Quality indicators for the diagnosis and treatment of breast cancer integrated assistance: A critical appraisal / Indicadores de calidad para el diagnóstico y tratamiento del cáncer de mama en el proceso asistencial integrado de cáncer de mama

Introduction Quality indicators (QIs) are essential for adequate control of the health care management process, recognizing areas of improvement and providing solutions. We aimed to evaluate the Integrated Breast Cancer (BC) Care Process QIs. Methods We studied 487 consecutive BC cases diagnosed from November 1st, 2013, to November 30th, 2019, in a Spanish healthcare area, and we estimated the associated QIs. Results Four indicators did not meet the standards and were analysed based on related sociodemographic and clinical variables. The surgical delay after a multidisciplinary team discussion (mean 64%, IQR 59.6–68.5) was lower in elder people (p=0.027), and early histological grades (p=0.019) and stages (p=0.008). The adjuvant treatment delay (mean 55.7%, IQR 51.1–60.3) was lower in advance stages (p=0.002) and when there was no reoperation (p=0.001). The surgical delay after inclusion (mean 83.2%, IQR 79.3–87.2) was lower in early histological grades (p=0.048). The immediate reconstruction (mean 42.3%, IQR 34.0–50.5) reached 72.3% in young women compared to 11.8% in older than 70 years (p=0.001) and it was higher in early stages (45.3% vs 36.2%; p=0.049). Conclusion The study of QIs evaluated their compliance and analysed the variables influencing them to propose improvement measures. Not all the indicators were equally valuable. Some depended on the available resources, and others on the mix of patients or complementary treatments. It would be essential to identify the specific target populations to estimate the indicators or provide standards stratified by the related variables (AU)

Introducción Los indicadores de calidad (IC) son esenciales para el adecuado control del proceso asistencial en el sistema sanitario, permitiendo el reconocimiento de áreas de mejora y proporcionando soluciones. Nuestro propósito ha sido evaluar los IC en el proceso asistencial integrado cáncer de mama (CM). Métodos Se estudiaron 487 casos consecutivos de CM diagnosticados desde noviembre de 2013 hasta 2019 en un área sanitaria de España y se estimaron los IC asociados. Resultados Cuatro indicadores no cumplieron los estándares de calidad y fueron analizados en función de las variables sociodemográficas posiblemente relacionadas. El retraso quirúrgico tras el comité multidisciplinar (media 64%, rango intercuartílico [IQR] 59,6-68,5) fue menor en pacientes más mayores (p=0,027), y en grados histológicos (p=0,019) y estadios (p=0,008) más tempranos. El retraso en el tratamiento adyuvante (media 55,7%, IQR 51,1-60,3) fue menor en estadios más avanzados (p=0,002) y cuando no hubo necesidad de rescisión (p=0,001). El retraso quirúrgico tras la inclusión en lista de espera (media 83,2%, IQR 79,3-87,2) fue menor en grados histológicos más tempranos (p=0,048). La reconstrucción inmediata (media 42,3%, IQR 34,0-50,5) se realizó en un 72,3% de las mujeres jóvenes comparado con tan solo un 11,8% de las mayores de 70 años (p=0,001) y fue mayor en estadios tempranos (45,3% vs. 36,2%; p=0,049). Conclusión El estudio de los IC evaluó su cumplimiento y analizó las variables que los influencian para proponer medidas que los mejoren. No todos los indicadores pudieron evaluarse de igual forma. Algunos dependieron de los recursos disponibles, otros del tipo de paciente y otros de los tratamientos complementarios. Sería necesario identificar las poblaciones diana para estimar los IC más adecuados o proporcionar estándares estratificados por las variables relacionadas (AU)

Quality indicators for the diagnosis and treatment of breast cancer integrated assistance: A critical appraisal.

INTRODUCTION: Quality indicators (QIs) are essential for adequate control of the health care management process, recognizing areas of improvement and providing solutions. We aimed to evaluate the Integrated Breast Cancer (BC) Care Process QIs. METHODS: We studied 487 consecutive BC cases diagnosed from November 1st, 2013, to November 30th, 2019, in a Spanish healthcare area, and we estimated the associated QIs. RESULTS: Four indicators did not meet the standards and were analysed based on related sociodemographic and clinical variables. The surgical delay after a multidisciplinary team discussion (mean 64%, IQR 59.6-68.5) was lower in elder people (p=0.027), and early histological grades (p=0.019) and stages (p=0.008). The adjuvant treatment delay (mean 55.7%, IQR 51.1-60.3) was lower in advance stages (p=0.002) and when there was no reoperation (p=0.001). The surgical delay after inclusion (mean 83.2%, IQR 79.3-87.2) was lower in early histological grades (p=0.048). The immediate reconstruction (mean 42.3%, IQR 34.0-50.5) reached 72.3% in young women compared to 11.8% in older than 70 years (p=0.001) and it was higher in early stages (45.3% vs 36.2%; p=0.049). CONCLUSION: The study of QIs evaluated their compliance and analysed the variables influencing them to propose improvement measures. Not all the indicators were equally valuable. Some depended on the available resources, and others on the mix of patients or complementary treatments. It would be essential to identify the specific target populations to estimate the indicators or provide standards stratified by the related variables.

Longitudinalidad en atención primaria y polifarmacia. Una revisión sistemática / Longitudinality in Primary Care and Polypharmacy. A Systematic Review

El objetivo de este trabajo es recopilar, evaluar e interpretar las evidencias disponibles sobre la relación existente entre el grado de longitudinalidad en atención primaria (AP) y la prevalencia de polifarmacia y sus problemas asociados. Siguiendo la declaración PRISMA realizamos una revisión sistemática de la literatura en las bases de datos PubMed y Scopus. El cribado por títulos y resúmenes, y la revisión de referencias realizados de forma independiente por 2 autores detectó 16 trabajos de potencial interés. Tras la revisión independiente de todos los originales, 4 fueron descartados por no satisfacer los criterios de inclusión. Los 12 trabajos seleccionados, 9 estudios de cohortes retrospectivos y 3 estudios transversales, estudiaban la relación de la longitudinalidad en AP, medida con diversos índices cuantitativos, con la prevalencia de polifarmacia y otros problemas terapéuticos asociados, como las prescripciones inadecuadas, las duplicidades o las interacciones medicamentosas. Todos mostraban una relación significativa, frecuentemente fuerte (RR>2 o<0,5), entre los indicadores de longitudinalidad y las diversas variables dependientes. Aunque nuestro conocimiento podría mejorar mediante estudios prospectivos que evaluaran directamente la longitudinalidad y su repercusión en los problemas por exceso de medicación, con las evidencias existentes, se puede afirmar que la protección y la promoción de la longitudinalidad en la AP es un elemento clave para el control de la polifarmacia y los problemas asociados (AU)

The aim of this work was to collect, evaluate and interpret the available evidence on the relationship between continuity in primary care (i.e., longitudinality), and the prevalence of polypharmacy and its associated problems. Following the PRISMA reporting statement, we carried out a systematic review of the literature searching PubMed and Scopus databases. The screening of titles and summaries and the review of references carried out independently by two authors detected 16 works of potential interest, of which 4 were discarded after the independent review of all the originals because they did not meet inclusion criteria. The 12 papers selected studied the relationship between Longitudinality, measured with various quantitative indices, and the rate of polypharmacy or various associated problems, such as duplicate drugs, inadequate prescriptions or drug interactions. They all showed a significant relationship, often strong (RR>2 or<0.5), between longitudinality indicators and the various dependent variables. Although our knowledge could be improved by prospective studies that more directly evaluate longitudinality and its impact on problems due to excess medication, with the existing evidence, we can affirm that the protection and promotion of continuity in primary care can be a key element for the control of polypharmacy and associated problems (AU)

[Longitudinality in Primary Care and Polypharmacy. A Systematic Review]. / Longitudinalidad en atención primaria y polifarmacia. Una revisión sistemática.

The aim of this work was to collect, evaluate and interpret the available evidence on the relationship between continuity in primary care (i.e., longitudinality), and the prevalence of polypharmacy and its associated problems. Following the PRISMA reporting statement, we carried out a systematic review of the literature searching PubMed and Scopus databases. The screening of titles and summaries and the review of references carried out independently by two authors detected 16 works of potential interest, of which 4 were discarded after the independent review of all the originals because they did not meet inclusion criteria. The 12 papers selected studied the relationship between Longitudinality, measured with various quantitative indices, and the rate of polypharmacy or various associated problems, such as duplicate drugs, inadequate prescriptions or drug interactions. They all showed a significant relationship, often strong (RR>2 or<0.5), between longitudinality indicators and the various dependent variables. Although our knowledge could be improved by prospective studies that more directly evaluate longitudinality and its impact on problems due to excess medication, with the existing evidence, we can affirm that the protection and promotion of continuity in primary care can be a key element for the control of polypharmacy and associated problems.

Galaxolide and tonalide modulate neuroendocrine activity in marine species from two taxonomic groups.

Galaxolide (HHCB) and tonalide (AHTN) are polycyclic musk compounds (PMCs) used in household and personal care products that have been included on the list as emerging contaminants of environmental concern due to their ubiquity in aquatic and terrestrial environments. There still exists a dearth of information on the neurotoxicity and endocrine disrupting effects of these contaminants, especially for marine and estuarine species. Here, we assessed the neuroendocrine effects of HHCB and AHTN using adult clams, Ruditapes philippinarum, and yolk-sac larvae of sheepshead minnow, Cyprinodon variegatus. The clams were treated with concentrations (0.005-50 µg/L) of each compound for 21 days. Meanwhile, sheepshead minnow larvae were exposed to 0.5, 5 and 50 µg/L of HHCB and AHTN for 3 days. Enzyme activities related to neurotoxicity (acetylcholinesterase - AChE), neuroendocrine function (cyclooxygenase - COX), and energy reserves (total lipids - TL) were assessed in R. philippinarum. Gene expression levels of cyp19 and vtg1 were measured in C. variegatus using qPCR. Our results indicated induction of AChE and COX in the clams exposed to HHCB while AHTN exposure significantly inhibited AChE and COX. Gene expression of cyp19 and vtg1 in yolk-sac C. variegatus larvae exposed to 50 µg/L AHTN was significantly downregulated versus the control. The results of this study demonstrate that HHCB and AHTN might pose neurotoxic and endocrine disrupting effects in coastal ecosystems.

Potential of environmental concentrations of the musks galaxolide and tonalide to induce oxidative stress and genotoxicity in the marine environment.

Polycyclic musk compounds have been identified in environmental matrices (water, sediment and air) and in biological tissues in the last decade, yet only minimal attention has been paid to their chronic toxicity in the marine environment. In the present research, the clams Ruditapes philippinarum were exposed to 0.005, 0.05, 0.5, 5 and 50 µg/L of the fragrances Galaxolide® (HHCB) and Tonalide® (AHTN) for 21 days. A battery of biomarkers related with xenobiotics biotransformation (EROD and GST), oxidative stress (GPx, GR and LPO) and genotoxicity (DNA damage) were measured in digestive gland tissues. HHCB and AHTN significantly (p < 0.05) induced EROD and GST enzymatic activities at environmental concentrations. Both fragrances also induced GPx activity. All concentrations of both compounds induced an increase of LPO and DNA damage on day 21. Although these substances have been reported as not acutely toxic, this study shows that they might induce oxidative stress and genotoxicity in marine organisms.

A multibiomarker approach to assess toxic effects of wastewater treatment plant effluents and activated defence mechanisms in marine (Ruditapes philippinarum) and fresh water (Corbicula fluminea) bivalve species.

Since it has been demonstrated that urban effluents can have adverse effects on aquatic organisms, a multibiomarker study was used to evaluate the effects of wastewater treatment plant (WWTP) effluents discharged into the marine and freshwater environments on clams in Cádiz, Spain. One bioassay was performed in the Bay of Cádiz, exposing Ruditapes philippinarum (marine) to a reference site as well as two sites close to WWTP discharges for 14 days. A second bioassay was performed in the Guadalete River, exposing Corbicula fluminea (fresh water) to three sites for 21 days. The biomarkers analysed included defence mechanisms and various toxic effects. Results indicated that WWTP effluents activated defence mechanisms and induced toxic effects in clams exposed to both environments, thus indicating bioavailability of contaminants present in water. Elevated enzymatic activity was found in clams deployed in La Puntilla and El Trocadero compared to control clams and those exposed to the reference site, and 96% of clams deployed at G2 in the Guadalete River died before day 7. Clams exposed to G1 and G3 indicated significant differences in all biomarkers analysed with respect to control clams (p < 0.05). Both species were sensitive to contaminants present in studied sites. This is the first time that these species were used in cages to assess the environmental risk of wastewater effluent discharges in freshwater and marine column environments. The multibiomarker approach provided important ecotoxicological information and is useful for the assessment of the bioavailability and effect of contaminants from WWTP effluents on marine and fresh water invertebrates.

Avoidance behaviour of the shrimp Palaemon varians regarding a contaminant gradient of galaxolide and tonalide in seawater.

The musk fragrances galaxolide (HHCB) and tonalide (AHTN) are compounds of emerging concern that have been found in various environmental compartments. The present study addressed the ability of HHCB and AHTN to elicit the avoidance response in the estuarine shrimp Palaemon varians and to predict the population immediate decline (PID) of P. varians when exposed to HHCB and AHTN by integrating both avoidance (non-forced exposure) and lethality (forced exposure) responses. The avoidance response was tested in a non-forced multi-compartmented static system, in which the shrimps could move freely among the compartments with different concentrations. The shrimps (n = 3 shrimps per compartment/concentration; 18 shrimps per system) were exposed to a gradient (0, 0.005, 0.05, 0.5, 5 and 50 µg/L) of both substances and their positions were checked at every 20 min for a 3 h period. The results from 24-h forced exposure showed no dose-response relationship and the highest percentage mortality was 17% for HHCB at 0.005 and 0.5 µg/L. In the 3-h non-forced exposure to a gradient of HHCB and AHTN, significant concentration-dependent spatial avoidance was observed for both substances. The shrimps avoided the lowest concentration of HHCB and AHTN (0.005 µg/L) by 15% and 16%. The avoidance increased significantly (p < 0.005) to a 61% and 57%, respectively, for the highest concentration (50 µg/L). The population immediate decline was driven by the avoidance behaviour of the shrimps rather than mortality. These results indicated that the aversiveness of HHCB and AHTN might have serious consequences for habitat selection processes by organisms.

Health status alterations in Ruditapes philippinarum after continuous secondary effluent exposure before and after additional tertiary treatment application.

A mobile pilot plant was set up in a wastewater treatment plant (WWTP) in southwest Spain to address potential adverse effects of effluents as a whole contaminant, which are discharging into marine environments. Ruditapes philippinarum specimens were exposed to different effluent concentrations (50%, 25%, 12.5%, 6.25%, and 3.15%) during seven days. After effluent exposure, lysosomal membrane stability alterations (LMS), changes in the energy status storage (total lipids content (TLP) and in the mitochondrial electron transport (MET), inhibition of inflammatory mechanisms (cyclooxygenase activity (COX)), and neurotoxic effects (acetylcholinesterase (AChE) were determined in exposed organisms. Furthermore, potential toxic reduction in the effluent was analysed by the application of an additional microalgae tertiary treatment called photobiotreatment (PhtBio). Results after PhtBio confirmed the toxic effect reduction in exposed organisms. Neuroendocrine effects, alterations in energy budget and in lipid storage revealed alterations in clam's health status causing stress conditions after effluent exposure.

Biochemical responses of Solea senegalensis after continuous flow exposure to urban effluents.

Urban effluent potential toxicity was assessed by a battery of biomarkers aimed at determining sub-lethal effects after continuous exposure on the marine organism Solea senegalensis. Specimens were exposed to five effluent concentrations (1/2, 1/4, 1/8, 1/16, 1/32) during 7-days, simulating the dispersion plume at the discharge point. Three different groups of biomarkers were selected in the present study: biomarkers of exposure (Phase I: EROD and DBF; Phase II: GST), biomarkers with antioxidant responses (GR and GPX) and biomarkers of effects (DNA damage and LPO). Additionally, a biological depuration treatment (photobiotreatment (PhtBio)) was tested in order to reduce the adverse effects on aquatic organisms. Effluent exposure caused sub-lethal responses in juvenile fish suggesting oxidative stress. After PhtBio application, concentrations of the major part of measured contaminants were reduced, as well as their bioavailability and adverse effects.

Response of gene expression in zebrafish exposed to pharmaceutical mixtures: Implications for environmental risk.

Complex mixtures of pharmaceutical chemicals in surface waters indicate potential for mixture effects in aquatic organisms. The objective of the present study was to evaluate whether effects on target gene expression and enzymatic activity of individual substances at environmentally relevant concentrations were additive when mixed. Expression of zebrafish cytochrome P4501A (cyp1a) and vitellogenin (vtg) genes as well as activity of ethoxyresorufin-O-deethylase (EROD) were analyzed after exposure (96h) to caffeine-Caf, ibuprofen-Ibu, and carbamazepine-Cbz (0.05 and 5µM), tamoxifen-Tmx (0.003 and 0.3µM), and after exposure to pharmaceutical mixtures (low mix: 0.05µM of Caf, Ibu, Cbz and 0.003µM of Tmx, and high mix: 5µM of Caf, Ibu, Cbz and 0.3µM of Tmx). Pharmaceuticals tested individually caused significant down regulation of both cyp1a and vtg, but EROD activity was not affected. Exposure to low mix did not cause a significant change in gene expression; however, the high mix caused significant up-regulation of cyp1a but did not affect vtg expression. Up-regulation of cyp1a was consistent with induction of EROD activity in larvae exposed to high mix. The complex mixture induced different responses than those observed by the individual substances. Additive toxicity was not supported, and results indicate the need to evaluate complex mixtures rather than models based on individual effects, since in environment drugs are not found in isolation and the effects of their mixtures is poorly understood.

Environmental risk assessment of effluents as a whole emerging contaminant: Efficiency of alternative tertiary treatments for wastewater depuration.

Emerging contaminants (ECs) and regulated compounds (RCs) from three different WWTP effluents were measured in the current study. The efficiency of two tertiary treatments, Photobiotreatment (PhtBio) and Multi-Barrier Treatment (MBT), for removing contaminants was determined. Results indicated different percentages of removal depending on the treatment and the origin of the effluent. Risk Quotients (RQs) were determined for different species of algae, Daphnia, and fish. RQ results revealed diverse risk values depending on the bioindicator species. Tonalide, galaxolide (fragrances), and ofloxacin (antibiotic) were the most persistent and harmful substances in tested effluents. "Negligible risk" category was reached since a wide diversity of ECs were removed by MBT with high removal percentages. Contrarily, PhtBio was effective only in the depuration of certain chemical compounds, and its efficiency depended on the composition of the raw effluent.

Are combined AOPs effective for toxicity reduction in receiving marine environment? Suitability of battery of bioassays for wastewater treatment plant (WWTP) effluent as an ecotoxicological assessment.

Ecotoxicological assessment of three different wastewater treatment plant (WWTP) effluents D1, D2 and D3 was performed before and after tertiary treatment using combination of advanced oxidation processes (AOPs). A multibarrier treatment (MBT) consisting of microfiltration (MF), hydrogen peroxide photolysis (H2O2/UVC) and catalytic wet peroxide oxidation (CWPO) was applied for all effluents. Sparus aurata, Paracentrotus lividus, Isochrysis galbana and Vibrio fischeri, representing different trophic levels, constituted the battery of bioassays. Different acute toxicity effects were observed in each WWTP effluents tested. The percentage of sea urchin larval development and mortality fish larvae were the most sensitive endpoints. Significant reduction (p < 0.05) of effluent's toxicity was observed using a classification pT-method after MBT process. Base on obtained results, tested battery of bioassays in pT-method framework can be recommended for acute toxicity preliminary evaluation of WWTP effluents for the marine environment.

Is the step-wise tiered approach for ERA of pharmaceuticals useful for the assessment of cancer therapeutic drugs present in marine environment?

Methotrexate (MTX) and tamoxifen (TMX) cancer therapeutic drugs have been detected within the aquatic environment. Nevertheless, MTX and TMX research is essentially bio-medically orientated, with few studies addressing the question of its toxicity in fresh water organisms, and none to its' effect in the marine environment. To the authors' knowledge, Environmental Risk Assessments (ERA) for pharmaceuticals has mainly been designed for freshwater and terrestrial environments (European Medicines Agency-EMEA guideline, 2006). Therefore, the purpose of this research was (1) to assess effect of MTX and TMX in marine organism using the EMEA guideline, (2) to develop an ERA methodology for marine environment, and (3) to evaluate the suitability of including a biomarker approach in Phase III. To reach these aims, a risk assessment of MTX and TMX was performed following EMEA guideline, including a 2-tier approach during Phase III, applying lysosomal membrane stability (LMS) as a screening biomarker in tier-1 and a battery of biochemical biomarkers in tier-2. Results from Phase II indicated that MTX was not toxic for bacteria, microalgae and sea urchin at the concentrations tested, thus no further assessment was required, while TMX indicated a possible risk. Therefore, Phase III was performed for only TMX. Ruditapes philippinarum were exposed during 14 days to TMX (0.1, 1, 10, 50 µg L(-1)). At the end of the experiment, clams exposed to environmental concentration indicated significant changes in LMS compared to the control (p<0.01); thus a second tier was applied. A significant induction of biomarkers (activity of Ethoxyresorufin O-deethylase [EROD], glutathione S-transferase [GST], glutathione peroxidase [GPX], and lipid peroxidation [LPO] levels) was observed in digestive gland tissues of clams compared with control (p<0.01). Finally, this study indicated that MTX was not toxic at an environmental concentration, whilst TMX was potentially toxic for marine biota. This study has shown the necessity to create specific guidelines in order to evaluate effects of pharmaceuticals in marine environment which includes sensitive endpoints. The inadequacy of current EMEA guideline to predict chemotherapy agents toxicity in Phase II was displayed whilst the usefulness of other tests were demonstrated. The 2-tier approach, applied in Phase III, appears to be suitable for an ERA of cancer therapeutic drugs in the marine environment.

General stress, detoxification pathways, neurotoxicity and genotoxicity evaluated in Ruditapes philippinarum exposed to human pharmaceuticals.

A battery of biomarkers was evaluated on Ruditapes philippinarum exposed during 14 days to caffeine, ibuprofen, carbamazepine and novobiocin (0.1, 1, 5, 10, 15, and 50µgL(-1)). The battery included general stress (lysosomal membrane stability - LMS) analysed in the hemolymph, and biochemical biomarkers analysed in digestive gland tissues including: biomarkers of phase I (etoxyresorufin O-deethylase - EROD, dibenzylfluorescein dealkylase - DBF), phase II (gluthathione-S-transferase - GST), oxidative stress (gluthathione reductase - GR, gluthathione peroxidase - GPX, lipid peroxidation - LPO), neurotoxicity (acetylcholinesterase activity - AChE), and genotoxicity (DNA damage). Pharmaceuticals tested induced the sublethal responses (even at the environmental range 0.1µgL(-1)). At this low concentration; caffeine, ibuprofen and carbamazepine decreased the LMS significantly compared with controls (p<0.05). The four compounds induced significantly the detoxification metabolism and oxidative stress (p<0.05). Neurotoxicity was noticed in clams exposed to caffeine and carbamazepine (p<0.05). Ibuprofen, carbamazepine and novobiocin produced genotoxic effects (p<0.05). Results from this research validate the use of biomarkers when assessing the effects of pharmaceuticals within a marine environmental risk assessment framework, using as a laboratory bioassay model the species R. philippinarum.

In situ evaluation of wastewater discharges and the bioavailability of contaminants to marine biota.

Marine sediment quality of wastewater discharges areas was determined by using in situ caged clams Ruditapes philippinarum taking into account the seasonality. Clams were caged in sediment directly affected by wastewater discharges at four sites (P1, P2, P3, P4) at the Bay of Cádiz (SW, Spain), and one reference site (P6). Exposure to contaminated sediments was confirmed by measurement of metals and As, PAH, pharmaceutical products and surfactants (SAS) in bottom sediments. Biological effects were determined by following biomarkers of exposure (activities of 7-ethoxyresorufin O-deethylase - EROD, dibenzylfluorescein dealkylase - DBF, glutathione S-transferase - GST, glutathione peroxidase - GPX, glutathione reductase - GR and acetylcholinesterase - AChE), effects (lysosomal membrane stability - LMS, DNA damage and lipid peroxidation - LPO), energy status (total lipids - TLP and mitochondrial electron transport - MET), and involved in the mode of action of pharmaceutical products (monoamine oxidase activity - MAO, alkali-labile phosphates - ALP levels and cyclooxygenase activity - COX). In winter, urban effluents were detoxified by phase I biotransformation (CYP3A-like activity), phase II (GST), and the activation of antioxidant defence enzymes (GR). Urban effluents lead to the detoxification metabolism (CYP1A-like), oxidative effects (LPO and DNA damage), neurotoxicity (AChE) and neuroendocrine disruption (COX and ALP levels) involved in inflammation (P1 and P2) and changes in reproduction as spawning delay (P3 and P4) in clams exposed in summer. Adverse effects on biota exposed to sediment directly affected by wastewater discharges depend on the chemical contamination level and also on the reproductive cycle according to seasonality.

Yes, caffeine, ibuprofen, carbamazepine, novobiocin and tamoxifen have an effect on Corbicula fluminea (Müller, 1774).

Reports indicating the presence of pharmaceutical in fresh water environment in the ngL(-1) to µgL(-1) range are occurring with increasing frequency. It is also a fact that pharmaceuticals may produce adverse effects on aquatic organisms. Nevertheless, there is still a lack of knowledge regarding how these emergent contaminants may affect aquatic biota. The goal of this research was to evaluate the sublethal responses in Corbicula fluminea such as, general stress (lysosomal membrane stability [LMS]), biomarkers of phase I and II (etoxyresorufin O-deethylase [EROD], dibenzylfluorescein dealkylase [DBF], gluthathione-S-transferase [GST]), oxidative stress (gluthathione reductase [GR], gluthathione peroxidase [GPX], lipid peroxidation [LPO]), and biomarkers of effect (DNA damage) after 21 days of exposure to caffeine, ibuprofen, carbamazepine, novobiocin and tamoxifen at 0.1, 1, 5, 10, 15, 50µgL(-1). Environmental concentrations tested in this study caused general stress and produced changes on biomarkers tested. LMS, responses from phase I and II enzymatic activity, oxidative stress, and biomarker of effect represent important ecotoxicological information, and will provide a useful reference for the assessment of selected drugs and the effects which these compounds may have on aquatic invertebrates, using C. fluminea as a bioindicator species.

Toxicological evaluation of sediment samples spiked with human pharmaceutical products: Energy status and neuroendocrine effects in marine polychaetes Hediste diversicolor.

There is a lack of studies about the ecotoxicology of pharmaceutical products on marine environment. To predict possible adverse effects of pharmaceutical products on benthic biota, polychaetes Hediste diversicolor were exposed for 14-days to pharmaceutical-spiked sediments under laboratory conditions. Carbamazepine (CBZ), ibuprofen (IBP) and propranolol (PRO) at concentrations of 500ngg(-1), 50ngg(-1), 5ngg(-1), 0.5ngg(-1) and 0.05ngg(-1), fluoxetine (FX) and 17α-ethynylestradiol (EE2) at concentrations of 100ngg(-1), 10ngg(-1), 1ngg(-1), 0.1ngg(-1) and 0.01ngg(-1), including environmental concentrations (underlined), were spiked in marine sediment samples. After the exposure, cellular energy status (total lipids content - TLP; and mitochondrial electron transport activity - MET), metabolism of monoamines (monoamine oxidase activity - MAO) and inflammation properties (cyclooxygenase activity - COX) were observed in polychaetes. CBZ increased TLP content and MET activity, and decreased MAO activity in polychaetes. IBP did not interfere on the TLP level, but on the MET and MAO activities (environmental concentrations). FX did not cause changes in the energy status. Therefore, environmental concentration diminished MAO activity. EE2 did not affect the energy status, however, MAO activity was significantly lower in polychaetes exposed to environmental concentration. PRO increased TLP level in polychaetes, but not MET activity. MAO activity was significantly lower for polychaetes exposed to environmental concentration. Except FX, all pharmaceuticals showed anti-inflammatory properties confirmed by the decrease of COX activity. Pharmaceutical products affected H. diversicolor physiology and health. As a benthic top predator, adverse effects on sea-worms can potentially culminate in ecosystem perturbations.

Assessing potential risks of wastewater discharges to benthic biota: an integrated approach to biomarker responses in clams (Ruditapes philippinarum) exposed under controlled conditions.

Marine clams Ruditapes philippinarum were exposed under laboratory conditions to sediments sampled at five sites affected by wastewater effluents at the Bay of Cádiz (SW, Spain). Contamination and early biological stress were determined. Metabolism and antioxidant system differed according to seasons. Health status diminished in summer. Metabolism of detoxification, and oxidative effect were related to concentration of metals, PAH, secondary alkane sulfonates (SAS) and antibiotics in winter. Antioxidant system and DNA damage were linked to metals and pharmaceutical products. Phase I and antioxidant system were associated to PAH and SAS in summer. Oxidative stress and effects were related to pharmaceuticals. Phase II was linked to metals and pharmaceuticals. Seasonality of sediment contamination by organic compounds and biological responses was determined. Clams were useful bioindicators, since the set of biomarkers applied was validated as potential tools for sediment quality assessment of wastewater discharges areas.

A candidate short-term toxicity test using Ampelisca brevicornis to assess sublethal responses to pharmaceuticals bound to marine sediments.

Lethal and sublethal responses related to different phases of metabolism (phases I and II enzymatic activities), neurotoxicity (acetylcholinesterase activity), oxidative stress (lipid peroxidation and antioxidant enzyme activities), and genetic damage (DNA strand breaks) were analysed to assess the possible adverse effects of pharmaceuticals bound to marine sediments. The crustacean amphipod Ampelisca brevicornis was chosen as the bioindicator species. Organisms were exposed for 10 days to sediment spiked with pharmaceutical compounds frequently used and previously detected in the environment: carbamazepine (CBZ), ibuprofen (IBP), fluoxetine (FX), 17α-ethynylestradiol (EE2), propranolol (PRO), and caffeine (CAF). Short-term bioassay to evaluate amphipod mortality was recommended to assess pollution by CBZ, FX, and PRO. IBP and PRO were metabolized by phases I and II detoxification enzymatic activities. Oxidative stress was caused by PRO and CAF. Contrary to expected results, DNA damage (strand breaks) decreased after the exposure of amphipods to sediment spiked with IBP, FX, EE2, PRO, and CAF (including environmental concentrations). FX was neurotoxic to amphipods. The battery of biomarkers tested allowed the assessment of bioavailability, oxidative stress, genotoxicity, and neurotoxicity of the pharmaceuticals analysed. The results of this study suggested that pharmaceutical products at concentrations currently found in the environment might cause a wide variety of adverse effects (based on laboratory studies). The results obtained here are useful for environmental risk assessment of marine sediments contaminated by pharmaceuticals. Nevertheless, more research is needed using field-based marine sediments.