Groundwater contamination by pharmaceuticals, which belong to the category of contaminants of emerging concern (CEC) or emerging organic pollutants (EOP), has been receiving increasing attention in the fields of environmental engineering, hydrology and hydrogeochemistry since the last decades of the twentieth century.
Pharmaceuticals are suspected to provoke long-term effects in aquatic ecosystems even at low concentration ranges (trace concentrations) because of their bioactive and chemically stable nature, which leads to recalcitrant behaviours in the aqueous compartments, a feature that is typically associated with the difficulty in degrading these compounds to innocuous molecules, similarly with the behaviour exhibited by persistent organic pollutants. Furthermore, continuous release of medical products in the water cycle poses concerns about bioaccumulation and biomagnification phenomena. As the vulnerability of groundwater systems is increasingly recognized even from the regulating authority (the European Medicines Agency, EMA), environmental risk assessment (ERA) procedures, which is required for pharmaceuticals appliance for marketing authorisation and preventive actions urged to preserve these environments.
In the last decades of the twentieth century, scientific research efforts have been fostered towards deeper understanding of the interactions of groundwater transport and attenuation mechanisms with the chemical nature of polluting agents. Amongst the multiple mechanisms governing solutes mobility in groundwater, biotransformation and biodegradation play a crucial role in determining the evolution of the system (as identified by developing concentration fields) in the presence of organic compounds, such as pharmaceuticals. Other processes that might impact on pharmaceuticals fate in groundwater include classical advective-dispersive mass transfer, as well as geochemical reactions, such as adsorption onto soils and dissolution / precipitation.
One major goal in the field of environmental protection and risk mitigation is the development of mathematical formulations yielding reliable predictions of the fate of pharmaceuticals in aquifer systems, eventually followed by an appropriate quantification of predictive uncertainty and estimation of the risks associated with this kind of contamination.
General problem Pharmaceuticals represent a serious threat to aquifer systems because of their bioactive nature, which makes them capable of interacting directly with therein residing living microorganisms and yielding bioaccumulation and biomagnification phenomena. Occurrence of xenobiotics in groundwater has been proven to harm the delicate equilibria of aquatic ecosystems in several ways, such as promoting the growth of antibiotic-resistant bacteria or causing hormones-related sexual disruption in living organisms in surface waters. Considering then the role of groundwater systems as main worldwide drinking water resources, the capability of pharmaceuticals to interact with human tissues poses serious concerns also in terms of human health. Indeed, the majority of pharmaceuticals do not degrade in groundwater, where get accumulated due to their continuous release in the environment. Then, these compounds reach subsurface systems through different sources, such as hospital effluents, wastewaters and landfill leachates, which clearly risk contaminating drinking water.
Most detected pharmaceutical classes The main pharmaceutical classes detected in worldwide groundwater systems are listed below. The following categorisation is based on a medical perspective and it is often referred to as therapeutic classification. Antibiotics Estrogens and hormones Anti-inflammatories and analgesics Antiepileptics Lipid regulators Antihypertensives Contrast media Antidepressants Antiulcer drugs and Antihistamines
Pharmaceutical class Pharmaceuticals antibiotics sulphamethoxazole, triclosan, lincomycin estrogens and hormones 17-β estradiol, estrone anti-inflammatories and analgesics diclofenac, paracetamol, ibuprofen antiepileptics carbamazepine lipid regulators clofibric acid antihypertensives atenolol antidepressants benzodiazepine contrast media iopamidol
+ Examples of the pharmaceuticals often detected in worldwide groundwater.
Chemical aspects relevant to aquifer systems dynamics The chemical structure of pharmaceuticals affects the type of hydro-geochemical processes that mainly impacts on their fate in groundwater and it is strictly associated with their chemical properties. Therefore, a classification of pharmaceuticals based on chemical classes is a valid alternative to the purpose of understanding the role of molecular structures in determining the kind of physical and geochemical processes affecting their mobility in porous media.
With regard to the occurrence of medical drugs in subsurface aquatic systems, the following chemical properties are of major interest: Solubility in the aqueous phase Pharmaceuticals solubility in water affects the mobility of these compounds within aquifers. This feature depends on pharmaceuticals polarity, as polar substances are typically hydrophilic, thereby showing marked tendency to dissolve in the aqueous phase, where they become solutes. This aspect impacts on dissolution / precipitation equilibrium, a phenomenon that is mathematically described in terms of the substance solubility product (addressed in many books with the notation ). Lipophilicity, often measured through the so-called octanol-water partition coefficient (typically addressed as ) Large values outline the non polar character of the chemical species, which shows instead particular affinity to dissolve into organic solvents. Therefore, lipophilic pharmaceuticals are markedly subjected to the risk to bioaccumulate and biomagnificate in the environment, consistent with their preferential partition with the organic tissues of living organisms. Sufficiently large pharmaceuticals are in fact subjected to specific tiers in the environmental risk assessment (ERA) procedure (to be supplied for the marketing authorisation application) and are highlighted as potential sources of bioaccumulation and biomagnification according to the EMA guidelines. Lipophilic compounds are then insoluble in water, where they persist as a separated phase from the aqueous one. This renders their mobility in groundwater basically decoupled with dissolution / precipitation mechanisms and attributed to the mean flow transport (advection and dispersion) and soil-mediated mechanisms of reaction (adsorption). Affinity of sorption onto the soils This feature is expressed in terms of the so-called organic carbon-water partition coefficient, that is usually referred to as and is an intrinsic property of the molecule. Acidic character Molecules behaviour in relation to aqueous dissociation reactions is typically related to their acid dissociation constants, that are typically outlined in terms of their coefficients. Affinity to redox reactions, even in the context of bacterially-mediated metabolic pathways The molecular structure of xenobiotics typically outlines the existence of several possible reaction pathways, which are embedded in complex reaction networks and are typically referred to as transformation processes. With reference to organic compounds, such as pharmaceuticals, innumerable kinds of chemical reactions exist, most of them involving common chemical mechanisms, such as functional groups elimination, addition and substitution. These processes often involve further redox reactions accomplished on the substrates, which are here represented by pharmaceutical solutes and, eventually, their transformation products and metabolites. These processes can be then classified as either biotic or abiotic, depending on the presence or absence of bacterial communities acting as reaction mediators. In the former case, these transformation pathways are typically addressed as biodegradation or biotransformation in the hydrogeochemical literature, depending on the extent of cleavage of the parent molecule into highly oxidized, innocuous species.
Transport and attenuation processes The fate of pharmaceuticals in groundwater is governed by different processes. The reference theoretical framework is that of reactive solute transport in porous media at the continuum scale, that is typically interpreted through the advective-dispersive-reactive equation (ADRE). With reference to the saturated region of the aquifer, the ADRE is written as:
Where represents the effective porosity of the medium, and represent - respectively - the spatial coordinates vector and the time coordinate. represents the divergence operator, except for when it applies to , where the nabla symbol stands for gradient of . The term denotes then the pharmaceutical solute concentration field in the water phase (for unsaturated regions of the aquifer, the ADRE equation has a similar shape, but it includes additional terms accounting for volumetric contents and contaminants concentrations in other phases than water), while represents the velocity field. is the hydrodynamic dispersion tensor and is typically function of the sole variable . Lastly, the storage term includes the accumulation or removal contribution due to all possible reactive processes in the system, i.e., adsorption, dissolution / precipitation, acid dissociation and other transformation reactions, such as biodegradation.
The main hydrological transport processes driving pharmaceuticals and organic contaminants migration in aquifer systems are: Advection Hydrodynamic dispersion The most influential geochemical processes, also referred to as reactive processes and whose effect is embedded in the term of the ADRE, include: Adsorption onto soil Dissolution and precipitation Acid dissociation and aqueous complexation Biodegradation, biotransformation and other transformation pathways
Advection
Advective transport accounts for the contribution of solute mass transfer across the system that originates from bulk flow motion. At the continuum scale of analysis, the system is interpreted as a continuous medium rather than a collection of solid particles (grains) and empty spaces (pores) through which the fluid can flow. In this context, an average flow velocity can be typically estimated, which arises upscaling the pore scale velocities. Here, the fluid flow conditions ensure the validity of the Darcy's law, which governs the system evolution in terms of average fluid velocity, typically referred to as seepage or advective velocity. Dissolved pharmaceuticals in groundwater are transferred within the domain along with the mean fluid flow and in agreement with the physical principles governing any other solute migration across the system.
Hydrodynamic dispersion
Hydrodynamic dispersion identifies a process that arises as summation of two separate effects. First, it is associated with molecular diffusion, a phenomenon that is appreciated at the macroscale as consequence of microscale Brownian motions. Secondly, it includes a contribution (called mechanical dispersion) arising as an effect of upscaling the fluid-dynamic transport problem from the pore to the continuum scale of investigation, due to the upscaling of local dishomogeneous velocities. The latter contribution is therefore not related to the occurrence of any physical process at the pore scale, but it is only a fictitious consequence of the modelling scale choice. Hydrodynamic dispersion is then embedded in the advective-dispersive-reactive equation (ADRE) assuming a Fickian closure model. Dispersion is felt at the macroscale as responsible of a spread effect of the contaminant plume around its center of mass.
Adsorption onto soil