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Pharmaceuticals and healthcare: The new pollutants in our environment

Introduction

Medicines are referred to by the acronym PPCPs (Pharmaceuticals and Personal Care Products). This term encompasses all products used by individuals for health reasons, cosmetic needs, or by agro-industry to improve the growth or health of livestock. PPCPs include a wide range of chemical substances, such as prescription and over-the-counter drugs.

The environmental problem posed by these drugs arises from the fact that they are designed to have effects on living organisms and that they can be released into the environment, even in small quantities. Indeed, these molecules, which must be absorbable, water-soluble or fat-soluble, and relatively persistent in the body to produce an effect [1], can be eliminated via urine at more than 80% without transformation [2]. This raises several questions concerning their potential impact on fauna and flora. The first detection of the presence of drugs in water dates back to 1976 [3], as reported by the National Academy of Pharmacy in 2008. Since then, numerous studies have confirmed the ubiquitous presence of these substances in surface and groundwater [4-9], as well as in fish tissues [10,11]. By the early 2000s, more than 80 pharmaceutical substances had already been detected in wastewater treatment plant (WWTP) effluents and surface water [12].

Definition

Medicines are products used to prevent, diagnose and treat diseases, constituting one of the most commonly used tools in medicine, present during almost every consultation. They form a complex class of widely used compounds, with hundreds of new molecules synthesized each year to replace obsolete compounds. A drug generally consists of an active part, the active ingredient, which is responsible for its effects on the human body, and one or more inactive parts called excipients.

The notion of a drug is strictly defined by the Public Health Code, which stipulates that a drug is any substance or composition presented as having curative or preventive properties with regard to human or animal diseases. This definition includes dietary products containing non-food chemical or biological substances, but giving the product therapeutic properties or specific characteristics sought in dietary therapy. However, products used for disinfecting premises and for dental prostheses are not considered drugs.

When a product appears to meet both the definition of a medicinal product and that of other categories of products regulated by Community or national law, it is, in case of doubt, considered to be a medicinal product.

The raw materials potentially at the origin of a medicinal product are called drugs (it is important to note that the English term "drug" translates as "medicine" and not as "drug"). However, most of the current active ingredients are prepared by complete chemical synthesis or by semi-synthesis from natural substances.

To exert their curative or preventive actions, medicinal products enter the body, sometimes acting remotely and in a diffuse manner. Their path can be schematized in several successive "phases" which can also intertwine. At each moment, the medicinal product is in one or more diffusion "compartments". The passage from one compartment to another is done through a "barrier", which has an anatomical and functional existence. The crossing of these barriers, as well as its importance, depends on the physicochemical properties of the drug and the nature of the barrier.

History

In the Middle Ages and until the beginning of the 19th century, the healing of diseases was strongly influenced by "magico-religious" practices, such as bloodletting (phlebotomy) used to "extirpate evil". However, as early as the 16th century, Paracelsus, a Swiss alchemist and physician born in 1494, already anticipated the need to develop a specific medicine for each disease. This century marks a new era, propelled by advances in chemistry and physiology, allowing researchers to isolate active ingredients from known substances. For example, in 1803, morphine was isolated from plants by Friedrich Adam Satürner. This ability to isolate active ingredients paved the way for the synthesis of drug molecules: after extracting acetylsalicylic acid from willow bark, Charles Frédéric Gerhardt, then Félix Hoffmann, succeeded in synthesizing this molecule in 1853, thus marking the birth of aspirin, marketed for the first time in 1893. At the beginning of the 20th century, only a dozen synthetic molecules and a hundred natural products were considered drugs. However, the 20th century was marked by the rise of synthetic drugs produced by pharmaceutical laboratories. In the 21st century, we have hundreds of synthetic molecules, whose physicochemical properties allow them to cross biological membranes.

Classification of drugs

Drugs are classified into different families, themselves subdivided into groups and subgroups to facilitate their therapeutic application. The classification criteria are as follows (Vicens, 2002): (i) mode of action, (ii) origin, (iii) chemical nature, (iv) modality of action, and (v) spectrum of action.

Drug classification is an essential approach that allows therapeutic substances to be grouped according to their characteristics, mode of action, origin, chemical nature, and therapeutic applications. This classification facilitates their prescription, management, and clinical use. Here is a detailed overview of the main criteria used to classify drugs.

Classification by mode of action

The mode of action of drugs refers to the way in which they exert their therapeutic effect in the body. According to this criterion, drugs are classified into different categories:

• Drugs acting on the central nervous system (CNS): These include analgesics, anesthetics, sedatives, hypnotics, and antipsychotics. These drugs influence the functioning of the brain and spinal cord.
• Cardiovascular drugs: These are used to treat diseases of the heart and blood vessels, such as antihypertensives, diuretics, and antianginals.
• Drugs acting on the immune system: This category includes immunosuppressants, used in particular in the prevention of transplant rejection, and immunostimulants, such as vaccines and immunoglobulins.
• Antimicrobials: These are used to treat infections caused by bacteria, viruses, fungi, or parasites. This category includes antibiotics, antivirals, antifungals, and antiparasitics.

Classification by origin

Medicines can also be classified according to their origin, whether natural or synthetic:

• Medicines of natural origin: These are extracted from plants (herbal medicine), animals (for example, insulin extracted from the pancreas of pigs or cattle), or minerals (lithium salts for the treatment of bipolar disorders).
• Synthetic medicines: These are entirely manufactured by chemical processes in the laboratory. The majority of modern medicines belong to this category.
• Biotechnological medicines: This class includes medicines produced by biotechnology, such as therapeutic proteins (recombinant insulin, monoclonal antibodies) and vaccines.

Classification by chemical nature

The chemical nature of a drug refers to the chemical structure of the active molecule. This classification is used mainly by chemists and pharmacists to understand the relationship between the chemical structure of a drug and its pharmacological activity:

• Alkaloids: Molecules of plant origin, often with powerful pharmacological properties (morphine, atropine).
• Beta-lactam antibiotics: Includes penicillins and cephalosporins, characterized by the presence of a beta-lactam nucleus.
• Steroids: Includes corticosteroids and hormonal contraceptives, characterized by their four-ring structure.
• Amines: Drugs such as amphetamines or antihistamines, containing an amine group in their structure.

Classification by action procedure

The mode of action describes how drugs interact with their biological target:

• Enzyme-inhibiting drugs: These block the activity of specific enzymes, for example, angiotensin-converting enzyme (ACE) inhibitors used to treat high blood pressure.
• Receptor drugs: These bind to cell receptors to activate or inhibit their function. Receptor agonists and antagonists are common examples.
• Antimitotic drugs: Used in chemotherapy, these drugs inhibit cell division by disrupting mitosis.

Classification by spectrum of action

The spectrum of action refers to the range of diseases or organisms that the medicine can treat:

• Broad-spectrum drugs: Able to treat a wide range of conditions. For example, some broad-spectrum antibiotics can treat different bacteria.
• Narrow-spectrum drugs: Specific to a disease or a narrow group of organisms. For example, some antivirals are effective only against a specific type of virus.

ATC (Anatomical Therapeutic Chemical) classification

The World Health Organization (WHO) has developed the ATC classification, which is one of the most widely used classifications worldwide. This hierarchical classification is based on the organ or system on which the drug acts, its therapeutic and pharmacological properties, and its chemical structure:

• First letter (level 1): Anatomical class, corresponding to the system on which the drug acts (example: C for the cardiovascular system).
• Second letter (level 2): Therapeutic class, describing the therapeutic purpose of the drug (example: C09 for drugs acting on the renin-angiotensin system).
• Third and fourth letters (levels 3 and 4): Pharmacological and chemical class, specifying the mechanism of action and the type of molecule (example: C09A for angiotensin-converting enzyme inhibitors).
• Fifth letter (level 5): Indicates the specific active substance (example: C09AA05 for enalapril).

Some examples of each class [13] are presented in the table below:

Table 1: Examples of classes of some drugs

Global consumption of medicines

Medicines for human use

About 3,000 pharmaceutical substances are used in the European Union. Among them, antibiotics, used in human and veterinary medicine, are the most widely used, with consumption reaching 12,500 tons per year over the last decade [14]. Industrialized countries are the largest consumers of pharmaceutical products: Europe, North America and Japan account for about 80% of the global market, as illustrated by the following graph. The Americans dominate with a 38% market share, followed by the Europeans, who hold 17% of the global medicines market. Japan (12%) and emerging countries, such as Brazil and China (8%), share the rest of the market.

The drugs generating the most turnover are mainly those intended to treat diseases of the cardiovascular system and the central nervous system, followed by those used for the digestive system, respiratory diseases, and finally anti-infectives.

Veterinary medicines

The veterinary medicines market is relatively small, representing only 4% of the human medicines market. A study reveals the quantities of antibiotics, antiparasitics and hormones used in Europe: 221 tonnes are intended for the treatment of metabolic and digestive tract disorders, 120 tonnes for diseases of the central nervous system, 60 tonnes for haematopoietic diseases, and 52 tonnes for musculoskeletal disorders [15].

Antibiotics represent 18% of the turnover of veterinary medicines, and their use has increased considerably with the rise of intensive livestock farming. In animal husbandry, antibiotics are also used as growth promoters. In addition, steroid hormones, such as estrogens and testosterone, are used systematically as growth hormones.

Table 2: Examples of veterinary medicines

Sources of pharmaceutical substances in the environment

Pharmaceutical products, after exerting their pharmacological action, are excreted into water via urine or feces, in the form of unchanged parent compounds and/or active metabolites. These substances enter aquatic systems by various means and to varying degrees [16-18]. They can move up the aquatic trophic chain, ending up in surface water, groundwater, and even tap water.

Contaminating drugs include both human and veterinary drugs.

Medicines for human use

In industrialized countries, domestic, hospital or industrial effluents are largely channeled to a collection network which constitutes, at its end, a major point source of discharges. Ideally, these effluents are directed to collective wastewater treatment plants. However, some of these effluents may directly reach surface water without prior treatment in certain situations, such as the absence of a connection to a wastewater treatment plant (WWTP), leaks in the collection networks, or the discharge of untreated effluents during episodes of heavy rainfall. The latter case occurs in combined collection networks, where rainwater and urban wastewater are mixed and evacuated by storm overflows to avoid overloading the treatment plants.

Veterinary medicines

The main source of introduction of veterinary medicines into the environment is their common use in domestic or farm animals, whether to stimulate their growth or to treat their diseases. These medicines, often identical to those used in humans, can be excreted by animals in unchanged or metabolized form. However, unlike human medicines, the routes of dissemination of veterinary medicines into the environment are generally more direct due to the absence of systems dedicated to the collection and treatment of effluents.

The case of aquaculture is particularly worrying: the medicines are directly dispersed in the water used for breeding, which allows their migration to groundwater or other resources potentially intended for the production of drinking water. For livestock, residues of drugs used for growth or disease treatment are often present in liquid and solid effluents (manure, excrement, slurry, etc.), which are either directly disposed of on pastures or spread on soils after collection in soilless livestock farms. These residues can then reach surface or groundwater through leaching or washing.

Concentrations reported in the environment

The concentrations of drugs reaching surface waters depend on several factors, some of which are theoretically predictable, such as the metabolism and degradability of the substances, and others unpredictable, such as inadequate elimination [19]. These products then end up in wastewater networks, where they are treated with variable efficiency in treatment plants. Another source of contamination of the natural environment, often neglected, comes from drugs thrown away with household waste, which can pollute soil and groundwater if buried in landfills [20]. The concentrations of these substances in the environment are the subject of periodic literature reviews that summarize a large number of results from specific measurements [1-9-21,23]. The following table illustrates the range of mean concentrations of some drugs, including ciprofloxacin (antibiotic) and ibuprofen (anti-inflammatory), reported in Europe in different compartments:

Table 3: Range of mean concentrations reported in Europe in different compartments for ibuprofen and ciprofloxacin.

Fate in ecosystems

Degradation

The decomposition of drugs depends on many factors, including their chemical structure, the pH of the environment, the formation of ligands, the presence of bacteria, as well as photodegradation.

Hydrolysis

Hydrolysis is a major degradation pathway for drugs, explaining why these molecules are rarely detected in the environment [24-25]. Degradation occurs upon contact with water or moisture.

Photodegradation

Photodegradation is the main degradation pathway for photosensitive molecules. This phenomenon depends on factors such as sunlight, water depth, and turbidity [26]. Verma's studies on the behavior of tetracycline in different types of water have shown that the half-life of tetracycline varies depending on the environment and exposure to light: in the presence of light, the half-lives are 32 days in distilled water, 2 days in river water, and 3 days in marsh water. In the absence of light, these half-lives increase to 83, 18, and 13 days, respectively. Photodegradation of a drug can lead to a decrease in its therapeutic efficacy and, in some cases, lead to the formation of products with adverse or toxic effects.

Biodegradation

Data on drug biodegradation are abundant in the treatment of wastewater [27]. In contrast, biodegradation in soils and natural waters is much less well documented. One study [28] examined the biodegradation of 18 antibiotics under anaerobic conditions, revealing that there was no biodegradation for 17 of the 18 molecules studied, including erythromycin, tetracycline, chlortetracycline, amoxicillin, trimethoprim, sulfamethoxazole, ofloxacin and vancomycin. Another study showed that tylosin is rapidly degraded in aerobic conditions in the excreta of cattle, chickens and pigs, with respective half-lives of 6.2 to 7.6 days [29].

Persistence in sediments

Knowledge on the fate of drugs in sediments is very limited [30]. However, many antibiotics have been detected in sediments at sometimes high concentrations. For example, tylosin has been measured at concentrations up to 578 ng/kg, and even up to 2640 ng/kg in Italy [31]. Erythromycin has been found at concentrations of 400 to 600 ng/kg in the Po, while ibuprofen (220 ng/kg) and spiramycin (up to 2900 ng/kg) have been detected in the sediments of the Lambro River [31]. The half-life of oxytetracycline in fish farm sediments has been estimated to be about three months [31], while the half-lives of quinolones and tetracyclines in sediments range from a few weeks to several months [32].

Although this compartment of the river environment is far from inert, sediments contain microorganisms capable of metabolizing these substances, and high concentrations have been observed. This is particularly the case for tetracyclines [33], estrogens [34,35], or antiparasitics such as ivermectin [36]. Antibiotic residues present in sediments can alter the composition of the microflora, thus promoting the selection of antibiotic-resistant bacteria [37].

Mobilization in soils

In soils, the mobility of drugs is determined by a combination of several factors, such as their chemical structure, their solubility in water, as well as soil pH, cation exchange capacity, limestone content, organic matter content, and temperature. Quinolones and tetracyclines are considered highly adsorbable, which limits their mobility. Aga et al. (2003) [38] demonstrated that in amended soils, the detectable concentrations of these substances decreased from 225 μg/kg to 110 μg/kg after 7 days, and to 5 μg/kg after 28 days of application. In contrast, sulfonamides are considered highly mobile [39].

Behavior in wastewater treatment plants

Studies have shown that some antibiotics, such as fluoroquinolones, diminopyrimidines and sulfonamides, are poorly degraded in wastewater treatment plants (WWTPs). Tunc and Aksu (2005) [40] demonstrated that penicillin G is effectively removed by water treatment processes such as biosorption and activated carbon adsorption. Depending on the treatment process used, sulfamethoxazole removal rates range from 5% to 80% [41], while macrolides have depuration rates below 33%, and quinolones are strongly adsorbed on biological sludge [42]. Giger (2000) [27] reported degradation rates of ciprofloxacin ranging from 55% to 75% after aerobic treatment of municipal effluents. Numerous studies have highlighted the presence of antibiotic residues in surface water, groundwater, WWTP effluents, sediments, and living organisms.

After administration, the drug is metabolized and excreted, thus reaching wastewater. The residues, whether transformed or not, are discharged to the wastewater treatment plant. The effectiveness of the treatment to eliminate these residues depends on the physicochemical characteristics of the drug and the nature of the treatment process. However, a variable portion of the recalcitrant drug residues is discharged via the wastewater treatment plant effluents, where they eventually reach natural watercourses, thus interacting with aquatic organisms [43].

State of contamination of aquatic environments

Since the 1980s, many pharmaceutical molecules have been detected in the environment. Their presence has been established on a global scale, both in the effluents and sludge of urban wastewater treatment plants and in aquatic environments and soils. The first detection of drugs in water dates back to 1976 [44]. Since then, many studies have confirmed the ubiquity of these substances in rivers and groundwater [45]. By the early 2000s, more than 80 pharmaceutical substances had been measured, including in wastewater treatment plant (WWTP) effluents and surface water [46].

Animals can also be a source of environmental pollution through veterinary products, including antiparasitics and antibiotics. These products, administered to animals, can end up in the environment via their excrement (spreading of manure, contamination of meadow soils) or through the external use of medications [47]. Once in the environment, these products and their metabolites can contaminate soils, then reach surface waters through runoff, and groundwater through infiltration [48]. Soil contamination can also occur when sewage sludge is spread on agricultural fields, causing runoff to surface waters as well as drainage to groundwater [49]. In addition, veterinary pharmaceuticals can enter the aquatic system through the spreading of manure on fields or through their direct use in aquaculture, where they end up directly in surface waters and can be adsorbed in sediments [50].

Due to their multiple sources and physicochemical properties, pharmaceutical substances are widely distributed in aquatic systems, so much so that they can be described as ubiquitous. Numerous studies have highlighted their presence in surface and groundwater [51], as well as in drinking water [52]. The presence of nonsteroidal anti-inflammatory drugs, synthetic estrogens, stimulants and antibiotics is particularly well documented.

The active substances contained in these drugs have very varied chemical structures. Once these drugs are metabolized in the body, they are mainly excreted in the feces and urine, before being released into wastewater systems (for human drugs) or into soils (for veterinary drugs). Thus, these drug residues inevitably end up in the environment, and potentially in our drinking water sources [53].

Surface waters

Indeed, drug residues that are not retained or eliminated in wastewater treatment plants are discharged into surface waters via their effluents. Although their concentrations can be reduced by dilution or photodegradation, the latter varies considerably depending on the molecules, as shown by various studies [54]. Many classes of antibiotics are frequently detected in surface waters. Among these, macrolides such as lincomycin [55,56], clarithromycin, erythromycin, and roxithromycin [57], as well as tylosin [58,59], are often present. Fluoroquinolones such as ciprofloxacin and norfloxacin [60], tetracyclines such as chlortetracycline [60], and sulfonamides, including sulfadiazine [61] and sulfamethoxazole [57,56], have also been detected. Traces of antibiotics were found in 50% of the waters of the 139 sites studied in the United States.

Groundwater

Heberer et al. (2002) [46] reported concentration differences for many drugs in Berlin groundwater intended to supply a drinking water treatment plant. The concentrations observed were as follows: diclofenac (nes - 380 ng/L), gemfibrozil (nes - 340 ng/L), ibuprofen (nes - 200 ng/L), ketoprofen (nes - 30 ng/L), primidone (nes - 690 ng/L), phenazone (nes - 1,250 ng/L), propylphenazone (nes a - 1,465 ng/L), N-methylphenacetin (phenacetin metabolite, nes - 470 ng/L), salicylic acid (nes - 1225 ng/L), fenofibrate (nes - 45 ng/L), gentisic acid (nes - 540 ng/L), and clofibric acid (nes - 7300 ng/L).

Sacher et al. (2001) found pharmaceutical molecules in 39 of 105 groundwater samples in Germany, with concentrations in the order of 10 ng/L, including β-blockers, analgesics, carbamazepine, diclofenac, antibiotics, and iodinated contrast agents such as iopamidol. In addition, Holm et al. (1995) [62] also reported the presence of sulfonamides, propylphenazone, and di-allyl barbituric acid in soils in Denmark, resulting from discharges from the pharmaceutical industry.

Water intended for human consumption

Tap water is generally considered to be free of any pollutants due to drinking water treatment. However, although in the majority of cases the analyses do not reveal the presence of pharmaceutical residues, several studies have detected drug molecules in drinking water [63]. For example, anticancer drugs such as methotrexate and bleomycin [64], as well as carbamazepine and gemfibrozil [65,66], have been found. Diazepam has also been detected at concentrations of 19.6 to 23.5 ng/L [67]. A review of drinking water contamination worldwide identified the following maximum concentrations (in ng/L) for various compounds: bezafibrate (27 - Germany), bleomycin (13 - United Kingdom), clofibric acid (270 - Germany), carbamazepine (258 - United States), diazepam (23.5 - Italy), diclofenac (6 - Germany), gemfibrozil (70 - Canada), phenazone (400 - Germany), propylphenazone (120 - Germany), and tylosin (1.7 - Italy) [68]. These results highlight the limitations of treatment methods, as substances such as gemfibrozil and carbamazepine are not completely retained, even in plants using ozonation and activated carbon, these compounds having been found in the waters of four of the ten cities using these combined treatments [69]. In Berlin, tap water samples showed concentrations of up to 170 ng/L for clofibric acid, 80 ng/L for propylphenazone, and traces of diclofenac [70]. In France, a recent study revealed the presence of several substances in drinking water, including amitriptyline (nd - 1.4 ng/L), carbamazepine (nd - 43.2 ng/L), diclofenac (nd - 2.5 ng/L), ibuprofen (nd - 0.6 ng/L), ketoprofen (nd - 3.0 ng/L), naproxen (nd - 0.2 ng/L), paracetamol (nd - 210.1 ng/L), and caffeine (nd - 22.9 ng/L), in correlation with the concentrations observed in the effluents of wastewater treatment plants [71]. The same team had already published results showing the presence of paracetamol (up to 211 ng/L), caffeine and diclofenac in several drinking water reservoirs in Hérault [72]. Diazepam was detected in almost half of the water samples from sewage treatment plants, but at concentrations not exceeding 4 ng/L. The degradation of diazepam by direct ozonation is slower than its reaction with O• radicals, but the efficiency of this treatment remains limited to about 24% [73].

V-Transfer and accumulation in living organisms

Many studies have revealed the presence of contaminants, whether metallic or lipophilic organic, in various aquatic organisms such as algae, higher plants, invertebrates, as well as vertebrate species such as fish and mammals. The concentrations of these pollutants can be higher in these organisms than in their immediate environment (water and sediments) or their food [74-77]. These phenomena are known as bioaccumulation, bioconcentration or biomagnification.

There are several reasons to study the bioaccumulation of substances in organisms. First, these so-called "bioaccumulator" organisms can be used as indicators to assess the level of environmental contamination. Second, the consumption of contaminated organisms, such as fish or molluscs, can potentially have impacts on the health of consumers. Finally, the response of an organism to a toxic substance depends on the amount of this substance that reaches the target organ or tissue, depending on its bioavailability.

Drug residues

* Residues are defined as active substances or their metabolites remaining in meat or other foodstuffs from animals that have received medicinal treatment [78]. Regulation 470/2009 of the European Parliament and of the Council specifies that residues include any pharmacologically active substance, whether active substances, excipients or metabolites present in the fluids and tissues of animals after the administration of medicinal products, which could end up in foodstuffs produced by these animals. The concept of residues in foodstuffs has evolved during the second half of the 20th century, leading to the establishment of thresholds such as the no-effect level, the acceptable daily intake and maximum residue limits (MRLs) in foods [79]. This evolution reflects advances in toxicological risk assessment, as well as in analytical sciences and pharmacokinetics. MRLs in various commodities (muscle, liver, kidney, fat, milk, egg) are determined to minimise the risk of consumer exposure, taking into account dietary habits. The establishment of MRLs may also include considerations related to food technology or good practices in animal husbandry and the use of veterinary medicinal products. 

* Human medicinal product residues mainly come from hospital effluents and wastewater drainage networks containing patient excreta. These effluents, loaded with residues, are treated in wastewater treatment plants before reaching the aquatic environment. On the other hand, veterinary residues enter the environment directly without going through a treatment process. Monitoring effluents from veterinary use is complex, because livestock effluents can infiltrate groundwater through percolation of animal excreta (during grazing) and through the spreading of agricultural slurry. In industrial livestock effluents, concentrations of up to several milligrams of tetracyclines per gram of pig or sheep manure have been detected [80].

Studies in Asia have shown that nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetylsalicylic acid (aspirin), diclofenac, and ibuprofen, which inhibit both isoforms of cyclooxygenase (cox-1 and cox-2), enzymes involved in prostaglandin synthesis, are responsible for the disappearance of vultures feeding on diclofenac-treated livestock [81]. Paracetamol, an analgesic and antipyretic that appears to inhibit cyclooxygenase in the central nervous system without peripheral effects, is thought to cause increased sensitivity to this molecule in fish, which have a cox-2 homologue. Antibiotics, for their part, are regularly detected in the aquatic environment [82,83], where selection pressure favors the spread of antibiotic resistance within bacterial populations on a global scale. Beta-adrenergic receptors, found in the liver and muscles of trout, suggest that these fish may have a similar sensitivity to humans to these molecules. In addition, some neurotropic compounds have been identified in trout, where they play a role in controlling prolactin secretion, suggesting a similar sensitivity to neurotropic compounds in these fish.

* Food contamination by drug residues is a concern that cannot be ignored. Several factors can contribute to this contamination:

• Veterinary use for production: Some drugs, such as antibiotics or hormones, are administered to animals for production purposes. It is likely that residues of these substances are present in the flesh of animals intended for consumption, as well as in milk and its derivatives. Other drugs used in veterinary therapy may also be affected.
• Contaminated soil: Soils contaminated by livestock excrement, which may contain drug residues, are sometimes used for crop production, which can lead to crop contamination.
• Sewage sludge spreading: Soils can also be contaminated by drugs or their metabolites present in sewage sludge, which is often spread on agricultural fields.

Studies on the evaluation of antibiotic residues in raw milk in African countries have highlighted the presence of these residues. In Morocco, inhibitory substances were detected in raw milk, pasteurized milk, yogurt and curdled milk called "Raïbi" in the regions of Rabat and Kénitra [84]. According to this study, 42.87% of raw milk, 6.65% of pasteurized milk, and 3.33% of "Raïbi" could be contaminated by antibiotic residues. In Algeria, 89.09% of milk from livestock farms in the Wilayas of Blida, Algiers, Tipaza, and Médéa showed positive results for tetracycline residues, and 65.46% for beta-lactam residues [85]. About 29% of milk samples produced in western Algeria contained residues of antibacterial agents [86]. In the Algiers region, 9.87% of raw milk samples were contaminated with penicillin and/or tetracycline residues in 97.33% of cases, and with macrolides and/or aminoglycosides in 2.67% of samples tested positive [87].

In Mali, the prevalence of antibiotic residues in raw cow's milk has been estimated at between 6% and 16% of positive samples [88], compared to 24.7% in Côte d'Ivoire [89].

Acute toxicity of pharmaceutical substances

Pharmaceutical substances for human use do not generally appear to present acute toxicity. Indeed, the majority of these compounds have acute toxicity values greater than 1 mg/L. When these values are compared to the maximum concentrations measured in the environment, whether in wastewater treatment plant effluents or in natural waters, the toxicity values are significantly higher than the observed environmental concentrations. This suggests that, under current conditions, these substances do not pose an immediate risk of acute toxicity to aquatic organisms.

Regulatory Framework

The first European directive on pharmaceutical regulation was put in place in 1965. Directive 65/65/EEC defined for the first time what a medicinal product is and established the principle of marketing authorisation (MA). This directive aimed to harmonise the legislative, regulatory and administrative provisions relating to medicinal products within Europe, by establishing a system of prior authorisation for any marketing of a new medicinal product. The main objective was to avoid disasters such as that of thalidomide in the early 1960s, where thousands of babies were born with malformations after their mothers took this sedative during pregnancy. This tragedy highlighted the crucial importance of having authorisation before any medicinal product can be marketed.

Ten years later, in 1975, two new directives, 75/318/EEC and 75/319/EEC, were drafted. Directive 75/318/EEC dealt with the control of proprietary medicinal products and introduced analytical, toxico-pharmacological and clinical standards and protocols for the testing of these products in the countries of the European Union. In order to harmonise the decisions of the Member States concerning marketing authorisations, Directive 75/319/EEC set up the Committee for Proprietary Medicinal Products (CPMP), composed of representatives of the Member States and the European Commission, responsible for giving an opinion on the conformity of proprietary medicinal products. This directive also aimed to facilitate the free movement of proprietary medicinal products within the Union and to avoid controls already carried out in one Member State being repeated in another.

In 1981, specific directives for veterinary medicinal products were adopted. Directive 81/851/EEC concerned the harmonisation of the legislation of the different Member States, supplemented by Directive 81/852/EEC which detailed the testing procedures to ensure the quality, safety and efficacy of veterinary medicinal products. These directives aimed to harmonise analytical, toxico-pharmacological and clinical standards and protocols for the testing of veterinary medicinal products. The environmental impact of medicinal products is already taken into account in current European regulations or those in preparation for the marketing authorisations of medicinal products for human or veterinary use. However, these regulations do not cover all the possible ecological consequences, particularly in the long term, of the discharge of residues of these medicinal substances and their metabolites. To date, there is no governmental standard imposing limits on the concentration of medicinal products in natural waters.

Treatment methods for water polluted by drugs

The evolution of regulations concerning drug discharges has stimulated the development of new treatment processes. The choice of a purification method depends on the origin, the nature of the pollution, as well as its form. The processes commonly used in the treatment of water contaminated by drugs are as follows:

Adsorption

Adsorption, not to be confused with absorption, is a surface phenomenon by which gas or liquid molecules attach themselves to the solid surfaces of adsorbents according to various processes. The molecules thus attached are called "adsorbates". If the energetic or kinetic conditions allow the molecule to penetrate into the adsorbent phase, we then speak of absorption [90,91]. Some minerals, such as clays or zeolites, are excellent adsorbents because of their very large specific surfaces.

There are two types of adsorption, depending on the mechanisms involved:

• Physical adsorption (or physisorption): This type of adsorption is due to the electrostatic attraction of a solute by a polarized surface, thus maintaining electro-neutrality. The binding energies involved are relatively weak, such as Van der Waals forces. The species thus adsorbed retain the water molecules associated with them. Several layers of atoms or molecules can form on the surface in this way. Physical adsorption is generally reversible. The ability of a material to retain cations by physical adsorption is called cation exchange capacity.
• Chemical adsorption (or chemisorption): In this case, the molecule adheres to the surface by additive chemical bonds. This type of adsorption is irreversible and forms a specific monomolecular layer. This chemical bond is specific, meaning that it only forms between elements with a compatible electronic configuration [92]. Surface complexation occurs when a metal ion reacts with an anionic group functioning as an inorganic ligand, thus creating chemical bonds with the ions in solution.

Biological processes

Biological purification processes are commonly used for the treatment of pharmaceutical products [93,95]. However, these processes are not always suitable for industrial effluents, due to the high concentrations of pollutants, their toxicity, or their very low biodegradability. For pharmaceutical products that are not well suited to biological treatment, it is necessary to use more efficient reactive systems than those adopted in conventional purification processes. In addition, these biological processes generate significant quantities of biological sludge that require additional treatment.

Biodegradation is more effective for wastewater with a COD/BOD5 ratio of less than 2, but it is severely limited when this ratio exceeds 5 [96]. The COD/BOD5 ratio, also called the degree of biochemical degradation, is used to measure the biochemical degradability of pollutants in wastewater. The closer this ratio tends to zero, the higher the quantity of compounds that cannot be biochemically degraded [97].

Advanced oxidation processes

Advanced oxidation processes (AOPs) were developed with the aim of creating rapid, less expensive treatment techniques that are better suited to refractory and/or toxic organic compounds. AOPs are treatment methods that use highly reactive radical intermediates, particularly hydroxyl radicals (HO•), at room temperature. The development of these processes for the treatment of water contaminated by organic matter aims to exploit the non-selectivity and rapidity of HO• radical reactions. Although HO2• free radicals and their conjugate base O2•- are also used in degradation processes, their oxidizing power is much lower than that of hydroxyl radicals [98].

Hydroxyl radicals were chosen among the most powerful oxidants applicable to water remediation because they meet a set of essential criteria:

• Absence of secondary pollution: Hydroxyl radicals do not generate polluting by-products.
• Non-toxicity: These radicals are non-toxic, making them safe to use.
• Non-corrosiveness: They are not corrosive to equipment, extending the life of treatment facilities.
• Cost-effectiveness: AOPs must be economically viable to be widely adopted.
• Ease of handling: Hydroxyl radicals are relatively simple to handle under standard treatment conditions.

Therefore, only halogen- and metal-free, oxygen-based oxidants such as ·OH, O2, O3 and H2O2 are considered particularly attractive for water treatment.

Photochemical processes

The degradation of organic micropollutants can be achieved by various photochemical processes, which require either an artificial source of radiation [99] or irradiation by solar radiation [100]. However, most of these methods require a long treatment time and a large amount of energy, and it is rare to obtain a complete degradation of the pollutants. The degradation efficiency by photochemical advanced oxidation processes (AOPs) can be significantly improved by using photocatalysis, whether homogeneous or heterogeneous [101].

Homogeneous processes, such as H2O2 photolysis or the photo-Fenton process, take place in a homogeneous medium, where the reactants are uniformly dissolved in the solution. In contrast, heterogeneous processes involve the use of semiconductors such as TiO2 or ZnO for catalysis. These semiconductors facilitate the degradation of pollutants when exposed to light, by generating highly reactive free radicals that attack the molecules of micropollutants, thus leading to their decomposition.

Photolysis of H2O2/UV

The photolysis of H2O2 (UV/H2O2 system) is particularly interesting because it is relatively inexpensive, as shown by the numerous large-scale implementations of this process. Indeed, the additional cost associated with the use of H2O2 is lower than the cost generated by the electrical consumption required to achieve the same level of oxidation using only UV irradiation [102].

When H2O2 is exposed to UV wavelengths between 200 and 280 nm (with an absorption maximum at 260 nm), it decomposes, generating hydroxyl radicals ·OH. This process is characterized by a high quantum yield, with the formation of two radicals ·OH per absorbed photon [103-104].

The hydroxyl radicals thus produced are extremely reactive and can effectively degrade micropollutants present in water, making this process efficient and economically viable for large-scale water treatment:

The rapid production of OH radicals in the UV/H2O2 system allows the initiation of radical mechanisms, where the degradation of organic contaminants occurs mainly by oxidation via OH radicals. Thus, the rate of chemical oxidation of contaminants is directly related to the formation of these hydroxyl radicals. Therefore, it is crucial to operate under conditions that favor efficient photolysis of hydrogen peroxide. However, the efficiency of this process is limited by the very low absorption coefficient of H2O2 (L mol^-1 cm^-1 at the maximum wavelength, λ_max), which reduces its overall efficiency.

Regarding the rehabilitation of solid matrices, such as contaminated soils, treatments based on photolysis (UV or UV/H2O2) show very limited efficiency. This limitation is mainly due to the low penetration of UV radiation inside the solid matrix, which restricts possible oxidation reactions and, consequently, the degradation of contaminants.

Photo-Fenton (homogeneous photocatalysis)

The photo-Fenton process is based on the Fenton reaction, which combines the action of H2O2 (oxidizing agent) and Fe²⁺ (catalyst) with UV/visible irradiation for wastewater treatment. UV/visible irradiation plays a crucial role by significantly increasing the rate of HO• radical formation, which is achieved by two main mechanisms: on the one hand, the acceleration of the Fenton reaction, and on the other hand, the photolysis of Fe(III) and hydrogen peroxide. However, the contribution of H2O2 photolysis in the photo-Fenton process is considered negligible, since hydrogen peroxide absorbs very little UV/visible radiation. This process is therefore mainly effective due to the enhancement of the Fenton reaction and the photolysis of Fe(III), which together maximize the generation of hydroxyl radicals necessary for the oxidation of contaminants.

The efficiency of photo-Fenton treatment depends mainly on the concentrations of Fe³⁺ and H₂O₂ ions, as well as the light intensity. In general, as the concentration of Fe²⁺ and/or H₂O₂ increases, the amount of OH radicals produced increases, leading to a higher degradation rate. However, too high concentrations of these reagents can reduce the efficiency of the process by increasing the rate of parasitic reactions, which consume OH radicals without contributing to the degradation of contaminants.

The degradation rate remains relatively high as long as H₂O₂ is available, and then becomes mainly dependent on photochemical reactions once H₂O₂ is consumed. Although this process is less affected by solution turbidity compared to other photolysis processes, it is still influenced by it.

The advantages of the photo-Fenton process over the classical Fenton reaction are as follows:

• Additional ·OH radical supply: Photoreduction of Fe(III) generates additional ·OH radicals, increasing the efficiency of the process.
• In situ production of ferrous ions: Fe(III) is reduced to Fe²⁺ under irradiation, which then catalyzes the Fenton reaction, continuously regenerating ·OH radicals.
• Minimization of ·OH reduction by Fe²⁺: Fe²⁺ is introduced in catalytic quantity and is regenerated in situ, reducing the loss of ·OH radicals by reaction with Fe²⁺ [105].

These characteristics make the photo-Fenton process particularly effective for the treatment of refractory organic contaminants in wastewater.

Heterogeneous Photocatalysis (TiO2/UV)

The oxidation of organic pollutants by heterogeneous photocatalysis, as in the TiO₂/UV process, has been the subject of numerous studies in recent years. A comprehensive literature review has been published, highlighting the various applications of semiconductors in photocatalysis [106].

The electronic structure of semiconductors is characterized by a fully filled valence band and a completely empty conduction band. When a semiconductor such as TiO₂ is irradiated by UV photons whose energy is greater than or equal to the energy difference between the valence band and the conduction band (called the "energy gap"), an electron from the valence band is excited and passes into the conduction band, which creates a free electron in the conduction band (denoted e⁻BC) and leaves behind a hole in the valence band (denoted h⁺BV).

This process can be represented by the following equation:

TiO2+hν → eBC−+hBV

• e⁻BC (electron in the conduction band): This electron can participate in reduction reactions by combining with electron-accepting species, such as dissolved oxygen, to form superoxide radicals (O2−O2−).
• h⁺BV (hole in the valence band): This hole is a positively charged region that can participate in oxidation reactions, by reacting with water molecules or hydroxyl ions to produce hydroxyl radicals (⋅OH⋅OH), which are extremely reactive and capable of oxidizing organic pollutants.

These hydroxyl radicals and other reactive species generated by photocatalysis are responsible for the degradation of organic contaminants present in water, making the TiO₂/UV process very effective for the treatment of wastewater containing refractory pollutants.

For heterogeneous photocatalysis to be effective, the photon energy must be adapted to the absorption of the semiconductor, rather than to that of the contaminants to be oxidized, as is the case in a homogeneous photolysis process. For TiO₂, the energy difference between the valence and conduction bands is 3.02 eV, which requires radiation with a wavelength λλ less than or equal to 400 nm [107]. The excited entities (electrons and holes) formed can then recombine, be trapped, or react on the catalyst surface, either with an electron acceptor (such as an oxidant) or with an electron donor (such as a reductant). This process results in the formation of hydroxyl radicals (⋅OH⋅OH) on the catalyst surface by oxidation of adsorbed water molecules, hydroxide ions, or surface titanol groups (-TiOH). In parallel, superoxide radicals (O2−O2−) and perhydroxyls are also generated by the reactions between excited electrons and adsorbed oxygen.

The main reactions involved in the TiO₂/UV process are as follows [107]:

 The ·OH radical can thus be regenerated from the hydrogen peroxide formed [108-109].

Both e⁻BC (electrons in the conduction band) and h⁺BV (holes in the valence band) entities can directly contribute to the degradation of organic compounds at the catalyst surface, as their potential is sufficient to reduce or oxidize many organic molecules, respectively: between +0.5 and -1.5 V/ESH for electrons, and between +1 and 3.5 V/ESH for holes [108-111]. In addition, these entities play a crucial role in the formation of radicals in the medium. For example, holes can react with hydroxide ions or water molecules to form hydroxyl radicals, while conduction band electrons can be captured by oxygen molecules to generate O2- radicals or hydrogen peroxide in the presence of protons. TiO₂ has been extensively studied at concentrations in the range of 1 to 5 g L⁻¹. This semiconductor is biologically and chemically inert, stable in acidic and basic media, insoluble, non-toxic, and less expensive than other catalysts such as ZnO, Fe₂O₃, CdS or ZnS. It can be used either in suspension or immobilized [112]. A major advantage of this process is that it can be used with both artificial light and sunlight, which avoids the use of UV or xenon lamps, while obtaining comparable degradation rates [113].

Electrochemical methods

Advanced oxidation electrochemical processes reduce or eliminate the use of chemical reagents by producing oxidants, particularly hydroxyl radicals (OH), directly in the reaction medium electrochemically, either directly or indirectly. In general, two main groups of electrochemical processes are distinguished for generating hydroxyl radicals: directly by anodic oxidation, or indirectly via the Fenton reagent, the latter being a coupling between the Fenton reaction and electrochemistry [114,115].

This process requires high oxidation potentials, which results in significant electrical energy consumption. Much of this energy is dissipated in parasitic reactions, including the production of oxygen (O₂). In addition, the reaction of hydroxyl radicals with organic pollutants is limited to the electrode surface, which limits their efficiency. The amount of hydroxyl radicals formed in the case of metal oxide electrodes is generally not sufficient to ensure complete mineralization of the pollutants, and only some compounds are reasonably oxidized [116]. However, the efficiency of this process can be significantly improved by the use of boron-doped diamond (BDD) anodes, although this technology is currently limited by its relatively high cost.

Many indirect electro-oxidation methods promoting the in situ generation of oxidizing agents such as hydrogen peroxide or hydroxyl radicals [117] have been developed in recent years for the treatment of waters heavily loaded with organic matter. Among these processes, electro-Fenton is distinguished from other advanced oxidation processes (AOP) by the in situ generation of the Fenton reagent, which leads to the production of hydroxyl radicals ·OH in a homogeneous medium. It is therefore an electrochemically assisted Fenton reaction.

One of the main advantages of this process lies in the catalytic generation of hydroxyl radicals using dissolved oxygen (compressed air) as the sole reagent, which is converted into H₂O₂. Furthermore, the ferrous ion is continuously regenerated by a redox cycle, which allows the reaction to be maintained without the need to add large quantities of reagents. Unlike other processes, the electro-Fenton does not generate ferric hydroxide precipitates, due to the low concentration of ferrous or ferric ions used as catalyst, which simplifies the treatment and improves the overall efficiency of the process.

Continuous production of H₂O₂ in aqueous media is achieved by the two-electron reduction of molecular oxygen on a suitable cathode, such as mercury blanket [118], modified graphite [119], carbon felt [120], or an oxygen diffusion cathode [121]. Although the process is commonly used with a platinum (Pt) anode, other anode materials, such as PbO₂, can also be employed [122]. The choice of the electrode material should be based on fundamental criteria, including a high overpotential for hydrogen evolution at the cathode and a high overpotential for O₂ evolution at the anode [123,124]. The carbon felt cathode has the advantage of a very large specific surface area, thus facilitating the reduction of oxygen to generate hydrogen peroxide. One study showed that H₂O₂ electrogeneration is ten times higher with carbon felt than with graphite, due to its large specific surface area [125]. However, another study pointed out that this porosity could limit the efficient mass transport of pollutants to be treated inside the pores of the electrode [126]. Among the different methods available, we opted for the use of photodegradation, a technique widely used in the treatment of liquid effluents contaminated by drugs.

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