This pre-core test indicator and its threshold values are yet to be commonly agreed in HELCOM and the presented thresholds are furthermore not currently approved EQS values, but provisional proposals. The indictor is included as a test indicator for the purposes of the 'State of the Baltic Sea' report, and the results are to be considered as intermediate.
A major source of pharmaceuticals in the environment is the excretion of active substances consumed by humans (and animals). Diclofenac enters WWTPs and is subsequently transferred to rivers and the marine environment, where biota can consequently be exposed. Current data indicate that in many instances pharmaceuticals, including diclofenac, are not effectively degraded in conventional WWTPs and are sufficiently persistent to pass through treatment processes and reach surface waters (Tixier et al., 2003). However, other sources have been shown or suggested, including the recreational use of waters (especially in lakes and rivers, Atlasi et al 2012) and the spreading of WWTP sludges on land (Lindim et al., 2016). Sources such as hospitals, pharmaceutical manufacturers, sewer overflow or leakage, septic tanks, agriculture and storm water run-off are also relevant to consider as potential pathways of introduction to the Baltic Sea.
The sections described below are considered to be potentially relevant compartments to analyse diclofenac for the evaluation of environmental status. A combined approach using monitoring or assessment of one or several of these may provide the most appropriate indicator approach.
In the HELCOM BASE pilot project sales statistics were collected for Russia on 87 pharmaceutical preparations registered for use in 2009-2010, including diclofenac. Calculations were made to estimate the total usage of diclofenac in the St.Petersburg region (HELCOM 2014). Four major forms of diclofenac containing pharmaceutical products were sold: creams, injections, pills and suppositories.
Sales of Non-Steroid Anti-Inflammatory creams for topical (external) application during one year (May 2012-April 2013) in Russia totalled 33.9 million packages. Voltaren and Diclak were the two leading products sold, with 4.7 million packages each. One 20 g unit of 1% Voltaren Gel contains 0.2 g diclofenac, with larger packages of 50g, 75g and 100 g also available on the market. Diclak gel is available as similar packages with a 1% concentration and as a 5% preparation in 50 g tubes. Yearly sales of Diclak corresponds to 2.13 tonnes of diclofenac. However, the proportion of Diklak sold with an active ingredient of either 5% or 1% is not known. Therefore, the total consumption of diclofenac for external application is estimated from these data as 14 million units per year, or 2.8 tonnes. Based on calculations, the external application use of diclofenac in St. Petersburg is estimated at 170 kg. Sales of pills, injections and suppositories by three leading brands are shown in Results table 1. The total annual consumption of diclofenac through pharmaceutical preparations other than creams for topical application is estimated at 20 tonnes, with an estimated sale of 27 million diclofenac units in 2011. In 2010 hospitals purchased 900,000 packages for injections and <100,000 in the form of pills, totalling an annual consumption of 20 tonnes (HELCOM 2014).
Results table 1. Indicative annual consumption of three brands of pharmaceutical preparations containing diclofenac in Russia (reproduced from HELCOM 2014).
(number of items)
Based on the above data the consumption of these pharmaceutical preparations for the St. Petersburg area is estimated to be 700 kg per annum. If all the diclofenac were to enter the sewage system, the concentrations could reach 850 ng/L (HELCOM 2014).
Similarly, in a recent data compilation covering reported data that encompassed circa 25% of the Baltic Sea catchment population it was estimated that diclofenac was amongst the 20 most sold pharmaceuticals in the region, with sales of >12 t /year (Unesco and HELCOM, 2017). In other studies changes in national consumption have also been documented, with a general increase in sales being observed (Baranauskaitė and Dvarionienė, 2014), though in instances were legislation has changed the opposite trend has also been observed (Lember et al., 2016).
Other trends in sales can also offer interesting insights into diclofenac usage that may be relevant for understanding how it is discharged into the environment. A summary of sales in Sweden between 2010 and 2016 indicated that while prescribed medication decreased the total sales value of diclofenac (kg) remained somewhat stable, with sales of non-prescribed medication increasing (Results figure 1).
Results figure 1. Annual sales value of diclofenac (kg) for the whole of Sweden, 2010-2016 as provided by the Swedish Medical Products Agency.
The modelling of diclofenac sales/usage, in conjunction with other variables such as WWTP removal rates, has also been successfully utilised in recent studies to estimate river area exceeding European environmental quality standards (Johnson et al., 2013), to consider future challenges in management (Baranauskaitė and Dvarionienė, 2014), and to follow annual trends and predict discharges to the Baltic Sea (Lember et al., 2016) or river basins (Lindim et al., 2016). The latter study was followed up with a detailed prediction on discharges to the Baltic Sea, including gaining high correlations with measured environmental data from the Stockholm region where wastewater effluent is discharged to the Baltic without significant river transport (Lindim et al., 2017).
Information on the sale of diclofenac is considered to be a potentially relevant proxy to be used in the evaluation of environmental status. However, reporting would be required for the entire catchment region and some understanding of the discrepancy between sales and use may need to be developed, as well as the consideration seasonal aspects (e.g. elevated usage during winter months) and population demographics (e.g. age).
Diclofenac was regularly detected amongst the 20 highest pharmaceutical concentrations in WWTP waters and sludges (Results table 2), and conventional treatment methods generally showed no major removal of it during processing, circa 1% from the aqueous phase (Unesco and HELCOM, 2017). Low removal patterns in WWTPs have generally been observed previously, where concentrations of diclofenac decreased by 11 and 28% between influent and effluent waters (Andersson et al. 2006, Fick et al. 2011; Miljøministeriet, Naturstyrelsen, 2015), and in some cases effluent concentrations were higher than those in the influent waters (HELCOM 2014, Zorita et al., 2009). It has also been suggested that diclofenac may be capable of altering microbial communities within WWTPs with consequent effects of WWTP function (Kraigher et al., 2008). Moreover, recent studies comparing WWT processes have shown there to be a wide range of removal rates dependent on the type of process employed and that environmental conditions at or surrounding individual WWTPs may have an influence (reviewed in Vieno and Sillanpää, 2014 and Lonappan et al., 2016). This phenomenon might be explained by the liberation of diclofenac from conjugated metabolites during bacterial treatment (HELCOM 2014), or by re-solubilisation of sediment/sludge associated diclofenac. In other words, diclofenac is partially present in the sewage in a conjugated form, due to the metabolic processes in the organism that first ingested the substance, the conjugates not being formed during the WWTP process (Peres and Bacrelo 2008), and may result in a re-release of diclofenac into the environment (Zorita et al., 2009).
Results table 2. Diclofenac concentrations from screening studies, scientific literature and data compilations. Ranges are given where data are from extensive spatial or temporal collection.
Means of 60-370
Means of 30-370
Mean: 939 Maximum: 3000
Mean: 368 Maximum: 933
Mean: 260 Maximum: 360
Means of 250-800
Mean: 884 Maximum: 2000
Mean: 1124 Maximum: 2755
Mean: 359 Maximum: 710
Means of 1000-2250
Unesco and HELCOM, 2017
Lindholm-Lehto et al., 2016
Äystö et al., 2014
Mean: 420 Maximum: 640
Mean: 810, Maximum: 2100
Mean: 3290, Maximum: 13000
Mean: 2444, Maximum: 4300
Ternes et al. 2003
Quintana & Reemtsma 2004
Unesco and HELCOM, 2017
Monitoring (2016) HELCOM DATA CALL
Means of 429-3280
Muter et al., 2017.
Mean 676 Maximum 7000
Mean 158 Maximum 510
Mean 334 Maximum 5000
Lilja et al. 2010
Andersson et al. 2006
Fick et al. 2011
Remberger et al. 2009
Bendz et al. 2005
Breitholtz et al., 2012*
Zorita et al., 2009
Fick et al., 2015
Haglund, 2017 - unpublished.
Mean 408 Maximum 741
Means of 350-620
Mean 355 Maximum 514
Means of 510-550
Note1: values for untreated sewage sludges for reporting HELCOM Contracting Parties were: mean: 79 ng/L and maximum: 250 ng/L. Untreated, digested and composted sludges contained diclofenac at circa 100, 100 and 10 µg/kg d.w., respectively (Unesco and HELCOM, 2017).
Note2: Reported data from HELCOM Contracting Parties include the following number of data items (number of individual WWTPs): Germany – 155 + 5 (11 and 5), Finland – 40 (13), Estonia – 6 (3), Denmark – 17 (6), and Sweden – 9 + >28 (3 and >4).
*Constructed wetlands, tertiary WWT process.
A detailed study of pharmaceuticals in the St Petersburg area, the HELCOM BASE pilot project, indicated that seasonal and environmental factors (e.g. rainfall) may also influence the discharge rates from WWTPs (HELCOM 2014). In summer months the average influent concentration was 408 ng/L (rage of 154-741 ng/L, equivalent to 138-615 g/day), whereas effluent discharge water concentrations were on average 355 ng/L (range of 154-514 ng/L, equivalent to 180-485 g/day). During winter the average concentration of diclofenac in effluent waters was higher than in summer, 530 ng/L (range 440-630 ng/L, equivalent to 369-658 g/day); despite the lower average influent concentrations of 350 ng/L (range 160-1700 ng/L, equivalent to 228-1205 g/day) (Results figure 2).
Results figure 2. Estimated summer (orange shades, top) and winter (blue shades, bottom) diclofenac discharge in influent (darker colours) and effluent (paler shades) at St. Petersburg WWTP.
This could relate to differences in the daily discharge estimates in effluent water in winter (average of 477 g/day) as compared to summer (average of 323 g/day), driven by increased use of diclofenac during the cold period of the year, but it is also possible that metabolites are more readily produced in summer or are hydrolysed back to diclofenac in winter via biological/chemical processes and/or that sludge/sediment bound diclofenac in WWTPs is re-released and enters effluent waters. Such dynamics could result in the retention of higher concentrations of diclofenac within the WWTP during warmer summer months and stronger discharges during winter.
At the central waste water treatment plant in St. Petersburg the influent water is a mix of domestic wastewater and rainwater, thus meteorological conditions have an impact on water volumes in the process. Factors such as rainfall, which showed a potential correlation with effluent discharge concentrations (R2 = 0.41, Results figure 3), may therefore influence the discharge rates (or concentrations in discharge waters), influencing the concentrations of diclofenac discharged and potentially the transfer distances from WWTPs.
Results figure 3. Correlation between diclofenac discharge in effluent waters and rainfall during summer sampling events at St. Petersburg WWTP.
This pilot study indicated that the concentration of diclofenac in the WWTP was only two times lower than a scenario in which all sold diclofenac were to enter the sewage system, and that the upper level of diclofenac discharged from the city of St. Petersburg to the Baltic Sea would be 1.1 kg/day, an annual load of circa 400 kg (HELCOM 2014). Averaging the load to the annual water volume of 78.9 km3 (2,500 km3/s) of the river Neva, gives an average expected surface water concentration of diclofenac in the water flowing into the Gulf of Finland of 4-5 ng/L (HELCOM 2014). This estimated concentration is close to the newly proposed threshold value of 5 ng/L, assuming that usage and discharge rates remain at the current level and that accumulation within the discharge zone does not take place over longer time periods.
Rivers act as major pathways for the transport of diclofenac from WWTPs to the Baltic Sea environment and elevated concentrations have been detected in the waters of numerous rivers that subsequently enter the Baltic Sea (Results table 3).
Results table 3. Diclofenac concentrations in river waters and sediments from screening studies, scientific literature, and data compilations. The limit of quantification (LOQ) in the Swedish screenings studies was 10 ng L-1
Mean: 102 Maximum: 230
Unesco and HELCOM, 2017*
Miljøministeriet, Naturstyrelsen, 2015
Monitoring (2016) HELCOM DATA CALLL
Mean: 61 Maximum:130
Monitoring (2016) HELCOM DATA CALL
Mean: 23 Maximum: 55
Means of 5.1 - 187
Monitoring (2014-6) HELCOM DATA CALL
Median: 150 Maximum: 1200
Monitoring (2015-6) HELCOM DATA CALL
Slupia River, mean: 93
Borecka et al., 2015
Monitoring (2016) HELCOM DATA CALL
Uppsala: 28, 90, 290, 880
River Piteå: 3.5, 0.19, 0.85, 3.1
Fick et al. 2011
Bendz et al. 2005
Remberger et al. 2009
Lindim et al., 2016
Case study (2016) HELCOM DATA CALL
*This data compilation includes some of the data shown below for individual countries but is dominated by data from German rivers. Reported data from HELCOM Contracting Parties include the following number of data items (number of individual rivers): Germany – 1649 (124), Finland – 18 (4), Estonia – 12 (5), Denmark – 5 (4), and Sweden – 2 (2).
HELCOM DATA CALL Denotes data reported by countries in response to the HELCOM data call in Autumn 2017. This data represents additional data from the 2015-2016 data that has been collected since the data call for used as the basis for the Unesco and HELCOM, 2017 report. Data is summarised as maximum and mean values where possible, though 'less-than' values, where values are determined as less than the LOQ, are not currently included. Where 'less-than' values occurred no mean value is calculated and only a maximum value provided. The dates provided in brackets indicates the year(s) for which data are reported.
Initial data seems to indicate that concentrations detected in river waters may vary seasonally, peaking in January and February (Results figure 4). The reasons behind this could relate to levels of usage in these months (i.e. higher usage in colder months) or to degradation and water treatment processes (e.g. the function of WWTPs or rainfall and discharge rates).
Results figure 4. Mean diclofenac concentrations in 15 Polish rivers sampled across the year (in 2016). Error bars represent Standard Error (SE), n =15.
Elevated concentrations have been recorded, particularly in the immediate vicinity of WWTPs, though the limited data that is currently available indicates that concentrations of diclofenac often decrease quite rapidly with distance from the point of discharge, i.e. WWTPs (Results figure 5); a factor that requires further detailed studies.
Results figure 5. Diclofenac concentrations in samples with increasing distance from the point of discharge. Data are shown for the River Aura (red)*, River Seinäjoki and Kyrö (blue)*, River Kyrönjoki (black)**, and River Aurajoki (purple)** (Vieno, 2007* and Lindqvist et al. 2005**). Concentrations upstream of the discharge points (discharge point being 0 km) were: 4, 0, 0 and 6 ng/L, respectively.
It should however be noted that concentrations above proposed threshold values have still been recorded in both Baltic Sea waters and in Baltic Sea biota. This foments a number of potentially important considerations, such as the importance of WWTPs in close proximity to Baltic Sea coastal waters, the lack a complete understanding of the fate of diclofenac (e.g. data on sediments along pathways and within the Baltic Sea), and the importance of targeted sampling and analysis. For example, targeting potential indicator species that may encounter highly elevated concentrations, i.e. those that are passive filter feeders or those that traverse the marine-freshwater gradient via breeding or feeding life phases, and subsequently feed into the marine food web, is of high importance.
Of the data compiled for the Status report on pharmaceuticals in the Baltic Sea (UNESCO and HELCOM, 2017), within the pharmaceutical category anti-inflammatory and analgesics, diclofenac was the most frequently detected substance in samples compiled from the marine environment; representing 257 water samples. The highest concentrations of 54 ng/L was recorded in the south-western Baltic. The substance was detected in 54 (21%) of water samples and exceeded the proposed threshold value for diclofenac concentration in 6 samples from south-western Baltic Sea. The analytical limit for 83 (32%) samples where diclofenac was not detected were unknown or were higher than the threshold value, meaning the absence of concentrations above the threshold non-detection cannot be assured.
The new HELCOM data call (PRESSRURE and State&Consevation 2017) allowed new data to be compiled on observation of diclofenac in open sea and coastal waters. Altogether 60 observation were reported for the period 2014 and 2017 (and not included in the Unesco and HELCOM 2017 report) were supplied by Denmark, Germany, Latvia, Poland and Sweden. Five observations where the threshold value was exceeded were identified in marine waters, though analytical limits mean that in several cases the status can not be assessed with complete certainty (Key message figure 1).The highest measured concentration - 15.6 ng/l – was observed in the south-west Baltic Sea. Exceedances of the threshold were also observed in the Gdansk basin and Bothnian Bay.
Analysis of diclofenac in in sediments is scarce, with 15 individual samples taken in coastal water of Sweden and Estonia during screening studies. The substance was detected in 4 (27%) samples from coastal waters in the Bothnian Bay, with the highest concentration of 3,5 µg /kg d.w. The analytical limit for the other samples tested was above 10 µg /kg d.w., thus the absence of concentrations above the threshold cannot be assured.
The compiled data were obtained either from regular monitoring observations or from screening studies and cover almost all sub-basins of the Baltic Sea. Nonetheless, a significant part of the data remains uncertain due methodological issues and the associated detection limits.
Data regarding concentrations of diclofenac in Baltic Sea biota is currently extremely limited. It has however been detected in bile samples from European perch (Perca uviatilis) in a small number of samples (5 of 50) in the Stockholm region. Concentrations ranged between 0.53 and 5.2 µg/kg w.w. (Karlsson and Viktor, 2014), above the proposed threshold level (1 µg/kg w.w.) in three of five cases.
Currently data on diclofenac are obtained from a limited number of monitoring observations and mainly from screening studies, though coverage is inclusive of a large area of the Baltic Sea. Nonetheless, greater spatial and temporal coverage is required from all compartments with relevance to this indicator, especially the concentrations of diclofenac in Baltic Sea water and biota. Knowledge of how well samples represent a larger area (i.e. the appropriate HELCOM assessment units) needs to be developed to define the most suitable monitoring strategy and time series data will enable detailed trend based evaluations. Bearing in mind that diclofenac might be deposited to sediments, further detailed studies on fate and potential release/transfer are required. Furthermore, a high priority will be to focus the development of clear agreements regarding analytical methodologies to ensure the highest quality data can be obtained and that analytical limits do not prevent good status assessment within marine environments downstream of source discharge points.
Due to the fact that the monitoring of pharmaceuticals is generally at an early stage, no evaluation of the environmental status and no sub-basins spatial analysis has yet been made for this indicator. It is recommended that monitoring should be carried out for several years before a decisive status evaluation is done.