Determination of cytostatic drugs in Besòs River (NE Spain) and comparison with predicted environmental concentrations

Abstract

The number of cytostatic drugs used in cancer treatments is wide and increases every year; therefore, tools have been developed to predict their concentration in the environment to prioritize those for monitoring studies. In the present study, the predicted environmental concentrations (PECs) were calculated according to consumption data in Catalonia (NE Spain) for 2014. According to PECs and to the most widely reported compounds, 19 cytostatics were monitored in two sampling campaigns performed along the Besòs River. A total of seven drugs were detected at levels between 0.5 and 656 ng L. PEC and measured environmental concentrations (MECs) were compared in order to validate PECs. The PEC/MEC ratio presented a good agreement between predicted and measured concentrations confirming the PEC estimations. Mycophenolic acid, prioritized as the compound with the highest PEC, was detected at the highest concentrations (8.5-656 ng L) but showed no risk for aquatic organisms (risk quotient <1) considering acute toxicity tests performed in Daphnia magna.

Antineoplastic Agents: Environmental Prevalence and Adverse Outcomes in Aquatic Organisms

“…In addition to hospital effluent and WWTP influent, antineoplastics were often detected in WWTP effluents, surface waters, and even groundwater in one study (López‐Serna et al 2013). All 5 of the antineoplastics we studied were measured in WWTP effluents and surface waters (Figure 2), with maximum surface water concentrations ranging from 0.00017 to 0.065 µg/L for cyclophosphamide (Zuccato et al 2000; Buerge et al 2006; Moldovan 2006; Ferrando‐Climent et al 2014; Franquet‐Griell et al 2017; Azuma 2018), 0.00014 to 0.0139 µg/L for ifosfamide (Buerge et al 2006; Franquet‐Griell et al 2017), 0.039 to 0.056 µg/L for 5‐fluorouracil prodrugs (Azuma 2018), 0.0052 µg/L for methotrexate (Ferrando‐Climent et al 2014), and 0.025 to 0.21 µg/L for tamoxifen and its associated metabolites (Roberts and Thomas 2006; Coetsier et al 2009; Ferrando‐Climent et al 2014; Franquet‐Griell et al 2017; Azuma 2018) across the different studies. In addition, a number of less frequently studied antineoplastic compounds were detected in surface waters, including bicalutamide and capecitabine, measured at 0.25 and 0.02 µg/L in Japan (Azuma 2018); bleomycin, measured at 0.017 µg/L in the United Kingdom (Aherne et al 1990); and erlotinib, chlorambucil, and megestrol, measured in Spain at 0.004, 0.005, and 0.006 µg/L, respectively (Franquet‐Griell et al 2017).…”

“…Epirubicin was also detected in urban effluent in Spain (Gómez‐Canela et al 2012) at 24.8 µg/L, and doxorubicin was identified in WWTP influent at 0.003 µg/L (Negreira et al 2014). Lastly, the tyrosine kinase inhibitor erlotinib, prescribed to treat lung and pancreatic cancers, was detected in hospital effluent, WWTP influent, WWTP effluent, and surface water at concentrations as high as 0.004, 0.01, 0.004, and 0.004 µg/L, respectively (Isidori et al 2016; Franquet‐Griell et al 2017).…”

Environmental Risk Assessment for the Active Pharmaceutical Ingredient Mycophenolic Acid in European Surface Waters

“…In 2016, Franquet‐Griell et al () published 9/9 MPA surface water MECs for Spain, ranging from 0.0128 to 0.0562 µg/L (mean: 0.0217 µg/L), in the lower, heavily industrialized and urbanized River Llobregat in the south of Barcelona with a total of nearly 5 million people, and followed it through drinking water treatment to the finished water, where it was no longer detected (0/2; LOQ of 0.0001 µg/L; Franquet‐Griell et al ). In the River Besòs in Catalunya, Spain, which runs through “a heavily populated and industrialized area, receiving the authorized discharges of 27 [STPs], 219 industries and 12 hospitals” in northern Barcelona, Franquet‐Griell et al () measured cytostatic APIs. (Note that MPA is cytostatic only insofar as cell growth that depends on purine biosynthesis without salvaging pathways is inhibited, but not a cytostatic in the sense of classical cell division inhibitors, even though it is included in Franquet‐Griell et al .)…”

“…In 2016, Franquet-Griell et al (2016) published 9/9 MPA surface water MECs for Spain, ranging from 0.0128 to 0.0562 µg/L (mean: 0.0217 µg/L), in the lower, heavily industrialized and urbanized River Llobregat in the south of Barcelona with a total of nearly 5 million people, and followed it through drinking water treatment to the finished water, where it was no longer detected (0/2; LOQ of 0.0001 µg/L; Franquet-Griell et al 2016 , 2019;38:2259-2278 the target compound detected at the highest levels and was present mainly in the lowest, most urbanized river stretches, in 7/19 samples at 0.0131 to 0.0895 µg/L (mean: 0.018 µg/L, with nondetects counted as half the LOQ) in May and in 4/19 samples at 0.0085 to 0.656 µg/L (mean: 0.0474 µg/L, with nondetects counted as half LOQ) in July, with the latter, higher concentrations attributed by the authors to low water flow in summer. The dilution factor of the River Besòs is given as 1.2, showing very low dilution and a high fraction of treated wastewater (Franquet-Griell et al 2017c). The median combined MEC in Catalunya is just below 0.001 µg/L in view of many nondetects in the upper River Besòs, which is far lower than the refined use-based PEC for the whole of Spain assuming 73.1% STP removal of approximately 0.040 µg/L and lower again by another factor of 2 than the surface water PEC of 0.0774 µg MPA/L calculated by Franquet-Griell et al (2015) themselves.…”

“…This provisional PNEC ABR of 64 µg MPA/L can now be compared with the PECs for STPs and surface water and with the highest MECs available. The highest use-based refined PEC STP was 8.83 µg MPA/L (Table 2), whereas the highest STP effluent MEC was 4.19 µg/L (Singer et al 2016); the corresponding risk quotients were 0.138 and 0.065, respectively, EMA EU PEC = MPA PEC based on overall European amounts of MPA and mycophenolate mofetil (MPM), no human metabolism beyond hydrolysis of MPM to MPA and no STP removal included, default dilution factor of 10 (European Medicines Agency 2015); ePiE PEC = geographical information system-based surface water PEC according to Oldenkamp et al (2018); MEC = maximum, 90th percentile and median of 110 available surface water measured environmental concentrations (MECs) from Switzerland, Spain, and Poland (based on Rossi and Cheseaux 2013;Franquet-Griell et al 2016, 2017cGiebułtowicz and Nałecz-Jawecki 2016); PEC = predicted environmental concentration; MPM = mycophenolate mofetil; STP = sewage treatment plant; NA = no data available.…”