Pharmaceuticals and Pollution: Comparison
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Environmental pollution is a growing threat to natural ecosystems and one of the world’s most pressing concerns. The increasing worldwide use of pharmaceuticals has elevated their status as significant emerging contaminants. Pharmaceuticals enter aquatic environments through multiple pathways related to anthropogenic activity.

  • aquatic pollution
  • biodiversity
  • biomonitoring
  • ecotoxicology

1. Introduction

Human activities such as industrialization, urbanization, and economic development contribute synergistically to increased environmental pollution in aquatic habitats, such as rivers, lakes, and marine environments [1]. Chemical pollutants, such as heavy metals and industrial and pharmaceutical chemicals, can disrupt the balance of essential nutrients and oxygen levels, impair water quality, and make toxic or unsuitable conditions for aquatic life [2]. Water pollution can also harm biodiversity and disrupt photosynthesis in aquatic plants, significantly impacting ecosystems relying on these plants [3]. Both terrestrial and aquatic plants can absorb pollutants from water (as their main nutrient source) and transfer them through the food chain to animals and humans [4]. Pharmaceutical drugs and their metabolites contribute to water pollution by entering water bodies, disrupting the normal biological processes of aquatic organisms, and leading to the development of drug-resistant strains of bacteria [5]. In aquatic environments, including surface water, urban wastewater, wastewater treatment plants, groundwater, drinking water, and even seawater, the concentration range of predominant individual pharmaceutical compounds is typically observed to be between nanograms per liter (ng/L) to micrograms per liter (μg/L). Nevertheless, effluent from treatment plants that receive waste from pharmaceutical manufacturing facilities has been documented to contain concentrations as high as several milligrams per liter (mg/L) [6]. Furthermore, the distribution of pharmaceuticals in aquatic environments is geographically specific and contingent upon drug use patterns [7].
In recent decades, a major concern has arisen due to the increasing use of pharmaceutical products and their detrimental effects on the environment, wildlife, and humans [8]. Hignite and Azarnoff were the pioneering authors who initially documented the existence of pharmaceutical compounds in both wastewater and natural water during the late 1970s [9]. Since then, ourthe comprehension of pharmaceuticals’ origins, fate, and ecotoxicity has advanced [10,11,12][10][11][12]. Pharmaceuticals are chemicals for diagnosing, preventing, and treating humans and animals [13]. They are vital to modern human and veterinary medicine, and their use is rising worldwide because of population increase, aging demographics, economic expansion, and the rising demand for animal protein in intensified food production [8,14][8][14]. Pharmaceuticals are one of the few chemical groups explicitly designed to act on living organisms. Pharmaceutical active chemicals (PhACs) are the biologically active components of pharmaceutical medications. These PhACs may be natural or synthetic chemical compounds typically found in therapeutic and veterinary medicines.
Over the past twenty years, the negative effects of pharmaceutical products on the environment, wildlife, and humans have been recognized as a serious problem that must be addressed globally [8,15,16,17,18,19][8][15][16][17][18][19]. Slowly degradable or non-degradable PhACs pose a unique risk when they enter, remain, or disperse in the environment and are thus considered environmentally persistent pharmaceutical pollutants (EPPPs). The extensive consumption of numerous pharmaceutical products results in their subsequent release into the environment, making them serious emerging contaminants. [5,12,20][5][12][20]. Multiple mechanisms and pathways aid PhACs and their metabolites enter aquatic environments such as seas, rivers, and aquaculture facilities [21,22,23,24][21][22][23][24]. These pathways include the excessive use of pharmaceutical products like antibiotics, β-blockers, psychoactive substances, endocrine disruptors, analgesics, anticancer drugs, and non-steroidal anti-inflammatory drugs (NSAIDs), as well as processes such as oxidation, photolysis, wastewater treatment plants, pharmaceutical manufacturing, and improper medication disposal [6,19,25,26,27][6][19][25][26][27]. Additively, microplastics can also carry pharmaceutical elements and metabolites, increasing environmental exposure [28]. Due to their massive global consumption and the inability of organisms to completely metabolize drugs [29[29][30][31],30,31], pharmaceutical residues in aquatic environments and their long-term toxic effects on living organisms are becoming more of a concern [21,26,30,32,33][21][26][30][32][33].
According to the existing literature, antibiotics are the most frequently identified pharmaceuticals in aquatic environments, followed by non-steroidal anti-inflammatory drugs (NSAIDs) and psychotropic substances [34]. Antibiotics are chemical compounds that can eradicate or impede the proliferation of pathogens. Consequently, they have been extensively employed in the management, regulation, and prevention of infectious diseases in humans, animals, and plants [35,36][35][36]. Multiple antibiotics have been documented to exhibit high levels of toxicity towards various aquatic organisms, as indicated by toxicity unit values above 100 for acute toxicity and 1000 for chronic toxicity. Erythromycin exhibited the highest level of toxicity among the antibiotics, as indicated by its elevated acute and chronic toxicity unit values [37,38][37][38].
Analgesics and NSAIDs are PhACs that are extensively utilized on a global scale [39]. These substances are commonly prescribed for analgesic purposes in human medical treatment. However, they are also frequently available for purchase without a prescription, commonly referred to as “over-the-counter” medications. Certain NSAIDs may not elicit immediate physiological responses but instead exert long-term effects on specific organisms. As an example, Cleuvers [40] reported that naproxen exhibited an EC50 (half maximal effective concentration) value of 174 mg/L and a NOEC (no-observed-effect concentration) value of 0.15 mg/L for Daphnia magna. Based on studies conducted by Martins et al. [41] and Załeska-Radziwiłl et al. [42], ciprofloxacin exhibited an EC50 value of 65.3 mg/L for Daphnia magna, while the NOEC value was 0.156 mg/L.
Psychiatric medications are pharmacological agents that possess psychoactive properties, influencing the internal neurochemical processes of the brain and the central nervous system. Therefore, these pharmaceuticals manage mental and neurological disorders [43,44][43][44]. In aquatic environments, the most frequently identified psychiatric pharmaceuticals include antidepressants, anxiolytics, and antiepileptic drugs (AEDs). According to Duarte et al. [45], the administration of fluoxetine, a psychiatric medication, resulted in significant DNA damage in meagre (Argyrosomus regius) when exposed to a concentration of 3 μg/L, as compared to the control group. Additionally, Aguirre-Martínez et al. [46] emphasized the significant DNA damage caused by carbamazepine, a psychiatric medication, to Corbicula fluminea. Notably, even at the lowest dose examined (0.1 μg/L) and after an exposure period of 21 days, carbamazepine had a considerable impact on DNA integrity.
Pharmaceuticals exhibit significant diversity in their physicochemical qualities, resulting in a wide range of biological variances. The water solubility, hydrophobicity, volatility, and other similar properties of substances can significantly influence their actions and ultimate destiny within aquatic ecosystems. The fate of pharmaceuticals is influenced by various factors, including dissociation constants (pKa), solid–water distribution coefficients (Kd), organic carbon-based sorption coefficients (log Koc), and octanol-water partition coefficients (Kow). These factors play a role in determining the extent of sorption, partitioning, hydrolysis, photodegradation, and biodegradation processes [47,48,49][47][48][49]. Furthermore, it should be noted that numerous pharmaceuticals possess acidic and/or basic functional groups, hence allowing for the existence of anionic, cationic, neutral, or zwitterionic forms under varying pH values [50]. The variability of these factors is contingent upon the pKa and Kow values of the molecule, as stated by Patel et al. [6]. The significance of chirality in relation to the environmental destiny of pharmaceuticals is noteworthy, because approximately 50% of pharmaceutical products are marketed and distributed as individual enantiomers [51]. Enantioselective reactions involve the subjection of a certain enantiomer to distinct biotransformations compared to its enantiomeric counterpart [52].
To evaluate the environmental hazards associated with pharmaceuticals, it is imperative to consider many factors, such as the quantities in which they are used, their physicochemical characteristics, and their potential for ecotoxicity. The necessity for conducting risk assessment analysis arises from several factors, including the high solubility of the substance in water, its ability to persist in the environment, its tendency to accumulate in organisms, and its potential to induce toxicity and carcinogenicity. Indeed, this endeavor has a significant level of difficulty. Low concentrations of pharmaceutical environmental residues can potentially cause acute and chronic impacts on microorganisms, flora, and fauna. The observed effects encompass a spectrum of metabolic alterations and disruptions in hormonal equilibrium. Organisms other than the specified target species may experience adverse effects. Although present in tiny amounts, below the established threshold, certain pharmaceutical substances have the potential to inflict serious adverse effects due to the intricate interactions exhibited by diverse pharmaceutical mixes within the environment [6].
For the quantification of PhACs in water or soil sediments, various analytical biochemical methods have been utilized, including liquid chromatography-mass spectrometry (LC-MS), gas chromatography-MS (GC-MS), solid-phase extraction (SPE), hydrophilic interaction liquid chromatography (HILIC), and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) [53,54][53][54]. Nevertheless, in recent decades, technological advances in molecular biotechnology have improved the measurement and monitoring of pharmaceutical compounds’ ecotoxicological effects on water quality by applying and validating new biological indicators, such as bioassays and biomarkers [8,55,56,57,58,59,60,61,62][8][55][56][57][58][59][60][61][62].
The impact of human activities on different ecosystems is widely recognized, resulting in significant changes that include species extinction and biodiversity alterations. Cardinale et al. [63] highlighted that these changes can negatively affect ecosystem functioning. Hence, there is a demand for non-invasive assessments of biodiversity. According to Shim et al. [64], all living organisms release genetic material into the environment via various means, such as feces, urine, gametes, and epidermal cells, leaving detectable remnants of their DNA. In this context, biotechnological techniques based on next-generation sequencing (NGS), such as environmental DNA (eDNA) metabarcoding, can serve as a powerful bioindicator for detecting and evaluating the impacts of various pollutants, such as pharmaceutical compounds, on the diversity and composition of bacterial communities and other microorganisms such as microalgae (phytoplankton), protista, and metazoa [65,66,67,68,69][65][66][67][68][69]. Such techniques may also prove helpful for estimating the composition of animal and plant communities, including the genetic diversity of these species and their response to disease outbreaks resulting from changes in pathogen fitness and genotype–environment interactions due to the presence of specific PhACs [70]. The technique of eDNA metabarcoding entails an in-depth, thorough analysis of DNA sequences derived from environmental samples within a particular ecosystem [62,71,72,73,74][62][71][72][73][74]. The novel concept of eDNA metabarcoding, which offers to bypass many of the problems of thorough conventional research, is gaining traction as an effective and powerful approach to measuring biodiversity, albeit with pros and cons.

2. Pharmaceuticals and Pollution: Routes and Pathways

Many PhACs and byproducts exist in rivers, lakes, and groundwater [26]. Due to their widespread use, persistence, and bioaccumulation potential, several classes of PhACs have been identified as hazards to human and environmental health. They primarily infiltrate waterways through wastewater treatment plants, improper drug disposal, and human and animal waste (Figure 1).
Figure 1. Main pathways of pharmaceutical aquatic pollution (WWTPs: wastewater treatment plants).
PhACs can alter aquatic systems’ nutrient cycling, energy transmission, and microbial community composition, resulting in altered reproduction and development, as well as changing the behavior and survivability of almost all aquatic vertebrates and invertebrates [50,76][50][75]. Moreover, low antibiotic concentrations are associated with the survival and spread of antibiotic-resistant bacteria (ARBs) and antibiotic resistance genes (ARGs), which endanger human and animal health. Indeed, chronic exposure to trace amounts of PhACs in potable water or the consumption of contaminated aquatic organisms may result in medication resistance. To reduce PhACs’ contamination of water bodies and soil, upgrading treatment facilities or implementing new treatment methods is imperative. Depending on persistence, bioaccumulation, and exposure, pharmaceutical pollution varies by region and water body. Nevertheless, it is important to note that while conventional pollution typically has a more detrimental impact on hosts or pathogens when present in higher quantities, emerging pollutants such as pharmaceuticals can often exert their effects even at lower doses, usually after long-term exposure [6,77,78][6][76][77]. This phenomenon can be attributed to the specific manner in which these chemicals target conserved pathways [79][78]. The sensitization of the public, proper use and disposal, waste management, and purification have been proposed as essential measures to reduce pharmaceutical pollution and its potential adverse health and environmental effects [80][79]. Table 1 summarizes the main sources and the corresponding effects of these PhACs.
Table 1. Overview of the primary sources and associated environmental effects and health risks of PhACs.
Pharmaceuticals Sources Effects References
Antibiotics Contamination of water bodies from human and veterinary medicine wastes.
  • Induce an increase in ARBs and (ARGs);
  • Disrupt the equilibrium of natural microbial communities in water bodies;
  • Affect the cycling of nutrients and the overall functioning of the ecosystems;
  • Cause potential long-term effects on human health.
 [81,82,83,84,85,86,87,88,89,90,91][80][81][82][83][84][85][86][87][88][89][90]
Hormones and endocrine-disrupting chemicals (EDCs) Enter the aquatic environment through agricultural and livestock manure, excretion (e.g., urine and feces), improper disposal.
  • Contribute to hormone pollution and ultimately disrupt the endocrine systems of aquatic organisms;
  • Induce developmental abnormalities in fish;
  • Alter sex ratios and reproductive success in fish populations;
  • Affect the growth and development of aquatic organisms;
  • Affect human endocrine systems by chronic exposure to low levels of hormone contaminants in potable water or consuming contaminated aquatic organisms.
 [92,93,94,95,][9496,][9597,][9698,][9799,100][91][92][93][98][99]
Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) Main pathways to the aquatic environment: human excretion, the inappropriate disposal of unused medications, wastewater discharges from pharmaceutical and healthcare facilities.
  • Induce long-lasting ecotoxic effects on the biotic components of ecosystems;
  • Induce detrimental effects on plants, including growth inhibition, cellular and root damage, and metabolic disorders;
  • Influence the behavior, reproduction, growth, and development of fish, amphibians, and invertebrates;
  • Cause bioaccumulation in aquatic predators through the food chain;
  • Affect the microbial communities of aquatic ecosystems and disrupt essential ecological processes.
 [27,101,,105][27102,][100103,][101][102]104[103][104]
Psychotropic and antiepileptic drugs Enter water bodies through human excretion, and wastewater systems via sewage or septic tanks
  • Inhibit the growth of aquatic organisms;
  • Alter fish, invertebrates, and other aquatic organisms’ behavior, reproduction, and physiological functions;
  • Disrupt natural ecological processes and aquatic ecosystem populations.
 [43,44,106,107,108][43][44][105][106][107]
β-blockers Infiltrate the aquatic environment through human excretion, and wastewater systems via sewage or septic tanks
  • Alter fish pulse rate and other cardiovascular-related physiological processes;
  • Induce testosterone disruption, decrease fertility, reproduction rates, and aberrant behavior in aquatic organisms;
  • Affect microbial communities within wastewater treatment facilities.
 [109,110,111,112][108][109][110][111]
Chemotherapy and anticancer drugs Introduction to the aquatic environment via human excretion and the incorrect disposal of unused medicines
  • Affect organisms’ growth, development, and reproduction by interfering with normal cell division and DNA replication;
  • Induce toxic effects at environmental concentrations on fish, invertebrates, and other aquatic organisms;
  • Disrupt microbial communities in the environment, including soil and water microbial communities, through alterations in the growth and activity of beneficial microbes, leading to microbial population imbalances and disturbances in ecological processes.
 [113,114,115][112][113][114]

2.1. Antibiotics

Antibiotics are frequently employed in human as well as animal medicine for the purpose of treating bacterial infections. Penicillins, cephalosporins, lincosamides, macrolides, tetracyclines, sulfonamides, and quinolones are among the most frequently utilized classes of antibiotics in human medicine [89][88]. After ingestion, humans and animals frequently excrete antibiotics. Antibiotics and their constituents can also be released from untreated or inadequately treated effluents if conventional wastewater treatment methods are ineffective at removing them [35,36][35][36]. The excessive utilization of agricultural practices, such as farming and raising livestock, may be another source that contributes to the release of antibiotics into the surrounding environment. Due to their vast utilization, the discharge of antibiotic-containing effluent into rivers, lakes, or other water bodies contributes significantly to pharmaceutical pollution [81,84,87,88,91,116][80][83][86][87][90][115]. Despite utilizing advanced treatment methods like activated carbon adsorption, ozone treatment, or other advanced methods, completely eradicating antibiotic residues from enriched wastes may not be achievable. Furthermore, the persistence of antibiotics in the environment can be attributed to their resistance to degradation [86][85]. Hence, antibiotics in the environment can potentially contribute to developing and spreading antibiotic resistance in microorganisms, posing significant challenges in treating infections. It can also exert selective pressure by disturbing the equilibrium of microbial communities in water bodies, thereby affecting nutrient cycling and the overall ecosystem functioning. This disturbance contributes to the emergence and dissemination of antibiotic-resistant bacteria (ARBs) and antibiotic resistance genes (ARGs) [82,83][81][82].

2.2. Hormones and Endocrine-Disrupting Chemicals

Endocrine-disrupting chemicals (EDCs) are naturally occurring or artificially produced compounds that interfere with the normal functioning of hormones in the body. Hormones such as estrogen are integral endocrine system components [117][116]. According to the United States Environmental Protection Agency (EPA), an EDC is an exogenous substance that possesses the capacity to interfere with the synthesis, secretion, transport, metabolism, receptor binding, or clearance of endogenous hormones, thereby inducing modifications in the endocrine and homeostatic systems [118,119][117][118]. EDCs are commonly found in a variety of everyday products, such as human and animal medications (e.g., diethylstilbestrol), cosmetics (e.g., triclosan), food and beverage packaging (e.g., perfluorochemicals, bisphenol A, phthalates), toys (e.g., lead and cadmium), industrial solvents or oils and their by-products (e.g., dioxins and polychlorinated biphenyls), and pesticides (e.g., dichlorodiphenyltrichloroethane and chlorpyrifos) [120,121,122][119][120][121]. EDCs can be classified into four distinct groups based on their source: industrial (e.g., dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (including pesticides, insecticides, herbicides, phytoestrogens, and fungicides), residential (such as phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (including birth control pills, hormone replacement therapy, and parabens) [118,123,124][117][122][123]. Pharmaceutical EDCs can enter the environment through excretion and improper disposal [92,96,98][91][95][97]. Since hormones regulate human and animal physiological processes, their release into the environment through agricultural and livestock manure runoff can contribute to environmental pollution and ultimately disrupt the endocrine systems of aquatic organisms, resulting in reproductive and developmental abnormalities, altered sex ratios, and stunted growth and development [93,94,95,97,99,100][92][93][94][96][98][99]. Estrogenic hormones, such as estradiol and ethinyl estradiol (i.e., a synthetic estrogen present in contraceptive medications), are of special concern. The presence of these hormones has been linked to the occurrence of feminization effects in fish populations. Exposure to these hormones can induce the development of intersex traits, characterized by both male and female characteristics within a single individual, as well as the disturbance of normal reproductive processes. Fish feminization can have significant implications for population dynamics and reproductive success. It can sometimes lead to population declines or the extinction of endangered species [125,126][124][125]. Although the direct impact of hormone-contaminated water on human health is not yet fully understood, scientists continue to investigate the potential risks since it is believed that chronic exposure to low levels of hormone contaminants in potable water or consuming contaminated aquatic organisms may subtly affect human endocrine systems [127][126].

2.3. Analgesics and Nonsteroidal Anti-Inflammatory Drugs

Analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly employed to manage pain and inflammation. The detection of analgesics and NSAIDs in both ground and surface water, such as lakes and rivers, has become prevalent due to their extensive utilization. Minute amounts of NSAIDs have been identified in various environmental matrices such as soil, wastewater, surface water, groundwater, sediments, snow, and drinking water [39,104][39][103]. Despite negligible detectable environmental concentrations, NSAIDs have long-lasting ecotoxic impacts on the biotic components of ecosystems [103,104][102][103]. According to Feng et al. [128][127], daily NSAID consumption exceeds 30 million doses and is rising swiftly. Due to their stability and resistance to degradation, these compounds can persist in the environment and accumulate over time. NSAIDs can enter the environment through various routes, but human excretion is the most common. The inappropriate disposal of unused medications further contributes to NSAID pollution [129][128]. Additionally, pharmaceutical manufacturing and healthcare facility effluent discharges can release NSAIDs into the environment. NSAIDs can influence organisms’ behavior, reproduction, growth, and development. For instance, NSAIDs such as ibuprofen and diclofenac have been associated with impaired reproduction and aberrant development in fish. In addition, repeated exposure to NSAIDs may cause bioaccumulation in aquatic organisms. Bioaccumulation can occur through the food chain, leading to elevated levels of NSAIDs in predators that consume contaminated prey. NSAIDs can influence the microbial communities of aquatic ecosystems by inhibiting the development and activity of beneficial bacteria, resulting in population imbalances among microorganisms and disruption of essential ecological processes [101,102][100][101].

2.4. Psychotropic and Antiepileptic Drugs

Psychotropic medications and AEDs are commonly employed in managing mental health disorders, such as anxiety and depression, addiction, seizures and convulsions, and chronic pain management. Researchers have discovered traces of psychotropics and AEDs in aquatic environments, implying their widespread presence. Psychotropic and AED drugs infiltrate the environment primarily through human excretion following their use as medications. The active compounds of psychotropic medications are metabolized within the body, and the residues are excreted through urine and feces. Also, these drugs can infiltrate wastewater systems via sewage or septic tanks [43,44,108][43][44][107]. Studies have demonstrated that exposure to psychotropic medications can induce alterations in the behavior, reproductive patterns, and physiological functions of fish, invertebrates, and other aquatic organisms [106[105][106],107], contributing to further disrupting the natural ecological processes and aquatic ecosystem populations.

2.5. β-Blockers

β-blockers are a class of pharmaceutical drugs (competitive antagonists) that inhibit the activity of adrenergic β-receptors in the sympathetic nervous system. The broad range of pathologies for which β-blockers are prescribed has resulted in an annual consumption increase of more than treble [130,131][129][130]. Although β-blockers have significant therapeutic value, they can potentially contribute to pharmaceutical pollution and have environmental effects. The increased consumption of β-blockers has led to increased tracing in the environment, and their presence has been detected in several bodies of water [132,133][131][132]. The administration of β-blockers has the potential to exert adverse effects on fish, as evidenced by their ability to induce alterations in pulse rate and other cardiovascular-related physiological processes. They have been found to have various impacts on aquatic organisms, such as causing disruption in testosterone levels, reducing fertility and reproduction rates, and inducing abnormal behavior [109,110,111][108][109][110]. β-blockers can alter the activities and functions of microorganisms involved in decomposing organic matter during treatment within wastewater treatment facilities [112][111].

2.6. Chemotherapy and Anticancer Drugs

Chemotherapy and anticancer medications may pose risks as pharmaceutical pollutants when discharged into the environment [115][114]. Human excretion is the primary source after administering these medications to cancer patients. However, the incorrect disposal of unused medicines can contribute to chemotherapy drug pollution. Typically, conventional wastewater purification processes are ineffective at removing chemotherapy drugs. Thus, these drugs can enter the environment through treated effluents [114,134][113][133]. Certain chemotherapy drugs are designed to be exceedingly robust and resistant to degradation to exert their therapeutic effects on the human body. This stability will also allow them to endure for extended periods in the environment and, consequently, may accumulate over time, resulting in long-term exposure in particular regions [114,135][113][134]. Chemotherapeutic medications may adversely affect aquatic organisms and other non-target species [113][112]. They can affect the growth, development, and reproduction of organisms exposed to them by interfering with normal cell division and DNA replication. Several investigations have demonstrated toxic effects at environmental concentrations on fish, invertebrates, and other aquatic organisms [114][113]. Additionally, chemotherapy drugs can disrupt the growth and activity of soil and water microbial communities in the environment, leading to population imbalances and disturbances in ecological processes.

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