The Spreads and the Uniqueness of the Controversial Toxic Pharmaceutic Contrast Agents and Their Remediation.

The ongoing gadolinium toxicity concerns have resulted in progressive regulations and restrictions of gadolinium-based contrast agents (GBCAs). However, there are no regulations regulating Gd levels in the water sector to date. Therefore, the fast spreading of the anthropogenic Gd in the various hydrosphere, which serves as a source of drinking water for the populace, is worrisome. Evidently, with no hope of breaking this increasing trend any time soon due to the increasing demand for MRI administration. Sadly, conventional wastewater and advanced water treatment do not adequately remove GBCAs from water. Instead, it risks transforming them into a more toxic Gd from its chelated complex through unintentional degradation. This transformation led to undue exposure to its potential ecotoxicity and adverse human health effects like acute renal adverse reactions, acute non-renal adverse reactions, body pains, chronic skin changes, twitching or weakness, chronic eyes, and cognitive, u-like symptoms, and digestive symptoms. Therefore, an affordable and manageable hybrid water treatment system is proposed suitable for reclamation of free and chelated Gd in aquatic environments.

due to seven unpaired 4f electrons with a total angular momentum of J L S 7/2 with a hexagonal close-packed structure crystal (Dan'kov et al., 1998). The Magnetic and electronic properties of the bulk and the surface of Gadolinium metal in its ferromagnetic ground state and paramagnetic high-temperature phase are represented in Figure 1. Figure 1: (a) and (b) illustrate the spin-resolved spectral DOS of the ferromagnetic state and total spectral DOS of the paramagnetic state of bulk gadolinium at the Fermi energy, respectively, as projected to the 2D Brillouin zone. The darker region depicts the bigger values of the spectral DOS. Gadolinium ortho-aluminate is an example of rare earth compounds, ABO 3 , where A is a rare-earth ion and B represents another trivalent ion, e.g., Fe 3 or A1 3+, which crystallize in a tinkered perovskite structure (space group D" -Pbnm) which shows the orthorhombic unit cell and also the eudocubic cell. The orthorhombic cell dimensions of GdAlO 3 are a = 0.5247 nm, b-0. 5304 nm, c= 0.7447 nm, in such a way that the shift of the pseudocubic cell is very little (a'-=0.3730nm, b'-0.3730nm, c' =c =c-0.3723nm, and the angle, = -90.60). This dimension is signi cant because, for a cubic lattice, the magnetic dipole interaction eld on a particular ion disappears in both the ferromagnetic state (all magnetic moments parallel) and for the simple antiferromagnetic state (all nearest neighbors antiparallel) as a result of the ions in a spherical sample . The detailed structure was described by Geller and Bala in I956 as reported by (Cashion et al., 1970) and shown diagrammatically in Figure 2.
Gd 3+ is located in a local environment of low symmetry, with just a mirror plane perpendicular to the c-axis. The supposed crystalline electric eld acting on the Gd 3 ions in gadolinium aluminate has not been directly veri ed yet; however, the experiments reported in 1964 by White R.L and his team on electron spin resonance of gadolinium ions in the isomorphous diamagnetic host yttrium aluminate indicate that the anisotropy forces in the antiferromagnetic are as a result of the crystalline electric eld effects state. (Cashion et al., 1970). MRI scanning involves applying proton nuclear magnetic resonance (NMR) for medical tomography; the protons scanned are those of the water molecules in the scanned region. A critical factor in uencing the scanned image quality is the rate at which excited protons in the scanned area relax, emitting radiofrequency photons as they fall from the upper to the lower energy state in the magnetic eld. The shorter the relaxation time takes, the better the quality of the image (Cash, 2016). Gadolinium is the rst pure element to exhibit ferromagnetic at near ambient temperature, except for the other three 'classic' metals, nickel, cobalt, and iron. This distinctive magnetic feature of Gd has found relevant industrial applications such as magnetic refrigerators and enhanced M.R. diagnostics. For example, its application in MRI provides highquality images with a non-invasive diagnosis of myocardial, oncologic, in ammatory, orthopedic, and neurological vascular diseases ( Besides gadolinium, manganese (Mn), a transition metal, has the second-highest paramagnetic moment because the Mn +2 ion has 5 unpaired electrons in its 3d shell. Based on this property, an attempt was made to use manganese as a chelated paramagnetic contrast agent called mangafodipir trisodium (Mn-DPDP) and commercially named Teslascan®. However, the manganese chelate was withdrawn from the U.S. and the E.U. marketplace in 2003 and 2010. The withdrawal was due to unsatisfactory clinical performance and concerns over its toxicity, resulting in poor patronage. Thus, to date, the gadoliniumbased contrast agent remained the most popular and utilized contrast agent. Unarguably, many crucial life-saving medical information that is otherwise impossible with other imaging modalities have been obtained by physicians using Gadoliniumbased contrast-enhanced MRI for diagnostic imaging since 1988, and it is still considered relatively safer and preferred over Nonetheless, the toxicity of gadolinium salts also requires that the chelation of Gd 3+ ions with appropriate multidentate for its safe usage in biomedical applications and to improve its water solubility (Lohninger, 2020; Fox-Rawlings and Zuckerman, 2019; McDonald et al., 2018; Pen eld and Reilly, 2007). The bounded complexes, also known as "Gadolinium-based contrast agents (GBCAs)," contain gadolinium ions and a chelate / a ligand /a carrier, which secures the gadolinium ion rmly. This adjunct typically formed the different nomenclature of commercial GBCAs (Kanda et al., 2016). However, despite the chelation of gadolinium ions, GBCAs also degrade invitro through transmetallation with a higher degradation and deposition incidence in the brain (Pen eld & Reilly, 2007). Higher degradation susceptibility is associated more with the linear GBCA chelates than the macrocyclic chelates due to their transmetalation in vitro. Approved Commercial chelated gadolinium can be grouped according to some critical molecular design parameters which are responsible for the differences in their thermodynamic stability constants and kinetic stability; (a) Type of the chelating moiety: the linear open-chain molecules chelate, or the macrocyclic molecules chelates where Gadolium ion is enclosed in the preorganized cavity of the ligand, (b) ionicity: the ionicity of the complex varies from neutral to tri-anionic agents, and (c) the presence or absence of an aromatic lipophilic residue required for protein binding (Port et al., 2008). There are reported differences in the thermodynamic and kinetic behaviors, even among contrast of same chelation type. It is, therefore, complicated to assume similar kinetic and thermodynamic behaviors invitro of GBCAs of the same chelate type as strongly argued by the proponent of GBCAs safety. The kinetic stability of a gadolinium complex, rather than its thermodynamic stability, dictates its in vivo toxicity (Sherry et al., 2009;Boyken et al., 2019). The idea of kinetic and thermodynamic stability of GBCAs is currently under critical discussion, being a controversial topic that has birthed a renewed curiosity in the physicochemical characteristics of gadolinium chelates administered during contrast-enhanced MRI (Port et al., 2008).
The ligand on a linear chelate has a tail that wraps partially enclosing the atomic Gd, which is a exible structure and facilitates the easy release of free Gd. In contrast, the ligand on a macrocyclic chelate produces a cast-iron-like structure that completely embeds the Gd atom (Fox-Rawlings & Zuckerman, 2019). Thus, the four covalent bonds in a cyclic chelate must be simultaneously broken before Gd can be freed. The linear and macrocyclic structures are depicted in Figure 3. Consequent to this nding, the macrocyclic GCBAs, and selected linear ionic GCBAs are more favorably disposed to by the regulatory agencies to use as contrast agents in recent times. Presently, efforts are in place to phase out linear GBCAs from medical treatment and their replacement by the macrocyclic and nonionic forms to reduce the chance of its de-chelation and potential toxicity (Choi and Moon, 2019; Guo et al., 2018). As a result, a total decline of 70% in sales of linear GBCAs between 2009 and 2016 was observed using 10-year data from hospitals and pediatric clinics in 2017. On the other hand, the sales of the macrocyclic GBCAs rose to 82 % within the same period, 2018), as presented in Figure 4. Compared to the macrocyclic chelates, the low administration of the linear chelates probably accounts for the observed higher occurrence of the latter in surface and drinking water in recent times (Rogowska et al., 2018).

Current Gbcas Approval Status
In conjunction with the European Union in a swift reaction to the concerns about Gd toxicity, the European Medicine Agency has On the other hand, the US FDA initially declined to restrict using any of the Nine (9) different GBCAs, including those reportedly linked to higher gadolinium retention in the brain. The US FDA's position was due to a lack of substantial evidence on the effect of gadolinium on the human body, even though its advisory body held a contrary view. However, after a series of meetings to address these concerns between 2006 and 2010, it mandated that all approved GBCAs add some speci c changes to its labeling in clinical Pharmacology and the Patient instruction sections bearing a warning precaution concerning its retention in patients having unhealthy kidneys (glomerular ltration rate or GFR < 30 mL/min/1.

Anthropogenic Gadolinium As A Global Threat In Water
Several constituents have been described as emerging pollutants originating from pharmaceuticals and personal care products GBCAs are unintentionally destabilized during conventional or advanced water treatment yielding to rapid transmetallation of GBCAS into free toxic Gd. Consequently, there is an urgent need to recover the controversial anomaly Gd during the water and wastewater treatment process to prevent the inadvertent consumption of Gd through drinking water, beverages, and other processed or raw foods. Similarly, at present, the amount of anthropogenic Gd detected in tap and surface water is relatively small, ranging from 100 to 1100 ng L-1, which makes some opines that the ingestion and retention of such a low quantity of gadolinium as observed in brains seems more of a curiosity than a health concern. (Fox-Rawlings and Zuckerman, 2019; Garcia et al., 2017). However, the latter author admitted that the long-term sequestration of any toxic metal, even in an inert state, in a sensitive structure such as the brain, is perturbing. They also feared that there could be a point in its lifespan where pathological or other processes could release gadolinium and pose a risk for the local deposition concentration of gadolinium to reach either pathological levels or directly cause harm to human organs (e.g., vascular emboli). In the same vein, the potential harm of continual exposure to low levels of Gd contaminated water, particularly However, some of the publications reviewed in this paper have reported anomaly gadolinium in river water, seawater, groundwater, and tap water in developed cities and less populated locations without developed health facilities, as presented in Table 3.  Table 2 summarizes the geographies' spread of anomaly Gd in aquatic systems and sediments reported within the last two decades from all the six regions and across different localities except the Middle East. The positive anomalies spread of Gd in the aquatic space are anthropogenic and are more likely to be attributable to magnetic resonance imaging (MRI) (Bau & Dulski, 1996) Table 2, it can be observed that almost all known water sources, including surface waters (rivers, ocean, seawater, and stream), municipal water supplies, Groundwater, and steams, across the globe are reportedly contaminated with Gd anomaly. The list reported in this review is by no means exhaustive because the detection of Gd in the aquatic and sediment systems is ongoing research. The risk associated with each identi ed water source varies considerably, and different priority attention and treatment techniques may be required. Most of the reported Gd anomaly incidence is found in the river and surface water that are highly dynamic reservoirs of various wastewater e uents. However, considering the natural hydrological cycle, there is no gainsaying that there could be a knock-on-effect from one source to another as the water moves through different

Technologies for GBCAs Remediation in water
It is evident from the preceding that anomaly Gd contamination in water systems is a global threat that requires urgent appropriate actions regardless of the prevailing controversies. This position was also collaborated by (Ebrahimi & Barbieri, 2019). Therefore, a search for an effective treatment for removing anomaly gadolinium in water is critical to protect abiotic and biotic elements in the ecosystems due to its high toxicity (Rogowska et al., 2018;Gwenzi et al., 2018). Literature has reported several techniques employed to recover free metallic Gd and GBCAs from different aqueous solutions. However, most of the works reported removing free Gd using different techniques rather than GBCAs, which is the most sough (El-Sofany, 2008; Li et al., 2015; Zheng et al., 2019). Separation of GBCAs from wastewater had received lesser attention probably because it is relatively easier to separate the free Gd from an aqueous solution than the complex GBCAs, which is more challenging to treat by conventional technique. Indeed, the dissociation constant, thermodynamics, and kinetic stability among GBCAs types (linear and macrocyclic) limit their separability behaviors (Rogowska et al., 2018;Runge, 2018). The different remediation techniques for GBCAs within the last two decades are presented in Table 3. N/S = Not-speci ed The reverse osmosis separation technique activated carbon adsorption process, biological lters, and Ozonation are popular techniques reportedly applied to remediate GBCAs in an aqueous solution with widely varying e ciencies. The adsorption process is a simple design, low cost, and effective method for treating and removing inorganic and organic contaminants in water and wastewater. Gadolinium chelates removal in wastewater and drinking water through activated carbon adsorption is generally considered ineffective due to its low absorption capacity (Cyris, 2013). However, Elizalde-González et al. (Elizalde-González et al., 2017) achieved an adsorption capacity of 70 -90 % for selected GBCAs using three different optimized carbon samples (commercial activated carbon, activated carbon obtained from guava seeds, activated carbon obtained from avocado).
The highest removal was achieved with the commercial carbon sample, followed closely by the Avocado carbon. According to the authors, the pH, and the number of functional groups on the carbon, speci cally, the phenolic functional groups, played a signi cant role in the removal e ciency. Unfortunately, its e ciency was dramatically reduced when model urine was treated, an observation attributed to the competing urine components, limiting the adsorption capacity. The limitation in the adsorption techniques is that its e ciency varies with Sorbent's types and the aqueous solutions' characteristic nature. Most of the sorbents are only effective for removing free Gd rather than the GBCAs except for the limited success reported by Elizalde-González et al.
The observed limitation is attributable to the problem of fouling caused by other molecules present in the urine. Fouling is a common problem in the adsorption process that causes a signi cant decrease in the adsorption capacities of Sorbent; therefore, further research is required to tackle this gap.
Due to its solubility and chemical reactivity, the ozonation technique is strongly reactive and selective in water pollution control. The technique effectively inactivates micro-organisms and decomposes organic pollutants in water and wastewater treatment The membrane separation is a favorite water treatment technology for removing pollutants from water and wastewater streams for re-use through a selectively permeable barrier. The barrier is usually a thin sheet of material separating substances based on their chemical and physical characteristics under a driving force (Brose et al., 2002;Ezugbe and Rathilal, 2020). The membrane technology's aims to produce high mechanical strength materials and an excellent and high degree of selectivity of the desired permeate, which comes in different modules including; Membrane ltration that is pressure-driven processes (micro ltration, ultra ltration, nano ltration, and reverse osmosis), Pressure and thermal Driven Processes (Membrane distillation), Non-pressure driven process (Forward Osmosis, Liquid membrane) and Non-pressure electricity-driven processes electrodialysis (Shen,

Perspective
It is pertinent to note that up to date, only a handful of research has reported the removal of GBCAs in the wastewater treatment process in the last two decades. Most research in this area focused on removing free Gd rather than the GBCAs, the pharmaceutical form of the anomaly Gd in water. Therefore, people probably ingest a minute quantity and concentration of dechealated Gd via drinking contaminated municipal tap, domestic well water, beverages, or consuming contaminated food ingredients (meat, seafood, and vegetables) unwittingly. The several studies that reported low-level gadolinium concentration in the brain tissues and bones of patients who had never received any GBCA reinforced this possibility (Fox-Rawlings & Zuckerman, 2019). The increasing spread of anomaly Gd across the continents suggests that it is crucial to investigate the probable presence of anomaly Gd in new localities that are not yet investigated, especially those with a relatively high MRI examination per capita. A sporadic increase in the concentration of Gd in Berlin within just three years suggests an imminent danger as similar trends could be discovered in other locations where anthropogenic Gd are previously detected at lower concentrations or where they were earlier non-existent (Tepe et al., 2014). Hence, it is strongly recommended that communities where anomaly Gd is yet to be investigated or previously reported to be free of Gd should be monitored. The observed precarious Gd spreads and the gloomy future projections call for appropriate authorities to protect groundwater and surface water from impending Gd pollution disasters. In the same vein, it is needful to examine the possible presence of Gd in the tissues of people with no previous record of GBCAs administration particularly, those living in localities with highly exposed drinking water sources. Such information from volunteers is required to form part of the much-sought data about the environmental fate of Gd in different ecosystems and its possible bioaccumulation in the human body through contaminated water.
Current understanding justi es the urgent need to search for appropriate, effective, and economical technology to prevent the entering of controversial anthropogenic Gd metal into our water systems as an alternative to the high energy dependent reverse osmosis (Prathna et al., 2018). Earlier, Brünjes and Hofmann had suggested that each MRI examination should be followed by collecting the patient's urine to halt the spread of Gd contamination in drinking water. However, the sustenance of this recommendation should be a concern. Firstly, the urine collection period recommended by the authors remained inde nite for apparent reasons; it is known that differences in molecular properties signi cantly determine the elimination behavior of GBCA; therefore, the elimination of each GBCA in vivo is quite different even at a very slight difference in its molecular properties and also depends on many interactive factors with the endogenous biomolecules (Aime, 2019). Moreover, considering the heterogeneity in human socio-cultural and religious perceptions, the required stakeholders' cooperation in other localities where such practice is required can hardly be assured. This can be inferred from the medical staff's initial skepticism in Germany, as revealed by the authors. Ultimately, the search for an effective and manageable treatment technique to treat this relatively new microcontaminant becomes imperative, just like other well-recognized emerging pharmaceutical contaminants.
To this end, we suggest a hybrid system that synergistically combines the dechelation of GBCAs via a commercial chemical coagulation process using ferric or aluminum salts (Lewis salts). The reaction results in an acidic microenvironment, thereby acidifying the GBCAs for easy degradation or transmetallation to release free Gd ion ( The proposed hybrid technique is expected to provide a relatively economical alternative to reverse osmosis because lowpressure-driven adsorption is required. However, the possible challenges in the proposed hybrid technique include.
i. Excess Fe or Al or/ and newly formed metal ligands as secondary pollutants during coagulation and occulation processes.
ii. Inability to effectively and completely degrades linear and macrocyclic chelates in a single pretreatment technique, particularly under simulated natural environment for practical industrial applications.
These possible challenges offer vast opportunities for future research in nding possible means to circumvent them.

Conclusion
Anthropogenic Gd chelates are undoubtedly emerging microcontaminants in different water resources across the continents regardless of population and number of MRI per capita. Higher trends and spreads of anomaly Gd are expected based on the increasing diagnostic requirements such as the one necessitated by the SARS -CoV-2-related heart damage. Besides, GBCAs administration is still permitted by the regulatory agencies because of the risk-bene ts considerations and non-availability of a suitable substitute for the time being. Arguably, the inability to set the necessary limits to the toxic metal in the water system is due to the Gd anomaly's unknown long-term effects on the aqueous ecosystem. In our opinion, it is crucial to urgently set a precautionary limit while investigating the controversies concerning its deposition's clinical effects on human tissues. The Although, the reverse osmosis membrane technique, a high-pressure technique, has shown promising results for eliminating GBCAs. It is, however, a costly option available in state-of-the-earth plants; therefore, the wastewater treatment researchers and designers are required to pick up the much-desired challenge of developing an affordable and effective technique for the removal of the ubiquitous Gd contrast agent in the water space. To this end, the proposed hybrid in-situ treatment system that degrades the complex GBCAs in the wastewater system may be considered a feasible and promising alternative treatment for the micro contaminant GBCAs. This is necessary to safeguard our aquatic foods and drinking water from gadolinium contamination. Additionally, success in this direction potentially bene ts from the use of Gd as a valuable tracer of pharmaceuticals microcontaminants in wastewater because of its persistence, reliability, coupled with the fact that it is cheaper to measure accurately even at very low concentrations (Tepe et al Availability of data and materials Not applicable.

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Competing interests The authors declare no con ict of interest  Pathway leading to the release of GBCAS / anthropogenic Gd into the drinking water system/beverage