee SEA-006 0 DE 7

Ibuprofen 0.011 Mellanfjärden SEA-012 11 SE 5

Ibuprofen 0.01 Grabow SEA-006 33 DE 7

Ibuprofen 0.0074 Sandholmen SEA-017 2 SE 6

Ibuprofen 0.0061 South Sandholmen SEA-017 2 SE 6

Ibuprofen 0.0015 Pitsund 0 SE 6

Ibuprofen 0.0011 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Ibuprofen 0.0011 Yttre Fjärden SEA-015 6 SE 3

Ibuprofen 0.00077 Sandholmen SEA-017 2 SE 6

72 (88)

Ibuprofen 0.00048 Hemlunda SEA-017 2 SE 6

Ibuprofen 0.0003 South Sandholmen SEA-017 2 SE 6

Ibuprofen 0.0003 Hemlunda SEA-017 2 SE 6

Ibuprofen 0.00025 Pitsund 0 SE 6

Ibuprofen 12* Helsinki coast, 1000 m from Viikinmäki WWTP discharge pipe


2

Ibuprofen-COOH 0.0058 Sandholmen SEA-017 2 SE 6

Ibuprofen-COOH 0.0049 South Sandholmen SEA-017 2 SE 6

Ibuprofen-COOH 0.0039 Hemlunda SEA-017 2 SE 6

Ibuprofen-COOH 0.0013 Pitsund 0 SE 6

Ibuprofen-COOH 0.00063 Sandholmen SEA-017 2 SE 6

Ibuprofen-COOH 0.00051 South Sandholmen SEA-017 2 SE 6

Ibuprofen-COOH 0.0005 Pitsund 0 SE 6

Ibuprofen-OH 0.0061 Sandholmen SEA-017 2 SE 6

Ibuprofen-OH 0.0049 South Sandholmen SEA-017 2 SE 6

Ibuprofen-OH 0.0016 Pitsund 0 SE 6

Ibuprofen-OH 0.0012 South Sandholmen SEA-017 2 SE 6

Ibuprofen-OH 0.0012 Sandholmen SEA-017 2 SE 6

Ibuprofen-OH 0.0005 Pitsund 0 SE 6

Iopamidol 0.09 Wismarbucht SEA-005 34 DE 7

Iopamidol 0.065 Pommersche Bucht SEA-007 0 DE 7

Irbesartan 0.00115 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Ketoprofen 0.0088 Mellanfjärden SEA-012 11 SE 5

Ketoprofen 0.0017 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Ketoprofen 0.0017 Yttre Fjärden SEA-015 6 SE 3

Ketoprofen 0.0012 Sandholmen SEA-017 2 SE 6

Ketoprofen 0.0012 South Sandholmen SEA-017 2 SE 6

Ketoprofen 20* Helsinki coast, 1000 m from Viikinmäki WWTP discharge pipe


2

Metoprolol 0.055 Wismarbucht SEA-005 34 DE 7

73 (88)

Metoprolol 0.042 Pommersche Bucht SEA-007 0 DE 7

Metoprolol 0.037 Unterwarnow SEA-005 34 DE 7


Metoprolol 0.024 Arkonasee SEA-006 0 DE 7

Metoprolol 0.018 Kleines Haff SEA-007 30 DE 7













Metoprolol 0.0016 Yttre Fjärden SEA-015 6 SE 3

Metoprolol 0.0016 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Metoprolol 40* Helsinki coast, 1000 m from Viikinmäki WWTP discharge pipe


2

Metoprolol 25* Helsinki coast, 800 m from Viikinmäki WWTP discharge pipe


2

Metoprolol 8* Helsinki coast, 4000 m east from Viikinmäki WWTP discharge pipe (reference)


2

Naproxen 39 Helsinki coast, 1000 m from Viikinmäki WWTP discharge pipe


2

Naproxen 0.014 Wismarbucht SEA-005 34 DE 7

Naproxen 0.01 Mellanfjärden SEA-012 11 SE 5

Naproxen 0.0056 Sandholmen SEA-017 2 SE 6

Naproxen 0.0055 South Sandholmen SEA-017 2 SE 6

74 (88)

Naproxen 0.0017 Yttre Fjärden SEA-015 6 SE 3

Naproxen 0.0017 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Naproxen 0.0012 Pitsund 0 SE 6

Naproxen 0.00046 Hemlunda SEA-017 2 SE 6

Naproxen 12* Helsinki coast, 800 m from Viikinmäki WWTP discharge pipe


2

Oxazepam 0.0019 AL365_ODER,0005LA SEA-007 0 DE 1

Oxazepam 0.00085 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 6

Oxazepam 0.00085 Yttre Fjärden SEA-015 6 SE 3

Oxazepam 0.0007 AL385B_ODER,0004LA SEA-007 0 DE 1

Oxazepam 0.0004 MM0803_52,0006LA SEA-013 0 DE 1

Oxazepam 0.0004 AL365_360,0005LA SEA-004 0 DE 1

Oxazepam 0.0003 AL385B_30,0004LA SEA-006 0 DE 1


Oxazepam 0.0003 HE316_360,0004LA SEA-004 0 DE 1


Oxazepam 0.0003 AL385B_360,0004LA SEA-004 0 DE 1

Paracetamol 0.36 South Sandholmen SEA-017 2 SE 6

Paracetamol 0.22 Sandholmen SEA-017 2 SE 6

Paracetamol 0.17 Hemlunda SEA-017 2 SE 6

Paracetamol 0.11 Pitsund 0 SE 6

Phenazone 0.504 Pommersche Bucht SEA-007 0 DE 7

Phenazone 0.103 Wismarbucht SEA-005 34 DE 7

Phenazone 0.065 Unterwarnow SEA-005 34 DE 7

Phenazone 0.058 Pommersche Bucht SEA-007 0 DE 7

Phenazone 0.034 Wismarbucht SEA-005 34 DE 7

Primidone 0.0058 AL365_ODER,0005LA SEA-007 0 DE LC-MS/MS 1

Primidone 0.004 AL365_109,0005LA SEA-006 0 DE LC-MS/MS 1



75 (88)

Primidone 0.0037 AL385B_ODER,0004LA SEA-007 0 DE LC-MS/MS 1




Primidone 0.0035 AL385B_109,0004LA SEA-006 0 DE LC-MS/MS 1










Primidone 0.0024 MM0803_65A,0006LA SEA-007 0 DE LC-MS/MS 1

Primidone 0.0024 MM0803_66,0006LA SEA-006 0 DE LC-MS/MS 1



Primidone 0.0024 MM0803_65B,0006LA SEA-006 0 DE LC-MS/MS 1




Primidone 0.0022 HE316_152,0004LA SEA-006 0 DE LC-MS/MS 1











76 (88)














Primidone 0.0011 MM0803_BB3,0006LA SEA-017 0 DE LC-MS/MS 1

Rosuvastatin 0.00062 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Rosuvastatin 0.00062 Yttre Fjärden SEA-015 6 SE 3

Salicylic Acid 0.014 Sandholmen SEA-017 2 SE 6

Salicylic Acid 0.012 Hemlunda SEA-017 2 SE 6

Salicylic Acid 0.011 South Sandholmen SEA-017 2 SE 6

Salicylic Acid 0.01 Pitsund 0 SE 6

Sertraline 0.0121 Mellanfjärden SEA-012 11 SE 15

Sotalol 0.024 Unterwarnow SEA-005 34 DE 7

Sotalol 0.006 Pommersche Bucht SEA-007 30 DE 7

Sotalol 0.005 Pommersche Bucht SEA-007 30 DE 7

Sotalol 0.00024 Yttre Fjärden SEA-015 6 SE 3

Sotalol 0.00024 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Sulfamethoxazole


Sulfamethoxazole


Sulfamethoxazol 0.02 Kleines Haff SEA-007 30 DE 7

77 (88)

e

Sulfamethoxazole


Sulfamethoxazole


Sulfamethoxazole


Sulfamethoxazole


Sulfamethoxazole


Sulfamethoxazole


Sulfamethoxazole


Sulfamethoxazole


Sulfamethoxazole


Tramadol 0.00069 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Tramadol 0.00069 Yttre Fjärden SEA-015 6 SE 3

Trimethoprim 0.00023 Yttre Fjärden SEA-015 6 SE 3

Trimethoprim 0.00023 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

Venlafaxine 25* Helsinki coast, 1000 m from Viikinmäki WWTP discharge pipe


2

Venlafaxine 14* Helsinki coast, 800 m from Viikinmäki WWTP discharge pipe


2

Venlafaxine 0.001 Yttre Fjärden SEA-015 6 SE 3

Venlafaxine 0.001 Yttre Fjärden-Surface sea water 3 km downstream of WWTP outlet from city of Gävle.

SEA-015 6 SE 3

References

1 BSH Bundesamt für Seeschifffahrt und Hydrographie

78 (88)

2 Turja R., Lehtonen K.K., Meierjohann A., Brozinski J.-M., Vahtera E., Soirinsuo A., Sokolov A., Snoeijs P., Budzinski H., Devier M.-H., Peluhet L., Pääkkönen J.-P., Viitasalo M., Kronberg L. (2015). Marine Pollution Bulletin 97(1-2):135-49.

3 Löfgren, H. and Gottby, L. (2012). Miljögifter i Gävleborg, resultat från verifieringar 2009 – 2011. Rapport 2012:4, Länsstyrelsen Gävleborg.

4 Törneman, N., Hallgren, P. and Bjarke M. (2014). Screening Report 2013. Occurrence of additional WFD priority substances in Sweden. Sweco Environment AB, on assignment from the Swedish Environmental Protection Agency.

5 Andersson, J., Woldegiorgis, A., Remberger, M., Kaj, L., Ekheden, Y., Dusan, B., Svenson, A., Brorström-Lundén, E., Dye, C. and Schlabach, M. (2006). Results from the Swedish national screening programme 2005. Subreport 1: Antibiotics, anti-inflammatory

6 Remberger, M., Wiklund, P., Woldegiorgis, A., Viktor, T., Kaj, L. and Brorström-Lundén, E. (2009). Anti-inflammatory and analgesic drugs in WWTP influent and effluent streams and the occurrence in the aquatic environment. Report B1810 from the Swedish En

7 State Agency of Environment, Nature Protection and Geology of Mecklenburg-Vorpommern

POCIS Polar Organic Chemical Integrative Sampler

LC-MS/MS Liquid chromatography-tandem mass spectrometry

*** missing area code means that the sample point is just outside the defined borders of the sub-basin

79 (88)

Appendix 2


SEDIMENT

Pharmaceutical Concentration, µg/kg dw

Location, name Location, HELCOM sub-basin, Level 2***


Reporting country

Analytical method

Reference

Diclofenac 3,5 Hemlunda SEA-017 2 SE 3

Diclofenac 3,1 Pitsund 0 SE 3

Diclofenac 0,85 South Sandholmen SEA-017 2 SE 3

Diclofenac 0,19 Sandholmen SEA-017 2 SE 3

Ibuprofen 45 Tallinn_sed2 SEA-013 14 EE LC-MS-MS/GC-MSD

2

Ibuprofen 11 Pärnu_sed2 SEA-011 16 EE LC-MS-MS/GC-MSD

2

Ibuprofen 6 Sandholmen SEA-017 2 SE 3

Ibuprofen 0,97 Hemlunda SEA-017 2 SE 3

Ibuprofen 0,74 Pitsund 0 SE 3

Ibuprofen 0,21 South Sandholmen SEA-017 2 SE 3

Naproxen 0,31 Pitsund 0 SE 3

Naproxen 0,29 Hemlunda SEA-017 2 SE 3

Paracetamol 69 Hemlunda SEA-017 2 SE 3

Paracetamol 64 Pitsund 0 SE 3

Paracetamol 42 South Sandholmen SEA-017 2 SE 3

Paracetamol 18 Sandholmen SEA-017 2 SE 3

Salicylic Acid 3,9 Pitsund 0 SE 3

Salicylic Acid 3,6 Hemlunda SEA-017 2 SE 3

Salicylic Acid 0,9 Sandholmen SEA-017 2 SE 3

Salicylic Acid 0,5 South Sandholmen SEA-017 2 SE 3

Sulfadiazine 47 Turku archipelago, Fish farm "FIN2"

SEA-014 9 FI 1

Sulfadiazine 23 Turku archipelago, Fish farm "FIN2"

SEA-014 9 FI 1

80 (88)

Sulfadiazine 3,2 Turku archipelago, Fish farm "FIN1"

SEA-014 9 FI 1

Sulfadiazine 2,3 Turku archipelago, Fish farm "FIN1"

SEA-014 9 FI 1

Sulfamethoxazole

101 Turku archipelago, Fish farm "FIN2"

SEA-014 9 FI 1

Sulfamethoxazole

41 Turku archipelago, Fish farm "FIN2"

SEA-014 9 FI 1

Sulfamethoxazole

7,1 Turku archipelago, Fish farm "FIN1"

SEA-014 9 FI 1

Sulfamethoxazole

3,6 Turku archipelago, Fish farm "FIN1"

SEA-014 9 FI 1

Trimethoprim 8,9 Turku archipelago, Fish farm "FIN2"

SEA-014 9 FI 1


SEA-014 9 FI 1


SEA-014 9 FI 1

References

1 Muziasari W. I., Managaki S., Pärnänen K., Karkman A., Lyra C., Tamminen M., Suzuki S., Virta M. (2014). Sulphonamide and Trimethoprim Resistance Genes Persist in Sediments at Baltic Sea Aquaculture Farms but Are Not Detected in the Surrounding Environment.

2 Estonian Environmental Research Centre (2012). Euroopa Liidu prioriteetsete ainete nimekirja potentsiaalsete uute ainete esinemise uuring Eesti pinnaveekogudes II

3 Remberger, M., Wiklund, P., Woldegiorgis, A., Viktor, T., Kaj, L. and Brorström-Lundén, E. (2009). Anti-inflammatory and analgesic drugs in WWTP influent and effluent streams and the occurrence in the aquatic environment. Report B1810 from the Swedish Environmental Research Institute IVL

LC-MS-MS Liquid Chromatography-tandem Mass Spectrometry

GC-MSD Gas Chromatography-Mass Selective Detector


81 (88)

Appendix 3


BIOTA

Pharmaceutical Concentration, µg/kg ww

Location, name sample type

Location, HELCOM sub-basin, Level 2***


Reporting country

Analytical method

Reference

Alfuzosin 13,08 Askeröfjorden eel, muscle

0 SE 2

Alfuzosin 5,7 Askeröfjorden flounder, muscle

0 SE 2

Alprazolam 19,46 Askeröfjorden eel, muscle

0 SE 2

Atorvastatin 1,7 Askeröfjorden eel, muscle

0 SE 2

Bisoprolol 102,4 Askeröfjorden blue mussel

0 SE 2

Bromocriptine 108,78 Askeröfjorden blue mussel

0 SE 2

Carbamazepine 140,68 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Chlorpromazine 7,1 Askeröfjorden flounder, muscle

0 SE 2

Cilazapril 8,7 Askeröfjorden blue mussel

0 SE 2

Ciprofloxacin 8,5 Kalmarsund Atlantic cod, muscle

SEA-010

18 SE HPLC 3

Ciprofloxacin 7,9 Gothenburg, Swedish west coast

Atlantic cod, muscle

SEA-001

41 SE HPLC 3

Ciprofloxacin 7 Gothenburg, Swedish west coast

Atlantic cod, muscle

SEA-001

41 SE HPLC 3

Clemastine 3,1 Askeröfjorden eel, muscle

0 SE 2

Clonazepam 13,1 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Clotrimazole 76,88 Askeröfjorden flounder, muscle

0 SE 2

82 (88)

Codeine 83,26 Askeröfjorden flounder, muscle

0 SE 2

Cyproheptadine 8,1 Askeröfjorden blue mussel

0 SE 2

Diclofenac 5,2 Käppala European perch, bile

SEA-012

11 SE UFLC 1


SEA-012

11 SE UFLC 1


SEA-012

11 SE UFLC 1


SEA-012

11 SE UFLC 1


SEA-012

11 SE UFLC 1

Dicycloverine 25,84 Askeröfjorden eel, muscle

0 SE 2

Dicycloverine 6,7 Askeröfjorden flounder, muscle

0 SE 2

Dihydroergotamine

32,22 Askeröfjorden eel, muscle

0 SE 2

Diphenhydramine

153,44 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Dipyridamole 159,82 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Donepezil 2,7 Askeröfjorden eel, muscle

0 SE 2

Duloxetine 89,64 Askeröfjorden blue mussel

0 SE 2

Eprosartan 96,02 Askeröfjorden blue mussel

0 SE 2

Erythromycin 12,7 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Etonogestrel 7,7 Askeröfjorden blue mussel

0 SE 2

Felodipine 147,06 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Felodipine 64,12 Askeröfjorden flounder, muscle

0 SE 2

83 (88)

Fluoxetine 4,1 Askeröfjorden eel, muscle

0 SE 2

Flutamide 14,1 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Haloperidol 6,1 Askeröfjorden flounder, muscle

0 SE 2

Ibuprofen 2,4 Käppala European perch, bile

SEA-012

11 SE UFLC 1

Irbesartan 38,6 Askeröfjorden eel, muscle

0 SE 2

Irbesartan 10,1 Askeröfjorden blue mussel

0 SE 2

Ketoconazol 70,5 Askeröfjorden flounder, muscle

0 SE 2

Ketoconazol 9,7 Askeröfjorden blue mussel

0 SE 2

Loperamide 166,2 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Maprotiline 172,58 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Maprotiline 3,7 Askeröfjorden flounder, muscle

0 SE 2

Memantine 1,1 Askeröfjorden eel, muscle

0 SE 2

Mianserin 13,7 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Miconazol 115,16 Askeröfjorden blue mussel

0 SE 2

Mirtazapine 121,54 Askeröfjorden blue mussel

0 SE 2

Norfloxacin 9,1 Askeröfjorden blue mussel

0 SE 2

Orphenadrine 0,32 Askeröfjorden eel, muscle

0 SE 2

Oxazepam 6,7 Askeröfjorden eel, muscle

0 SE 2

Oxazepam 1,2 Käppala European perch, bile

SEA-012

11 SE UFLC 1


SEA-012

11 SE UFLC 1

84 (88)

Oxazepam 0,38 Gällnö European perch, bile

SEA-012

11 SE UFLC 1


SEA-012

11 SE UFLC 1


SEA-012

11 SE UFLC 1


SEA-012

11 SE UFLC 1


SEA-012

11 SE UFLC 1


SEA-012

11 SE UFLC 1

Paroxetine 5,1 Askeröfjorden flounder, muscle

0 SE 2

Pizotifen 0,7 Askeröfjorden eel, muscle

0 SE 2

Ranitidine 15,1 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Ranitidine 11,1 Askeröfjorden blue mussel

0 SE 2

Sertraline 11,7 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Sertraline 0,7 Käppala European perch, bile

SEA-012

11 SE UFLC 1

Sulfamethoxazole

51,36 Askeröfjorden flounder, muscle

0 SE 2

Tamoxifen 57,74 Askeröfjorden flounder, muscle

0 SE 2

Tramadol 178,96 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Tramadol 127,92 Askeröfjorden blue mussel

0 SE 2

Trihexyphenidyl 185,34 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Trihexyphenidyl 134,3 Askeröfjorden blue mussel

0 SE 2

Trihexyphenidyl 4,7 Askeröfjorden flounder, muscle

0 SE 2

85 (88)

Venlafaxine 2,1 Askeröfjorden eel, muscle

0 SE 2

Zolpidem 44,98 Askeröfjorden blue mussel

0 SE 2

Zolpidem 14,7 Ryaverket, 6,5 km nedströms utsläpp

blue mussel

SEA-001

41 SE 2

Zolpidem 10,7 Askeröfjorden 0 SE 2

References

1 Karlsson, M. and Viktor, T. (2014). Miljöstörande ämnen i fisk från Stockholmsregionen 2013. Report B2214 from the Swedish Environmental Research Institute IVL.

2 Fick, J., Lindberg, R.H., Kaj, L. and Brorström-Lundén, E. (2011). Results from the Swedish national screening programme 2010. Sub-report 3: Pharmaceuticals. Report B2014 from the Swedish Environmental Research Institute IVL.

3 Johansson, M., Lindberg, R., Wennberg, P. and Tysklind, M. (2003). Redovisning från nationell miljöövervakning 2003. Screening av antibiotika i avloppsvatten, slam och fisk under 2002/2003. Miljökemi, Umeå Universitet.

HPLC - High-performance Liquid Chromatography

UFLC - Ultra Fast Liquid Chromatography


86 (88)

87 (88)

Background report on pharmaceutical concentrations and effects in the Baltic Sea This report has been published with financial support from the Interreg Baltic Sea Region Programme 2014 to 2020 via the Swedish Environmental Protection Agency (SEPA) in its capacity as the coordinator of the Policy Area Hazards of the EU Strategy for the Baltic Sea Region. HELCOM Contracting Parties have contributed with data to this background report. The contents of this working paper do not necessarily reflect the views, policies or recommendations of SEPA or HELCOM. The report has not been reviewed by HELCOM Working Groups. The report was written by Pär Hallgren and Petra Wallberg (Sweco Environment AB). Graphic production by Christoph Kircher (Sweco Position AB) and Lisa Sjölund (Sweco Position AB). The project was managed by Jenny Hedman, the Swedish EPA.

Policy Area Hazards

Policy Area Hazards - Prevent pollution and reduce the use of hazardous substances in the Baltic Sea Region – provides a platform for cooperation, contribute to regional policy development and act as a link between policy and implementation to reduce the input of hazardous substances to the Baltic Sea. A part of the

European Union Strategy for the Baltic Sea Region (EUSBSR), the first macro-regional strategy in Europe.