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This book gathers the main international research findings on non-steroidal anti-inflammatory drugs (NSAIDs) as emerging contaminants in water. It focuses on the major routes of exposure, and the destinations and life cycles of NSAIDs in water, as well as the manifestations of toxicity in different organisms. It also reviews the methods used in the detection, analysis and quantification of NSAIDs in water as well as the biological and chemical methods of removing them. Lastly, the book offers an overview of the legal frameworks in place and provides conclusions and recommendations for the future.

Given its scope, the book is an indispensable resource for scientists in academia and industry, as well as for decision-makers involved in contamination assessment and environmental analysis and NGOs interested in the problem of water contamination by NSAIDs.

Inhaltsverzeichnis

Frontmatter

Introduction and Historical Findings That Focused Nonsteroidal Anti-Inflammatory Drugs as Emerging Pollutant

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most consumed pharmaceuticals worldwide due to their significant anti-inflammatory and antipyretic properties. These drugs are mainly excreted from the body in their metabolized form and may enter into the environment through different pathways. In wastewater treatment plants (WWTPs), these contaminants are mainly removed by biological treatment processes. However, even after these treatments, high concentrations of these drugs have been found in WWTPs effluents, surface water, and drinking water. NSAIDs are likely to bioaccumulate in aquatic organisms such as Mytilus galloprovincialis. Furthermore, toxic effects such as oxidative stress, developmental abnormalities, hepatotoxicity, immunosuppressive effects, and hematological alterations have been found in several freshwater species exposed to these pollutants. Therefore, NSAIDs are a threat to the human being as well as to our environment. This review comprehensively discusses the worldwide consumption of NSAIDs, their occurrence in the aquatic environments, and the toxic effects produced by these drugs in nontarget organisms. This is to raise awareness of the negative consequences of their occurrence in freshwater ecosystems and promote the creation of new alternatives for their removal from water.
Gustavo Axel Elizalde-Velázquez, Leobardo Manuel Gómez-Oliván

Overview of Non-steroidal Anti-inflammatory Drugs as Emerging Contaminants

Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most used pharmaceuticals in the human and veterinary medicine, and it has been demonstrated that their widespread consumption all over the world has led to their ubiquitous occurrence in water environment. Nowadays, there exist strong evidence about the presence of different NSAIDs, such as diclofenac, naproxen, ketorolac, ibuprofen, ketoprofen, and salicylic acid, among others, which are found in concentrations in the range of ng/L to mg/L on different water bodies. Besides, the toxicological effects that NSAIDs cause in aquatic organisms have been evaluated by working groups all over the world. Thus, the aim of this review is to provide a detailed overview about the presence of NSAIDs in aquatic environmental, in particular to summarizing the main toxicological effects on living organisms and occurrence in water bodies that has been documented.
Alejandro Mejía-García, Hariz Islas-Flores, Leobardo Manuel Gómez-Oliván, Nely SanJuan-Reyes, José Mario Ortega-Olvera, María Dolores Hernández-Navarro

Worldwide Occurrence, Detection, and Fate of Nonsteroidal Anti-inflammatory Drugs in Water

Abstract
Finding over-the-counter drugs such as NSAIDs in wastewater is somewhat expected and understandable; however, finding them on surface or groundwater is more worrisome as it demonstrates, in part, the inefficiency of the methods used today to treat wastewater as well as practices of inadequate use and indiscriminate disposal of these emerging contaminants.
The objective of this chapter is to provide a systematic review of the worldwide occurrence of NSAIDs in three environmental reservoirs of water (saline and fresh and groundwater) and in drinking water.
Our results showed that the worldwide distribution of studies on the subject is practically concentrated in Asia and Europe. Acetaminophen, diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, mefenamic acid, and salicylates are the NSAIDs investigated and most frequently detected in all studies.
Since 2010, research on the occurrence of NSAIDs in environmental water reservoirs has been continuous and consistent. However, the analysis of river waters is much more abundant than those of seas, groundwater, or drinking water. Fortunately in recent years, research has focused on the development of more sensitive but at the same time simpler methods for the detection of NSAIDs in water bodies. Moreover, during the article screening process, we found that in recent years, publications related to toxicity studies in diverse model organisms have increased.
Concentrating the information available to date on the quantities of NSAIDs found in different aquatic ecosystems, through different methods of extraction and analysis, is very useful to direct future research, to design more efficient strategies to minimize the ecological impact of these water pollutants, and to develop evidence-based regulation.
Lucila I. Castro-Pastrana, Erika Palacios-Rosas, M. Luisa Toledo-Wall, Mónica Cerro-López

Quantification of Non-steroidal Anti-inflammatory Drug in Water

Abstract
This chapter discusses the main reasons for viewing non-steroidal anti-inflammatory drug (NSAIDs) as emerging contaminants. Their access routes into the environment are specified, in particular into natural and wastewater, and current evidence about their possible toxic effects is described. Mention is made of the most commonly used methods for routine determination from sampling to final quantification of NSAIDs in water samples of diverse origins. The most important aspects of sampling, extraction, and concentration, including microextraction methods, are detailed. The methods most commonly used in separation, identification, and quantification of NSAIDs in water are described. These methods include, in particular, gas and liquid chromatography systems and capillary electrophoresis that are coupled to different detectors. It was concluded that it is necessary to develop new methodologies that allow continuous monitoring at even lower costs than presently available.
Keila Isaac-Olivé, Eunice Olivé-Alvarez, Amado E. Navarro-Frómeta, Ninfa Ramírez-Durán, Enrique Morales-Avila, Liliana Aranda-Lara, Horacio Sandoval-Trujillo, Pablo Moreno-Pérez

DNA Alterations and Cellular Damage Induced by Non-steroidal Anti-inflammatories on Different Species of Fish

Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs used to reduce inflammation, pain, and fever by inhibiting the enzyme cyclooxygenase (COX 1 and COX 2). These drugs have been positioned among the most consumed worldwide. After their biotransformation in the body, they are eliminated as metabolites, and also in the environment they can undergo transformations, generating products that are more toxic than the original molecule. Several studies have shown that NSAIDs are not eliminated in conventional treatments used by wastewater treatment plants and represent a continuous contribution to the environment, causing significant effects on biota. However, there has been little attention given to the study of its toxic effects on aquatic organisms. The objective of this chapter is to review, compile, and analyze the oxidative damage induced by NSAIDs in different aquatic organisms, to evaluate the ecotoxicological effects of this type of drugs.
Nely SanJuan-Reyes, Leobardo Manuel Gómez-Oliván, Ricardo Pérez-Pastén Borja, Hariz Islas-Flores, Marcela Galar-Martínez, Sandra García-Medina

Teratogenesis and Embryotoxicity Induced by Non-steroidal Anti-Inflammatory Drugs in Aquatic Organisms

Abstract
The continuous elimination of pharmaceutical products to water sources has become a worldwide problem and has been getting considerable attention due to the effects that this compounds have induced in aquatic organisms, specifically non-steroidal anti-inflammatory drugs (NSAIDs), one of the most representative group of medications and the most consumed around the world, highlighting the teratogenic and embryotoxic effects induced by NSAIDs on early life stages of different organisms being this the most vulnerable stages in development; the main representants of NSAID group (diclofenac, ibuprofen, naproxen, ketoprofen, paracetamol, acetylsalicylic acid) have induced adverse embryonic effects, which can be consider for the development of strategies for an appropriate disposal of pharmaceutical residues, as well as establish maximum permissible limits for its emission to the environment.
Itzayana Pérez-Alvarez, Hariz Islas-Flores, Leobardo Manuel Gómez-Oliván, Octavio Dublán García

Ecotoxicological Effects of the Drug Paracetamol: A Critical Review of Past Ecotoxicity Assessments and Future Perspectives

Abstract
Paracetamol (also designated as acetaminophen) has been systematically reported to occur in the aquatic environment, giving rise to serious concerns related to its ecotoxicological profile, final environmental fate, and potential biological interactions. In fact, the existing data concerning the toxicology of such drug shows its involvement in multiple adverse effects at several organs and tissues, a reality that also occurs in aquatic organisms of varied types, trophic levels, and habitats. From such data, it is possible to ascertain about the putative environmental risk posed by such drug, namely, by exerting deleterious irreversible effects in non-target organisms at low levels of exposure. The present article intends to critically present a comprehensive series of studies addressing the ecotoxicity of paracetamol, evidencing its deleterious nature, the extent of the problem, and alternative methods to determine the potential threat that it may constitute.
Bruno Nunes

Adverse Effects Induced by Nonsteroidal Anti-inflammatory Drugs on Freshwater Invertebrates

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of molecules representing one of the most relevant therapeutic class found in the aquatic ecosystems worldwide. NSAIDs are commonly and extensively used for their analgesic, antipyretic and anti-inflammatory properties to cure pain and inflammation in both human and veterinary therapy. Because of the huge, continuative and increasing use, as well as their specific pharmacokinetic properties, after medical use they are excreted in their native form or as metabolites and enter the aquatic ecosystems. A number of monitoring surveys has reported levels of NSAIDs exceeding 1 μg/L in influent and effluents of Wastewater Treatment Plants (WWTPs), while lower concentrations have been found in surface waters, ranging in the ng/L – μg/L range. Among NSAIDs, paracetamol, diclofenac, and ibuprofen are the most detected therapeutics found in aquatic ecosystems. Although the concentrations of these molecules in surface waters are quite low, their high biological activity might confer them a potential toxicity towards non-target aquatic organisms. The present chapter aims at reviewing the adverse effects induced by paracetamol, diclofenac, and ibuprofen towards different freshwater invertebrates belonging to different taxa. Although acute toxicity of paracetamol, diclofenac, and ibuprofen occur only at high, unrealistic concentrations, sublethal effects were caused by low, environmentally relevant concentrations of these drugs. For these reasons, further studies represent a priority in order to enlarge the knowledge on NSAID toxicity towards aquatic organisms and to shed light on their real ecological hazard towards aquatic communities.
Marco Parolini

Ibuprofen and Diclofenac: Effects on Freshwater and Marine Aquatic Organisms – Are They at Risk?

Abstract
Pharmaceuticals are included in the group of emergent pollutants due to their characteristics and potential negative effects. They remain mostly unregulated or are undergoing currently some sort of regularization process. Diclofenac, for instance, has been included in a watch list of substances for European Union-wide monitoring and the priority list of the Water Framework Directive (WFD) of the European Union. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a varied and chemically heterogeneous group of mainly anti-inflammatory, analgesic, and antipyretic drugs, reducing symptoms of inflammation, pain, and fever, respectively. They are widely employed and have been detected in freshwater, seawater, and sediment. Nevertheless, they are found as mixture instead of single compounds. In this chapter, we have tried to summarize how to assess the risk due to the occurrence of pharmaceuticals in aquatic ecosystems. We have focused on the mixture of diclofenac and ibuprofen using acute and sublethal toxicity data for different aquatic species. It has been presented new strategies as adverse outcome pathway to improve the understanding of the toxicity of these compounds. Although gaps of the information are pointed out, the risk levels associated with the occurrence of these compounds in aquatic ecosystems will range between no risk or high risk, depending on concentrations and environmental conditions.
Chiara Trombini, Julián Blasco, Miriam Hampel

Toxicity Assessment of Acetylsalicylic Acid to a Freshwater Fish Cyprinus carpio: Haematological, Biochemical, Enzymological and Antioxidant Responses

Abstract
Pharmaceutical pollution is a global threat to the biosphere causing significant environmental health concern. A wide range of pharmaceuticals (antibiotics, nonsteroidal anti-inflammatory drugs, beta-blockers, etc.) are widely used in human and veterinary medicine, agriculture and aquaculture purposes to protect the life against various diseases and to improve human health. The extensive use of these compounds may enter the environment through discharge of domestic waste waters, excretion via water and sewage treatment systems which may affect the aquatic organisms. Aspirin (acetylsalicylic acid, ASA) is one of the most commonly used nonsteroidal anti-inflammatory drug (NSAIDs) worldwide and has been detected in aquatic bodies. Therefore, it is important to gain knowledge about the toxicity of acetylsalicylic acid in aquatic organisms. Here we have administered 100 and 200 mg L−1 of acetylsalicylic acid, to a freshwater fish Cyprinus carpio fingerlings, and have studied its effects on haematological, enzymological biochemical and antioxidant parameters. When compared to control, acetylsalicylic acid-treated fish showed a significant (P < 0.05) decline in haemoglobin (Hb), haematocrit (Hct) and red blood cell (RBC) levels throughout the study period (12 days). On the other hand, a significant (P < 0.05) increase was observed in white blood cell counts (WBC), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC) values. Acetylsalicylic acid induced a hyperglycaemic condition compared to control, whereas the level of proteins was declined. A significant decrease in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity was noted in acetylsalicylic acid-treated groups (except 21st day in ALT activity and 21st day in AST activity). Significant alterations in various antioxidant parameters such as superoxide dismutase (SOD), lipid peroxidase (LPO), catalase (CAT) glutathione (GSH) and glutathione S-transferase (GST) were observed in ASA-treated groups compared to the control group. From the results, it is noteworthy that the drug ASA even at considerable environmental concentrations causes negative impacts on the health of aquatic organisms. The alterations of these parameters can be effectively used to monitor the impact of pharmaceutical drugs in the aquatic environment.
Graphical Abstract
Subramaniam Siddeswaran, Sathisaran Umamaheswari, Mathan Ramesh

Contemporary Methods for Removal of Nonsteroidal Anti-inflammatory Drugs in Water Reclamations

Abstract
Global water quantity and quality are anticipated to decrease in the coming decades, as a result of both increasing global populations and the effects of climate change. Reusing and recycling water is a key part of reducing the pressure on our existing water supplies and the aquatic environment. However, the occurrence of nonsteroidal anti-inflammatory drugs (NSAIDs) in secondary, and in some tertiary, treated effluents- and sewage-impacted water bodies is one of the major obstacles for the implementation of water reuse. For several decades, NSAIDs have been extensively used for therapeutic purposes in both humans and domestic livestock. The negative effects of NSAIDs on aquatic biota are just beginning to be realized. Currently, intensive treatments are required to remove effectively NSAIDs from recycled treated effluent in order to minimize or eliminate risks to human health and aquatic environment. In this chapter, we focus the discussion on contemporary methods for NSAID removal including biological, physical, chemical, and combined process that may provide a more effective and efficient alternative.
Luong N. Nguyen, Audrey S. Commault, Donna Sutherland, Galilee U. Semblante, Seungdae Oh, Long D. Nghiem

Photo-Fenton Treatment of a Pharmaceutical Industrial Effluent Under Safe pH Conditions

Abstract
This chapter aims to present the effect of treating a pharmaceutical industrial effluent by photo-Fenton catalyzed with a Fe-pillared bentonite. XRD proved the pillaring process successful, and by N2 physisorption, it was established that the specific surface area of bentonite (34 m2/g) increased to 277 m2/g and pore volume increased from 0.058 to 0.106 cm3/g. Active Fe species were identified by Mössbauer spectroscopy. The effect of reaction variables such as catalyst loading, pH, H2O2 concentration, and initial concentration of total organic carbon (TOC) is also presented. It was concluded that to reach near 100% mineralization, an acidic pH (2.7) should be observed. A high mineralization under these conditions, however, does not directly correlate with a low toxicity. Actually, the oxidative stress biomarkers only decreased when pH was not modified (pH = 8) albeit the attained mineralization was only 51%. It is worth noticing that the use of pillared clays allows carrying out photo-Fenton treatment under pH conditions other than acidic. The synthesized catalyst exhibited magnetism and this can be used for an easier recovery.
Reyna Natividad, Arisbeth Mendoza, Sharon E. Brewer, Sandra Luz Martínez-Vargas, J. L. Pérez-Mazariego, Karen Adriana Novoa, Leobardo Manuel Gómez-Oliván, Rubi Romero

Use of Membrane for Removal of Nonsteroidal Anti-inflammatory Drugs

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) belong to most used pharmaceuticals in human and veterinary medicine, the emerge of drugs in the environment is a concern subject. The contamination is due to the consumption and the excretion of large quantities of pharmaceuticals via urine and feces in wastewaters. In this chapter, the reader will have an overview of the use of different types of membranes and their combined method in the removal of NSAIDs and demonstration that the use of membrane could be an environment-friendly methodology that enhances its efficiency in the removal of these compounds.
Rosa María Gómez-Espinosa, Daniel Arizmendi-Cotero

Nanotechnologies for Removal of Nonsteroidal Anti-inflammatory Drug from Wastewater

Abstract
Nowadays, our world faces one of the greatest challenges in terms of water consumption due to its growing population and demanding economic development. Water pollution is taking place at a rate and grade that make the advancement in water treatment technologies a research priority on several fronts, including those needed from the environmental and health standpoints. Today, one of the major concerns for allowing water reuse and providing safe drinking water supply is related to the presence of natural organic matter (NOM) and micropollutants in raw water. Among the latter, pharmaceutical compounds (PhCs) stand out, as they could partially or totally resist conventional removal treatments. Nonsteroidal anti-inflammatory drugs (NSAIDs) are especially ubiquitous PhCs due to their extensive prescription, and, consequently, they are often detected in hospital effluents, surface water bodies, sewage treatment plants (STP) effluents, and soil matrices. Therefore, NSAIDs wastewater removal is becoming a major concern in environmental protection. New technologies capable of efficiently removing them have been developed in the last few decades, and, within them, nanotechnology has risen as a promising tool to aid these technologies to accomplish their goal. In this chapter, the most common approaches to treat NSAIDs-containing wastewater are addressed, including adsorption, photocatalysis, and electrocatalysis; besides, recent advances on nanotechnological applications to improve their performance are covered.
Monica Cerro-Lopez, Jorge Jiménez Cisneros, Miguel A. Méndez-Rojas, Lucila I. Castro-Pastrana

Biological Technologies Used for the Removal of Nonsteroidal Anti-inflammatory Drugs

Abstract
Chronic pain is one of the most important causes of disability worldwide and represents a major public health challenge. The presence of inflammation is a common underlying mechanism of chronic pain. Nonsteroidal anti-inflammatory drugs (NSAIDs), COX2-selective and non-selective, showing analgesic and anti-inflammatory properties, are useful options for the treatment of chronic pain. Non-metabolized pharmaceutical products and their metabolites are excreted and enter sewage as biologically active substances. The accumulation of emerging pollutants, such as active pharmaceutical ingredients and their metabolites in the aquatic environment, has recently become a serious problem due to their bioaccumulation and ecotoxicity potential that affects living organisms. Pharmaceutical products considered as emerging pollutants are partially removed during the treatment of wastewater that contains them and are detected in groundwater, surface water, and wastewater effluent, as well as in drinking water at concentrations ranging from a few nanograms per liter to 15 μg/L. The elimination of these contaminants is essential due to the toxicity that causes in the organisms. Biological techniques that include microorganisms in their processes could be more effective for the elimination of pharmaceutical contaminants compared to the physicochemical techniques currently used.
Ninfa Ramírez-Durán, Lorna Catalina Can-Ubando, Gauddy Lizeth Manzanares-Leal, M. P. A. Moreno-Pérez, Keila Isaac-Olivé, Angel Horacio Sandoval-Trujillo

Risk Evaluation and Legal Framework of the Nonsteroidal Anti-inflammatory Drugs Around the World

Abstract
Ecological risk assessment is generally carried out to assess the dose that may be harmful to particular species found in the freshwater. The ecological risk assessment is generally expressed through RQ or hazardous quotient, RQ < 0.1 suggests no risk, 0.1 ≤ RQ ≤ 1.0 suggests medium risk, and RQ > 1.0 suggests high risk to that particular species. Regarding this, the risk of nonsteroidal anti-inflammatory drugs (NSAIDs) has been particularly studied by several researchers in many countries because they are pharmaceuticals of high consumption by the population due to their analgesic, anti-inflammatory, and antipyretic properties, as well as their occurrence in different water bodies at different concentrations and the toxic effects reported in organisms that are exposed to them. Due to the results obtained, they have also been considered for future regulations, and in particular, diclofenac was added to the list of priority substances of the European Commission which should be monitored as water pollution agents in the European Union. In this chapter we will discuss some of these risk assessment studies as well as the legislation proposed by some countries for their regulation.
Jesus Daniel Cardoso-Vera, Hariz Islas-Flores, Nely SanJuan-Reyes, Leobardo Manuel Gómez-Oliván

Conclusions

Abstract
The book Non-Steroidal Anti-Inflammatory Drugs in Water: Emerging Contaminants and Ecological Impact includes knowledge about the problem of the presence of NSAIDs in aquatic ecosystems, their effects on aquatic organisms, and useful methods to reduce their impact on the environment. This chapter summarizes the main conclusions about the history of NSAIDs as emerging pollutants, their presence in water bodies around the world, toxic effects of these compounds on aquatic organisms, effective chemical and biological methods for their removal, and the legal framework for presence of these compounds in water bodies in the world.
Leobardo Manuel Gómez-Oliván
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