The potential ecotoxicological impact of pharmaceutical and personal care products on humans and freshwater, based on USEtox™ characterization factors. A Spanish case study of toxicity impact scores.

Pharmaceutical and personal care products (PPCPs) are being increasingly included in Life Cycle Assessment studies (LCAs) since they have brought into evidence both human and ecological adverse effects due to their presence in different environmental compartments, wastewater facilities and industry. Therefore, the main goal of this research was to estimate the characterization factors (CFs) of 27 PPCPs widely used worldwide in order to incorporate their values into Life Cycle Impact Assessment studies (LCIA) or to generate a toxicity impact score ranking. Physicochemical properties, degradation rates, bioaccumulation, ecotoxicity and human health effects were collected from experimental data, recognized databases or estimated using EPI Suite™ and the USEtox™ software, and were subsequently used for estimating CFs. In addition, a Spanish toxicity impact score ranking was carried out for 49 PPCPs using the 27 newly calculated CFs, and 22 CFs already available in the literature, besides the data related to the occurrence of PPCPs in the environment in Spain. It has been highlighted that emissions into the continental freshwater compartment showed the highest CFs values for human effects (ranging from 10-9 to 10-3Cases·kg-1), followed by emissions into the air (10-9 to 10-5Cases·kg-1), soil (10-11 to 105Cases·kg-1) and seawater (10-12 to 10-4Cases·kg-1). CFs regarding the affectation of freshwater aquatic environments were the highest of those proceeding from emissions into continental freshwater (between 1 to 104PAF·m3·day·kgemission-1) due to the direct contact between the source of emission and the compartment affected, followed by soil (among 10-1 to 104PAF·m3·day·kgemission-1), and air (among 10-2 to 104PAF·m3·day·kgemission-1) while the lowest were the CFs of continental seawater (among 10-28 to 10-3PAF·m3·day·kgemission-1). Freshwater aquatic ecotoxicological CFs are much higher than human toxicity CFs, demonstrating that the ecological impact of PPCPs in aquatic environments must be a matter of urgent attention. According to the Spanish toxicity impact score calculated, the PPCPs with the highest impact are hormones, antidepressants, fragrances, antibiotics, angiotensin receptor blockers and blood lipid regulators, which have already been found in other kinds of score rankings. These results, which were not available until now, will be useful in order to perform better LCIA studies, incorporating the micro-pollutants whose CFs have been estimated, or in order to carry out single hazard/risk environmental impact assessments.

Dose-response behavior of the bacterium Vibrio fischeri exposed to pharmaceuticals and personal care products.

The presence of pharmaceuticals and personal care products (PPCPs) in the environment has become a real and widespread concern in recent years. Therefore, the primary goal of this study was to investigate 20 common and widely used PPCPs to assess their individual and combined effect on an important species in one trophic level, i.e., bacteria. The ecotoxicological effects of PPCPs at two different concentration ranges were determined in the bacterium Vibrio fischeri using Microtox(®) and were statistically analyzed using three models in the GraphPad Prism 6 program for Windows, v.6.03. A four-parameter model best fit the majority of the compounds. The half maximal effective concentration (EC50) of each PPCP was estimated using the best-fitting model and was compared with the results from a recent study. Comparative analysis indicated that most compounds showed the same level of toxicity. Moreover, the stimulatory effects of PPCPs at environmental concentrations (low doses) were assessed. These results indicated that certain compounds have traditional inverted U- or J-shaped dose-response curves, and 55% of them presented a stimulatory effect below the zero effect-concentration point. Effective concentrations of 0 (EC0), 5 (EC5) and 50% (EC50) were calculated for each PPCP as the ecotoxicological points. All compounds that presented narcosis as a mode of toxic action at high doses also exhibited stimulation at low concentrations. The maximum stimulatory effect of a mixture was higher than the highest stimulatory effect of each individually tested compound. Moreover, when the exposure time was increased, the hormetic effect decreased. Hormesis is being increasingly included in dose-response studies because this may have a harmful, beneficial or indifferent effect in an environment. Despite the results obtained in this research, further investigations need to be conducted to elucidate the behavior of PPCPs in aquatic environments.

Ecotoxicity and environmental risk assessment of pharmaceuticals and personal care products in aquatic environments and wastewater treatment plants.

A wide range of pharmaceuticals and personal care products (PPCPs) are present in the environment, and many of their adverse effects are unknown. The environmental risk assessment of 26 PPCPs of relevant consumption and occurrence in the aquatic environment in Spain was accomplished in this research. Based on the ecotoxicity values obtained by bioluminescence and respirometry assays and by predictions using the US EPA ecological structure-activity relationship (ECOSAR™), the compounds were classified following the Globally Harmonized System of Classification and Labelling of Chemicals. According to the criteria of the European Medicines Agency, the real risk of impact of these compounds in wastewater treatment plants (WWTPs) and in the aquatic environment was predicted. In at least two ecotoxicity tests, 65.4 % of the PPCPs under study showed high toxicity or were harmful to aquatic organisms. The global order of the species' sensitivity to the PPCPs considered was as follows: Vibrio fischeri (5 min) > Vibrio fischeri (15 min) > algae > crustaceans > fish > biomass of WWTP. Acetaminophen, ciprofloxacin, clarithromycin, clofibrate, ibuprofen, omeprazole, triclosan, parabens and 1,4-benzoquinone showed some type of risk for the aquatic environments and/or for the activated sludge of WWTPs. Development of acute and chronic ecotoxicity data, the determination of predicted and measured environmental concentrations of PPCPs, the inclusion of metabolites and transformation products and the evaluation of mixtures of these compounds will allow further improvements of the results of the ERAs and, finally, to efficiently identify the compounds that could affect the environment.

Ranking of concern, based on environmental indexes, for pharmaceutical and personal care products: an application to the Spanish case.

A wide range of Pharmaceuticals and Personal Care Products (PPCPs) are present in the environment, and many of their adverse effects are unknown. The emergence of new compounds or changes in regulations have led to dynamical studies of occurrence, impact and treatment, which consider geographical areas and trends in consumption and innovation in the pharmaceutical industry. A Quantitative study of Structure-Activity Relationship ((Q)SAR) was performed to assess the possible adverse effects of ninety six PPCPs and metabolites with negligible experimental data and establish a ranking of concern, which was supported by the EPA EPI Suite™ interface. The environmental and toxicological indexes, the persistence (P), the bioaccumulation (B), the toxicity (T) (extensive) and the occurrence in Spanish aquatic environments (O) (intensive) were evaluated. The most hazardous characteristics in the largest number of compounds were generated by the P index, followed by the T and B indexes. A high number of metabolites has a concern score equal to or greater than their parent compounds. Three PBT and OPBT rankings of concern were proposed using the total and partial ranking method (supported by a Hasse diagram) by the Decision Analysis by Ranking Techniques (DART) tool, which was recently recommended by the European Commission. An analysis of the sensibility of the relative weights of these indexes has been conducted. Hormones, antidepressants (and their metabolites), blood lipid regulators and all of the personal care products considered in this study were at the highest levels of risk according to the PBT and OPBT total rankings. Furthermore, when the OPBT partial ranking was performed, X-ray contrast media, H2 blockers and some antibiotics were included at the highest level of concern. It is important to improve and incorporate useful indexes for the predicted environmental impact of PPCPs and metabolites and thus focus experimental analysis on the compounds that require urgent attention.

Consumption and occurrence of pharmaceutical and personal care products in the aquatic environment in Spain.

The occurrence of sixty pharmaceutically active compounds (PhACs), twenty metabolites and eight personal care products (PCPs) in the aquatic environment in Spain and their predicted environmental concentrations (PECs) were calculated and compared with measured environmental concentrations (MECs) obtained from relevant published research. The occurrence in the aquatic environment was calculated through a mass balance approach considering the following: the number of pharmaceutical prescriptions issued, the amount of pharmaceutical discharged without consumption, consumption, self-medication, pharmacokinetics, treatment in wastewater facilities and discharged to aquatic environment. The estimation of consumption of active compounds of pharmaceuticals was conducted by at least one of the following methodologies: number of commercial packages sold, data for the number of defined daily dose per 1000 inhabitants per day (DHD), and pattern of treatment. Comparison of these methodologies for some compounds showed similar estimated consumption ranges. The highest pharmaceutical occurrence in the aquatic environment was for acetaminophen glucuronide, Galaxolide®, Iso-E-super®, acetaminophen, valsartan, amoxicillin, 2-hydroxy-ibuprofen, iopromide, omeprazole, carbamazepine 10, 11-epoxide, iopamidol, salicylic ß-d-O-glucuronide acid, Tonalide®, acetylsalicylic acid (ASA), clarithromycin and iohexol, with releases between 5 and 600 ty(-1). The relation of PEC/MEC was calculated for 58% of the compounds under study, and 64.7% of them had PEC/MEC ratios between 0.5 and 2. PEC values were mostly overestimated (57.4%). The predicted concentrations for pharmaceutical and personal care products (PPCPs) that had a high occurrence in the aquatic environment were very close to the measured concentrations. This research provides information that had not been calculated and analyzed previously, at least for Spain. Estimation of the PECs for pharmaceutical, personal care products and metabolites is a useful tool for identifying compounds that should be considered for environmental concern, and such estimations could be used to improve environmental risk assessment studies.