Ecopharmacovigilance

Pharmaceuticals are widely used in human and veterinary medicines, agriculture, and aquaculture purposes to save life, because they are designed to specifically interact with biochemical mechanisms of a higher vertebrate species at low concentrations. These compounds are known as emerging contaminants and have attracted significant interest in recent years because their presence and their consequences had gone unnoticed so far. Among these pollutants, one of the most important groups and currently more studied by the ecopharmacovigilance are pharmaceuticals. The indiscriminate use of these compounds and their improper disposal have generated income of pharmaceuticals to aquatic ecosystems by municipal, hospital, and industrial discharges, which has caused various toxic effects on the environment.

The aim of this chapter is to review, compile, and analyze reports on the occurrence of pharmaceuticals around the world, and its major toxic effects in aquatic organisms, as well as the legislation of these compounds, to evaluate the potential environmental health impacts of trace levels of these pharmaceuticals in aquatic environments.

The presence of pharmaceuticals in the environment is an issue that has taken on importance since the 1990s, when the first cases of harmful effects to organisms caused by exposure to these compounds present in the environment were demonstrated, and which currently continues emerging as an area whose knowledge increases day by day. Recent studies report that there is literature that in some way is related to the PiE since the 1950s; in this chapter, we will make a brief account of some of the important historical events that led to the term that encompasses this type of studies, ecopharmacovigilance, and how it began to develop knowledge about the life cycle of PiE.

Medicinal products are considered emerging pollutants due to their possible noxious effects on both the environment and living organisms. These anthropogenic pollutants enter the environment mainly through industrial activities, human excretions, the disposal of unused medicines, and agricultural use.

For research to be carried out on the ecotoxicological risks of pharmaceutical pollutants, it is necessary – from the perspective of environmental fate – to have an overview of the main concepts on how pharmaceuticals enter the environment and move or undergo transformations into the ultimate toxicants that can cause adverse effects in living organisms.

In this work, we describe and provide examples of the most relevant pharmaceutical properties related to the different environmental fate processes. Additionally, we provide some insights on the predicted impact of said properties on the persistence, bioaccumulation, and toxic potential of several drugs.

There is a need for further optimization of the characterization of the environmental risk of emerging pollutants, such as pharmaceuticals, in addition to a harmonized risk assessment approach for most regions of the world.

Understanding the fates and effects of drugs on the environment allows us to conclude that the best way to reduce the presence of pharmaceuticals in the environment, and thus reduce exposing living organisms to them, is a synergy between achieving an adequate removal of these pollutants through the development of research and technology and slowing down the indiscriminate disposal of these compounds, educating the population on the rational and informed selection, use, and disposal of these products.

Roughly 4,000 pharmaceuticals are manufactured and marketed in the world for use in the treatment, prevention, and diagnosis of diverse diseases in humans and animals. Once their role in body systems has been accomplished, these compounds are excreted from the body, having aquatic ecosystems as their final destination. Pharmaceuticals are also released into the environment as a result of manufacturing processes and inadequate disposal of unused or expired medications. The environmental concentrations that have been detected in water systems are usually at trace levels (ng L⁻¹ to μg L⁻¹) since removal in sewage treatment plants is not significant for most pharmaceuticals as these facilities have not been designed to reduce or eliminate these contaminants, representing instead a continuous contribution to the environment. Effluents have been identified as the main entry route of pharmaceuticals into the environment. This chapter aims to review, compile, and analyze research studies on the occurrence of pharmaceuticals in the environment.

In this chapter, for articles addressing drugs as pollutants of natural and wastewater, we discuss the temporal distribution of studies, as well as the main countries of origin for such studies. Focus is given to those articles with more than 200 citations. The main sampling techniques, sample extraction, and detection methods accepted by the USEPA and USGS (based on LC-MS/MS and LC-MS) are reviewed, as well as those methods not based on MS, between 2014 and 2017. From this analysis, we propose directions for future research. Finally, a case study is presented that addresses the analysis of the surface waters of the Izúcar de Matamoros region and the Atoyac River in Puebla, as well as the Zahuapan River in Tlaxcala, Mexico. By GC/MS, quantitative determination of naproxen, diclofenac, and triclosan, at stations on the Zahuapan (Tlaxcala), Atoyac, and Nexapa (Puebla) rivers, was performed during the period of 2012–2013. We found that 30% of the publications related with drugs as pollutants of natural and wastewater were published between 2014 and 2017. Spain has published the most of such articles (accounting for 25% of all publications). Three of the articles have more than 1,000 citations. HPLC/MS/MS was the most commonly used method, followed by GC/MS. However, less sophisticated detection alternatives were also used. GC/MS was used to demonstrate the presence of naproxen, diclofenac, triclosan, and carbamazepine in the Mexican Central Plateau and the inability of the wastewater treatment plants (WWTPs) to remove completely these contaminants.

Pharmaceuticals are widely used in human and veterinary medicine as well as agriculture and aquaculture to heal and save lives since they have been designed to interact specifically with biochemical mechanisms in higher vertebrate species at low concentrations. However, adverse effects on nontarget species may be possible despite the generally low toxicity of these compounds in mammalian species and the low levels found in the environment. The level of damage induced on aquatic organisms depends on the concentration to which they are exposed, the biological activity and toxicity of the pharmaceutical, its history of use, and its persistence in the environment. Studies on the ecotoxicity of pharmaceuticals are limited in number and are based primarily on acute toxicity studies and a few results about chronic effects on aquatic species. This chapter seeks to conduct an up-to-date review of published reports dealing with ecotoxicological studies of pharmaceuticals in aquatic organisms.

As stated in previous chapters, the earliest studies on quantification of pharmaceutical concentrations in the environment and induction of toxic effects on organisms date back to the 1990s. Since then, concern regarding the presence of trace concentrations of these emerging pollutants and the health risk they represent has increased in various sectors of society in different parts of the world. While this field of study has yet to be developed, joint efforts have been initiated to mitigate the possible ecotoxicological effects of these contaminants and regulate their presence in surface water, groundwater, and even drinking water. This chapter aims to make a breakdown of current information regarding the progress in legislation on pharmaceuticals in the environment, focusing first on a global vision and the actions proposed by the European Community and subsequently on the efforts made by different countries as well as the World Health Organization. The viewpoints of some pharmaceutical manufacturers and the existing hospital legislation on pharmaceuticals in the environment have been incorporated, since these entities represent two of the most important entry routes of pharmaceuticals into the environment. Lastly, the prospects and initiatives on this matter proposed for the year 2018 are briefly discussed.

This chapter aims to present the fundamentals, important variables, and pharmaceuticals removed by ozonation and Fenton, which are only two of the current existing advanced oxidation processes. Some toxicological information regarding pharmaceuticals oxidized by ozonation is also included. Some strategies to improve such processes, like adding a catalyst, light, or electrical current, are also analyzed. Thus, this chapter intends to present general but fundamental aspects of the aforementioned processes.

In this chapter, basic concepts of advanced oxidation processes (AOP) are cited, such as photolysis, photocatalysis, and semiconductors used as photocatalysts. This is important since the wastewater pollution with drugs, coming from domestic use, hospitals, and industry is not only an environmental problem but social too. Pharmaceutical case study is shown to exemplify the photocatalytic degradation of different drugs contained in wastewater taken directly from some currents in the pharmaceutical industry, such as diclofenac, acetaminophen, naproxen, and ibuprofen, using modified TiO₂ catalysts with different tin contents.

The rejection of emerging contaminates, which are associated with potential adverse human-health effects, such as endocrine-disrupting compounds, emerging disinfection by-products, pharmaceutical residues, personal care products, and organic compounds, have increase the interest for membranes applications.

Previous reports using a membrane as a filter have contributed to an improved understanding of rejection mechanisms for emerging contaminates; for example, microfiltration, ultrafiltration, nanofiltration, and reverse osmosis have been investigated.

In this chapter, they are going to find an information about the role of membrane on emerging contaminant removal and, likewise, characteristics of emerging contaminants, membrane classification, sources and levels of drugs in wastewater, and removal of emerging contaminants using membranes.

Pharmaceutical products are substances used mainly for therapeutic purposes. They include a broad group of medications such as antidepressants, antibiotics, bactericides, and personal hygiene products. At world level, 100,000 tons of active pharmaceutical ingredients are manufactured yearly. In general, they have a molecular mass of <500 Da and are composed of chemically complex molecules which vary as to molecular weight, structure, and function. They are lipophilic polar molecules with more than one ionizable group, and some of them are moderately water-soluble. In recent decades, these compounds have been considered contaminants of emerging concern since they are released into the environment and are not monitored. Pharmaceuticals commonly detected in effluents include acetylsalicylic acid, diclofenac, ibuprofen, paracetamol, benzodiazepines, carbamazepine, fibrates, tetracyclines, macrolide and β-lactam antibiotics, penicillins, quinolones, sulfonamides, fluoroquinolones, and chloramphenicol, among others. Pharmaceuticals like cyclophosphamide, erythromycin, naproxen, and sulfamethoxazole persist for periods of more than 1 year in the environment, while clofibric acid can persist for several years. Pharmaceutical contaminants have been found at concentrations of ng/L to several 100 μg/L. The potential effect of exposure to complex mixtures of pharmaceuticals at low concentrations (<1,000 ng/L), independently of the individual effect induced by each contaminant, remains unknown. One strategy for the removal of these pharmaceutical contaminants is microbial bioremediation, which is used to transform or remove these contaminants and reduce their toxicity in the environment.

The population growth in the last years in the world has increased the demands of products at general level and has brought with it an accelerated industrial development, accompanied by a large list of emerging pollutants added to the environment in the different phases of its life cycle, among which are different pharmaceutical products for veterinary and human consumption, as well as their metabolites. In recent years, it has become aware of this serious problem of environmental pollution, creating new terms such as “ecopharmacovigilance.” The responsibility of researchers in these areas for both design and evaluation of new pharmaceuticals is to seek new ecosystem-friendly alternatives for the detection and degradation of these pharmaceuticals that allows the decontamination of aquifers, soil and air, products of the manufacture, and biodegradation of the original customer.

Nanotechnology offers the opportunity of efficiently removing several types of pollutants present in today’s wastewater. There are several different nanomaterials available (carbon nanotubes, graphene, graphene oxide, metal oxides, nanoclays, among several others) which have been explored for wastewater remediation. Pharmaceuticals and personal care products such as antibiotics, hormones, antipyretic drugs, triclosan, etc. represent an emerging type of pollutant in surface and drinking water; and exposure represents a risk for both environment and human health. As conventional technologies used for wastewater treatment do not completely remove these residues, nanomaterials may offer an efficient alternative for water treatment and remediation systems in place of conventional technologies. This chapter provides a comprehensive summary of several nanomaterials that, due to their unique physical and chemical properties, are useful in different remediation approaches for the removal of such emerging contaminants from wastewater. Water treatments like adsorption/absorption of contaminants and photocatalysis from advanced oxidation processes that use nanomaterials to increase their efficiency are addressed in this chapter. Nanomaterials are promising components in the development of innovative and efficient environmental cleaning processes and water purification.

The increase in levels of pharmacological substances in the environment and their potential adverse effects on biological systems are a problem of global relevance that will pose greater challenges to countries with high rates of population growth. There is evidence that the incorporation of pharmacological substances into organisms and ecosystems puts genetic diversity, species diversity, and community diversity at risk.

There are several pathways through which waste pharmaceuticals can reach to organisms; the main one is through sewage discharge into aquatic ecosystems affecting organism such as microorganisms, fishes, and invertebrates, which can be consumed by higher trophic levels and cause trophic cascade effects. Also the use of treated wastewater for agricultural irrigation can affect the plants which are at the base of the trophic chain. Most of the studies about the effect of pharmaceutical on organisms have omitted to test nonlethal effects, such as change in behavior, reproduction, and stress and changes in community composition and structure. The few studies that have addressed these effects have showed that these changes can affect organisms’ survival or reproductive success, which are linked to their biological fitness, and can affect population and community dynamics and precede species extinctions.

Due to the vulnerability of Mexican species and ecosystems to human pressures, it is necessary to begin evaluating and carrying out actions that minimize the risks to biodiversity of drug contamination. The areas in which this type of action would be necessary are those in which it finds a high biological diversity with a high percentage of endemic or endangered species, as well as in ecosystems where ecological processes are fundamental to the maintenance of biodiversity and environmental services at the regional level.

In recent years environmental research has centered on emerging contaminants, outstanding among which are pharmaceutical products. Although pharmaceuticals have been detected in aquatic ecosystems only at trace levels, they have been shown to induce toxic effects in aquatic organisms since they are designed to be biologically active in living organisms and persistent to biodegradation and to have long half-lives. Effluents from domestic, hospital and industrial sources, sewage treatment plant effluent, and the inappropriate disposal of unused or expired medicines are the principal sources of emission of pharmaceuticals into the environment. Conventional methods of wastewater treatment prove insufficient for the complete removal of pharmaceuticals; however, research is now being focused on advanced oxidation processes to remove pharmaceutical products. Information on the fate and effects of pharmaceuticals in the environment provides the groundwork from which to assess their environmental risk and identify possible risk management strategies, as well as for putting in place stricter regulations on the fate of this type of contaminants.