Environmental Pollution 187 (2014) 170e181

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Prevalence and sunlight photolysis of controlled and chemotherapeutic drugs in aqueous environments Angela Yu-Chen Lin*, Yen-Ching Lin, Wan-Ning Lee Graduate Institute of Environmental Engineering, National Taiwan University, 71, Chou-Shan Rd., Taipei 106, Taiwan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 11 October 2013 Received in revised form 2 January 2014 Accepted 3 January 2014

This study addresses the occurrences and natural fates of chemotherapeutics and controlled drugs when found together in hospital effluents and surface waters. The results revealed the presence of 11 out of 16 drugs in hospital effluents, and the maximum detected concentrations were at the mg L
1 level in the hospital effluents and the ng L
1 level in surface waters. The highest concentrations corresponded to meperidine, morphine, 5-fluorouracil and cyclophosphamide. The sunlight photolysis of the target compounds was investigated, and the results indicated that morphine and codeine can be significantly attenuated, with half-lives of 0.27 and 2.5 h, respectively, in natural waters. Photolysis can lower the detected environmental concentrations, also lowering the estimated environmental risks of the target drugs to human health. Nevertheless, 5-fluorouracil and codeine were found to have a high risk quotient (RQ), demonstrating the high risks of directly releasing hospital wastewater into the environment. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Chemotherapeutic drugs Controlled drugs Sunlight photolysis Occurrence Natural attenuation

1. Introduction Occupational exposure to chemotherapeutics and controlled drugs has long been recognized as a potential health hazard. However, exposure to chemotherapeutic drugs (e.g., medications for treating cancer) and controlled drugs, such as narcotics, is not limited to the pharmacies and hospitals where these drugs are prepared and administered to patients. In fact, exposure is likely to occur through environmental waterways, which potentially impact human populations and local ecological systems. Many of these compounds are chemically and biologically active and cause significant toxicity after prolonged exposure (Stambaugh et al., 1976; Henschel et al., 1997; Musiatowicz et al., 1997; Mankes and Silver, 2013). Chemotherapeutics are used in cancer treatment, and the existing research has primarily addressed occupational exposure. Genotoxic and mutational changes have been identified in healthcare workers, and chemotherapeutic drugs have been found in their urine (Cavallo et al., 2005; Laffon et al., 2005). Evidence also exists for increased teratogenesis rates and adverse reproductive outcomes, as well as increased cancer incidence in healthcare workers (Martin, 2005; Meijster et al., 2006). Cyclophosphamide, ifosfamide, methotrexate, 5-fluorouracil, taxol, vinca alkaloids and platinum compounds are commonly used chemotherapeutic agents. Cytostatic compounds are generally polar and have been

* Corresponding author. E-mail address: [email protected] (A.Y.-C. Lin). 0269-7491/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.envpol.2014.01.005

detected in hospital wastewaters, the influents and effluents of WWTPs and surface waters (Ternes and Joss, 2006; Weissbrodt et al., 2009; Kosjek and Heath, 2011). According to a review by Kosjek and Heath (2011), past studies have primarily focused on hospital effluents, and only a few have studied environmental samples and their fate. Most cytostatic compounds are not likely to undergo biodegradation or volatilization, and very limited studies have been reported regarding sunlight photolysis (Kosjek and Heath, 2011). The term “controlled drugs” refers to several very different, chemically unrelated classes, including narcotics, amphetamines, illicit substances, and non-narcotic drugs. Opium-based controlled drugs, such as morphine and codeine, have long been used for conditions ranging from postoperative pain to cancerous pain (Hamilton and Baskett, 2000). When taken in clinical doses, opiates and many other controlled drugs are powerful analgesics; when used in super-clinical doses, these drugs often confer a high or an otherwise pleasurable state of consciousness. Thus, these drugs are often sought for their paraclinical properties and are easily abused. Aside from their illicit nature, the common and wide-ranging clinical uses of controlled drugs result in their release into hospital wastes; waste run-off into nearby water sources is a major concern for water safety reasons. Cocaine, methadone, fentanyl and methamphetamine have been found in tap water in Spain (Rosa Boleda et al., 2011). Furthermore, codeine and methamphetamine were detected in source water in the USA (Stackelberg et al., 2007; Jones-Lepp et al., 2012). However, limited information has been reported on their fate in natural surface water.

A.Y.-C. Lin et al. / Environmental Pollution 187 (2014) 170e181

Natural attenuation mechanisms involve biotic and abiotic processes such as hydrolysis, photodegradation, irreversible sorption and redox reactions. The type and degree of attenuation processes that occur determine the subsequent environmental fate (occurrence and distribution) of contaminants and are essential when considering risk assessment and management. Sunlight phototransformation has been reported to be a significant natural attenuation process that reduces the detected concentrations of various pharmaceuticals in aqueous environments. Photodegradation may occur via direct and indirect photolysis. Direct photolysis occurs through light absorption by the chemical itself and leads to chemical bond cleavage. Indirect photolysis involves light absorption by dissolved organic matter (DOM), nitrates and nitrites in an aqueous environment, producing reactive species that react with target analytes. Bicarbonate has also been recently documented as a significant photosensitizer (Wallace et al., 2010; Lin et al., 2013). NSAIDs, b-blockers, hormones and cephalosporin antibiotics have all been found to be susceptible to natural sunlight photodegradation, with half-lives ranging from minutes to a few days (Wang and Lin, 2012; Lin and Reinhard, 2005; Piram et al., 2008; Tixier et al., 2003). This investigation addresses the occurrence and natural photolysis fate of the most common and widely used anticancer drugs and controlled drugs and reports the potential risks to human health and ecosystems associated with detected environmental concentrations. To our knowledge, this is the first work to simultaneously analyze these two very biologically active groups of pharmaceuticals at the ng L
1 level and is the first report to investigate the photodegradability and comprehensively discuss the overall natural attenuation processes of many of these target compounds.

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2. Methods 2.1. Chemicals and materials All standards were of 98% purity, and all chemicals were LC grade or ACS grade. The providers and purities of these compounds are given in Text S1 (Supporting Information). 2.2. Sampling The rivers, hospital wastewaters and sewage treatment plants in Taipei and Kaohsiung were selected for study sampling. Thirteen hospitals (H1eH13), 20 surface river samples (S1eS20) and one wastewater treatment plant (WWTP; WA) were the subject of the study, as shown in Fig. 1. The selected sampling sites were used to identify the source and influence of contaminants on the quality of nearby rivers with the greatest impact on those bodies of water (i.e., hospitals with more admissions/ beds and WWTPs with higher daily volumes of wastewater and regional discharges). The hospital wastewater treatment plant samples were composite samples and directly collected from pipeline effluents, and the sewage treatment plant samples were collected from influents and effluents. Both influents and effluents were sampled according to the hydraulic retention time of the treatment units and were collected as 24-h composite samples to avoid variations over the sampling day. 2.3. Sample preparation and analyses All of the samples were collected in amber glass bottles (triplicate samples) and stored in ice packed coolers. The samples were then vacuum-filtered through 0.45and 0.22-mm disk filter paper (ADVANTEC, Toyo Roshi Kaisha, Ltd., Japan) and stored at 4  C in the dark before undergoing solid-phase extraction (SPE). Detailed SPE procedures, chromatographic separations and quantification are described in detail in the Supplementary Information. In brief, the target compounds were classified into the following three categories: Group-1: cyclophosphamide, ifosfamide, methotrexate, vinorelbine, vinblastine, vincristine, paclitaxel, morphine and codeine; Group-2: methamphetamine, meperidine, cocaine, methadone, fentanyl and sufentanil; and Group-3: 5-fluorouracil. Oasis MAX cartridges (Waters, Milford, MA, USA) (for Group-1 and Group-2) and ENVI-Carb/NH2 cartridges (Supelco, Bellefonte, PA, USA) (for Group-3) were selected for positive and negative mode analytes, respectively, based on the physicochemical properties and extraction efficiency of the three groups.

Fig. 1. Sampling locations in the Taipei and KaohsiungePingtung regions.

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Table 1 Recoveries and method detection limits of controlled substances and anticancer drugs in DI water, river waters and hospital/wastewater treatment plant effluents. Compounds

MDL in DI water (ng/L)

MDL in hospital wastewater (ng/L)

MDL in WWTP effluents (ng/L)

R Value of calibration curve in solvent (CaleISesolvent)

DI water

0.1 1 0.2 1 5 0.1 0.02 0.5

0.1 4 0.8 1 10 0.4 0.4 1

0.4 10 4 10 10 0.4 1 1

0.9974 0.9986 0.9996 0.9992 0.9985 0.9996 0.9994 0.9999

100 98 99 103 87 95 94 92

       

2 5 3 6 9 7 6 3

105 105 103 103 95 96 95 97

       

3 18 7 7 17 5 3 4

105 98 102 102 98 96 92 82

       

8 11 4 5 9 5 4 4

106 116 101 108 85 92 103 88

       

5 10 4 4 1 8 7 4

95 100 101 100 94 96 97 94

       

3 4 2 5 8 6 3 1

98 86 101 108 100 99 117 90

       

11 9 3 4 15 6 2 3

5 0.2 0.2 1 1 5 1 5

5 0.8 0.8 4 1 5 4 10

10 0.8 0.8 4 4 5 4 10

0.9996 0.9995 0.9985 0.9981 0.9977 0.9997 0.9996 0.9998

98 94 94 101 93 110 104 107

       

3a 5 5 10 11 8 6 6

100 108 104 102 107 115 101 103

       

8b 9 5 2 7 6 6 10

96 106 103 108 99 100 92 107

       

4a 2 5 5 14 4 6 7

100 105 113 104 106 76 111 116

       

12b 8 3 7 11 8 3 10

96 97 94 96 98 97 96 109

       

6a 3 3 9 5 5 7 9

95 101 98 95 87 115 102 121

       

8b 28 11 2 9 13 13 22

Level 1: Group-1 ¼ 0.1 mg/L, Group-2 ¼ 0.01 mg/L, Concentrate 500 times. Level 2: Group-1 ¼ 0.02 mg/L, Group-2 ¼ 0.002 mg/L, Concentrate 500 times. RSD, relative standard deviation. a 5-Fluorouracil ¼ 0.4 mg/L, Concentrate 125 time, intra-day. b 5-Fluorouracil ¼ 0.4 mg/L, Concentrate 125 time, inter-day.

Level 1 Relative Recovery  RSD (%)

River water Level 2 Relative Recovery  RSD (%)

Level 1 Relative Recovery  RSD (%)

Hospital wastewater Level 2 Relative Recovery  RSD (%)

Level 1 Relative Recovery  RSD (%)

Level 2 Relative Recovery  RSD (%)

A.Y.-C. Lin et al. / Environmental Pollution 187 (2014) 170e181

Controlled drugs Methamphetamine 0.1 Codeine 1 Methadone 0.2 Meperidine 1 Morphine 2 Cocaine 0.1 Fentanyl 0.02 Sufentanil 0.1 Cytotoxic chemotherapy drugs 5-Fluorouracil 5 Cyclophosphamide 0.2 Ifosfamide 0.2 Paclitaxel 1 Methotrexate 1 Vinorelbine 1 Vinblastine 0.2 Vincristine 1

MDL in river water (ng/L)

A.Y.-C. Lin et al. / Environmental Pollution 187 (2014) 170e181 Chromatographic separation of analytes was performed using an Agilent 1200 module (Agilent, Palo Alto, CA) equipped with a SunFire C18 column (150  4.6 mm i.d., 5 mm) (Waters, Wexford, Ireland). Quantification was performed using the internal standard method and performed using the multiple reaction monitoring (MRM) mode of a Sciex API 4000 liquid chromatographyemass spectrometry (Applied Biosystems, Foster City, CA) system with positive and negative electrospray ionization (ESI). The 14 internal standards used in this study were morphine-d3, codeine-d3, ifosfamide-d4, methotrexate-d3, vinorelbine-d3 bitartrate, vincristine-d3 sulfate, paclitaxel-d5, 5-fluorouracil-15N2, cocaine-d3, (þ/
) methamphetamine-d9, fentanyl-d5, methadone-d9, sulfentail-d5 and meperidine-d4. 2.4. Quality assurance and quality control Two hundred milliliter sample aliquots were spiked in triplicate at high and low concentrations. The absolute recoveries and inter- and intraday accuracy data for the target compounds in different matrices are shown in Tables S3 and S4 (Supporting Information). Calibration curves were made using five points and Group-1 and Group-3 standards fell in the range of 0.5e400 mg L
1; Group-2 standards were in the range of 0.05e40.0 mg L
1. The detection (LOD) and quantification limits (LOQ) were defined as the concentrations in DI water resulting in peak areas with signal-to-noise ratios (S/N) of 3 and 10, respectively. The target compound LODs ranged from 0.0025 to 0.5 mg L
1, and the LOQs ranged from 0.005 to 1 mg L
1 (Table S5). The overall method detection limits (MDLs) were 0.02e5, 0.02e5, 0.1e10 and 0.4e10 ng L
1 for DI water, river water, hospital wastewater and WWTP effluents, respectively (Table 1). The recoveries were investigated at two concentrations for the Group-1 and Group-2 target compounds (0.1 mg L
1 and 0.02 mg L
1 for Group-1; 0.01 mg L
1 and 0.002 mg L
1 for Group-2), and their relative recoveries were strong for the three following water matrices: DI water (87e110% and 95e115%), river waters (82e108% and 76e116%) and hospital wastewaters (94e109% and 87e121%). For Group-3 (5fluorouracil), the recoveries were 95e100% for the different water matrices (Table 1). 2.5. Photolysis experiments Grab samples (2e3 L) were collected from the Jin-Mei River, JMR (southern Taipei) in amber glass bottles in May 2013 and filtered through 0.22-mm cellulose acetate membrane filters (Advantec, Toyo Roshi Kaisha, Ltd., Japan) to remove bacteria and particulates. Photochemical experiments were conducted in a sunlight simulator (Suntest CPS; Atlas, Chicago, IL, USA) equipped with a 1.5-kW xenon arc lamp as the radiation source and the irradiation intensity was set at 700 W m
2. Special inner and outer glass filters were fitted to remove UV wavelength transmissions below 290 nm (with total passing wavelengths of 290e800 nm). Different water matrices (DI water, decarbonated JMR and JMR) were spiked with selected target compounds (initial concentration ¼ 20 mg L
1) and placed in capped quartz glass reaction tubes (1.6 cm i.d.  13.5 cm depth, volume 27 mL) and then exposed to irradiation from a sunlight simulator maintained at 20  1  C with a thermostat. Dark control solutions of the same concentrations were scrupulously maintained in darkness. The pH values of the spiked DI water samples were adjusted to 7.0, and the pH values of the spiked JMR water samples were maintained at the original pH, 7.4. All experiments were conducted in triplicate. For the decarbonation experiments, the pH of JMR was first adjusted to 4.5 by adding 1 M hydrochloric acid, followed by bubbling nitrogen through the solution to remove carbon dioxide; the pH was then adjusted back to 7.4 with 1 M NaOH, and the samples were spiked with individual standards for subsequent irradiation. 2.6. Incubation test An incubation test was conducted in the dark at 20  C for ifosfamide, methamphetamine, morphine and codeine (5 and 20 mg L
1) in DI water and JMR for 14 days. A total of 0.1% (w/v) sodium azide was added to a portion of the samples to eliminate microorganisms.

3. Results and discussion The physicochemical properties, uses, and urine excretion rates for the 16 target controlled drugs and chemotherapeutic compounds are presented in Table S6. 3.1. Target compounds in hospital effluents, surface waters and WWTPs The Taipei and KaohsiungePintung regions were selected as study sites because they are densely populated and contain WWTPs and many hospitals/medical centers. Fig. 1 presents a map of the two studied areas with the sampling sites marked. In these regions, waste streams containing large quantities of medications discarded

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by hospitals may significantly impact the receiving surface water systems. According to Taiwan’s Environmental Protection Administration, waste streams from hospitals are treated only to meet minimal effluent standards (defined as a biological oxygen demand of 30 mg L
1, a chemical oxygen demand of 100 mg L
1, suspended solids of 30 mg L
1, a true color of 550 color units and 200,000 CFU/ 100 mL of Escherichia coli). These standards are insufficient to ensure the removal of the large quantity of drugs present in hospital waste effluents. The hospitals in Taipei were selected because they are the largest in terms of the number of admissions, patients/day and number of beds, representing the greatest cumulative medication use. Out of a total of 112 medical centers and hospitals, the seven selected hospitals together represent 37% of the entire outpatient and inpatient population of the Taipei region (BNHI, 2013). Consequently, the Taipei region (having 2848 people/km2) was not only the most likely source of target compounds and likely to represent the worst-case scenario in Taiwan, but it also provides us with an idea of how other mega cities around the world can be contaminated with these drugs. In contrast, the hospitals selected from the KaohsiungePingtung (with 664 people/km2) area are small to medium-sized and therefore represent the other end of the size spectrum. Table 2 lists the occurrence of controlled and chemotherapeutic substances in hospital effluents, river waters and WWTPs in the Taipei and KaohsiungePintung regions. As expected, the target analytes are occurring at much higher frequencies and concentrations in the Taipei region than in the KaohsiungePintung region despite similar occurrence patterns in both areas. 3.1.1. Cytotoxic chemotherapy drugs All of the target chemotherapeutics were detected except for the three vinca alkaloids (vinorelbine, vinblastine and vincristine). Among the five cytotoxic chemotherapy drugs detected and shown in Table 2, 5-fluorouracil, cyclophosphamide and ifosfamide were widely distributed (>75%) and concentrations up to 1500, 1200 and 360 ng L
1 (median of 110, 160 and 9.0) were found in the hospital effluents and concentrations up to 160, 96 and 8.9 ng L
1 (median of 17, 3.2 and 2.2) were found in river waters. 5-Fluorouracil is an antimetabolite and its principal uses are to treat gastric, colorectal, pancreatic and breast cancers. Approximately 5e20% of 5-fluorouracil injected into the human body can be excreted in the urine (Straub, 2010; Besse et al., 2012). This compound was detected in hospital wastewaters, rivers and WWTPs, at concentrations of 46e1500 ng L
1, 5.0e160 ng L
1 and 280 ng L
1 (influent) and 80 ng L
1 (effluent), respectively. Mahnik et al. (2007) reported extremely high concentrations in the sewer of an oncological inpatient treatment ward (0.124 mg L
1) in Austria. Other studies from European countries detected 92 ng L
1 (Slovenia) and 27 ng L
1 (Switzerland) in hospital wastewaters (Kosjek et al., 2013; Kovalova et al., 2009). Cyclophosphamide and ifosfamide in particular are both isomeric alkylating N-lost derivatives with known mutagenic, carcinogenic, teratogenic and embryotoxic effects (Allwood et al., 2002; ASTA Medica, 1995; IARC, 1981). They are used to treat cancers and autoimmune diseases, such as lymphomas, some forms of brain cancer, leukemia and some solid tumors. Approximately 15e 25% or more of the quantity taken up by the human body can be excreted as the parent compound in the urine (Higby, 1980). These drugs were generally found in all hospital wastewaters (15e 1200 ng L
1 and 3.4e360 ng L
1, respectively) and rivers (0.9e 96 ng L
1 and 0.1e8.9 ng L
1, respectively) with slightly higher cyclophosphamide concentrations than those of ifosfamide in all cases. Cyclophosphamide and ifosfamide persist through wastewater treatment processes, as we observed similar concentrations

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Table 2 Concentrations of the target compounds in hospital effluents, surface waters and WWTP in the Taipei and KaohsiungePingtung regions. Compounds

Taipei region Controlled drugs Methamphetamine Codeine Methadone Meperidine Morphine Cocaine Cytotoxic chemotherapy 5-Fluorouracil Cyclophosphamide Ifosfamide Paclitaxel Methotrexate

Hospital wastewaters (n ¼ 7)

a

WWTP

Median (ng/L)

Detected Rangeb (ng/L)

Number of sites > MDL

Median (ng/L)

Detected Rangeb (ng/L)

Influent (ng/L)

Effluent (ng/L)

7 7 6 6 4 2 drugs 7 6 4 4 2

31 190 4.5 200 36 ND

12e240 4.5e700 1.7e200 89e1500 36e2400 6.3e130

12 6 4 1 1 0

3.0 ND ND ND ND ND

0.2e260 1.3e15 0.2e4.3 2.0 36 ND

270 41 2.7 ND 38 1.2

16 56 4.0 ND 29 0.6

120 660 13 4.2 ND

48e1500 20e1200 13e89 4.2e13 6.1e300

12 11 8 0 0

6.2 3.3 3.1 ND ND

5.0e70 1.9e13 1.9e8.9 ND ND

280 12 8.3 ND ND

80 15 10 ND ND

KaohsiungePingtung region Hospital wastewaters (n ¼ 6) Controlled drugs Methamphetamine 6 1.3 Codeine 4 67 Methadone 5 2.1 Meperidine 4 74 Morphine 2 ND Cytotoxic chemotherapy drugs 5-Fluorouracil 3 24a Cyclophosphamide 6 79 Ifosfamide 5 8.0 Paclitaxel 1 ND Methotrexate 1 ND b

Rivers (n ¼ 13)

Number of sites > MDL

Rivers (n ¼ 7) 0.1e17 58e180 0.2e70 1.7e350 130e220

7 0 4 0 0

0.3 ND 0.1 ND ND

0.1e1.0 ND 0.1e1.0 ND ND

46e510 15e720 3.4e360 16 24

6 7 6 0 0

56 1.1 2.1 ND ND

35e160 0.9e96 0.1e4.7 ND ND

0.5  MDL was used for ND for ‘median’ value estimation. Minimum to maximum detected values.

in the influent and effluent. Related studies have shown that both drugs are not easily degraded and removed by the activated sludge treatment process and could be found in hospital effluents and municipal sewage effluents (Kümmerer, 2001; Buerge et al., 2006; Besse et al., 2012). Kümmerer (2001) reported that the maximum detected concentration of ifosfamide measured in hospital effluents was 1914 ng L
1, with similar concentrations in sewage treatment plant influents and effluents (29 and 43 ng L
1, respectively). Buerge et al. (2006) also reported that the detected cyclophosphamide concentrations were similar in both WWTP influents and effluents. 3.1.2. Controlled drugs All of the target controlled drugs were detected except for sufentanil and fentanyl, which are highly lipophilic (log Kow > 3) and have molecular weights of >300 g/mol. These compounds are quickly absorbed and not easily excreted in urine (Boersma et al., 1991; Hassenbusch et al., 2004; Schäfer, 2010; Nendza and Müller, 2007). A high occurrence of controlled drugs was observed in the hospital effluents (the maximum concentrations ranged from ng L
1 to mg L
1 levels), and a much lower occurrence was observed in the receiving rivers. Methamphetamine was found at the highest frequency (in 34 out of 35 water samples) and at concentrations up to 270 ng L
1 (median 3.0 ng L
1), followed by codeine, methadone and meperidine, which occurred frequently (>10/13) in hospital effluents at significant concentrations (up to 700, 200 and 1500 ng L
1, respectively) but were absent (>50%) in surface water environments. Methamphetamine is a chiral compound and has S-(þ) and R(
) enantiomers. S-(þ)-Methamphetamine is available by prescription for the medical treatment of narcolepsy, attention deficit disorder and obesity. It greatly affects the central nervous system

and is commonly abused (Li et al., 2010). R-(
)-Methamphetamine is a vasoconstrictor and a component of multiple over-the-counter nasal decongestants (Mendelson et al., 2008). Methamphetamine was detected (with high concentrations, max ¼ 270 ng L
1) in all the samples except for one river water sample. This finding is similar to other previously published data. Research from the Netherlands detected methamphetamine in influents (up to 278 ng L
1) and effluents (up to 62 ng L
1) after conventional biological treatment (Van der Aa et al., 2013), Huerta-Fontela et al. (2008) has also reported its occurrence in influents (up to 277 ng L
1) and effluents (up to 90 ng L
1) in 42 WWTPs. Codeine, methadone, and meperidine are all opioids and have been used to treat varying degrees of pain relief; methadone is strong analgesic, and codeine and meperidine are weaker, shortacting analgesics. All of these compounds act directly on the central nervous system to alleviate pain (Chan, 2008). Codeine is widely used to treat mild to moderate abdominal pain, diarrhea and coughing (Yaster and Deshpande, 1988; ASHP, 2011; Sellin, 2000); only 4.9e8.3% of the administered dose is eliminated unchanged (Cone et al., 1991), and it can be converted to morphine in the liver (Pai et al., 2004). However, codeine was still detected at the second highest frequency and the second highest median concentration (93 ng L
1) in hospital effluents, reflecting its significant medical usage. Nevertheless, codeine is mostly absent in the river water samples; codeine was only detected in 6/13 river waters sampled in the Taipei region (median ¼ ND) and was absent in all the river waters sampled from the KaohsiungePingtung region. Methadone and meperidine were found to have occurrence patterns very similar to that of codeine. Although only approximately 5% of the administered dose of meperidine is eliminated unchanged upon urination (Aggregated Computational Toxicology

A.Y.-C. Lin et al. / Environmental Pollution 187 (2014) 170e181

Resource, 2012) (Judson et al., 2012) and approximately 5e50% is eliminated for methadone (Couper and Logan, 2004; CLIA, 2013), methadone and meperidine were frequently detected in significant amounts in hospital wastewaters (detection frequencies >10/13 and maximum concentrations of 200 and 1500 ng L
1, respectively) and were absent in most of the river waters. Methadone was only found in 8 (out of 20) river sampling sites at median concentrations (ND) and meperidine was only observed once in a trace amount (2.0 ng L
1). Two similar studies were conducted in Germany; Wick et al. (2009) found methadone in similar concentrations in WWTP influents and effluents, and Hummel et al. (2006) found concentrations below the LOQ (5 ng L
1) in surface water, with 25 ng L
1 in WWTP effluents and 50 ng L
1 in WWTP influents. The results here clearly indicate the susceptibility of codeine, methadone and meperidine to potential natural attenuation processes, given the high detection frequency and substantial concentrations of these compounds in hospital effluents when compared to the trace amounts (or in most of the cases ‘absence’) in surface waters. 3.2. Natural attenuation by photolysis For surface water systems, the three major attenuation processes reported are photolysis, biotransformation and sorption, and previous studies have shown that many pharmaceuticals are susceptible to these processes. Nevertheless, because many pharmaceuticals are known to survive the traditional wastewater treatment processes (including secondary treatments in many cases), biological degradation or removal through sorption are deemed less likely for compounds that were released to the natural surface water environments. A review paper by Kosjek and Heath (2011) reported that most cytostatic drugs show low biodegradability. Therefore, photolysis is an extremely significant process in determining the natural fate of these compounds. Currently, very limited information is available regarding the natural attenuation of these target compounds, especially by natural sunlight photodegradation. However, as photochemically active molecular degradation under sunlight involves compounds

175

with delocalized p-electrons (e.g., aromatic rings, conjugated double bonds and carbonyls), compounds such as codeine and morphine have the potential to undergo direct sunlight photolysis. Other target analytes can also be degraded by certain reactive  species (i.e., 1O2, OH, 3DOM* and CO2
3 ) that are produced by sunlight via the excitation of dissolved organic molecules (DOM) and nitrates/nitrites. Six target drugs, namely, cyclophosphamide, 5-fluorouracil, ifosfamide, methamphetamine, morphine and codeine, that occur at significant concentrations and frequencies were chosen for the photolysis analysis. Table 3 compiles the available information and results from this work. Indirect and direct photodegradation experiments were performed on ifosfamide, methamphetamine, morphine and codeine to test the degradation potential by natural sunlight irradiation. The photolysis potential of cyclophosphamide and 5-fluorouracil was demonstrated in our previous study (Lin et al., 2013) and is discussed here with that of the other four target compounds to better explain the observed occurrence data. The UVeVis absorption spectra of codeine, morphine and 5fluorouracil exhibited absorbance values at wavelengths >286 nm (the shortest wavelength received on the Earth’s surface) (Garrison et al., 1978) (Fig. 2). As expected from the UVeVis spectra, codeine, morphine and 5-fluorouracil were the only compounds to undergo direct photolysis, with half-lives of 6.8, 11, and 63 h (Lin et al., 2013), respectively. Pseudo-first order kinetics was applied, and the direct photolysis rate constants were measured in DI water under simulated sunlight. Although methamphetamine, ifosfamide and cyclophosphamide do not undergo direct photolysis, they are still susceptible to indirect sunlight photolysis in natural surface water environments. The JMR (pH ¼ 7.4, bicarbonate ¼ 1.65 mM, [NO3eN] ¼ 1.4 mg L
1, DOC ¼ 2.7 mg L
1) was used as a sample source for surface waters to study photodegradation. In comparison to the photolysis rates observed in DI water, the rates observed in JMR were greatly increased. Compounds that do not undergo direct photolysis, such as methamphetamine and ifosfamide, were able to degrade in irradiated JMR, showing half-lives of 18 and 38 h, respectively. Similarly, codeine, morphine and 5-fluorouracil all have enhanced

Table 3 Natural attenuation processes of the target compounds.a Target compound

Photolysis

Sorption

Hydrolysis

Biodegradation

Codeine

River water: 0.28 ± 0.04 hL1 River water: 2.57 ± 0.18 hL1

log Kow ¼ 0.89e1.19

No hydrolysis in 30 days

75% detection frequency) with high concentrations in both hospital effluents and rivers in Taipei and KaohsiungePingtung. Cyclophosphamide behaves similarly; its photolysis rate is not as fast in the JMR (halflive > days); this compound is again consistently found in significant concentrations in all our surface water samples. In contrast, codeine and morphine behave very differently. The fact that they are quickly photodegraded in the JMR waters (their half-lives extend from minutes to a few hours) explains their absence in many of our surface water samples, despite the fact that they are used often and detected frequently in hospital effluents. In addition, during a 14-day incubation test, morphine showed 33  4% biodegradation within one day; 25  9% of the codeine was degraded within 14 days. Extremely fast photolysis (half-life of 16 min) along with significant susceptibility to biodegradation and sorption explains why we only detected morphine once out of 20 total surface water samples. Despite the fact that we do not have sufficient natural attenuation information for methadone and meperidine, their high detection rates in wastewaters and absence in most surface waters are also likely a result of natural attenuation processes (similar to codeine and morphine). The photodegradation potential of methadone and meperidine requires further investigation. 3.3. Risk assessment and international comparison Photolysis can lower the environmental concentrations, which also lowers the estimated environmental risks to human health from the target drugs, including morphine. Despite these facts and given the wide occurrence of many other target drugs worldwide, an attempt was made to evaluate their environmental risk in Taiwan’s aquatic environments, as a case study, and to compare that risk to those in other countries. An environmental risk assessment of detected chemotherapeutics and controlled drugs was based on the environmental risk characterization ratios, calculated by taking the maximum measured environmental concentrations (MEC) divided by the reported minimum estimated predicted-no-effect concentration (PNEC) using the available ecotoxicological data. The PNEC data for the target drugs are provided and compared in

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177

Fig. 3. Photodegradation of (a) ifosfamide, (b) methamphetamine, (c) morphine and (d) codeine in DI, JMR, decarbonated JMR and in JMR spiked with increased concentrations of nitrates and fulvic acids. The initial concentration of all the target compounds was 20 mg/L. JMR water: pH, 7.4; alkalinity, 1.65 mM bicarbonate; 1.4 mg/L NO3eN; DOC, 2.7 mg/L.

Table 4. Table 4 lists the maximum MEC found in Taiwan and employs the lowest PNEC data available to calculate the RQ, thereby presenting the worst case scenario. A PNEC can be estimated by dividing the lowest no-observed-effect concentration (NOEC) for the most sensitive species by a factor of safety (Carlsson et al., 2006a, 2006b). Whenever the NOEC data were not available, values such as the lowest observable effect concentrations (LOEC) and critical environmental concentration (CEC) were used as the PNEC. As the ecotoxicity data are limited, the calculated RQ based on the inconsistently reported PNECs cannot accurately reflect the true levels of concern for all target analytes. The majority of the available PNECs are calculated based on the results of standard toxicity tests or the PNECECOSAR calculated from modeled Ecological Structure Activity Relationships (ECOSAR) software (USEPA, 2009). However, whenever the RQ exceeds one, the potential risk of this compound is clear and cannot be ignored. In this work, RQ values were calculated for both surface waters and wastewaters: RQsurface water indicates the existing risk of the target contaminant, while RQwastewaters represents a worst case scenario in which the rivers/receiving waters are entirely/mainly composed of wastewaters. With dilution and natural attenuation processes (especially photolysis), the RQsurface water values were all less than one, indicating that there was no immediate risk from the presence of these compounds in the monitored rivers. However, the RQ of codeine and 5-fluorouracil were both greater than one (12 and 15, respectively) in hospital wastewaters and were very close to one (0.9 and 0.8, respectively) for the WWTP effluents, clearly demonstrating the high risk of directly releasing hospital and WWTP effluents into the environment.

Fig. 4 lists the existing literature and the maximum concentrations of the target compounds found in hospital wastewater effluents, rivers and WWTP influents and effluents in different countries around the world. The PNEC for each target drug was also indicated (dashed line) in the figures. The numbers next to each country indicate the number of studies found. Codeine and 5-fluorouracil were both found to have RQwastewaters > 1 in other locations around the world. For codeine, the RQsurface water also was greater than one in the UK (RQ ¼ 14) and Germany (RQ ¼ 1.6). For the rest of the countries, including Romania, Spain, and the Netherlands, RQsurface water was very close to one. Codeine does not seem to be susceptible to WWTP treatments, as we observed similar concentrations in both the influents (41 ng L
1) and effluents (56 ng L
1). Related studies have shown that codeine was not easily degraded and removed by conventional sewage and sludge treatment processes, especially under high-dose conditions (Gómez et al., 2007; Kasprzyk-Hordern et al., 2009a, 2009b). Gros et al. (2010) also indicated no significant removal for codeine by most WWTPs in Spain (Gros et al., 2010), and studies by Berset et al. (2010) showed poor codeine removal (w10%) in the WWTPs of Switzerland. Considering this high occurrence worldwide, the low removal from WWTPs and the potential health risks, future risk assessments and investigations of codeine are necessary. 5-Fluorouracil has remained the most extensively used chemotherapeutic agent for the treatment of advanced colorectal cancer for >40 years (Van Cutsem et al., 2004). However, the occurrence of 5-fluorouracil has only been reported in three other European countries, Austria, Slovenia and Switzerland, with RQwastewaters of 1235, 0.9 and 0.3, respectively. For the first time, the

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Table 4 PNEC and the ‘worst case-scenario’ risk quotient (RQ) for the target compounds. Compounds

Codeine

Morphine Methadone

Meperidine Cocaine Methamphetamine Cyclophosphamide

Test-species

Calculated value (Fish) Calculated value (Fish) Calculated value (Daphnid) Calculated value (green algae) Calculated value Calculated value (Fish) Calculated value Calculated value (Fish) Pseudokirchneriella subcapitata (green algae) Calculated value (Fish) Calculated value Calculated value (Daphnid) Calculated value Pseudokirchneriella subcapitata (green algae) Daphnia magna (Invertebrate) Pseudomonas putida Pseudokirchneriella subcapitata (green algae) Daphnid magna (Invertebrate)

Ifosfamide

Methotrexate 5-Fluorouracil

Calculated value Calculated value (based on sales statistics) Calculated value Calculated value (Fish) Calculated value Pimephales promelas (Fish) Danio rerio (Fish) Xenopus laevis (Clawed toad)

Daphnid magna (Invertebrate)

Paclitaxel (Taxol)

Pseudokirchneriella subcapitata (green algae) Calculated value (based on NOECs from long-term tests with fish, Daphnia, green algae, and cyanobacteria) Calculated value (WWTP microorganism PNEC based on the biodegradation tests) Calculated value (yeastgenotoxicity-based microorganism) Calculated value (based on NOEC ¼ 104 ng/L, assessment factor:100) Calculated value (based on UK use)

Test-type

Ecotoxicity data*

CEC PNEC, 96 h, growth PNEC, 48 h, growth PNEC, 96 h, growth PNECECOSAR CEC PNECECOSAR CEC PNEC, 72e96 h, growth

26.62 mg/L 7438 ng/L 976 ng/L 183,450 ng/L 0.1 mg/L, 0.06 mg/L 22.615 mg/L 32.0 mg/L 326 ng/L 10.5 mg/L

CEC PNECECOSAR PNEC, 48 h, growth PNECECOSAR NOEC, 72 h, growth NOEC, 21 days, growth PNEC, 21 days, growth NOEC, 16 h, growth LOEC, 16 h, growth NOEC, 96 h, growth LOEC, 96 h, growth NOEC, 48 h, growth LOEC, 48 h, growth PNECECOSAR PNEC

4.657 mg/L 4.90 mg/L 5482 ng/L 2.30 mg/L >100 mg/L 56 mg/L 1.12 mg/L 1000 mg/L >1000 mg/L 250 mg/L 500 mg/L 1000 mg/L >1000 mg/L 11 mg/L 162 mg/L

PNECECOSAR CEC PNEC LOEC, 120 h, growth NOEC, 35 days, growth LOEC, 35 days, growth LOEC (growth), 120 h, growth LOEC (malformation), 120 h, growth LOEC, ISO 6341 NOEC, ISO 6341 LOEC, ISO 8692 NOEC, ISO 8692 PNEC

11 mg/L 2.6 mg/L 85000 ng/L 200 mg/L 32 mg/L 100 mg/L 200 mg/L

PNEC

900 mg/L

PNEC

2 mg/L

PNEC

100 ng/L

PNEC

0.74 mg/L

Highest measured concentrations (MEC) Hospital wastewaters

Rivers

700 ng/L

15 ng/L

2400 ng/L

Worst case-scenario (RQ ¼ MEC/PNEC)a WWTP

Highest RQ Wastewaters

Surface waters

56 ng/L

12

0.3

36 ng/L

29 ng/L

0.1

0.1  10
2

20 ng/L

0.4 ng/L

0.4 ng/L

0.2  10
2

0.4  10
4

1500 ng/L 130 ng/L

2.0 ng/L ND

ND 0.6 ng/L

0.3 0.3  10
1

0.4  10
3 e

240 ng/L 1200 ng/L

260 ng/L 13 ng/L

16 ng/L 15 ng/L

0.1 0.1

0.1 0.1  10
2

89 ng/L

8.9 ng/L

10 ng/L

0.8  10
2

0.8  10
3

300 ng/L

ND

ND

0.4  10
2

e

1500 ng/L

70 ng/L

80 ng/L

15

0.7

13 ng/L

ND

ND

0.2  10
1

e

10 mg/L 10 mg/L 1000 mg/L 100 mg/L 10 mg/L 0.2 mg/L

PNEC ¼ Predict No Effect Concentration, CEC ¼ Critical Environmental Concentration, NOEC ¼ No Observed Effect Concentration, LOEC ¼ Lowest Observed Effect Concentration. a Maximum values calculated from MEC/minimum PNEC. *Fick et al., 2010; USEPA, 2009; Grung et al., 2008; Escher et al., 2011; Zounková et al, 2007; Carlsson et al., 2006a; DeYoung et al., 1996; Egeler and Seck, 2008; Straub, 2010; Webb, 2004.

occurrence of meperidine is reported in this work, and no other information is currently available regarding its worldwide occurrence, fate and ecotoxicity. As the PNEC data are very limited for target compounds other than 5-fluorouracil and codeine, which have exhibited high levels of risk in aqueous environments, the true risk of the other target drugs with high detected concentrations remains unknown and necessitates further investigations.

4. Conclusion These results demonstrate the common occurrence of chemotherapeutics and controlled drugs for two biologically active groups of pharmaceuticals, not only in the wastewaters from hospitals and WWTPs but also in receiving surface water environments with the potential to become drinking water. Methamphetamine, codeine,

A.Y.-C. Lin et al. / Environmental Pollution 187 (2014) 170e181

Cyclophosphamide

Concentration (ng/L) PNEC

Rivers Maximum WWTP Influent

1,000

WWTP Effluent

100

*

*

10

Methamphetamine 10,000

10,000

PNEC

100

100

*

10

10

1

1

10,000

1,000

1,000

1,000

100

100

100

10

0.14

1

10 1

PNEC

*

10 1

*

Codeine 10,000

1,000 100

* *

*

5-Fluorouracil 10,000

*

Methadone

10,000

*

0.6

Morphine

Ifosfamide PNEC

PNEC

1,000

1,000

0.17

0.07

1

10,000

Cocaine

Hospital wastewaters Maximum

10,000

179

1,000

PNEC

10 1

100

* *

PNEC

10 1

Fig. 4. International comparison of the target compounds in hospital effluents, surface waters and WWTPs (PNEC: predict no effect concentration used in Table 3; x-axis numbers in “()” indicate the number of references used from each country; “*” indicates the compounds that were investigated but were not detected, ND).

methadone, meperidine, morphine, 5-fluorouracil, cyclophosphamide and ifosfamide are persistently detected in hospital effluents. After being released into receiving surface waters, these compounds are subjected to various natural attenuation mechanisms, which may significantly reduce their detected concentrations. Photolysis is a significant process in determining the natural fate, detected concentration and thus the environmental/human health risk of these target compounds. Compounds such as codeine and morphine were found to be significantly susceptible to natural sunlight photolysis, thus lowering their environmental concentrations. PNEC data are very limited for target compounds other than 5-fluorouracil and codeine, which have high levels of risk in wastewaters. The occurrence of these biologically active drugs cannot be ignored and warrant future investigations because significant amounts of these agents are being used and released into aqueous environments. Acknowledgments This work was supported in part by the National Science Council (NSC 101-2621-M-002-018) and in part by the National Health Research Institutes of Taiwan (NHRI-EX102-10120PC). Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.envpol.2014.01.005. References Allwood, M.C., Wright, P., Stanley, A., 2002. The Cytotoxics Handbook. Radcliffe MedicalPress, Oxford.

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