Accepted Manuscript

ANALYSIS OF THE PRESENCE OF ANTI-INFLAMMATORIES DRUGS IN

SURFACE WATER: A CASE STUDY IN BEBERIBE RIVER - PE, BRAZIL.

Tatiane Barbosa Veras, Anderson Luiz Ribeiro de Paiva, Marta Maria Menezes
Bezerra Duarte, Daniela Carla Napoleão, Jaime Joaquim da Silva Pereira Cabral

PII: S0045-6535(19)30183-3

DOI: 10.1016/j.chemosphere.2019.01.167

Reference: CHEM 23082

To appear in: Chemosphere

Received Date: 02 June 2018

Accepted Date: 27 January 2019

Please cite this article as: Tatiane Barbosa Veras, Anderson Luiz Ribeiro de Paiva, Marta Maria
Menezes Bezerra Duarte, Daniela Carla Napoleão, Jaime Joaquim da Silva Pereira Cabral,
ANALYSIS OF THE PRESENCE OF ANTI-INFLAMMATORIES DRUGS IN SURFACE WATER: A
CASE STUDY IN BEBERIBE RIVER - PE, BRAZIL., Chemosphere (2019), doi: 10.1016/j.
chemosphere.2019.01.167

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 ACCEPTED MANUSCRIPT

1 ANALYSIS OF THE PRESENCE OF ANTI-INFLAMMATORIES DRUGS IN

2 SURFACE WATER: A CASE STUDY IN BEBERIBE RIVER - PE, BRAZIL.

3 Tatiane Barbosa Veras1, Anderson Luiz Ribeiro de Paiva1, Marta Maria Menezes Bezerra Duarte1;

4 Daniela Carla Napoleão1, Jaime Joaquim da Silva Pereira Cabral1,2

5 1Federal University of Pernambuco, Recife, PE, Brazil

6 2University of Pernambuco, Recife, PE, Brazil.

8 tatiane_veras@yahoo.com.br (TBV), jcabral.ufpe@gmail.br (JJSPC), anderson.paiva@ufpe.br (ALRP),

9 mmmbduarte@gmail.com (MMMBD), danicarlan@gmail.com (DCN).

10 ABSTRACT

11 The contamination of water by drug residues has occurred all over the world, arousing interest of the

12 scientific community due to possible deleterious effects that can cause to human health and to

13 environment. Conventional treatment of water does not remove drug residues as they are not legislated.

14 Knowledge about the concentrations of exposure of drug residues in aquatic matrices generates subsidies

15 for these compounds to become candidates for future regulation. Beberibe river watershed, due to

16 urbanization, has been affected by domestic effluents causing problems in the quality of water bodies. An

17 old point of abstraction for public supply was abandoned some years ago and the uptake was installed

18 upstream at a new point without presence of domestic effluents. In this context, the present study

19 analyzed the presence of anti-inflammatories drugs in two points of Beberibe river, being Point 1 in a

20 preserved area, not presenting urbanization in its surroundings, and Point 2 in an area that suffers with

21 intense urbanization. During 6 months of surface water collection, contamination by diclofenac and

22 paracetamol were evaluated. The analyzes were performed with using Shimadzu HPLC equipment, with

23 an ULTRA C18 column with reverse phase analysis (5μm; 4.6 x 250 mm) and UV detection (SPD - 20A)

24 for wavelengths of 285 nm. Diclofenac had higher concentrations than paracetamol, being 0.193 and

25 0.042 mg L-1, respectively. The highest levels of concentration were presented in Point 2, probably due

26 to anthropogenic interference. In addition, it was observed that the highest concentrations were detected

27 during drought periods.

28

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29 Keyworks: drugs, water quality, aquatic matrices, public supply.

30

31 INTRODUCTION

32 The high rate of urban occupation and the expansion of industrial centers has progressively

33 increased the risk of contamination in aquatic environments located near these areas, leading to a

34 thorough discussion and generating new research related to the influence and consequences of

35 anthropogenic activities in the degradation of water resources. Concerns about water use and quality are

36 especially important, especially in places where water shortages occur, and there is a need for changes

37 that contribute to the provision of adequate quality water.

38 In addition to the parameters that are currently inserted in legislation that regulates water quality,

39 in recent years the occurrence of pharmaceutically active compounds (PhACs) in aquatic matrices has

40 been recognized as one of the growing problems in the environment and has increased the number of

41 researches (Carmona, et al., 2014; DaI et al., 2015; Americo-Pinheiro et al., 2017; Mutiyar et al., 2018).

42 In the last decade, advances in analytical chemistry have enabled the detection and quantification of lower

43 concentrations of chemicals in environmental samples, increasing drastically the number of

44 micropollutants that can be detected in nature (Valcárcel et al., 2011; NApoleão et al., 2013; Napoleão et

45 al., 2018). As a progressive increase in the amount of detectable PhACs, greater attention was devoted to

46 these compounds and became recognized as emerging pollutants (Heberer, 2002).

47 The emergent contaminants involve hundreds of compounds that have only recently been

48 detected in the different environmental compartments (soil, water and air), both being of anthropic origin

49 and of natural occurrence (Montagner et al., 2017). Emerging pollutants also refer to newly introduced

50 compounds in the environment (Gaffnei et al., 2014).

51 After the recognition of the pharmaceutically active compounds as emerging contaminants,

52 increasingly, studies and information were made available, leading authorities to reassess the need to

53 implement management strategies in search of a significant reduction of these contaminants in

54 environmental matrices. Most of the emerging contaminants, including drugs, are not yet monitored, their

55 toxicological effects are unknown or have no regulatory legislation (Garza-Campos et al., 2016), but can

56 be harmful to human health and the environment (Yao et al., 2017).

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57 The drugs belong to one of the most studied emerging classes of contaminants in the world

58 (being the second most studied in Brazil), since they are constantly released into the environment in large

59 quantities, in addition to being produced with the purpose of presenting biological effects (Montagner et

60 al., 2017). The pharmaceutical industry was the one that grew most with the evolution of the industrial

61 processes, making their outcome products become products of priority need.

62 Pharmaceutical residues reach the water bodies by various routes, and the main source is through

63 wastewater (Li, 2014). These chemical compounds can enter unchanged ecosystems or metabolites by

64 various means, and the main route is by renal excretion (Osawa et al., 2015). After its ingestion,

65 approximately 40 to 90% of the administered dose of drug is excreted in its unchanged form or as a

66 biologically active metabolite along with urine and feces in the domestic sewer (Valcárcel et al., 2011;

67 Américo et al., 2013). In many Brazilian cities not all domestic sewage is treated, but even in the treated

68 part, many pharmaceutical compounds are not degraded in sewage treatment plants, leading to

69 contamination of aquatic matrices such as rivers, lakes and surface waters.

70 Nonsteroidal anti-inflammatory drugs (NSAIDs) make up one of the most widely consumed

71 classes of pharmaceuticals (Lonappan et al., 2016) because of the ease of obtaining them, which are

72 normally sold without medical prescriptions, and constitute the most prescribed class of medications

73 doctors and dentists (Bisognin et al., 2018). These substances basically consist of a group of active

74 compounds to control inflammation, promote analgesia and combat hyperthermia (KrameR et al., 2015),

75 whose presence in the environment is potentiated due to the high consumption of these drugs and the

76 incomplete elimination in the ETSs (Valcárcel et al., 2011).

77 NSAIDs, as well as other classes of drugs, have also been detected in aquatic matrices with low

78 concentrations (ng L-1 to μg L-1), but despite these low concentrations, studies have shown that these

79 compounds are biologically active (Fent et al., 2006; Kramer et al., 2015; Stelato et al., 2016) and are

80 involved with local biota, significantly influencing the physiology, metabolism and behavior of the

81 species (Belisario et al., 2009).

82 In Brazil, water potability parameters are determined by standards set out in Annex XX of

83 Administrative Rule 5/2017 (former ordinance No. 2914/2011), published by the Ministry of Health.

84 Among other issues, this standard provides for acceptable water characteristics for consumption, and the

85 permissible concentrations for various chemicals that may pose a health risk, such as some
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86 agrochemicals. However, there is no drug limitation yet. The standards established for classification of

87 Brazilian water bodies, established by CONAMA Resolution No 357/05, also do not have limit values on

88 drug residues (BRASIL, 2005).

89 Globally, mainly due to the absence of conclusive toxicological data, there is still no legislation

90 focused on the levels of drugs in water for human consumption. In the United States, for new

91 pharmaceuticals to be approved, there is a requirement for the development of an environmental study for

92 the United States Food and Drug Administration (USFDA), which regulates the presence of

93 pharmaceutical substances in the environment. However, for drinking water, similarly to Brazil, the

94 Environmental Protection Agency of North America (USEPA) does not have official regulations for the

95 monitoring of pharmaceutical products in the environment (Kot-Wasik et al., 2006; USEPA, 2013).

96 The European Union also does not provide for maximum allowable concentrations for

97 pharmaceuticals in drinking water but points out that some drugs and endocrine disrupters are included in

98 lists of priority substances, watch lists, or lists of candidates for priority substances (candidate list) of

99 some international agencies (Lima et al., 2017). In this sense, identifying and understanding the risks to

100 human and environmental exposure associated with the presence of drugs in aquatic environments,

101 mainly because they are not contemplated in the current legislation, allows for the anticipation and

102 mitigation of damages.

103 The effects of concentration and distribution of pharmaceutical residues on the environment and

104 on humans are not yet fully understood (Schäider et al., 2014), but more recent studies have reported

105 some possible effects caused by the presence of in the environment (Montagner et al., 2017; Bisognin et

106 al., 2018; Mutiyar et al., 2018). The presence of these compounds in waters, especially in the water

107 supply and those used for their production, is a very significant issue and is related to the safety of human

108 and environmental health.

109 The objective of the present study was to evaluate the presence and concentration of the anti-

110 inflammatory drugs diclofenac and paracetamol in two points of Beberibe River (old and new uptake

111 point for water supply), located in the Metropolitan Region of Recife (RMR), between the cities of Recife

112 and Olinda, Pernambuco, Brazil.

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113 The existence of pollutants upstream or downstream of the water catchment points for the

114 population supply has significant relevance not only in the quantity and quality of water that will be

115 offered, but also in the economic aspect of the operation and maintenance for the treatment of the spring

116 water. In addition, it is important to evaluate the variability of the concentration of the compounds studied

117 when under rainy regimes.

118 The area of the study in question suffers constantly from pollution and contamination of sanitary

119 sewers. Therefore, the study for the optimization of the best point of abstraction, with lower amount of

120 pollutants, will be of great utility to Pernambucana Company of Supply in order to minimize costs,

121 capturing water of better quality possible. In addition, knowledge about the concentrations of exposure of

122 drug residues in aquatic matrices generates subsidies for these compounds to become candidates for

123 future regulation.

124

125 METHODOLOGY

126 Characterization of the study site

127 The area of the research project is located in the Metropolitan Region of Recife (RMR), on the

128 border between the cities of Recife and Olinda, in the catchment area of the Beberibe river in its middle

129 section, in the state of Pernambuco. The climate of the study area is characterized by not showing annual

130 variations of greater amplitude, where the seasons express a certain uniformity between spring/summer

131 (dry period) and autumn /winter (rainy season). According to the Pernambuco Water and Climate Agency

132 (APAC, 2014), rainfall is considered abundant in relation to other regions of the Northeast of Brazil, with

133 an average of 2,002.6 mm year-1, from 2003 to 2013.

134 According to the State Environmental Agency of Pernambuco (CPRH, 2018), the Water Quality

135 Maps of the Beberibe catchment area have a poor water quality index. Comprising a relatively dense

136 hydrographic network, the anthropic activities near the Beberibe River reflect directly on the quality of its

137 surface waters, as the water course frequently suffers from the inadequate disposal of sanitary sewage and

138 the input of waste, resulting in a considerable increase in the level of pollution. In addition, there is a

139 deficit in the basic sanitation system in the cities of Olinda and Recife, pointing to one more condition for

140 pollution to be aggravated by this source.

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141 In the studied section of the river Beberibe are inserted different landscapes, where in some

142 places it is still possible to observe the presence of native vegetation. To perform the present research,

143 two points were selected and properly georeferenced (new and old uptake point for water supply), with

144 Point 1 (P1: 7 °59'34'' S 34°54'964'' W) and point 2 (P2: 7°59'776"S 34°54'415'' W). Figure 1 shows the

145 location of sampling points in the Beberibe river basin.

146 Point 1 (close to new uptake for water supply) is located upstream of the BR-101 highway, with

147 little anthropogenic influence, presenting clear waters and surrounded by native vegetation, being

148 possible to observe a landscape of Atlantic forest with only minor changes. The section of the basin

149 upstream of Point 1 is occupied by farms, isolated dwellings and polyculture plantations. It has an

150 average width of 7 m and a water depth of approximately 20 cm.

151 Point 1 is near the current water uptake system of Beberibe river located in the neighborhood of

152 Guabiraba, close to highway BR-101 North, which was started by COMPESA (public water supply

153 company) some years ago. This catchment serves about 100,000 people among some neighborhoods of

154 Olinda and Recife. The average flow of water captured in the river is approximately 200 L s-1 in the rainy

155 months and has a drop in the driest months reaching about 150 L s-1 (COMPESA, 2018).

156 Point 2 (at old water supply abstractions station) is completely enveloped by an urbanized area

157 with few remnants of forest, where the presence of solid residues of domestic origin is constant, as well as

158 debris in its banks. The average width of point 2 is 6 m, with a water depth ranging from 20 cm to 30 cm.

159 At Point 2 there was the old uptake which started its operation in 1946, but has been abandoned

160 at the end of XX century because of poor water quality. Now at this location there is only the Pumping

161 Station of COMPESA, to distribute water for several neighborhoods and the uptake has been moved

162 upstream.

163

164 Effects of rainfall on drug concentration

165 In the present study, rainfall data were used, from the Alto da Bondade station of Water and

166 Climate Agency of Pernambuco State (APAC, 2018), to better understand the dilution of anti-

167 inflammatories at the points studied. This station is located in Olinda - PE, located in the Beberibe river

168 basin and is approximately 2 km from the studied section.

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169 In addition to the rainfall data, a better understanding of the variation of the residues of the

170 studied compounds was carried out to calculate the time of concentration of the Beberibe river basin

171 through the Kirpich formula (Equation 1):

172 (Tc= 57 (L3/H)0.385) (1)

173 being: L represents the length of the course (km) and H the difference of altitude (m).

174 Time of concentration is a concept defined in Hydrological Science to evaluate the response

175 of a watershed to a rainfall event. It can be understood as the time needed for a drop of rain to flow

176 from the most remote point in a watershed to the watershed outlet.

177 Concentration time is important to understand the river flow rate and consequent dilution after

178 precipitation starts.

179 Sample collection and drug analysis

180 The samples were collected from the two previously selected points of the Beberibe river, using

181 a 1.0 L amber glass, duly identified. The collectors were previously decontaminated with neutral

182 detergent (Extran®) and subsequently heated in the muffle at 400ºC to eliminate possible organic

183 residues.

184 Six collections were carried out at the two study points, in July/2016 (C1), August/2016 (C2),

185 September/2016 (C3), October/2016 (C4), November/2016 (C5) and December/2016 (C6). After

186 collection, the samples were refrigerated until the extraction and concentration of the analyzed drugs.

187 The analysis of the drugs was carried out at the Environmental and Quality Engineering

188 Laboratory (LEAQ) at the Chemical Engineering Department of the Federal University of Pernambuco

189 (UFPE). The contaminant extraction was done by solid phase (SPE) using strata - X polymer cartridges

190 operating in reverse phase (500 mg/6 mL - Allcrom). For this procedure peristaltic pump (Wilson) was

191 used operating at a flow rate of 10 mL min-1; the stationary phase was conditioned with two aliquots of 3

192 mL of acetonitrile (Merck), and then two aliquots of 3 mL of ultra pure water were added. Once the

193 cartridges had been conditioned, the effluent under study was then filtered and collected in a 5 mL

194 volumetric flask, and its volume measured with acetonitrile.

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195 The methodology of the drug analysis process (extraction, concentration and chromatography) of

196 the present article followed the validation carried out by Napoleão et al. (2013) for diclofenac and

197 paracetamol. With the preparation of the standards, the characteristic retention times of each drug were

198 determined, and then the analytical curves with a concentration range of 0.1 to 1 mg L-1 were

199 constructed. For the validation of the chromatographic method under study, the following validation

200 parameters were analyzed and determined: linearity (analysis based on correlation coefficient (r)), limit of

201 detection (LD), limit of quantification (LQ), precision and accuracy. Precision analysis was performed

202 based on the coefficient of variance (CV), while accuracy was determined based on the recovery method.

203 It is important to emphasize that the data dispersion was evaluated according to the procedures provided

204 by National Institute of Metrology, Quality and Technology (INMETRO), using seven (7) curves with

205 eight (8) different concentrations for each drug. These curves were analyzed in the high performance

206 liquid chromatography equipment coupled to ultraviolet spectrometry (HPLC/UV). It was also possible to

207 evaluate the dispersion of values using the Grubb's test, (Hubber et al., 2003). The values obtained were

208 found to be in compliance with the test performed for 95% confidence, ie, all values obtained were, if less

209 than 2,020 (reference value for seven measurements).

210 The determination of paracetamol and diclofenac concentrations was performed on Shimadzu

211 high performance liquid chromatography (HPLC) equipment, equipped with the ULTRA C18 reverse

212 phase column (5 μm, 4.6 x 250 mm) and UV detection (SPD-20A) for wavelengths equal to 285 nm. The

213 mobile phase employed was a solution of water acidified with 10% acetic acid and acetonitrile in a

214 volume ratio of 65:35. The furnace temperature of the equipment was maintained at 40 ± 1°C with the

215 flow of 1.00 mL min-1, pressure of 53 kgf cm -2 and injection volume of 20 ul. The wavelength used for

216 detection of the chromatographic peaks was 254 nm and detection of each compound was performed

217 based on their respective retention times, 6.5 min for diclofenac and 4.20 min for paracetamol.

218

219 RESULTS AND DISCUSSIONS

220 After the establishment of a method capable of identifying and quantifying the residues of the

221 studied compounds (diclofenac and paracetamol) in a safe and reliable manner, it was possible to analyze

222 the samples from the two points studied in the section of the Beberibe River.

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223 The drugs analyzed in the present research are not included in the current legislation and,

224 therefore, there is no regulation that refers to their presence, neither in water matrices nor in waters for

225 human consumption. Considering this reality, the results and discussions presented in the present research

226 were related to results on the occurrence of these same compounds in other published researches.

227

228 Diclofenac

229 Diclofenac residues were detected in 100% of the samples collected at the two points studied. In Table 1

230 it is possible to observe the concentrations of diclofenac at each sampling point during the study period.

231 Table 1 - Concentration of diclofenac, in mg L-1, in the Beberibe river, Pernambuco, from July to

232 December 2016.

Year 2016 DICLOFENAC (mg L-1)

month Point 1 Point 2

Jul 0.019 0.022

Aug 0.034 0.045

Sep 0.034 0.045

Oct 0.027 0.045

Nov 0.063 0.101

Dec 0.074 0.193

233

234 The concentration of diclofenac detected in the analyzed samples of the Beberibe River varied

235 between 0.019 and 0.193 mg L-1. Despite being considered a polluted river, in relation to the presence of

236 diclofenac some authors reported higher values of this compound, such as Américo-Pinheiro et al. (2017)

237 in Córrego da Onça, located in the municipality of Três Lagoas, Mato Grosso do Sul, which detected a

238 concentration of diclofenac up to 8.250 μg L-1.

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239 It can be seen from Table 1 that upstream of point 1 there are farms and scattered dwellings, the

240 population density is low, but even so, small concentrations of diclofenac have also been detected.

241 However, its highest concentration was recorded in point 2, located in a very urbanized area. The

242 presence of the drug is possibly related to the inadequate release of raw sewage directly into the waters of

243 the Beberibe river. It is known that after administration of a drug, a significant part of the parent

244 compound and / or its metabolites are excreted through the urine and feces, reaching the domestic and

245 hospital sewage. This pathway represents one of the major sources of these compounds in the

246 environment (Boxall, 2004; AMérico et al., 2012; Balakrishna et al., 2017; MirzaeI et al., 2017).

247 Similar results were found by Kramer et al. (2015) in the Alto Iguaçu Basin, Paraná, where they

248 detected the presence of diclofenac in some rivers. The authors found that the highest concentrations

249 found, especially in the Iguaçu River with values of 285 ng L-1, were associated with the presence of

250 large amounts of sewage due to urbanization in the studied areas.

251 This fact is worrying, as this drug, as well as others, causes different harmful effects to the

252 environment and to living beings, as verified by Dietrich et al. (2010) found that chronic exposure of

253 diclofenac to the organism Daphnia magna causes a delay in the reproduction period and also an increase

254 in the size of subsequent generations.

255 Still referring to ecotoxicity caused by diclofenac, Lonappan et al. (2016) reported adverse

256 effects on the structure and function of river biofilm communities in Quebec - Canada. A study conducted

257 by researchers in Canada and the United States of America exemplifies gastrointestinal toxicity in studies

258 for the determination of the compound in waters from industrial and urban effluents (Mohapatra et al.,

259 2014).

260 The presence of this drug was also observed in some sources outside Brazil: in some sections of

261 Beiyun River in China (Dai et al., 2015; Yang et al., 2017); in Danube, Sava, Velika Morava and Tisa

262 rivers, in Republic of Serbia (Kovačević et al., 2016); in Turia river, Spain (Carmona et al., 2014); in the

263 Wannsee and Tegel lakes in Germany (Heberer et al., 2004; Liu et al., 2018); in an urban area that

264 receives river in Nanjing, China (Liu et al., 2018); in the surface waters of Apatlaco River, Morelos State,

265 Mexico (Rivera-James et al., 2018).

266

267 Paracetamol
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268 In the analyzed samples, paracetamol was not detected in the samples collected in Point 1, but

269 was detected in Point 2 (Table 2), that is, at the point most impacted by urbanization and influenced by

270 domestic sewage.

271 Table 2 - Concentration of paracetamol (mg L-1), in Beberibe river, Pernambuco, from July to December

272 2016.

Year 2016 PARACETAMOL (mg L-1)

month Point 1 Point 2

Jul ND 0.003

Aug ND 0.006

Sep ND 0.020

Oct ND 0.038

Nov ND 0.038

Dec ND 0.042

273

274 When analyzing Table 2, it was observed that the highest concentration found in the studied

275 section of Beberibe river was 0.042 mg L-1 and in some samples the presence of paracetamol was not

276 detected. Although paracetamol has been detected in Beberibe River at relatively low concentrations,

277 studies have portrayed the presence of this drug in surface waters (Togola et al., 2008; Vulliet et al., 2009;

278 Gracia - Lor et al., 2011). In Yamuna River, one of the main tributaries of Ganges River -India, Mutiyar

279 et al. (2018) detected a paracetamol variation between 0.333 and 1.565 μg L-1, values similar to those

280 obtained in the present study.

281 The low levels and non-detection of paracetamol in some samples may be associated with the

282 biodegradation of the same, since, according to Henschel et al. (1997), paracetamol has a biodegradability

283 of 57% when free in the environment. Paracetamol can be degraded and removed at effluent treatment

284 plants (Heberer, 2002), minimizing its concentration in the environment, besides being a drug sensitive to

285 the photolysis process, as verified by Napoleão et al. (2018). The authors verified that after 60 min

286 exposure to the photolytic process, paracetamol undergoes a degradation of 78.50% ± 0.28, a fact that

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287 may have occurred in some of the collections, since in the Northeast of Brazil there is a high incidence of

288 solar radiation.

289 At the two points and in all the collections performed, the occurrence of paracetamol detected in

290 the studied section of Beberibe River presented a reduced concentration in comparison to the data of

291 diclofenac (Figure 2).

292 From the data of Figure 2, it can be affirmed that paracetamol was the drug that presented the

293 lowest detection and quantification index, and it is not possible to detect it in some of the samples.

294 Similar results were presented by Stelato et al. (2016), who analyzed the presence of some drugs in

295 Córrego do Veado /Limoeiro, São Paulo, and detected a higher concentration and frequency of diclofenac

296 in relation to paracetamol. Américo - Pinheiro et al. (2017), evaluated the presence of pharmacological

297 compounds in affluent and effluent water samples from a sewage treatment station located in Três

298 Lagoas-MS, and also detected a frequency and concentration of paracetamol inferior to diclofenac. Even

299 at low concentration levels, the presence of a pharmacologically active compound in the environment

300 may cause significant toxicological effects to the aquatic environment. In Korea, Kim et al. (2012) report

301 the decrease in juvenile survival (30 days after hatching) in Oryzias latipes exposed to paracetamol. In the

302 literature other toxicological effects caused by this drug in the environment are also mentioned, such as

303 the oxidative stress of two species of bivalves, namely the edible clams Venerupis decussata and

304 Venerupis philippinarum in a shallow lagoon on the northwestern Atlantic coast of Portugal (Antunes et

305 al., 2013) and in Hyalella azteca at Lake San Miguel Almaya, in Capuluac State of Mexico (Lucero et al.,

306 2015). In addition, genetic alterations were also associated with the presence of paracetamol in the

307 environment, as the example given by Nunes et al. (2004), in two species of aquatic plants, Lemna gibba

308 and Lemna minor, obtained from laboratory cultures in Portugal and in hemocytes of the freshwater

309 bivalve zebra mussel in northern Italy (Parolini et al., 2009).

310 The occurrence of paracetamol in environment and its consequences has been the subject of

311 research worldwide. The authors report the presence of paracetamol residues in aquatic matrices through

312 scientific studies developed in several countries, such as in drinking water reservoirs along the Largue

313 River in southern France (FARRÉ et al., 2008), on Acheloos River, West Greece (STAMATIS and

314 KONSTANTINOU, 2013) and Ouse and Foss rivers crossing the city of York, UK (BURNS et al., 2018).

315
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316 Variation of drug concentration in Beberibe river under influence of precipitation

317 During the analyzes, it was observed that the detection of the residues of the drugs studied and

318 the points in which they were found varied a little among the collections made. As previously noted, the

319 concentration of diclofenac and paracetamol in the studied section of Beberibe River can be influenced by

320 the local urbanization process, but, in addition, hydrological precipitation data are parameters that must

321 also be considered.

322 In the metropolitan region of Recife, the rainy season runs from March to August. From

323 September to February occurs the period of few rains, with November being the driest month. Data

324 provided by the Pernambuco State Agency for Water and Climate related to the average monthly rainfall

325 of the last ten years, from the nearest station in the study area (Olinda-Alto da Bondade 209), attest that in

326 July, when the presence of minors concentrations of drugs studied, one of the highest rainfall volumes of

327 the year occurred (279.05 mm), which may suggest a possible dilution of the analyzed analytes. Figure 3

328 shows by graphs the concentration variation of drug residues detected under different rainfall conditions.

329 In general, samples that were collected in the first campaigns, that is, in the rainier months of the

330 present research, presented a lower concentration of drugs than the samples collected during periods of

331 drought. During dry periods (September onwards), samples taken at Point 2, near the urban area, showed

332 an even greater increase in drug concentration, especially diclofenac.

333 Some authors have studied the seasonal variation of the drug concentration and observed that

334 certain chemical compounds presented higher concentrations during the dry season, since in this period

335 they do not undergo the natural dilution process of the water (Luque-Espinar et al., 2015). Burns et al.

336 (2000) analyzed the temporal and spatial variation of some drugs, including paracetamol, in Ouse River

337 and Foss River in the UK city of York and detected lower concentrations in the rainy season. Stamatis

338 and Konstantinou (2013) reported a slight decrease in paracetamol in the winter months on the Acheloos

339 river, Agrinio city in Greece Suggesting that their concentrations were influenced mainly by the dilution

340 of rainwater.

341 Similar results were also found by Pereira et al. (2015), where they analyzed the presence of 11

342 most consumed pharmaceutical products in Portugal in waste water treatment plants, among them

343 diclofenac, and detected higher concentrations of diclofenac in the dry period of the research.

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344 The catchment area of Beberibe river is small (23.7 km of course length and 52 m of

345 unevenness), so that the concentration time is less than 1 day. Thus, all precipitated rain in the basin

346 drains in less than 1 day after the end of the rain. In this sense, Table 03 shows in detail the concentration

347 of the drugs analyzed and the precipitation (APAC, 2018) from one day prior to collection.

348

349 Table 3 - Variation of the concentration of diclofenac and paracetamol residues identified in the Beberibe

350 river in the different collection periods, according to the rainfall.

Rainfall DICLOFENAC PARACETAMOL

Month
(mm) (mg L-1) (mg L-1)

Previous Day Collection Day Point 1 Point 2 Point 1 Point 2

Jul 19.5 1.7 0.019 0.022 ND 0.003

Aug 12.1 1.2 0.034 0.045 ND 0.006

Sep 1.1 0.0 0.034 0.045 ND 0.020

Oct 2.9 0.0 0.027 0.045 ND 0.038

Nov 1.0 0.0 0.063 0.101 ND 0.038

Dec 0.0 0.0 0.074 0.193 ND 0.042

351

352 The data presented in Table 03 confirm that, in general, the analyzed chemical substances, in the

353 studied section of the Beberibe river, have lower concentrations, when the collections are carried out the

354 day after the rainy event.

355 In contrast to the results found in the present study, some studies have detected higher levels of

356 pharmaceutical compounds in rainy periods (Kot-Wasik et al., 2016; Zhang et al., 2015). Yu et al. (2013)

357 detected higher concentrations of paracetamol and diclofenac during high rainfall at sewage treatment

358 plants serving a variety of communities in Riverside, Southern California. Lower concentrations of

359 diclofenac in the dry period were also reported by Stamatis and Konstantinou (2013) on the Acheloos

360 river, Agrinio city in Western Greece, probably due to its higher photodegradation and lower

361 consumption over this period of time.

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362 Stelato et al. (2016) showed an increase in the concentration of paracetamol and diclofenac

363 during the rainy season in Córrego do Veado/Limoeiro and Córrego do Cedro, located in the municipality

364 of Presidente Prudente, São Paulo. The authors explained that this fact may be associated to the drag of

365 solid waste from urban areas during periods of flooding, since the geomorphology of Presidente Prudente

366 is susceptible to flooding. In the same article another explanation reported that the higher occurrence of

367 drugs in the rainy season may be associated with changes in environmental characteristics that may have

368 contributed to the desorption of the highlighted compounds.

369 Once it has been released to water resources, a microcontaminant can be reduced in

370 concentration by natural removal mechanisms, so the analysis of the "destination" of a microcontaminant

371 in the water environment is based on the knowledge of its main characteristics and physicochemical

372 properties (Lima et al., 2017). In this context, Vieno and Sillanpää (2014) still point out that the

373 adsorption capacity depends on environmental factors, such as temperature, ionic strength, pH, among

374 others. Thus, the greater or lesser occurrence of pharmaceutical residues in the different seasons of the

375 year may be associated with changes in environmental characteristics.

376 Américo-Pinheiro et al. (2017) report that water temperature is closely related to the incidence of

377 sunlight in water bodies triggering the process of photodegradation of many compounds. This fact may

378 explain why the probability of detection of diclofenac in water decreases as the temperature of the

379 medium increases (Buser et al., 1998; Isidori et al., 2005; Américo-Pinheiro et al., 2017).

380 Studies have also shown that the influence of environmental parameters on the concentration of

381 paracetamol in this study suggests that the adsorption, biodegradation or photodegradation processes may

382 have favored the elimination of the compound (Henschel et al., 1997; Américo et al., 2009).

383 He first Brazilian federal legislation on standards of potability was created by Federal Decree

384 No. 79.367 of March 9, 1977, which established that the competence on the definition of potable water

385 standards for human consumption should be the responsibility of the Ministry of Health and that they

386 should be observed throughout the national territory. The most up-to-date version of the drinking water

387 policy in Brazil is found in Annex XX of Administrative Rule 5/2017 (former ordinance no. 2.914/ 2011),

388 which was published on October 3, 2017. There was no change in relation to the old ordinance No.

389 2.914/2011, which was already a more complete version both from the point of view of the

390 microbiological parameters and the chemical ones in relation to previous directives.
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391 Even though it is a version that is considered complete, more recent studies have increasingly

392 shown the need to include parameters related to drugs, since they are directly linked to the safety of

393 human and environmental health, causing different harmful effects to the environment and to living

394 beings . In this sense, since Point 1 is the new catchment point for water supply, this supply should be

395 considered safer because it presents lower concentrations of the analyzed drugs.

396 In addition, the information on drug concentrations detected in the present study serves as

397 parameters for comparative studies and alert for supply companies to analyze the importance of drugs

398 being legislated in order to avoid environmental problems.

399

400 FINAL CONSIDERATIONS

401 The two pharmaceutical compounds studied in the present study were detected during the

402 analyzes, and diclofenac was highlighted because it presented a higher concentration in the studied points

403 of the Beberibe river. Paracetamol was also detected, but at lower concentrations and frequency.

404 From the points where the collections were made, Point 2 presented higher concentrations of

405 both diclofenac and paracetamol. Probably, this fact is directly related to the collection site being located

406 in a completely urbanized area, where its waters serve as domestic sewage dumps, receiving daily high

407 pollutant loads. This is the reason, in general, for the occurrence of drugs in aquatic matrices.

408 Regarding the influence of rainfall on drug concentration, the results found that in most samples,

409 both diclofenac and paracetamol presented higher concentrations in the period with lower rainfall. This

410 variation may be associated to the higher dilution of these drugs caused in rainy periods.

411 The Beberibe River has been negatively highlighted with the presence of polluting loads in its

412 banks and in its waters. In general, the entry of fresh domestic effluents has affected the water quality of

413 this water source. Therefore, the presence of pharmaceutical contaminants may represent a significant risk

414 to the aquatic ecosystem.

415 The decision to abandon the old uptake point for public water supply some years ago was very

416 appropriate because of the domestic effluents and consequently new drugs that are coming to the

417 waterway. The new upstream uptake has much less contribution from household effluents, but needs to be

418 continuously monitored for the presence of drugs.

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419 The data obtained in the present study contribute information on the concentrations and

420 frequency of these compounds, providing an important baseline for future and more comprehensive

421 investigations. New research is needed to identify the risks of these compounds to the environment,

422 developing new techniques that can reduce them in sewage treatment plants, as well as in the elaboration

423 of norms and legislation that make the use of drugs better controlled.

424

425 ACKNOWLEDGEMENTS

426 The authors are grateful to FACEPE, CAPES and CNPq for their support in the several phases of the

427 research project.

428

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Figure 1 - Beberibe river basin, Pernambuco state.

Figure 2 - Concentrations of diclofenac and paracetamol detected in the 6 samples (CP 1, CP 2, CP 3, CP

4, CP 5 and CP 6) at the two study sites (PT 1 and PT 2) in Beberibe river.

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Figure 3 - Daily precipitation and concentration (mg L-1) of drug in points 1 and 2 located along the

Beberibe river. A) diclofenac, and B) paracetamol.

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HIGHLIGHTS

 Pharmaceutical compounds were detected in Beberibe river in an area without

sewage treatment

 Diclofenac was present in all samples. Paracetamol was also detected but at
lower frequency.

 Both diclofenac and paracetamol presented higher concentrations in the period

with lower rainfall