Paracetamol environmental remediation and ecotoxicology: a review

Abstract

Paracetamol, a common pain reliever, has seen a significant rise in use, particularly during the Coronavirus Disease 2019 (COVID-19) pandemic. This widespread consumption has led to increased levels of paracetamol in the environment through wastewater discharge. This raises concerns about its potential impact on aquatic ecosystems. Here, we review the state-of-the-art methods for removing paracetamol from wastewater, focusing on adsorption techniques. We explore how different materials and operational conditions influence the effectiveness of this approach. We also discuss the potential of combining adsorption with oxidative methods for enhanced removal. We further assess the environmental impact by critically examining the ecotoxicological effects of paracetamol on aquatic organisms. This analysis compares established toxicity values with those observed in studies using real wastewater samples. Finally, we highlight the specific needs for further research and development of efficient and sustainable strategies to mitigate paracetamol pollution, ensuring the safety of both human and aquatic life.

Introduction

Paracetamol, also called acetaminophen, is the most commonly employed analgesic worldwide and is recommended as a first-line therapy for pain conditions by the World Health Organization itself due to its wide availability and safety (Machado et al. 2015; Moore et al. 2015; Ennis et al. 2016). Due to its over-the-counter nature and low cost, it is one of the world’s most consumed drugs and the most commonly used analgesic (Bertolini et al. 2006; Żur et al. 2018). In 2020, its consumption was even greater, and it was recommended to combat mild symptoms of coronavirus disease (COVID-19), such as fever (Sohrabi et al. 2020). Paracetamol is a substance with very low biodegradation capacity, is bioaccumulative, and is detected in the environment at concentrations of up to 65 μg L⁻¹. Even at low concentrations, long-term exposure can damage various living organisms (De Gusseme et al. 2011; Li et al. 2014). In addition to its effects as an unaltered substance, when paracetamol is degraded, it forms 4-aminophenol, which is toxic and carcinogenic, causing mutagenic effects in human cells and even DNA cleavage (Żur et al. 2018).

Typically, wastewater treatment plants use activated sludge and other biological treatments, while water treatment plants use chlorine as a disinfection agent. The drawbacks of these methods for removal are that paracetamol can be toxic to the microorganisms in the sludge (Ahmad et al. 2022). In addition, paracetamol is not fully degraded by chlorine, with the risk of even forming disinfection by-products of higher toxicity than its unaltered molecular structure (Zwiener and Frimmel 2000; Snyder et al. 2004; Ternes et al. 2003). Thus, novel treatment possibilities have been developed in the last century, and some processes, such as adsorption, stand out due to their versatility and successful application both in effluent and water samples. Adsorption, a mass transfer-based separation method, has been used to successfully remove pollutants from diverse matrices (Abdel Maksoud et al. 2020; Kani et al. 2022; Osman et al. 2024).

This review examines paracetamol pollution, its ecotoxicological effects, and advancements in adsorption technologies for its removal from water, as shown in Figure 1. Unlike existing reviews that primarily focus on environmental concerns and adsorbent types, this work delves into critical operational factors like initial pH and adsorbent dosage considering synergistic effects and mechanistic insights. Moreover, most comprehensive works tend to reproduce the errors committed in the literature, such as linearization of the models and ill estimation of the thermodynamic parameters. This review undertakes a critical evaluation of the relationship between reported adsorption efficiencies and their demonstrably ecotoxicological effects, which is achieved through a comprehensive analysis and comparison of values reported within the extant literature. Thus, the comparative analysis presented by this review clearly elucidates knowledge gaps while mapping future research trajectories for strategies that no longer include systematic errors and unfocused results.

Fig. 1

Overview of the topics of this manuscript. This article presents the methods to remove paracetamol from aqueous media by adsorption, and the ecotoxicological effects of paracetamol

World distribution

Paracetamol is widely consumed as an isolated substance, and is also combined with more than 600 types of medications for allergy, cold, indisposition, and insomnia symptoms, as well as combined with other pain relievers and many other pharmaceutical products (Karimi et al. 2006; Meeus et al. 2013; Li et al. 2014; Gammoh et al. 2020). Furthermore, the environmental problems caused by paracetamol pollution are augmented by its unique chemical properties such as high stability, solubility, and hydrophilicity, as shown in Table 1.

Table 1 Chemical properties of paracetamol

Because of these properties, paracetamol has already been detected in surface water, drinking water, sewage treatment plants, and groundwater in several countries worldwide (Kolpin et al. 2002; Oulton et al. 2010; Birch et al. 2015). Overall, the pervasive presence of paracetamol in various water sources highlights its significant environmental impact. The variations in reported paracetamol detection levels across Asia, Europe, and North America likely stem from differences in population density and wastewater treatment practices. Studies suggest that stricter policies promoting sustainability and proper effluent treatment, as implemented in Europe and North America, can significantly reduce environmental paracetamol presence (Phong Vo et al. 2019). In Fig. 2, it visually depicts the global pervasiveness of paracetamol, with brown, pink, and blue colours representing its presence in groundwater, wastewater, and surface water, respectively.

Fig. 2

Visual and spatial distribution of the reports for paracetamol detection in environmental samples of groundwater, wastewater, and surface water between 2002 and 2024 (data presented in Table S1). Information regarding supplier and consumer countries was provided by market reports available at Globe Newswire (https://www.globenewswire.com/), Mordor Intelligence (https://www.mordorintelligence.com/), and the British Pharmacological Society (https://www.bps.ac.uk/)

In 2016, a study showed that paracetamol was detected in different water resources and even in 29 countries, with mean concentrations of 0.161 μg L⁻¹ and maximum environmental concentrations of 230 μg L⁻¹ (aus der Beek et al. 2016). The mean surface water paracetamol concentration varies from 0.055 ± 0.051 μg L⁻(Wiegel et al. 2004; Bound and Voulvoulis 2006; Gros et al. 2006); however, some studies have detected higher concentrations. For example, paracetamol was present in 80% of several rivers in South Korea, with contents up to 33 ng L⁻¹ (Kim and Carlson 2007; Kim et al. 2007). In Europe, France and Spain, for example, the frequency of detection of paracetamol in surface water was 28% to 41%, representing a concentration variation between 0.4 and 71 ng L⁻¹ (Vulliet and Cren-Olivé 2011; Vazquez-Roig et al. 2012). In the USA, concentrations of up to 10 μg L⁻¹ have been detected in surface waters (Fram and Belitz 2011), while in the United Kingdom, concentrations exceeding 65 μg L⁻¹ have been detected (Roberts and Thomas 2006). These findings indicate that paracetamol can be easily found in surface waters worldwide.

In European sewage treatment plants, it was detected at concentrations of up to 6 μg L⁻¹ (Ternes 1998). In hospitals and wastewater effluents, the concentrations are greater than or equal to 150 μg L⁻¹ (Wu et al. 2012). The paracetamol detection rate in China was greater than 95% in samples collected from treatment plants (Gao et al. 2016). The concentration in European Union treatment plants varies from 1 to 6 mg L⁻¹; in the USA, it is 0.11 µg L⁻¹ (Baeza et al. 2019, 2020). High concentrations have also been reported on Indonesia’s northern coast, reaching maximum concentrations of up to 610 ng L⁻¹ (Koagouw et al. 2021). In the USA, the concentration of paracetamol and detection frequency in one of the main water bodies of water abstraction were 2.5 to 17 ng L⁻¹ and 25%, respectively (Ferguson et al. 2013). The paracetamol concentration ranged from 0.1 to 300 μg L⁻¹ for the wastewater samples, with a detection frequency reaching 100%.

In Asia, the documented locations are close to megacities and nearby regions with high population density. In South Korea, for example, paracetamol was the drug responsible for 18 to 80% of the total drugs detected in effluents in 2007, increasing in concentration approximately 11 times over the years, from 6.8 to 75 μg L⁻¹ (Kim and Carlson 2007; Kim et al. 2007; Sim et al. 2010). In Europe, countries such as Greece and France have shown 100% paracetamol detection frequency in wastewater treatment plants (De Araújo et al. 2016, 2020), but the concentrations quantified only represented between 1 and 2% of the total amount of pharmaceutical compounds found in the wastewater samples (Rabiet et al. 2006). Moreover, in the USA, paracetamol is commonly administered in hospitals; therefore, its concentration in local hospital effluents was approximately three times greater than the typically observed concentration for these matrices, representing more than 45% of the total amount of pharmaceutical compounds in the hospital wastewater samples studied (Oliveira et al. 2015). Finally, in South America, the paracetamol concentration in sewage systems ranges from 9.2 to 29.2 μg L⁻¹ (Botero-Coy et al. 2018).

Regarding groundwater contamination, paracetamol pollution is commonly attributed to possible leakage from septic tanks and landfills, as the values found are similar to those reported for sites close to these places, which may contain concentrated pollutants in the range of 100 to 1000 ng L⁻¹ of paracetamol (Lapworth et al. 2012). However, studies related to identifying or quantifying paracetamol in groundwater are rare compared to those related to identifying or quantifying paracetamol in surface water and wastewater. In addition, reports on groundwater contamination by paracetamol may not adequately reflect the actual problem. For example, in Serbia and France, paracetamol was detected in 15% and 17% of the analysed groundwater samples, respectively (Grujić et al. 2009; Vulliet and Cren-Olivé 2011). In the USA, paracetamol concentrations were detected in broad ranges, ranging from 2.1 to 12.3 ng L⁻¹, with an incidence of approximately 13% (Conley et al. 2008), varying up to a maximum concentration of 1.9 μg L⁻¹ but corresponding to only 0.32% of the samples (Fram and Belitz 2011).

Despite discussing several works on paracetamol detection in different samples, its continuous entry into the environment as a contaminant in its original and metabolic form is expected, given its consumption profile. Thus, the total number of studies on determining paracetamol is still scarce (Phong Vo et al. 2019). The data presented in Table S1 showcases a concerning trend—significant variations in paracetamol concentration levels across different countries, regardless of the sample type (groundwater, wastewater, and surface water). While no clear geographical or sample-source patterns emerge, these findings raise serious concerns about the potential environmental risks associated with long-term paracetamol exposure on aquatic biota and other living organisms. This underscores the urgent need to develop and improve paracetamol control and remediation technologies to mitigate these potential environmental risks.

Adsorption

Adsorption consists of the transfer of a molecule from a fluid bulk to a solid surface. This process can occur due to physical forces or chemical bonds. In most cases, it is reversible, so it is responsible not only for the subtraction of substances but also for release (Lima et al. 2021; Vieira et al. 2022). Usually, adsorption is described at equilibrium, although some equations quantify the amount of substance attached to the surface depending on the concentration in the fluid. The most famous equations are the Langmuir and Freundlich equations, which are called isotherms because of their dependence on temperature, one of the most critical environmental factors that can affect the adsorption process (Suzuki 1990). This method has been successfully applied for the removal of various pharmaceutical compounds, such as aspirin, doxycycline, ketoprofen and ibuprofen (Akpotu and Moodley 2018; Fröhlich et al. 2019; Aniagor et al. 2021).

The great advantage of applying adsorption for paracetamol removal is its low cost, given that many adsorbents can be produced using residues of various kinds and resulting from several industrial processes (Ighalo et al. 2020; Vieira et al. 2022). The methods utilized for fabricating and designing the morphological and desired properties of adsorbents have improved in the last two decades. The main challenge is to optimize various variables that can influence the adsorption outcome and total efficiency, such as the initial pH, initial concentration of the paracetamol solution, dosage of the adsorbent, and contact time. In the following subsections, the outcomes described for different adsorption variables are thoroughly analysed and discussed to demonstrate how each factor’s variations can affect the result obtained.

Influence of pH

The pH of the aqueous medium greatly influences the amount of paracetamol molecules and the adsorption capacity since it affects the degree of adsorbate ionization, which affects the functional groups and properties of the adsorbent (Iftekhar et al. 2018). Regarding paracetamol adsorption, it is possible to observe in Table 2 that, for most studies, the maximum adsorption capacity (q_max) is reached at a pH closer to the so-called neutral state, which is between pH 6 and 7. This can be attributed to decreased repulsion forces because paracetamol is found in its non-ionic form, resulting from its pK_a value of 9.38. Moreover, the adsorbent surface is negatively charged at this specific pH range, resulting in electrostatic attraction (Al-Khateeb et al. 2014). However, these effects have still been observed at pH 8, where the adsorption efficiency decreases as the pH approaches 9 (Moussavi et al. 2016; Spessato et al. 2020; Thakur et al. 2020; Pauletto et al. 2021a, b; Streit et al. 2021).

Table 2 Paracetamol adsorption using different adsorbents in studies that considered the pH as a relevant variable for the efficiency (calculated concerning the reported q_max values)

In addition to the conclusions that can be drawn individually from analysing the morphological characteristics of each adsorbent and the relations implied from the pKa and pH values, more information regarding the effect of pH can be gathered by obtaining the point of zero charge (pH_pzc) of the adsorbent. The pH_pzc describes the pH at which the surface charge of the adsorbent is equal to zero; thus, when the adsorption process is ruled by electrostatic forces, no adsorption should occur at the pHpzc (Lyklema 1984). Moreover, even though pH plays a vital role in adsorption efficiency, its influence can be overcome depending on the pH_pzc of the adsorbent. For example, three different carbon samples produced using three different methods with pH_pzc values of 3.4, 5.4, and 8.9 were investigated for paracetamol adsorption at pH 2, 7, and 11. According to the results, the sample with the highest pH_pzc value (8.9) demonstrated higher q_max values, which were optimal at pH 7 and worse at pH 11, which should be expected according to the pKa value of paracetamol. However, the sample with the lower pH_pzc value (3.4) showed a greater affinity for paracetamol in all the studied pH ranges (Bernal et al. 2017).

Aside from the adsorbent perspective, similar results were observed for different materials with pH values ranging from 6 to 8, including activated carbons, biochar, graphene, and ashes. The small variations observed in this pH range can be attributed to specific characteristics of the functional groups present on the surface of the adsorbent, which influence the surface charge, resulting in the estimated pH_pzc of the adsorbent. This can become clearer if we compare activated carbon with graphene. The surface area, pH_pzc, and optimal adsorption pH for both materials were reported to be 1640 m² g⁻¹, 3.5, and 7.0 for activated carbon and 51.2 m² g⁻¹, 5.8, and 8.0 for graphene, respectively. The pHpzc of the materials varies, but their surface group chemistry differs given the starting feedstock for their synthesis. While graphene is more oxidized, the activated carbon sample shows less contribution of oxygen-containing groups, mostly carboxylic groups. Therefore, even though the activated carbon sample had a large surface area, the graphene sample reached a high adsorption capacity of 704 mg g⁻¹ while the activated carbon had a value of 411 mg g⁻¹ (Moussavi et al. 2016; Lima et al. 2019a).

Despite being published in much smaller amounts, there are paracetamol adsorption studies that point to reaching a higher q_max value under more acidic conditions such as pH 4, 3 and 2 (Galhetas et al. 2014; Lladó et al. 2015; De Araújo et al. 2016; Spessato et al. 2020). Although this could initially seem illogical or more likely associated with the type of adsorbent employed, these positive responses at different pH values could result from the dimerization of paracetamol molecules via Michael addition. Kekes et al. (2020) studied the formation of paracetamol dimers in the initial stages of the adsorption process, triggered by an unwanted chemical reaction from the use of manganese dioxide as an adsorbent. This leads to a better understanding of the mechanisms behind the adsorption efficiency and interactions between adsorbents and adsorbates, as further discussed in Section “Mechanism of adsorption”.

Influence of the adsorbent dosage

Most published studies do not provide information on the amount of dosage used in the experiments and are focused on providing more data regarding the adsorption capacity and initial paracetamol dosage, as previously mentioned in Table 2. It is noteworthy that, in many cases, higher dosages do not mean higher efficiency since the adsorbents can agglomerate, resulting in steric blocking of the adsorbent’s active sites. However, it is known that the removal percentage is favoured in most adsorption processes by increasing the adsorbent dosage. This behaviour is related to enhancing the number of activated sites available at the adsorbent surface for uptaking the adsorbate (Georgin et al. 2018, 2021; Franco et al. 2022).

It has been demonstrated by Gómez-Avilés and co-workers (2021) that as the dosage of activated carbon increases from 50 to 250 mg L⁻¹, its adsorption capacity towards paracetamol removal decreases, which can significantly affect the adsorption process. Furthermore, activated carbon is known as one of the most porous adsorbents. Thus, this tendency towards an efficiency decrease could be because of the greater availability of vacant adsorption sites when a more elevated dosage of adsorbent is utilized. In other words, the concentration of paracetamol is constant; however, the number of adsorption sites increases with increasing activated carbon dosage, and as a consequence, not all the activated carbon sites are occupied (Gómez-Avilés et al. 2021).

Different effects have been observed for paracetamol adsorption onto rice husk ash, whereas the removal efficiency and adsorption capacity increased as the adsorbent dosage increased, which can be attributed to the distinct morphological properties observed for rice husk ash compared with activated carbon (Thakur et al. 2020). While activated carbons tend to present a large surface area of more than 400 m² g⁻¹, the surface area of rice husk ash is approximately 150 m² g⁻¹. Moreover, since ashes are not functionalized with any surface groups, self-repulsion can occur between ash particles. Similar results have been obtained for a low surface area Ca(II)-doped chitosan/β-cyclodextrin composite (Rahman and Nasir 2020), indicating a relation between the surface area of the adsorbent and its optimal dosage.

Contact time and kinetic studies

The determination of an adequate contact time between the adsorbent and adsorbate is essential because it can directly influence the application of the scale-up process for the suitable foreseen contact time of a given adsorbent to take up the target adsorbate, which can reduce operational costs. Unfortunately, one limitation of the adsorption process is that the saturation of all active adsorbent sites can be slow. Luckily, the contact time needed for paracetamol removal has been reported to be much shorter than that needed for the adsorption of many other pollutants. In Table 3, it is shown that the contact time needed for several kinds of adsorbents was less than 180 min, which can be considered fast. In addition to the mean value, variations have also been reported, such as instantaneous 5 min saturation and relatively slower saturations reached after 200, 240, and 300 min.

Table 3 Contact time and kinetic model of best fit of the adsorbents used in paracetamol removal

Lladó et al. (2015), Spaltro et al. (2021), Patel et al. (2021), and Terzyk (2001) reported delayed contact times of 1000, 800, 720, and 400 min, respectively. These differences can be directly related to the textural characteristics of the adsorbent, such as its surface area, total pore volume, and pore size distribution. Usually, the surface area, total pore volume, and pore size distribution affect the adsorption capacity. For paracetamol uptake, the contact time will be influenced by overcoming steric hindrance and providing suitable geometrical accommodation of the paracetamol on the adsorbent’s active sites.

Generally, a fast initial adsorption rate is observed after the first minutes of adsorbate–adsorbent contact before slowing until equilibrium is established. Again, adsorptive processes with overall fast kinetics are advantageous because they can minimize operational costs, especially at industrial scales where the volume of treated effluent is large. Following the fitting of an appropriate kinetic model, the rate defining these processes and their general principles are investigated in adsorption kinetics studies. The most common adsorption kinetic models are the pseudo-first-order and pseudo-second-order models and the Elovich, Avrami, and Vermeulen models. The model’s main application is to describe the experimental data, which are generally evaluated through different statistical indicators, such as the determination coefficient (R²), adjusted determination coefficient (R²_adj), mean-square residual error (MSR), and average residual error (ARE).

As Table 4 shows, for most studies on paracetamol adsorption, the process was found to be better represented by pseudo-second-order methods, with the highest correlation coefficients and lowest ARE values. However, even though kinetics can provide details on the way the adsorbate interacts with the active sites of the adsorbent, there is no way to determine the energy of the interaction, the energy of the sites, or the geometric location of the paracetamol using this method. If we compare the research of Spessato et al. (2019) and Praveen Kumar et al. (2021), for instance, because chemisorption better fits pseudo-second-order kinetics, the authors initially speculate that this may be the adsorption process. However, while Praveen Kumar et al. (2021) indicated that the process is chemisorption without performing thermodynamic estimations, Spessato et al. (2019) confirmed that it is a physical process after determining thermodynamic parameters. It can be concluded from these remarks that (i) even though kinetic modelling is critical, it alone does not determine the total mechanism of adsorption; (ii) combining various models and estimations can provide a complete outlook of the adsorption process; and (iii) other analytical techniques should provide additional information to obtain an accurate adsorption mechanism.

Table 4 Adsorbents for removing paracetamol from aqueous media: parameters and q_max values

Studies whose data better fit the pseudo-first-order kinetic model were presented by Boudrahem et al. (2017) and Haro et al. (2021). Curiously, in both studies, activated carbon was the adsorbent, and for many other studies, the data better fit the pseudo-second-order data. The surface area ranged between 543 and 774 m² g⁻¹, which shows that the kinetics are not always directly dependent only on the textural properties of the adsorbent. A good statistical fit was also found for the Avrami model by Lima et al. (2019a) and Nguyen et al. (2020), who employed activated carbon produced from Brazilian nutshells (1640 m² g⁻¹) and commercial carbon (1284 m² g⁻¹), which corresponds to a possible particle nucleation process. Finally, the Elovich model, which appropriately represents adsorbents with heterogeneous sites, was also found to better represent the kinetic data for paracetamol adsorption by activated carbon produced from Butia capitata endocarp (Kerkhoff et al. 2021). A good level of accuracy of the adsorption processes is directly linked to modelling and the correct interpretation of kinetic data, and here, it should be noted that nonlinear regression should preferably be applied, as discussed in detail by Lima et al. (2021).

Effect of temperature on the adsorption capacity and equilibrium modelling

It is impossible to discuss the effects of temperature without discussing the interpretations provided by the adequate isothermal modelling of the data. Temperature plays a vital role in the adsorption process because it affects the availability of receptor sites and the motion of the adsorbate molecules, reflecting the extent to which interfacial phenomena occur when the system has already reached equilibrium. In this context, the application of isotherm models allows the visualization of different variables under a fixed temperature. Isothermal studies allow the study of the interaction mechanisms of the adsorbent with the adsorbate. Thus, the isotherms reveal whether adsorption occurs in monolayers or even forms multilayers (Foo and Hameed 2010). This knowledge can benefit industrial aims, helping to determine the effect of different temperatures on the adsorption capacity, which could influence the overall removal and permit some compensatory measures to avoid significant losses (Awad et al. 2019).

In addition to the possibilities presented in the previous paragraph, isotherm models also allow us to obtain values of the q_max of the adsorbent, which is helpful for estimating how many adsorbents it would take for the removal process to be satisfactory. In terms of cost‒benefit applications, it would be optimal if high efficiencies were always achieved in systems whose temperature is approximately 298.15 K. In addition to the isotherms, another crucial aspect to be analysed is the estimation of thermodynamic parameters, such as the standard enthalpy change (∆H°), standard entropy change (ΔS°), and standard Gibbs free energy change (ΔG°), which validates the data by introducing quantitative values. In Table 4, we summarize the information provided by several studies using different materials for paracetamol adsorption on the most relevant parameters under temperature and isothermal modelling.

Paracetamol studies have reported high efficiencies at room temperature, demonstrating the favourable application (ΔG° below 0) of several adsorbents developed by many research groups under real conditions—requiring less application of other energy sources—thus reducing the scaling of operating costs. In addition, it was also possible to observe that, for most studies, the temperature increase in the system could even decrease the overall efficiency. These results point to the exothermic nature (∆H° below 0) of the adsorbent, as has been reported for mesoporous silica wrapped with reduced graphene oxide/graphene oxide (Akpotu and Moodley 2018), biochar from Eucalyptus pruning residues obtained by the Kon-Tiki kiln method (Bursztyn Fuentes et al. 2020), activated carbon produced from olive stones (García-Mateos et al. 2015), and from Butia capitata endocarps (Kerkhoff et al. 2021).

Processes favourable to a temperature increase, i.e. endothermic processes (ΔH° above 0), have been reported for paracetamol uptake onto fly ash, carbon nanotube-COOH/MnO₂/Fe₃O₄ nanocomposites, and Fe(III)-based metal–organic framework-coated cellulose paper (Galhetas et al. 2014; Lung et al. 2021; Yılmaz et al. 2021). However, even though it appears to decrease, being endothermic is not an exclusivity of adsorbents that are not activated carbon, as reported by Yu et al. (2017), Nourmoradi et al. (2018), Nguyen et al. (2020), and Haro et al. (2021) for different activated carbons obtained from different sources. Usually, these studies relate the increase in efficiency obtained at higher temperatures to the increase in the solubility of the paracetamol molecules, in addition to the properties of the adsorbent used in the study. Nevertheless, as shown by Nguyen et al. (2020), despite conducting equilibrium investigations at 298 K, it was discovered that the process is endothermic, favouring 323.15 K when the thermodynamic parameters were estimated at various temperatures. Therefore, even though isotherm fitting can provide valuable information regarding the adsorption process, other analyses of the characteristics of the adsorbent and adsorbate also need to be performed.

Finally, the majority of research presented a ΔS° above 0, suggesting increased randomness in the solid/solution interface after the adsorption process (Bello et al. 2019). However, papers that reported a negative ΔS° indicate a decrease in the randomness of the system caused by a disturbance at the solid‒liquid interface during the adsorption process. However, through classic modelling, it is not possible to estimate ΔS° as a function of the equilibrium concentration, which can be achieved by employing novel thermodynamic models based on a grand canonical approach, which will not be discussed in this paper but can be found elsewhere (Sellaoui et al. 2017; Vieira et al. 2022).

Following the same interpretation of the statistical adjustments made in the kinetic studies, the isothermal parameters were adjusted to different isotherm models. Of the 30 studies investigated, 22 followed the Langmuir isotherm model, confirming a tendency for paracetamol molecules to be adsorbed on the surface of the materials through monolayers. This dominance can result from two possible contributions: (i) steric blocking because of the paracetamol size and (ii) a more homogeneous distribution of the molecules on the surface because of the consistent availability of adsorption sites.

In some papers, it was verified that the equilibrium data were best fitted to the Freundlich isotherm model, such as by Akpotu and Moodley (2018), Rahman and Nasir (2020), and Spessato et al. (2020). Oddly, each of these experiments used a composite adsorbent that was created by wrapping, doping, or aggregating two or more different materials. Thus, if we consider the type of adsorbent used, it is reasonable to expect that it will present a more heterogeneous surface, which is well represented by the Freundlich isotherm since it does not assume monolayer adsorption or the same energy adsorption sites (Mckay 1996).

The Sips model has also been used to demonstrate paracetamol adsorption behaviour with two different types of AC, as presented by Haro et al. (2021) and (Streit et al. 2021). The Sips isotherm, also known as the Langmuir–Freundlich isotherm, takes into account that the same species can be accommodated by occupying two adsorption sites simultaneously, suggesting a hybrid adsorption mechanism that relies more on the adsorbate than on the adsorbent. Finally, the use of less common isotherm models, such as the Liu and Redlich–Peterson models, has also been described elsewhere (Lima et al. 2019a, Gómez-Avilés et al. 2022, and Nourmoradi et al. 2018).

Even though the Liu isotherm model also comes from a joint approach of the Langmuir and Freundlich models, such as the Sip model, it discards the intrinsic basis assumptions. Instead, it introduces the concepts of different energy adsorption sites, which explains the discrepancies and heterogeneous adsorption behaviour (Liu et al. 2003). Contrary to the Sips model, however, all the effects observed are attributed to the adsorbent instead of the adsorbate. The Redlich–Peterson model proposes a three-parameter equation to overcome the drawbacks of the other two parameter models previously explored (Redlich and Peterson 1959). Of all isotherm models, the Redlich–Peterson model is possibly the least utilized equilibrium model because of inadequate fitting methods. Herein, it is essential to highlight that the nonlinearized isotherm model is chosen over its linearized form, mainly due to the inherent errors and deviations of using linearization, which can poorly influence thermodynamic and equilibrium results (Lima et al. 2020).

Effect of increased paracetamol concentration, entropy contribution, and molecular competition in single and binary systems

In the majority of previous studies, the paracetamol concentrations were generally about mg L⁻¹. It is noteworthy that the paracetamol levels utilized in standard adsorption papers are much greater than those found in actual environmental samples (ng L⁻¹ to µg L⁻¹), with few possible exceptions, such as for wastewater sampled near excessive use locations such as hospitals (Vieira et al. 2021). Lower environmental concentrations (ng L⁻¹ to µg L⁻¹) may explain why some reported adsorption capacities are lower than those observed in controlled experiments. At these lower environmental levels, the adsorbent reaches a local equilibrium, but not necessarily the maximum possible adsorption. This limited capacity can affect the design of fixed-bed absorbers, for example, which rely on factors like the maximum adsorption capacity (q_max) of the material.

In general, a mean value of five different paracetamol concentrations was employed in isothermal studies by several authors, who reported the same overall tendency of an increase in q_max values (mg g⁻¹) followed by a plateau representing the system’s saturation point. This behaviour may be related to two possible effects: (i) the increased concentration gradient and mass transfer and (ii) variations in textural parameters such as the specific surface area, pore size, and pore volume of the adsorbents. Of course, the combined contributions of these factors are also the most likely possibility to be investigated, considering that the first is not an exclusive effect for paracetamol, while the latter is unique for each study, resulting in an unimaginable set of combinations to investigate.

If we begin this discussion from the principles, we need to start by looking at the influence of the system’s entropy from a low-temperature standpoint (100.15 K), where thermodynamic equilibrium is reached, and the adsorbate is defined as a simple monomer. If all the chemical potentials ($\mu )$ of the adsorbate molecules are the same, there would not be any difference in the adsorption site coverage rate, leaving the complete surface coverage ruled by the ratio of adsorbate–adsorption sites (${\mu }_{A}={\mu }_{B})$. Thus, according to the numerical observation provided by Phares and Wunderlich (2012), the total energy needs to be continuous throughout the film between the liquid and solid phases. However, in modern adsorption, we work at temperatures higher than 298.15 K. Thus, the overall entropy is even greater. If the entropy is high, thermal agitation effects should be expected to limit the process on behalf of adsorbate hindrance over site availability.

Entropic effects can be even more severe in binary systems, where molecular structures and energy differences can vary intrinsically. The adsorption of paracetamol in the same system as ofloxacin, nimesulide, and phenol has been studied under different circumstances and from different perspectives by Thakur et al. (2020), Pauletto et al. (2021a) and Rad et al. (2015), respectively. Under real scenarios, complex mixtures of similar compounds are common because of the combined pattern of use harnessed for the selling and prescription of these compounds. Therefore, the analysis of competitive adsorption is fundamental since the presence of other compounds can impede paracetamol adsorption. Curiously, contrary effects were observed for the two pharmaceutical compounds: the adsorption of ofloxacin was suppressed by paracetamol, whereas nimesulide suppressed paracetamol adsorption. For phenol, no competitive effects were observed.

Mechanism of adsorption

We discussed the effect of the temperature, adsorbent dosage, and pH on the sorption capacity, and insights can be gathered from kinetics and equilibrium models. However, some papers do not provide clear information about the kind of interactions of paracetamol with the adsorbent surface. Approximately 20 publications were found to propose mechanisms of paracetamol adsorption based on physical interactions, as shown in Table 5. The physical interactions could be attributed to electrostatic interactions, hydrogen bonding, van der Waals forces, hydrophobic interactions, and π–π and n–π interactions. However, no studies have reported any evidence of chemisorption between paracetamol molecules and adsorbent surfaces.

Table 5 Mechanisms for paracetamol adsorption by adsorbents in aqueous media

Generally, the studies that propose an interaction mechanism have been performed using equilibrium and thermodynamic studies combined with FTIR analysis and other characterization techniques. Several other analyses can be utilized to elucidate the possible interaction mechanisms involved. These analyses are mainly based on the characterization of the adsorbent instead of the adsorbate. The pH_pzc provides essential information about possible electrostatic interactions. The surface area, total pore volume, and pore size distribution are textural adsorbent characteristics that can be attributed to pore filling. Herein, it is essential to highlight the nature of the adsorbent to determine the interaction type that occurs with the adsorbate; it is essential to know the chemical structure of paracetamol and perform isotherm equilibrium studies under experimental conditions that will permit the evaluation of whether the adsorption process will occur.

Additionally, to verify the nature of adsorption, the thermodynamic parameters (ΔG°, ΔH°, and ΔS°) should be estimated. For example, as mentioned earlier in the Spessato et al. (2019) study, the authors suggest that chemisorption occurs due to pseudo-second-order chemisorption. However, when performing the thermodynamic estimations, they found ΔG° values of − 24.4 ± 0.52 kJ mol⁻¹, which lie within the physical range defined in the literature, and they concluded that interactions of a physical (instead of chemical) nature are possible. However, if we look more carefully at the information presented and discussed in Table 4, we will soon observe that the process is physical in all cases since, for a chemical reaction to occur, the ΔH° must have a magnitude greater than 200 kJ mol⁻¹.

Textural characterization of the adsorbent

When adsorbent properties that affect the adsorption capacity are considered, we observed that the specific surface area is one of the most important textural characteristics affecting the sorption capacity. Concerning paracetamol uptake, verifying that the surface area textural characteristic does not always define whether the adsorbent will have a high sorption capacity is possible. One of the highest capacities obtained was 666.7 mg g⁻¹ using a 4 mm hydrogen sulphide CAT-Ox (commercial activated carbon) pellet, which presented a surface area of 983 m² g⁻¹ (Spaltro et al. 2021). On the other hand, Akpotu and Moodley (2018) synthesized three types of silica and observed that its adsorption capacity was relatively low even though the adsorbents had a surface area above 1000 cm³ g⁻¹. It is also possible to observe studies with low surface areas and even lower performances, such as the studies by Thakur et al. (2020) and Hamoudi et al. (2021), which reported adsorbents with areas of 127.5 m² g⁻¹ and 102.9 m² g⁻¹, reaching ${q}_{\text{max}}$ _s of only 7.6 mg g⁻¹ (10–100 mg L⁻¹) and 14.7 mg g⁻¹ (50–150 mg L⁻¹), respectively. On the other hand, there are also studies that show materials with low surface areas and good adsorption capacities, such as silica with a surface area of 50.9 cm³ g⁻¹, which obtained one of the highest capacities reported (q_max of 555.6 mg g⁻¹), as reported by Akpotu and Moodley (2018).

Several examples reported by several authors show that the surface area and ${q}_{\text{max}}$ are not related. Most studies have used AC, a highly porous material with high surface area availability. However, in the study by Spessato et al. (2019), activated carbon with a surface area of 2194 m² g⁻¹ was developed, obtaining a ${q}_{\text{max}}$ value of 356.3 mg g⁻¹, while Lladó et al. (2015) used activated carbon with an area of 1234 m² g⁻¹, with q_max equal to 261.0 mg g⁻¹. Moreover, the study by Wong et al. (2018), which produced an activated carbon adsorbent from spent tea leaves with a high surface area of 1202.8 m² g⁻¹, showed one of the worst performances, with a q_max of 59.2 mg g⁻¹, which was much smaller than that of other adsorbents with a smaller area. Moussavi et al. (2016) and Lung et al. (2021), who reported on adsorbents made from graphene and carbon nanotubes, reported that adsorbents with areas smaller than 51.2 m² g⁻¹ and 114.2 m² g⁻¹, respectively, exhibited excellent adsorption capacities of 704 mg g⁻¹ and 80.6 mg g⁻¹, respectively.

Therefore, given the cited examples, it is possible to say that in addition to the surface area, other textural characteristics, such as smaller adsorbent particles, efficient functional groups on the adsorbent, good pore structure, and adsorbent pH_pzc, play a greater role in the estimated q_max values. Generally, adsorbents with higher total pore volumes facilitate particle diffusion and mass transfer. Nevertheless, the presence of pores limits the penetration of the adsorbate into the internal pores of the adsorbent. Therefore, for larger pores, the speed of pollutant uptake increases.

Furthermore, the determination of the zeta potential of an adsorbent is crucial. The zeta potential measures the existing surface charges on the adsorbent surface when different pH solutions are utilized, which can indicate whether some potential electrostatic attraction could occur. Therefore, all of these characterization techniques for the adsorbent are necessary to elaborate upon the proposed adsorption mechanism. Additionally, special consideration should be given to the various adsorption kinetics and mass transfer rates for nonporous and porous adsorbents, as studied by Sircar (2018).

Coupled methods for paracetamol removal

Even though the adsorption method alone shows excellent results for treating effluents containing paracetamol, several studies have shown that coupled methods can achieve even better pollutant removal (Ceretta et al. 2020; Vieira et al. 2020). In the specific case of paracetamol removal, it was verified that photocatalysis is the preferred method by the majority of papers published after 2020. The great advantage of photocatalysis is its great mineralization capacity, as it does not generate secondary pollution (Li et al. 2021; Liu et al. 2021a; Ma et al. 2023; Zhang et al. 2023). However, its practical application remains challenging due to the low photocatalytic efficiency observed for complex samples with suspended solids that impair light penetration, augmenting the recombination of photogenerated charge carriers (Liu et al. 2021a). Therefore, many efforts have been made to improve this technology and lower operating costs by developing new catalysts (Liu et al. 2021b, 2022). Moreover, in addition to photocatalysis, other forms of paracetamol catalytic degradation, including electrocatalysis, Fenton oxidation, catalytic oxidation, ozonation and thermal activation, have been investigated in an enormous number of studies (Levanov et al. 2019; Huang et al. 2020; Luo et al. 2020; Sun et al. 2020; Li et al. 2021; Palas et al. 2021; Kohantorabi et al. 2022; Ji et al. 2023).

In terms of photocatalytic processes, photo-Fenton and photo-Fenton-like processes have demonstrated high efficiency towards paracetamol degradation, as demonstrated in the works by Giménez et al. (2020), Hinojosa Guerra et al. (2019), Orimolade et al. (2020), Venier et al. (2021) and Villota et al. (2018). The possible reason these methods are preferred over others is the highly established reproducibility of Fenton reactions, which can be activated by employing different iron-containing sources. To date, the shortcomings of this method are its elevated energy consumption and high need for acids and bases to restore the equilibrium between Fe²⁺ and Fe³⁺. For example, in a study where photo-Fenton and adsorption were used for paracetamol removal and compared, it was concluded that despite photo-Fenton having the clear advantage of higher efficiency in less time, adsorption is still a more viable alternative given its lower cost (Rad et al. 2015).

Most of the combined works use an advanced oxidation process coupled with adsorption to reach a high mineralization rate of the initial molecule, followed by the remediation of possible secondary pollutants generated during the process. It was concluded by Mojiri et al. (2019) that paracetamol removal was more efficient when using ozonation followed by adsorption than when these techniques were used in inverted order. Approximately 84.8% of the initial paracetamol concentration was removed using an ozone dosage of 15 mg L⁻¹. After treatment in the ozone reactor, the test solution was passed through a cross-linked chitosan/bentonite column, leading to an efficiency of 100%. The suggestion of using first the oxidative process and then adsorption made by Mojiri et al. (2019) is reinforced, as it was shown in the study by Shi et al. (2019) that if adsorption and ozonation are performed in an inverted order, the final efficiency is lower.

Another method studied is wet air catalytic oxidation, which also relies on generating highly oxidizing species; however, contrary to photocatalysis, air catalytic oxidation uses high pressures and temperatures (Hammedi et al. 2015). The wet air catalytic oxidation of paracetamol on activated carbon was investigated by Quesada-Peñate et al. (2012), who regenerated carbon using an autoclave reactor following adsorption via a sequential fixed-bed method. The initial activity of the catalyst seemed to be linked to the adsorption capacity of the activated carbon used as the catalyst and adsorbent. However, catalyst reuse in consecutive runs showed rapid surface area deterioration, followed by a decrease in catalyst performance. Both of these effects can be explained by the formation of irreversible oligomers adsorbed on the surface of the carbon, blocking the access of micropores and hindering both catalytic and adsorption sites. Therefore, it is speculated that better wet air oxidation performance could be achieved by using mesoporous AC; however, it would still have a limited number of recycles before being replaced, which increases the overall cost of the process.

In addition to advanced oxidation processes, other developments concerning classic water treatment methods have been carried out. As an example of improved coagulation performance, electrocoagulation appears to be a method that combines the advantages and roles of conventional coagulation, flotation, adsorption, electrochemical reactions and discharge, and precipitation (Shadmehr et al. 2019). Among its benefits is its high versatility, selectivity, and easy control (Thakur et al. 2009). On the other hand, many factors strongly influence this method’s efficiency since it is susceptible to shifts in various parameters (Moussa et al. 2017). Nevertheless, recent studies have successfully employed electrocoagulation for the removal of paracetamol, such as those by Kumari and Kumar (2021) and Negarestani et al. (2020). However, as demonstrated previously, a higher paracetamol removal efficiency was achieved by coupling any primary technique followed by adsorption. In this context, Titchou et al. (2021) investigated the removal of paracetamol and several other pharmaceutical pollutants through electrocoagulation combined with adsorption. They concluded that using these hybrid techniques is a good method for successfully treating real effluents containing various compounds, often under uncontrolled conditions.

Finally, new green strategies can be used to effectively utilize microorganisms and plants for wastewater treatment to remove various organic micropollutants, including paracetamol (Abdullah 2020). Phytoremediation, for example, employs the ability of plants to absorb and translocate organic and inorganic contaminants in wastewater treatment (Zeki and M-Ridha, 2020). In addition, it is also possible to associate other microorganisms in the same process, such as rhizobacteria, which play a crucial role in this process (Makkiya and Al-baldawi 2019). A study by Mohammed et al. (2021) used Alternanthera sp., a flowering plant in the family Amaranthaceae, which allowed the removal of 88.6% of paracetamol in the effluent studied without damaging the plant. The studies by Hasan et al. (2021), Dai et al. (2021), and Khoshvaght et al. (2021) also investigated the biodegradation of paracetamol by microorganisms, including bacteria, and obtained good removal rates.

Scale-up applications

Undeniably, the reckless and indiscriminate use of pharmaceutical compounds has begun to take a toll on the modern society we care for. Fortunately, significant efforts have been made towards developing several adsorbents with excellent properties for application in the control of various forms of pollution, including paracetamol. Nevertheless, it is indispensable that we start to look at these processes by simulating everyday situations and providing and analysing data closer to what would be obtained in real scenarios. Thus, understanding the desorption and reuse process under fixed-bed systems, optimizing pilot-scale plants, and integrating these systems into wastewater treatment plants are intrinsically connected. Furthermore, Fig. 3 shows that there is also a cyclic relationship between these factors since novel and more effective adsorbents are developed every day, and the operating conditions of wastewater treatment plants are constantly changing as the effluent changes over time.

Fig. 3

Effective paracetamol removal from the environment: (i) understanding desorption and fixed-bed systems, which is crucial for elucidating the kinetics and thermodynamics; (ii) optimization of scale-up column operations, ensuring efficiency at larger scales, bridging the gap between laboratory studies and practical applications; and (iii) integration with wastewater treatment plants and compatibility with existing treatment processes and infrastructure

As presented, for most processes, a reversible nature was reported, according to the interaction types presented, which aggregates to the regeneration capacity of the prepared material, associating its performance to the major advantage that is the possibility of reuse, maximizing adsorption technology in terms of economics and sustainability for industrial applications. Therefore, just as adsorbate retention is crucial, so too is an analysis of its regeneration potential. Sadly, authors are still resistant to including such investigations in their experimental planning, and only eight studies have reported data on the desorption and reuse capacity of the employed adsorbent for paracetamol removal. The recycling capacity ranged from two to five cycles within an acceptable performance rate, and the desorption process varied from using acid, base, or ethanol solutions to thermal treatments.

The lowest recycling potential was observed for charcoal, where the authors reported a significant decrease in efficiency after the second cycle. The desorption process consisted of using 0.1 M NaOH solution as the eluent and heating it at 323 K for 3 h (Boudrahem et al. 2017). Lima et al. (2019a) observed similar results for charcoal, which verified that the developed charcoal could be reused for up to four cycles, maintaining an efficiency of 74%. The desorption process was performed using a mixture of NaOH (0.1 mol L⁻¹) as the eluent with 20% ethanol (v/v). Akpotu and Moodley (2018) verified the same decrease in recycling potential for mesoporous silica, which maintained 75% efficiency after four cycles, using NaOH (0.01 mol L⁻¹) as the eluent Rahman and Nasir (2020), and Lung et al. (2021) reported higher efficiencies of six and five reuses with practically unaltered efficiencies. In both studies, HCl solutions (0.1 and 0.3 mol L⁻¹) were used for desorption. Yılmaz et al. (2021) reported that their adsorbent was stable for up to five cycles when pure ethanol was used as the eluent. Finally, Nguyen et al. (2020) and Gómez-Avilés et al. (2021) showed that thermal regeneration of the adsorbent is also a viable alternative for desorption without having observed losses in performance in comparison with any other solvent as an eluent in the process even under continuous flow systems.

Even though most of the studies were carried out in batch systems, works examining adsorption in continuous and flow systems could be found. This application is crucial, especially in light of the potential use of the generated adsorbents in large-scale applications and for handling enormous volumes. For example, reported García-Mateos et al. (2015) that activated carbon had high bed service times and reduced mass transfer zone heights due to favourable adsorption. The maximum capacity was 100 mg g⁻¹ for a concentration of 10 mg L⁻¹. The material showed high efficiency with fast adsorption and a reduced height of the column mass transfer zone. Positive results were also reported by Haro et al. (2021), who concluded that for a flow rate of 5 mL min⁻¹, the 0.5 g bed becomes practically saturated (95%) after the 200 mL treatment. Nevertheless, with 1 g in the bed, a surface that continues to adsorb paracetamol is still available.

Gómez-Avilés et al. (2021) reported that the penetration time increases with temperature in the same proportions as the capacity, reaching 217 mg g⁻¹ (at 293 K), 245 mg g⁻¹ (at 313 K), and 265 mg g⁻¹ (at 333 K). An increase in the flow rate diminishes the disruption time, but the volume of liquid that passes through the bed to the breaking point (C/C₀ = 0.05) is almost the same, and the mass transfer zone length does not change remarkably with the flow rate for the tested flow rate range, indicating that there is no outwards broadcast restriction. Furthermore, the calculated total uptake capacities in the bed were very similar [213.2 mg g⁻¹ (60.9 mL h⁻¹) and 215 mg g⁻¹ (180 mL h⁻¹)] in agreement with the rupture curves. Additionally, it was verified that an increase in the inlet concentration diminishes the penetration time and enhances the bed’s total uptake capacity. Finally, Yılmaz et al. (2021) verified a maximum capacity of 38.2 mg g⁻¹ for a concentration of 40 mg L⁻¹ and a 2 mL min⁻¹ flow rate for 45 cm of bed depth. According to the Thomas and Yoon–Nelson models, the simulated experimental results of column operations indicate a capacity of 20.8 mg g⁻¹.

Now that we have discussed desorption, recycling, and flow system applications, we can include the outlooks for paracetamol removal under conditions that simulate actual environmental samples. Of all the works investigated in this review, only six have conducted efficiency studies on paracetamol removal from actual or simulated effluent. In these studies, the goal was to observe the efficiency of an adsorbent developed for a mixture of paracetamol with different drugs and organic compounds, aiming for its real-scale application. In this case, the adsorption studies typically followed neutral pH and room temperature—although, in some cases, the dosage must be higher than that used in batch experiments, aiming at greater removal efficiency. Kerkhoff et al. (2021) reported a removal efficiency of 84.8% for a mixture containing paracetamol, ketoprofen, naproxen, ibuprofen, and common anions, such as Cl⁻ and CO₃²⁻. Lung et al. (2021) also achieved impressive results, removing 85.1% of paracetamol in an effluent sample containing eight drugs, two sugars, and eight other organic and inorganic compounds. Nevertheless, Lima et al. (2019a) reached even higher efficiencies, up to 98.8%, in two simulated hospital effluents containing several drugs in addition to organic and inorganic salts. A lower efficiency was reported by Yılmaz et al. (2021), who removed 67.4% of paracetamol from a synthetic mixture of various pharmaceutical compounds.

Even though the authors’ efforts are admirable in investigating and demonstrating the potential of their developed adsorbents under simulated conditions, in real wastewater treatment plants, the characteristics of the water samples will play a more significant role than other pharmaceutical compounds. The effects and influences of different water matrices were investigated by Nguyen et al. (2020). The samples included distilled water, tap water, groundwater, urban sewage, coastal water, and wastewater (from a water treatment plant). Despite the different pH values of each sample, the adsorbent presented q_max values ranging from 192 to 216 mg g⁻¹, showing that the adsorbent has great potential for complex samples. Praveen Kumar et al., (2021) demonstrated paracetamol removal in actual river samples containing inorganic ions and compared its efficiency to that of pure water systems. The removal percentage was little affected by the presence of common ions, reaching a removal of 91.3% and 98.6% for the pure water sample.

Ecotoxicology

Ecotoxicology is a branch of study that examines how toxins in the biosphere affect its inhabitants. René Truhaut coined the term ecotoxicology in 1969 (Kahru and Dubourguier 2010; Boros and Ostafe 2020). According to him, toxicology studies on the toxic effects caused by natural or synthetic pollutants on the constituents of ecosystems, vegetables, animals (including humans), and microbes are a branch of toxicology (Truhaut 1975). Due to environmental pollution caused by rapid industrial development and severe industrial accidents, ecotoxicology research has accelerated, and policies have been developed accordingly. This branch became vital to environmental and ecological assessment (Boros and Ostafe 2020).

While ecology focuses on interactions between organisms, distributions, and abundances of organisms, the behaviour of biological populations and communities, and the processes that can affect all these parameters, toxicology is concerned with understanding the types of effects caused by chemicals, the biochemical and physiological processes responsible for those effects, the relative reactions of different types of organisms to chemical exposures, and the relative toxicities of different chemicals. Ecotoxicology involves the integration of ecology and toxicology, and it is essential to understand and predict the effects of chemicals on natural communities under realistic exposure conditions (Chapman 2002).

The usual method used to analyse the quality and potential effects of discharged effluents on aquatic ecosystems is based on a set of physical–chemical parameters, such as pH, temperature, chemical oxygen demand, suspended solids, ammonia, nitrogen, nitrite, nitrate, and others, rather than on ecotoxicological aspects. However, water pollution includes a large number of compounds of different natures whose toxic effects and interactions are not always understood. Therefore, investigating single compounds does not always provide sufficient information to estimate the potentially toxic effects of the substances present in effluents, as synergistic or antagonistic effects of pollutants cannot be detected. In addition, the toxic effects of unknown and frequently undetermined substances in a complex mixture can be detected only by toxicity tests (Domínguez Henao et al. 2018).

Paracetamol metabolism

Even though paracetamol differs from typical nonsteroidal anti-inflammatory drugs because its analgesic and antipyretic effects do not rely on the inhibition of the cyclooxygenase enzyme in peripheral tissues, paracetamol is often found in pharmaceutical formulations combined with other classic anti-inflammatory drugs, such as ibuprofen (Hyllested et al. 2002). The pain-blocking mechanisms underlying the effects of paracetamol are related to the indirect blocking of cyclooxygenase receptors and the blocking of its enzymatic isoforms. Moreover, the mechanisms responsible for its antipyretic action are cerebral, resulting in vasodilation, increased sweating, and consequent loss of body heat (Chandrasekharan et al. 2002). Paracetamol is primarily metabolized in the liver by first-order kinetics, and its metabolism comprises three steps: glucuronide conjugation, sulphate conjugation, and oxidation via the cytochrome P450 enzymatic pathway, which produces a reactive metabolite called N-acetyl-p-benzoquinone imine (Forrest et al. 1982).

One of the major problems associated with this drug is the formation of toxic substances, such as N-acetyl-benzoquinone imine metabolites, during its degradation. Additionally, toxic substances can be formed in oxidative pathways in cases of overdose, resulting in severe effects on the organism, such as protein denaturation, lipid peroxidation, and damage at the DNA level (Antunes et al. 2013; Montaseri and Forbes 2018). Several studies have reported on the intoxication and organ damage caused by paracetamol in humans, highlighting its liver toxicity effects (Boyd and Bereckzy 1966; Mazaleuskaya et al. 2015). Approximately 56000 emergencies occurred. In addition, a troubling rise in paracetamol-related complications has been reported, with 26000 hospitalizations and 438 deaths occurring at overdoses exceeding between 150 and 200 mg kg⁻¹ body weight (Krauskopf et al. 2020; Thanacoody and Anderson 2020).

In the USA, for example, alarming cases of paracetamol poisoning have been reported, including acute poisoning (Chefirat et al. 2020). In summary, paracetamol can cause severe damage to the liver due to its hepatotoxicity if it is continuously consumed and in cases of poisoning (Rubenstein and Laine 2004; Larrey 2009). However, at normal therapeutic doses, N-acetylbenzoquinone imine undergoes rapid conjugation with glutathione and is subsequently metabolized to produce conjugates of cysteine and mercapturic acid (Sheen et al. 2002). In this context, because of short-term acute N-acetylbenzoquinone imine formation, long-term exposure in humans has not yet been widely studied and must be addressed (Mullins et al. 2020; Nunes 2020; Sousa and Nunes 2021). Thus, investigations have been conducted employing test animals, mice, and other aquatic organisms, such as fish and crustaceans.

In tests on animals, when exposed to small concentrations of paracetamol, several types of damage to the animals were detected, such as changes in the levels of various components of the liver due to increased oxidative stress (Olaleye and Rocha 2008). Alterations in the hypothalamic neurotransmission of rat offspring have also been detected, in addition to significant effects on dopaminergic and noradrenergic neurotransmission and alterations in the concentration of glutamic acid in the hypothalamus (Blecharz-Klin et al. 2019). The reproductive effects also include changes in sperm count and chromatin integrity at the DNA level (Abedi et al. 2017).

Moreover, regarding cerebral functions, changes in the profile of monoamines in the hippocampus, cortex, and striatum in the aminogram profile of the brain, alterations in dopaminergic and serotonergic neurotransmission, and alterations in cognitive performance and visual motor skills have been observed (Cechetti et al. 2012, Blecharz-Klin et al. 2014, 2017). In the studies by Blecharz-Klin et al. (2015), the main changes in amino acid levels are related to alanine and taurine, which affect noradrenergic and serotonergic neurotransmission and neurotransmission in the medulla. In turn, damage related to sexual hypothalamic differentiation, alterations in the sexual behaviour of adult male offspring, and increases in testis weight in adulthood have been reported Pereira et al. (2020).

Studies carried out in aquatic organisms have also revealed several changes that put aquatic biota survival at risk when exposed to any amount of paracetamol. For instance, Gutiérrez-Noya et al. (2021) reported that the presence of the drug reduced the survival rate and incidence of malformations in Cyprinus carpio by up to 90%. Males of Rhamdia quelen had an interruption of the hypothalamic-pituitary–gonadal axis after 21 days of exposure to paracetamol. Oxidative stasis, hematological changes, and hepatotoxicity have also been reported (Guiloski et al. 2017). Oxidative stress has also been reported in molluscs (Ruditapes philippinarum), which exhibit decreased metabolic capacity and neurotoxicity (Nunes et al. 2017). In the mollusc species Ruditapes philippinarum, toxic oxidative effects are generated by significant alterations in several parameters, such as superoxide dismutase activity and the reduced/oxidized glutathione ratio (Correia et al. 2016).

Environmentally relevant concentrations of Rhamdia quelen affected the antioxidant system of the gills and kidneys, with a reduction in the number of leukocytes and thrombocytes. It is pointed, therefore, paracetamol has genotoxic effects on the blood, kidneys, and gills, with osmoregulatory damage and a nephrotoxic effect (Perussolo et al. 2019). The drug caused liver damage in Xenopus embryos similar to that observed in mice (Saide et al. 2019). In the species Daphnia magna, there was an alteration in gene expression and redox homeostasis disruption caused by oxidative stress (Liu et al. 2019). In zebrafish, anxiolytic-type behavioural effects were observed (Giacomini et al. 2021). Danio rerio embryos exhibited morphological changes (Rosas-Ramírez et al. 2022). It can be concluded that, as in humans, paracetamol is potentially toxic to aquatic organisms and animals, causing mainly liver and kidney damage and oxidative stress at the DNA level.

Relevance of reported data in applied ecotoxicological research

Despite all efforts made by the scientific community, one of its major limitations is extending laboratory-scale results to real-life applications. As a result, many new adsorbents have been developed each year. However, it is known that activated carbon, a classical material, is still the choice made by industry, given its effectiveness in solving problems and preventing ecotoxicological effects after wastewater discharge. In this context, the performance of each reported activated carbon was compared with the ecotoxicological data reported for several species, including mammals and aquatic organisms, for which the performance of their adsorbents for paracetamol removal under actual conditions was investigated (Kerkhoff et al. 2021; Lung et al. 2021; Lima et al. 2019b; Yılmaz et al. 2021; Nguyen et al. 2020; Praveen Kumar et al. 2021). After the conversion, we compared the obtained values with the previously reported values. These results are presented in Table 6, where we classified the outcomes of the studies as effective if the final concentration of paracetamol in the actual or simulated effluent was lower than the critical ecotoxicological value.

Table 6 Toxicological effects of paracetamol on various species (columns 1–3), followed by the reference of studies that explored paracetamol removal from real or simulated wastewater samples and its conversion efficiency, as given in the formula below (columns 4 and 5). Column 6 shows whether the efficiency reported in the study was sufficient for preventing the occurrence of ecotoxicological effects

Kerkhoff et al. (2021) reported a removal efficiency of 84.8%, corresponding to a final concentration of 7.6 mg L⁻¹ of paracetamol in a mixture containing other pharmaceuticals and other anions. According to our analysis, this result means that even though the reported efficiency was high, it did not reach a significant level for all species studied except for male albino mice and Xenopus embryos. Nevertheless, these two species had higher critical values of 250 mg kg⁻¹ and 755.8 mg L⁻¹, respectively. Moreover, 7.6 mg L⁻¹ is a high value if we compare it with the ${C}_{0}$ values employed for other techniques, such as photocatalysis. Therefore, even though the results obtained by Kerkhoff et al. (2021) are promising, it is possible to say that this study did not stand out.

In one of the most complex effluent samples described, 85.1% of the remaining paracetamol was removed, corresponding to 1.5 mg L⁻¹ of paracetamol, which was proven to be effective for ecotoxicological damage control of three of the species described according to our analysis (Lung et al. 2021). In Table 6, we have described the conversion efficiency in the 1.5–14.8 mg L⁻¹ range because the author has proven to be statistically significant within the C₀ range between 10 and 100 mg L⁻¹. A comparison of the results of Yılmaz et al. (2021) and Nguyen et al. (2020) revealed that even though the lowest removal efficiency was reported for the former, it was more effective than for the latter, resulting in final paracetamol concentrations of 1.885 mg L⁻¹ versus 75.0 mg L⁻¹, respectively. The data reported by Nguyen et al. (2020) presented the same effectiveness as the work by Kerkhoff et al. (2021), while the results obtained by Yılmaz et al. (2021) were adequate for preventing ecotoxicological damage to Mala albino mice, Xenopus embryos and Daphnia magna. The study by Praveen Kumar et al. (2021) reached the same ecotoxicological efficiency as Yılmaz et al. (2021).

Lima et al. (2019a) reported a high efficiency of 98.8%, corresponding to 0.461 and 0.936 mg L⁻¹ of paracetamol in samples with initial concentrations of 40 and 80 mg L⁻¹, respectively. Even though the values reported by Lima et al. (2019a) were the lowest amounts of paracetamol in the final samples, they were still not sufficiently low for preventing ecotoxicological damage to Cyprinus carpio and Rhamdia quelen. Of all the organisms studied, however, these two species were the most sensitive to much lower paracetamol concentrations, in the order of 10^–4 mg L⁻¹, and none of the studies reported a sufficiently low concentration of the remaining paracetamol to be effective in preventing ecotoxicological damage.

Of the 42 situations analysed, only 14 presented favourable results, 3 were partially efficient, and 25 were ineffective compared to the critical ecotoxicological values reported for the species studied. Of the 14 favourable outcomes, six were obtained for the only mammal described (male albino mice), which was one of the two species for which all the studies were effective. Despite the wide range of reported conversion efficiencies, the critical ecotoxicological value for mammals is reported in mg kg⁻¹. Given the average weight of a mouse, it would require it to be intoxicated with large amounts of contaminated water. Nevertheless, over half of the situations investigated were proven to not be favourable. Some authors may justify that the effectiveness would be greater in actual samples where lower paracetamol concentrations would be found. However, this statement can be easily turned down by saying that the authors have used the chosen initial concentration because of its dependence on the adsorbent ${q}_{\text{max}}$ value, which would also change if the initial concentration of pollutant changes. Thus, the criteria and results that we have carefully established are valid.

Perspective

Given that paracetamol is consumed worldwide, it is impressive that there is not enough data available on its production, exportation, importation, and over-the-counter selling, making it difficult to visualize its circulation in the environment. If these forecasts cannot be made, then anticipating actions cannot be taken to control expected levels of pollution, which need to be adjusted according to paracetamol use by the population. Thus, the first knowledge gap contemplates the lack of market control and data accessibility regarding paracetamol, even in the scientific community. Although we have circled around and back to all environmental aspects regarding paracetamol, it is impossible to discuss the gaps and perspectives without including a significant viewpoint since most of the problems encountered regarding paracetamol pollution revolve back to pharmaceutical pollution control in general. To solve this problem, higher levels of cooperation between pharmaceutical industries and environmental analysis laboratories need to be discussed.

The second knowledge gap, which is also a possible reason why industries do not interact much with academic sectors, is the lack of fitness in data interpretation and effective troubleshooting, i.e. developing studies focused on solving problems instead of demonstrating the efficiency of said novel adsorbents by employing the same sequence of methodological steps that we, the audience, are accustomed to. Thus, even though the scientific method is correct and the data reported are valid, most studies do not address more severe problems that need to be solved. Therefore, as demonstrated and discussed, insufficient discussion is available on cost-effectiveness or understanding the interaction mechanisms involved. Hierarchical changes need to be made in how science is produced and demanded to overcome this problem.

Looking ahead, the focus in adsorption research is on developing more sophisticated models to predict phenomena and understand nanoscale adsorption mechanisms, particularly in the context of paracetamol pollution. Over the past decade, deep learning and machine learning have been instrumental in predicting adsorption data, evaluating variable impacts, and reducing treatment costs and time. Novel isotherm models based on statistical physics, including the grand canonical ensemble perspective, have enabled targeted enhancements in adsorbent structures, enhancing pollutant removal efficiency.

Since we have thoroughly analysed the relevance of the published data on efficiency by converting it to the remaining paracetamol concentration (mg L⁻¹) and later comparing the results to the critical ecotoxicological value for various organisms, the last perspective for future studies is that data transparency on adsorption efficiency for paracetamol control continues to be taken seriously. Therefore, while several advances have been made in this field, it is possible to see an increase in the number of academic texts and published papers that describe their data under actual or simulated conditions, considering the complex water samples found in wastewater treatment plants so that these novel technologies and materials can be applied quickly, even regionally. Thus, in the future, we can expect to see a shift from the majority of studies being conducted under batch-to-column mode, followed by more critical environmental and ecotoxicological assessments on the final treated sample obtained included in the efficiency percentage.

Conclusion

This review analysed more than 50 studies on the removal of paracetamol by adsorption. Although research on paracetamol remediation is less extensive than that on other pharmaceuticals, significant progress has been made. Key operational factors, such as the initial paracetamol concentration, adsorbent dosage, adsorbate solution pH, and contact time, are well understood and have been shown to influence process efficiency. Combining adsorption with other advanced oxidative degradation methods has proven to be successful, achieving maximal removal efficiency in shorter times and showing promising degradation rates for wastewater treatment. However, further research is needed to fully understand desorption and fixed-bed systems, optimize scale-up column operations, and integrate these methods into wastewater treatment plants. In general, the findings indicate that the adsorption process is most efficient at neutral pH and temperatures of approximately 20 °C. The Langmuir monolayer model often best represented the system’s equilibrium, with adsorption capacities reaching 555.6, 666.67, and 704 mg g⁻¹. Physical interactions, including hydrophobic interactions, π–π stacking, van der Waals forces, hydrogen bonding, and n-π interactions, are commonly involved in the adsorption process. Most studies demonstrated that regeneration using NaOH for desorption was feasible, maintaining a removal rate above 70% after five cycles. However, only six studies considered actual environmental conditions. When comparing the efficiencies reported in the studies to critical ecotoxicological values for seven different organisms, only 14 out of 42 situations resulted in positive outcomes, highlighting the crucial need for future research to prioritize ecotoxicological parameters as the primary measure of adsorption efficiency.