Chemosphere 120 (2015) 462–469

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Chemosphere

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Environmental Risk Assessment (ERA) of diclofenac and ibuprofen: Apublic health perspective

http://dx.doi.org/10.1016/j.chemosphere.2014.08.0200045-6535/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author at: Universidade Positivo, Programa de Pós Graduaçãoem Gestão Ambiental, Prof. Pedro Viriato Parigot de Souza, 5300, Campo Comprido,CEP 81.280-330 Curitiba, Paraná, Brazil. Tel.: +55 41 3317 3448.

E-mail addresses: javiers@terra.com.br (J.S. Gamarra Jr.), cmara@up.edu.br (C.M.Ribas de Oliveira).

1 Present address: Centro Universitário Campos de Andrade, Curso de Farmácia,Rua João Scuissiato, 1. Santa Quitéria, CEP 80.310-310 Curitiba, Paraná, Brazil. Tel.:+55 41 3219 4244.

2 Tel.: +55 41 3317 3448.3 Departamento de Engenharia Ambiental, Universidade Federal do Paraná, Centro

Politécnico - Setor de Tecnologia, Rua Francisco H. dos Santos 100, Jardim dasAméricas, CEP 81531-990. Curitiba, Paraná, Brazil.

Javier Salvador Gamarra Jr. a,b,1,2, Ana Flávia Locateli Godoi a,b,2,3, Eliane Carvalho de Vasconcelos a,b,2,Kennedy Medeiros Tavares de Souza b,2, Cintia Mara Ribas de Oliveira a,b,⇑a Graduate Program in Environmental Management, Universidade Positivo, 5300, Rua Prof. Pedro Viriato Parigot de Souza, Zip Code 81280-330, Curitiba, Paraná, Brazilb Undergraduate Program in Pharmacy, Universidade Positivo, 5300, Rua Prof. Pedro Viriato Parigot de Souza, Zip Code 81280-330, Curitiba, Paraná, Brazil

h i g h l i g h t s

� ERA was carried out for two NSAIDs in a Brazilian public health system.� Public health service caused environmental risk for diclofenac in 12 cities.� Ibuprofen usage in public health represented environmental risk in 51 cities.� Findings are relevant to support environmental politics on medicines.

a r t i c l e i n f o

Article history:Received 10 September 2013Received in revised form 13 July 2014Accepted 7 August 2014

Handling Editor: A. Gies

Keywords:PharmaceuticalsNSAIDsPredicted environmental concentrationPublic health system

a b s t r a c t

Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used in human and veterinary med-icine, representing potential aquatic environmental contamination. This study aimed to perform an Envi-ronmental Risk Assessment (ERA) of NSAIDs diclofenac (Dic) and ibuprofen (Ibu) in cities of the state ofParaná, Brazil, over the course of three years, by using available data from the Brazilian Public Health Sys-tem. The environmental risk (ER) was assessed by employing the European Medicines Agency (EMeA)approach, and predicted environmental concentrations (PECs) were calculated. The refined PECs consid-ered the drug metabolism and the excretion data, and also the sewage treatment plant removal rates ofbiological filters and activated sludge processes to define environmental scenarios. References to the pre-dicted no effect concentration (PNEC) for these pharmaceuticals were considered, and the PEC/PNEC ratiowas calculated; ratio values P1 suggested an ER. Environmental risk was conducted on several cities, andthe lack of an adequate sanitation system in the majority of Paraná cities forecasts a significant concernwith the exposure to possible environmental damages in those cities. The high PEC/PNEC ratios in severalcities showed that current usage patterns of these drugs constitute an environmental issue in need of res-olution by health and environmental authorities.

� 2014 Elsevier Ltd. All rights reserved.

1. Introduction and due to their intensive usage, studies on the environment have

Pharmaceuticals are among the most important technologiesmade to preserve and to restore health. Despite the benefits

been carried out on their impacts. These substances have beenconsidered as micropollutants (Sedlak et al., 2000) or microcon-taminants, with potential toxic effects (Hernando et al., 2006)and environmental damages; therefore, they could be handledas pesticides (Kümmerer, 2001) because they are specificallydesigned to be biologically active, like pesticides (Wang et al.,2010).

The pharmaceutical consumption (including prescription or non-prescription, production and sales, human and nonhuman uses)usually reaches from several to thousands of tons of pharmaceuti-cally active compounds (PhAcs) (Zuccato et al., 2000; Union ofConcerned Scientists, 2001; Bila and Dezotti, 2003), and the useand diversity is continuously increasing (Bound and Voulvoulis,2004).

J.S. Gamarra Jr. et al. / Chemosphere 120 (2015) 462–469 463

Brazil is one of the biggest pharmaceutical markets (Stumpfet al., 1999; Boehringer-Ingelheim, 2013), but according toStumpf et al. (1999), there has been no reliable data about usagepatterns or volume of medicine consumption within the country.

Non-steroidal anti-inflammatories (NSAIDs) are one of the mostused groups of medicines (Rang et al., 2004); including more thanfifty PhAcs (Rang et al., 2004).

Sewage water is the main entry point of pharmaceuticals intoaquatic environments (Bound and Voulvoulis, 2004; EuropeanMedicines Agency – EMeA, 2006; Gros et al., 2010), concerningtheir use, metabolism and excretion (households, farming – includ-ing slurry and manure – and hospitals) (Boxall, 2004). Releasesfrom manufacturing processes, agriculture and aquaculture, anddisposal of unused medicines and their containers must be classi-fied as aquatic contamination sources (Boxall, 2004).

When sewage (influent) is submitted to the treatment in con-ventional sewage treatment plants (STPs), PhAcs are not fullyremoved, and effluents still contain these substances (Ternes,1998; Stumpf et al., 1999; Zuccato et al., 2000; Tixier et al.,2003; Khan and Ongerth, 2004; Kosjek et al., 2007; Gros et al.,2010). Environmental Risk Assessment (ERA) methodologiesinvolve substantial criteria to evaluate the potential consequencesof pharmaceuticals into the environment, such as showed byEscher et al. (2011), Turkdogan and Yetilmezsoy (2009), Carlssonet al. (2006a, 2006b) and Huschek et al. (2004).

The study herein aimed to evaluate the environmental risksituation of the NSAIDs diclofenac (Dic) and ibuprofen (Ibu) basedon the distribution data of the public health system in Paraná,Brazil.

2. Materials and methods

ERA for Dic and Ibu was carried out using data from the Brazil-ian Public Health System (Sistema Único de Saúde – SUS) in Paraná(319 cities for Dic and 104 for Ibu) by means of an organized con-sortium called Consórcio Intergestores Paraná Saúde (ConsórcioIntergestores Paraná Saúde, 2006). For this study, acquisition pro-files were used to the ERA for the cities.

The modeling was carried out according to European MedicinesAgency’s (EMeA) guideline (EMeA, 2006), adapted with local data.

2.1. Consortium acquisition of diclofenac and ibuprofen

Pharmaceuticals acquisition data were gathered in three consec-utive years from available technical reports of the consortium(Consórcio Intergestores Paraná Saúde, 2005). The number of Dic(50 mg – PhAc) and Ibu capsules (300 mg – PhAc) acquired by eachcity each year was used to determine the total PhAc mass. The selec-tion criteria for cities involved those which have acquired at leastone of the pharmaceuticals in at least one of the three years consid-ered, as well as cities for which water consumption data wasavailable.

2.2. Diclofenac and ibuprofen environmental exposure calculation

The environmental risk was assessed concerning consumptionpatterns, based on the penetration factor – Fpen (Eq. (1)) thatwas used to calculate the predicted environmental concentration– PEC (Eq. (2)), according to the EMeA’s protocol (EMeA, 2006).

Fpenð%Þ ¼ consumption � 100DDD � inhab: � 365

ð1Þ

in which, consumption (mg year�1); DDD, (mg d�1 inhab.) is thedefined daily dose (Stuer-Lauridsen et al., 2000): for diclofenac,150 mg inhab.�1 d�1 and for ibuprofen 1200 mg inhab.�1 d�1

(WHO, 2000); inhab., is the number of inhabitants in eachcity, according to a Brazilian government institute called InstitutoBrasileiro de Geografia e Estatística – IBGE (IBGE, 2007); 365(d year�1).

PEC is the predicted compound concentration in an environ-mental compartment obtained by the combination of consumptionestimate, environmental input, environmental pathways andphysical–chemical properties.

Eq. (2) (adapted from EMeA, 2006) was applied to calculatephase one PEC (PEC surface water, crude PEC or worst case scenarioPEC – PECsw). The calculation of crude PEC in surface waterassumes (adapted from EMeA, 2006):

(a) The sewage system is the main entry for PhAcs.(b) The consumption was evenly distributed over the year for

the considered population (each sampled city).(c) It was not considered depletion data (degradation, STPs

retention).(d) It was not considered human metabolism.

PECsw ¼MDDinhab: � Fpen

CONSUMPTIONw:inhab: � DIL� 1000 ð2Þ

in which, PECsw (lg L�1) is the predicted environmental concentra-tion in surface waters, MDDinhab. (mg inhab.�1 d�1) is the maximumdaily dose consumed per inhabitant (225 mg inhab.�1 d�1 to dic-lofenac and 3600 mg hab.�1 d�1 to ibuprofen, reported by theUnited States Pharmacopeia and National Formulary (2003)), Fpen(%) (Eq. (1)), CONSUMPTIONw.inhab. (L inhab.�1 d�1) is the treatedwater consumption per inhabitant (Ministério das Cidades, 2006),as recommended by Kümmerer and Henninger (2003), which isapproximately the same as wastewater production (Von Sperling,1996), DIL is the dilution factor, in this case assumed as 2, corre-sponding to the effluent/surface water rate (1:1) (O’Brien andDietrich, 2004).

PEC’s refinement was carried out according to tier A of theEMeA model, including human metabolism, STPs removal ratesand ecotoxicological aquatic effects (Huschek et al., 2004) asparameters. In this phase, mass adjustments were carried out inaccordance with:

(a) diclofenac and ibuprofen human metabolism, based on uri-nary excretion – 65% for Dic (Fpenexcr Dic = mass * 0.65 –Eq. (3)) and 90% for Ibu (Fpenexcr Ibu = mass * 0.90 – Eq.(4)) (Hardman and Limbird, 2001) to calculate PECexcr forboth PhAcs, and

(b) STPs removal rates, using Brazilian data from Stumpf et al.(1999). Removal rates of Brazilian STPs were considered:trickling filter, with 9% of removal rate for diclofenac (Fpenfil-

ter Dic = mass * 0.91 – Eq. (5)) and 22% for ibuprofen (Fpenfil-

ter Ibu = mass * 0.78 – Eq. (6)) to obtain PECfilter; activatedsludge, with 75% of removal rate for both PhAcs (Fpensludge

Dic = mass * 0.25 – Eq. (7) and Fpensludge Ibu = mass * 0.25– Eq. (8)) to calculate PECsludge. The phase two PEC wascalculated using Eq. (2), after the mass adjustment.

PEC values of diclofenac and ibuprofen were grouped intofour concentration ranges, showing the cities’ percentage in eachone.

2.3. Risk quotient (RQ) determination (PEC/PNEC)

Phase two PEC (refined PEC) values were used to determine therisk quotient (RQ) (PEC/PNEC, where PNEC = predicted no effectconcentration) (Stuer-Lauridsen et al., 2000; Hernando et al.,2006) for every city for each considered year, for the three

464 J.S. Gamarra Jr. et al. / Chemosphere 120 (2015) 462–469

refinements – RQexcr, RQfilter, RQsludge. The PNEC obtained in theliterature was for diclofenac PNEC = 10 lg L�1 (chronic effect)and ibuprofen PNEC = 7.1 lg L�1 (acute effect) (Carlsson et al.,2006a). If the RQ P 1, an environmental risk was established. Lessthan 1 points to no environmental risk with care, if there is a pro-jection that indicates an increase in consumption of the studiedarea.

3. Results and discussion

According to the available governmental database from thestate of Paraná (Consórcio Intergestores Paraná Saúde, 2005) uponthe use of pharmaceuticals in the public health system, 319 cities(4709379 inhab., according to IBGE (2007)) purchased ffi2827 kgof diclofenac during the three-year period. 104 cities (1726789inhab., according to IBGE (2007)) purchased 1122 kg of ibuprofenin the considered years. The state had approximately 10200000inhab. (IBGE, 2007). The acquiring patterns for this period(Table 1) indicated an escalation of the dispensed amount inthe studied years for both pharmaceuticals. See Table 1 to verifydata of cities at environmental risk as outcome at least once inthis period. If those patterns have continued, then predictedamounts released into the aquatic environment will certainlyhave increased.

The data showed partial consumption patterns of both PhAcs inParaná, since they did not include the private sector, which pro-vides another important fraction of sales. The consumption datais also underestimated concerning the lack of information aboutover-the-counter drugs, as already mentioned as an issue in otherstudies in Germany and France (Ferrari et al., 2004). In addition,the different therapeutic practices in various countries accountfor disparities in production.

All sampled cities showed diclofenac phase one PEC valueshigher than EMeA threshold value (0.01 lg L�1), with variationfrom PECsw = 0.03 lg L�1 (data not shown) to 29.4 lg L�1 (Table 1).The lowest ibuprofen phase one value corresponded to the EMeAlimit value in two cities in the first year (data not shown) andreached 157 lg L�1 in Turvo (third year – 3rd, Table 1), the majorvalue found in this research.

Phase one PEC values indicated that the evaluation must pro-gress to step two of the ERA for several cities.

It is possible to identify cities that reduce their consumption ofibuprofen reduce the PEC and those that enhance such consump-tion increase the PEC values. The results on this environmental riskassessment are closely related to those reported by Huschek et al.(2004), since those authors observed that PEC values are affectedby yearly sales in a particular region.

Several studies based on the estimate of phase one PEC are pre-sented here for comparison. Carlsson et al. (2006a) calculated0.60 lg L�1 for diclofenac and 10 lg L�1 for ibuprofen concentra-tion, using the amount of sales in one year, DDD and MDD values,sewage production (200 L inhab.�1 d�1), EMeA’s standard Fpen(1%), and considering the total population of Sweden. Huscheket al. (2004) found 0.50 lg L�1 for diclofenac and 6 lg L�1 for ibu-profen, using a similar group of data, amount of sales in severalyears, DDD and MDD, same Fpen and wastewater production, con-sidering the population of Germany. Ferrari et al. (2004) used phar-maceutical amounts/year for France and Germany, selectingdifferent wastewater treatment plants for each country and theirtotal populations. Those authors calculated a diclofenac PECsw of0.48 lg L�1 in France and 1.81 lg L�1 in Germany. Jones et al.(2002) made an ERA for the 25 most important PhAcs in England,estimating PECsw for diclofenac of 0.80 lg L�1 and for ibuprofenof 4.96 lg L�1. Stuer-Lauridsen et al. (2000) reported the PEC valuefor ibuprofen of 8.90 lg L�1, also considering the same group ofdata. All the papers used dilution = 10.

3.1. Phase two PEC (refined PEC) for diclofenac and ibuprofen

The PEC refinement (phase two PEC) was estimated consideringthree factors: human metabolism and excretion, STP removal bytrickling filter and STP removal by activated sludge, according tothe previous item (2.3). The phase two PEC (PECexcr, PECfilter,PECsludge) results for sampled cities with ER are presented in per-centages in Table 2 for diclofenac and ibuprofen.

PECexcr values varied from 0.02 lg L�1 (data not shown) to19.1 lg L�1 for Dic (Table 2), and posed an ER in 5 cities in the sec-ond year (2nd) and in 8 cities in third year (3rd) (Table 3).

PECexcr values for Ibu varied from 0.01 lg L�1 (data not shown)to 141.3 lg L�1 in Turvo (3rd year) (Table 2). In the three-year per-iod, the number of cities in ER due to ibuprofen consumption wasgreatly increased (Tables 3 and 4).

In the next refinement step, for diclofenac PECfilter, the findingsvary from 0.02 lg L�1 to 17.7 lg L�1. In Table 2, it is possible toobserve the number of cities in ER had still been increasing. Whenanalyzing PECfilter for this pharmaceutical, an ER was identified for3 cities in 2nd and for 5 in the 3rd year (Table 3).

For ibuprofen PECfilter, the values were from 0.01 lg L�1 (Andirá,Palotina, Santo Antônio da Platina – data not shown) to 110 lg L�1

(Table 2). For ibuprofen, PECexcr and PECfilter results have corre-sponded to an ER for 3 cities, increasing progressively in the 2ndyear (ER for PECexcr = 19 cities, ER PECfilter = 14 cities), and in the3rd year (ER for PECexcr = 49 cities, for PECfilter = 44 cities and ERfor PECsludge = 6 cities) (Table 3). The number of cities with phasetwo PEC (PECexcr and PECfilter) values higher than 5 lg L�1 wasincreased in the considered years, for both PhAcs (Table 4).

To summarize phase two PECsludge results, the values were, fordiclofenac, from 0.01 lg L�1 to 4.8 lg L�1 (Table 2). Ibuprofen val-ues varied from 0.002 to 35.33 lg L�1, and there was no city withPECsludge higher than 5 lg L�1 in the first two years (Tables 2 and4). Ten cities were within that concentration range in the 3rd year,still reflecting the consumption increase (Table 4).

For diclofenac, Ferrari et al. (2004) registered PECeffl (efflu-ent) = 4.79 lg L�1 in France and 18.05 lg L�1 in Germany.

Huschek et al. (2004) also verified in Germany PECeffl for dic-lofenac in a three-year series (1999–2001), 1.37, 1.37 and1.43 lg L�1, and for ibuprofen in the same conditions, 4.34, 5.01and 5.76 lg L�1. Such values were not so high when compared tothose found in the present study in some cities (Table 2).

Carlsson et al. (2006a) reported in Sweden diclofenac PECsewage-

water = 1.1–1.3 lg L�1 and refined PECsw = 0.048 lg L�1. For ibupro-fen, the same authors obtained PECsewagewater = 0.28–0.33 lg L�1

and refined PECsw = 0.012 lg L�1.Considering particularities inherent to each paper (data source,

production of wastewater versus water consumption, variation onFpen, local realities, parameters of PhAcs consumption, applieddilution, PNEC data), the values have proximity, with variationnot higher than one order of magnitude in the majority of citiesanalyzed within this study.

In an adverse environment, because of the potential effect ofpollutants, like PhAcs, it is important to consider the sanitationconditions in the analyzed area. The worst-case PEC estimationswere mainly observed in cities with the lack of an adequate sanita-tion system and high acquisition patterns. According to Ministériodas Cidades (2006), more than 60% of the cities have no coverageand approximately only 7% of the cities studied for diclofenachad over 50% of coverage, while the cities studied for ibuprofenhad about 10% coverage.

The absence or scarcity of sanitary collection system as well asthe low availability of an effective treatment can forecast a consid-erable matter with the exposure to environmental risks and healthdamages in the cities of Paraná. It is possible to observe an increaseof PhAcs release into aquatic environment, particularly in surface

Table 1Diclofenac and ibuprofen acquisition pattern (mg) in cities from the Consórcio Intergestores Paraná Saúde which posed environmental risk; with population (inhab.), waterconsumption (L inhab.�1 d�1), percentage of sewage collection (%).

PhAc City Population (inhab.)a Acquisition (mg) Water consumption (L inhab.�1 d�1)b Sewage collection (%)b

First year Second year Third year

Diclofenac Adrianópolis 5582 1525000 1725000 6400000 97 0.0Altamira do Paraná 6675 1050 500 4925000 1825000 96 0.0Bom Jesus do Sul 3819 750000 1750000 500000 32 0.0Brasilândia do Sul 3341 1800000 3250000 2750000 108 0.0Conselheiro Mairinck 3441 400000 450000 4225000 120 42.9Diamante D’Oeste 1644 1100000 1500 000 720000 96 0.0Diamante do Sul 3027 850000 1125000 2750000 82 0.0Lindoeste 5741 925000 1975000 6224000 91 0.0Luiziana 6141 2050000 2125000 6175000 99 0.0Realeza 15193 1500000 3750000 21250000 124 0.0Três Barras do Paraná 9486 2350000 7800 000 2502000 103 2.2Ventania 9267 3200000 5000000 8475000 122 0.0

Ibuprofen Antônio Olinto 7166 1200000 900 000 2700000 94 0.0Arapongas 100855 9000000 18840000 39000000 125 30.4Astorga 24508 2100000 6600 000 9000000 125 56.6Boa Esperança 3838 900000 1206000 1470000 130 0.0Califórnia 7936 150000 600 000 4650000 170 0.0Campina da Lagoa 14440 780000 3000000 3600000 101 0.0Campo Bonito 5179 300000 570000 1020000 80 0.0Cândido de Abreu 16717 1200000 5400 000 6000000 98 15.4Candói 15315 1200000 4500 000 7500000 86 0.0Capanema 17405 1290000 3282000 7200000 224 0.0Castro 69472 9600000 17400 000 27000000 102 40.9Catanduvas 10864 360000 1926000 3000000 93 0.0Cerro Azul 16559 180000 1050 000 4380000 97 1.0Cruzeiro do Sul 4576 120000 1920000 4890000 123 0.0Diamante d’Oeste 1644 540000 600 000 1380000 96 0.0Doutor Camargo 5655 420000 480000 4050000 132 19.7Figueira 8634 660000 684000 4080000 114 0.0Floraí 5126 300000 1200 000 2250000 144 18.3Guaraniaçu 14025 450000 2778000 2760000 77 27.7Indianópolis 4097 120000 30000 2250000 127 0.0Itaguajé 4562 300000 390000 8100000 135 0.0Itaipulândia 8800 1500000 900 000 4800000 137 0.0Itaúna do Sul 4367 330000 276000 4590000 110 0.0Ivatuba 3009 420000 600 000 3390000 135 0.0Japira 4951 180000 462000 4050000 125 0.0Joaquim Távora 9503 3600000 6000 900000 112 72.6Juranda 7645 600000 1800 000 3600000 98 0.0Mallet 13189 1200000 1800 000 5700000 82 9.2Manoel Ribas 13742 300000 1386000 6000000 104 0.0Maria Helena 4865 180000 1800 000 2370000 127 0.0Marilândia do Sul 8948 240000 540000 1980000 106 0.0Marquinho 5617 60000 318000 2100000 82 0.0Nova América da Colina 3201 120000 540000 2250000 101 0.0Ourizona 3134 440000 1800 000 1950000 136 0.0Palmital 16540 1320000 1848000 4500000 97 0.0Paraíso do Norte 10738 1800000 3600 000 8250000 138 0.0Paulo Frontin 6570 480000 180000 2340000 106 0.0Pérola 7043 600000 1500 000 1950000 137 0.0Pinhalão 6578 420000 960000 2850000 104 3.6Rebouças 14191 1920000 4800 000 3120000 93 33.3Renascença 6525 60000 1362000 1200000 103 33.1Rio Bom 3065 180000 600 000 810000 121 0.0Rondon 8438 30000 900 000 5400000 131 24.1Santa Amélia 4244 1200000 1110000 1200000 87 0.0Santa Izabel do Oeste 11120 600000 2280000 3300000 108 0.0São João do Triunfo 12490 420000 600 000 3450000 96 1.1São Jorge do Ivaí 5223 612000 804000 2100000 192 90.9São Mateus do Sul 39105 2520000 7650000 14700000 122 1.4Tibagi 19925 2100000 6012000 6900000 118 32.7Turvo 14814 300000 1860000 46980000 83 0.0Wenceslau Braz 20067 600000 1320000 9900000 112 12.6

a Instituto Brasileiro de Geografia e Estatística – IBGE (2007).b Ministério das Cidades (2006).

J.S. Gamarra Jr. et al. / Chemosphere 120 (2015) 462–469 465

waters, in this case, since the sewage is, in most cases, released toreceptor waters in natura with evident expectation of environmen-tal impacts.

To make a comparison among different realities, in Europe, 80%of the wastewater is collected (O’Brien and Dietrich, 2004), which

allows one to understand that the results obtained with sewageproduction are adequate to that reality, as previously mentioned.Although, some studies use consumption water as a parameter(Kümmerer and Henninger, 2003) in a public health environmentcharacterized by massive consumption of medicines.

Table 2Diclofenac and Ibuprofen PEC refinement (phase two PEC) of cities (with ER as outcome at least once) from the Consórcio Intergestores Paraná Saúde in First (1st), Second (2nd)and Third (3rd) considered years to estimate Environmental Risk (ER) with calculation of the refined PECs, considering excretion (PECexcr.) and STPs remotion in biological filter(PECfilter) and activated sludge (PECsludge). Risk quocient (RQ) obtained after each refinement detached in gray when RQ P 1 indicates ER and hachured when outcome isEnvironmental Alert – EA (0.8 P RQ < 1).

466 J.S. Gamarra Jr. et al. / Chemosphere 120 (2015) 462–469

a The PNEC to calculate RQ is 10.0 lg L�1 for diclofenac and 7.1 lg L�1 for ibuprofen (Carlsson et al., 2006a,b).b To classify an outcome as environmental risk RQ P 1.c To classify an outcome as environmental alert 0.8 6 RQ < 1.

J.S. Gamarra Jr. et al. / Chemosphere 120 (2015) 462–469 467

Results for environmental risk estimate for diclofenac and ibu-profen were based on the European Model of Environmental RiskAssessment (ERA) from EMeA (EMeA, 2006), and they are pre-sented by number of cities in Table 3 (RQs – RQexcr, RQfilter, RQsludge)for Consórcio Intergestores Paraná Saúde. For diclofenac, ER wasestimated in 12 cities, while for ibuprofen, the total number was51 cities in the same condition, corresponding almost half of thesample.

The lowest ER estimated for diclofenac excretion (RQexcr) wasin Realeza (first year – 1st), while the highest one was in thesame city in third year (3rd), in a total of 13 cities with ER. Foribuprofen RQexcr Joaquim Távora had the lowest ER value (secondyear – 2nd) and Turvo had the highest in the third year. It isimportant to note that almost every city reaches ER values inthe 3rd year.

The lowest diclofenac ER values for biological filter scenario(RQfilter) were in Realeza and Três Barras do Paraná (a total ofeight occurrences). The lowest value for ibuprofen was estimatedin Joaquim Távora (2nd), while the highest one was in Turvo(3rd), following the pattern that began in the previous refine-ment. Notice that some cities with ER in the previous refinementare no longer in that situation (São Jorge do Ivaí and Rio Bom, fore.g.).

RQsludge for diclofenac showed the lowest values in ConselheiroMairinck and Realeza (first year) and the highest one in Bom Jesusdo Sul (2nd). For ibuprofen, Califórnia, Cerro Azul and Renascença

(1st) showed the lowest RQsludge values, and Turvo (3rd) kept thehighest risk. In this refinement, ER was still registered in a fewcities.

Despite the apparent small number of cities that reachedRQ P 1 for diclofenac (Table 3), it was emphasized that the con-sumption pattern tends to grow (Table 1), which could indicatean increase in the number of cities in ER in this PhAc. Ibuprofenshowed an even increasing pattern of consumption, which pointsto a probable rise of cities in ER, if the tendency can be corrobo-rated. The discussion about environmental alert could make thismatter more relevant.

The findings in the literature point to the following results forRQ. Stuer-Lauridsen et al. (2000) found RQ = 1 for ibuprofen usingstandard acute test; Jones et al. (2002) estimated ERA for diclofe-nac, RQ = 0.01 (standard acute test) and ibuprofen, RQ = 0.55;Ferrari et al. (2004) made ERA for diclofenac among other fivePhAcs, in France RQacute = 0.033 and RQchronic = 0.024, in GermanyRQacute = 0.124 and RQchronic = 0.09, using PECsw; Huschek et al.(2004) found RQ for diclofenac = 0.079 in Germany with acute test,and for ibuprofen, RQ = 0.19, with the same procedure; Carlssonet al. (2006a) obtained diclofenac RQ = 0.0048 (chronic data) andibuprofen RQ = 0.0017 (acute data).

The findings in the present work were consistent to the papersmentioned, and even higher in more than one order of magnitudein most cities, up to the result RQexcr of approximately 20 in Turvo(3rd) for ibuprofen.

Table 3Number of cities from Consórcio Intergestores Paraná Saúde with outcome environmental risk (ER) (RQ P 1) in the environmental risk analysis (ERA) for diclofenac (n = 319) andibuprofen (n = 104). It is considered the PEC refinement by excretion (PECexcr.) and by STPs removal (PECfilter and PECsludge) in first, second and third studied years.

Environmental risk – diclofenac number of cities Environmental risk – ibuprofen number of cities

Years First year Second year Third year First year Second year Third year

PECexcr. 0 5 8 3 18 46PECfilter 0 3 5 3 13 43PECsludge 0 0 0 0 0 1

Table 4Phase two PEC for diclofenac (n = 319) and ibuprofen (n = 104) concentration ranges after refinement considering respectively: urinary excretion of 65% and 90% (PECexcr),depletion by trickling filter (9% and 22% of removal rate) (PECfliter), depletion by activated sludge (75% of removal rate for both PhAcs) (PECsludge), identified for consortium cities inthe three studied year period, number of cities and percentile by each range.

Range (lg L�1) Number of citiesPECexcr

Percentage of cities (%)PECexcr

Number of citiesPECfilter

Percentage of cities (%)PECfilter

Number of citiesPECsludge

Percentage of cities (%)PECsludge

1st 2nd 3rd 1st 2nd 3rd 1st 2nd 3rd 1st 2nd 3rd 1st 2nd 3rd 1st 2nd 3rd

DiclofenacPEC > 5 15 38 82 4.70 11.91 25.70 07 29 63 2.19 9.09 19.75 0 0 0 0.00 0.00 0.005 P PEC > 1 241 239 212 75.55 74.92 66.46 236 238 227 73.99 74.61 71.16 24 66 116 7.52 20.69 36.361 P PEC > 0.1 59 40 25 18.50 12.54 7.84 72 49 29 22.57 15.36 9.09 278 239 194 87.15 74.92 60.82PEC 6 0.1 04 02 0 1.25 0.63 0.00 4 3 0 1.25 0.94 0.00 17 14 09 5.33 4.39 2.82

IbuprofenPEC > 5 06 37 60 5.77 35.58 57.70 05 21 54 4.81 20.19 51.92 0 0 10 0.00 0.00 9.625 P PEC > 1 53 39 34 50.96 37.50 32.69 47 52 39 45.19 50.00 37.50 12 42 59 11.54 40.38 56.731 P PEC > 0.1 37 25 09 35.58 24.04 8.65 42 26 10 40.38 25.00 9.62 72 51 31 69.23 49.04 29.81PEC 6 0.1 08 03 01 7.69 2.88 0.96 10 05 01 9.62 4.81 0.96 20 11 04 19.23 10.58 3.84

468 J.S. Gamarra Jr. et al. / Chemosphere 120 (2015) 462–469

It was proposed, in the cases 0.8 6 RQ < 1 that the RQ could beclassified as an environmental alert (EA) (see Table 3), especially incases in which consumption patterns could lead to an increase inamounts. Hernando et al. (2006), also detached RQ values lowerthan 1, indicating risk levels (0.01–0.1, low risk; 0.1–1, mediumrisk; and values >1, high risk).

The sanitation scenario in the study area indicates that PECexcr

values are appropriate for the ERA. Besides, diclofenac and ibupro-fen are relevant to the environment due to their inherentproperties:

– highly lipophilic [log Kow for ibuprofen vary from 3.5 (Stuer-Lauridsen et al., 2000) to 3.97 (Khan and Ongerth, 2004), andfor diclofenac = 4.51 (Khan and Ongerth, 2004)];

– environmental persistence, besides a continuous release intothe environment (Jones et al., 2002; Hernando et al., 2006;Carlsson et al., 2006a), though low (Jones et al., 2002);

– mechanisms of action common to several species (Stuer-Lauridsen et al., 2000; Carlsson et al., 2006a), and potential tox-icity (Carlsson et al., 2006b).

Cleuvers (2003) obtained results for diclofenac and ibuprofen incombination that showed higher toxic effects in daphnia and algae.Hernando et al. (2006) had also reported that diclofenac and ibu-profen may cause high risk to the environment.

Guidelines for the environmental management of pharmaceuti-cals as chemical pollutants must be encouraged mainly for:

(a) Promoting rational use of medicines (World HealthOrganization, 2002), to achieve consumption reduction(Daughton, 2003a).

(b) Proper disposal of medicines (Daughton 2003a, 2003b) ofunused and expired medicines (Bound et al., 2006).

(c) Adequate recommendations for proper labeling (Jones et al.,2002) of medicines about risks to the environment, including‘‘leaflets’’ with instructions (World Health Organization,2002) and educational practices to population and healthpractitioners (including alerts) (Daughton, 2003a).

(d) Public policies that address, besides the rational use, the co-responsibilities and co-participations on the entire life cyclesof medicines, for their proper management as environmen-tal pollutants (cradle-to-cradle stewardship) (Daughton,2003a, 2003b).

(e) Government regulations to force the pharmaceutical indus-try to establish the ERA of its products in countries withoutsuch regulations, like Brazil.

(f) Government actions to promote environmental and healtheducation to the population about rational use (WorldHealth Organization, 2002) and medicines as environmentalpollutants (Daughton, 2003a, 2003b).

(g) Insertion in the pharmaceutical sector of a new mentality,the environmental pharmacy, aiming to make the sectoractivities to include research, production, distribution, sales,uses and disposal to be environmentally friendly and to min-imize impacts on the environment, supported by the con-cepts of Green Pharmacy (Daughton, 2003a).

(h) The research and development of new pharmaceuticals mustbe based on green design, with enhanced delivery, creatingsynthetic transporters and reducing doses (Daughton,2003a).

4. Conclusion

RQ values for diclofenac (12 cities) and ibuprofen (51 cities)were compatible with environmental risk in the study area. RQresults showed an environmental alert status for some cities dueto the public health consumption for both pharmaceuticals in thearea. Changes in the consumption pattern may influence the ten-dencies toward environmental risk. This pattern must be moni-tored by health and environmental authorities to establish publicpolicies, in order to minimize possible environmental impacts.

Acknowledgement

This research was supported by Universidade Positivo (UP),Brazil.

J.S. Gamarra Jr. et al. / Chemosphere 120 (2015) 462–469 469

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