## 2.3.3. Pharmaceuticals and Veterinary Pharmaceuticals

Author: Thomas ter Laak

Reviewers: John Parsons, Steven Droge, Stefan Kools

Learning objectives:

You should be able to:

- understand what pharmaceuticals are and how pharmaceuticals can enter the environment
- understand how emissions and environmental concentrations of pharmaceuticals can be estimated / modeled

Keywords: emission, waste water treatment, disease treatment, mass balance modelling, human pharmaceuticals, veterinary pharmaceuticals

Introduction

Pharmaceuticals are used by humans (human pharmaceuticals) and administered to animals (veterinary pharmaceuticals).

The active ingredients used in human and veterinary medicine partially overlap, however, the major fraction of pharmaceutically active substances in use are restricted to human consumption. Next to that, some active ingredients are used in other applications as well, such as biocides or in plant protection products. In veterinary practice most of the applied pharmaceuticals are antibiotics and anti-parasitic agents, while in human medicine, pharmaceuticals to treat e.g. diabetes, pain, cardiovascular diseases, autoimmune disorders and neurological disorders make up a much larger portion of the pharmaceuticals in use. Worldwide pharmaceutical consumption has increased over the last century (several numbers are summarized here). It is expected that the consumption will further increase due to a wider access to pharmaceuticals in developing countries. Additionally, demographic trends such as aging populations often seen in developed countries can also lead to increased consumption of pharmaceuticals, since older generations generally consume more pharmaceuticals than younger ones (van der Aa et al. 2010). The widespread and increasing use and their biological activity makes them relevant for environmental research. Pharmaceuticals are specifically designed and used for their biological effect in humans or treated animals. For that reason, we know a lot about their potential environmental effects as well as on their application and emission. Below an overview is given on the emission, occurrence and fate(modeling) of pharmaceuticals in the environment.

Pharmaceuticals in the environment

Pharmaceuticals can enter the environment through various routes. Figure 1 gives an overview of the major emission routes of pharmaceuticals to the environment.

Figure 1. Pharmaceutical emissions routes to the (aqueous) environment. STP = sewage treatment plant (adapted from Schmitt et al., 2017).

Pharmaceutical are produced, transported to users (humans and/or animals), used by humans or animals. After use, the active ingredients are partially metabolized and both parent compounds and metabolites can be excreted by the users via urine and feces. For humans, the major routes are transport to wastewater treatment plants, septic tanks or directly emission to soil or surface water. For animals, and especially livestock, manure contains a major fraction of the pharmaceuticals that are excreted. These pharmaceuticals end up in the environment when animals are grazing outside or when centrally collected manure is applied as fertilizer on arable land. The treatment and further application of communal wastewater and manure varies between countries and regions. Subsequently, emissions can also vary leading to different compositions and concentrations of pharmaceuticals and metabolites in the environment. In Figure 2 concentration ranges of pharmaceuticals and some of their transformation products in the Meuse river and some tributaries are shown.

Figure 2. Pharmaceutical concentrations of pharmaceuticals in the River Meuse and some of its tributaries (adapted from Ter Laak et al. 2014). Parent pharmaceuticals are plotted in bleu, transformation products in red. Drawn by Wilma IJzerman.

Properties of pharmaceuticals and their behavior and fate in the environment

Pharmaceuticals in use are developed for a wide array of diseases and therapeutic treatments. The chemical structures of these substances are therefore also very diverse, considering their size, structural presence of specific atoms, and physicochemical properties such as their hydrophobicity, aqueous solubility and ionization under environmentally relevant pH values, as shown for some examples in Figure 3.

Figure 3. Examples of pharmaceuticals, illustrating the variable chemical structures. (Source: Steven Droge)

As a consequence of their structural diversity, the environmental distribution and fate of pharmaceuticals is also very variable. Nevertheless, pharmaceuticals have generally certain properties in common:

- Pharmaceuticals are designed to have a specific biological activity that determines their pharmacological application.
- Most pharmaceuticals are rather robust against metabolism of their users (humans or animals) in order to reach stable therapeutic levels inside the user.
- Pharmaceuticals are often relatively soluble in water, since their therapeutic application requires absorption and distribution to reach specific targets sites in living organisms. Aqueous solutions such as blood are often the internal transport medium. Less soluble pharmaceuticals are metabolized to allow renal excretion, leading to soluble metabolites.

These three generic properties also make them of environmental relevance since:

- Pharmaceuticals are likely biologically active in non-target organisms, thereby disturbing their behavior, metabolism or other functions.
- Pharmaceuticals are rather persistent in water treatment or the environment
- Pharmaceuticals and/or metabolites have rather high aqueous solubility which makes them mobile and as a consequence they may end up in (ground)water.
- Continuous use leads to continuous emission and subsequently continuous presence in environmental waters, this is called ‘pseudo persistence’.

Occurrence and modelling of human and veterinary pharmaceuticals in the environment

Pharmaceuticals in the environment have been studied since the 1990s. Most studies have been performed in surface waters, but wastewater (effluents), groundwater, drinking water, manure, soil and sediments were also studied. Pharmaceuticals have been observed in all these matrices in concentrations generally varying from µg/L to sub ng/L levels (Aus der Beek et al., 2016, Monteiro and Boxall, 2010). Various studies have related environmental loads and related concentrations to human consumption data. Basically such mass balance or studies that relate consumption in catchments of streams, lakes or rivers to environmental concentrations work according the following principle:

Modelling pharmaceuticals in the environment

The consumption of human pharmaceuticals, is relatively well documented and data are (publicly) available. Hence, based on consumption using several assumptions, environmental concentrations of pharmaceuticals can be related to consumption. This prediction works best for the most persistent pharmaceuticals, as these pharmaceuticals are hardly affected by transformation processes that can be variable as a result of environmental conditions. When loss factors become larger, they generally also become more variable, through seasonal variations in use as well as variation in loss during wastewater treatment and loss processes in the receiving rivers. This makes the loads and concentrations of more degradable pharmaceuticals more difficult to predict (Ter Laak et al., 2010).

Loads in a particular riverine system (such as a tributary of the river Meuse in the example below) can be predicted with a very simplified model. Here the pharmaceutical consumption over a selected period is multiplied by the fraction of the selected pharmaceuticals that is excreted unchanged by the human body (ranging from 0 to 1) and the fraction that is able to pass the wastewater treatment plant (WWTP) (ranging from 0 to 1):

When this is related to actual measured concentrations and loads calculated from these numbers, the correlation between predicted and measured loads can be plotted. Various studies have shown that environmental loads can be predicted within a factor of 3 for most commonly observed pharmaceuticals (see e.g., Ter Laak et al., 2010, 2014).

Figure 4. Measured versus predicted loads in a tributary of the Meuse river (adapted from Ter Laak et al., 2014)

For veterinary pharmaceuticals this so called ‘immision-emission balancing’ is more difficult for a number of reasons (see e.g., Boxall et al., 2003):

- First, veterinary pharmaceuticals are applied in different quantities and using different application routes in different (live-stock) animals.
- Second, animal excrements can be burned, stored for later use as fertilizes or directly emitted when animals are kept outside, leading to different emissions per route.
- Finally, the fate of pharmaceuticals associated with animal excrements to soil, groundwater and surface water is variable and poorly understood.

In a way the emissions and fate of veterinary pharmaceuticals is similar to emissions of pesticides used in agriculture. However, the understanding on loads entering the system and the fate related to the various emission routes and emissions in combination with a complex matrix (urine, feces manure) is more limited (Guo et al., 2016). As a consequence, environmental fate studies of veterinary pharmaceuticals often describe specific cases, or cover laboratory studies to unravel specific aspects of the environmental fate of these pharmaceuticals (Kaczala and Blum, 2016, Kümmerer, 2009).

Concluding remarks

Pharmaceuticals are commonly found in the environmental compartments such as surface water, soil, sediment and groundwater (Williams et al., 2016). Pharmaceuticals consist of a single or multiple active ingredients that have a specific biological activity. The therapeutic application and pharmacological mechanisms provide valuable information to evaluate the environmental hazard of these chemicals. Their physicochemical properties are of more relevance for the assessment of the environmental fate and exposure. The occurrence in the environment and the biological activity of this group of contaminants makes them relevant in environmental science.

References

Aus der Beek, T., Weber, F., Bergmann, A., Hickmann, S., Ebert, I., Hein, A., Küster, A. (2016). Pharmaceuticals in the environment-Global occurrences and perspectives. Environmental Toxicology and Chemistry 35, 823-835.

Boxall, A.B.A., Kolpin, D.W., Halling-Soerensen, B., Tolls, J. (2003). Are veterinary medicines causing environmental risks? Environmental Science and Technology 37, 286A-293A.

Guo, X.Y., Hao, L.J., Qiu, P.Z., Chen, R., Xu, J., Kong, X.J., Shan, Z.J., Wang, N. (2016). Pollution characteristics of 23 veterinary antibiotics in livestock manure and manure-amended soils in Jiangsu province, China. Journal of Environmental Science and Health Part B: Pesticides, Food Contaminants, and Agricultural Wastes 51, 383-392.

Kaczala, F., Blum, S.E. (2016). The occurrence of veterinary pharmaceuticals in the environment: A review. Current Analytical Chemistry 12, 169-182.

Kümmerer, K. (2009). The presence of pharmaceuticals in the environment due to human use - present knowledge and future challenges. Journal of Environmental Management 90, 2354-2366.

Monteiro, S.C., Boxall, A.B.A. (2010). Occurrence and fate of human pharmaceuticals in the environment. Reviews of Environmental Contamination and Toxicology 202, 53-154.

Schmitt, H., Duis, K., ter Laak, T.L. (2017). Development and dissemination of antibiotic resistance in the environment under environmentally relevant concentrations of antibiotics and its risk assessment - a literature study. (UBA-FB) 002408/ENG; Umweltbundesamt: Dessau-Roßlau, January 2017; p 159.

Ter Laak, T.L., Kooij, P.J.F., Tolkamp, H., Hofman, J. (2014). Different compositions of pharmaceuticals in Dutch and Belgian rivers explained by consumption patterns and treatment efficiency. Environmental Science and Pollution Research 21, 12843-12855.

Ter Laak, T.L., Van der Aa, M., Houtman, C.J., Stoks, P.G., Van Wezel, A.P. (2010). Relating environmental concentrations of pharmaceuticals to consumption: A mass balance approach for the river Rhine. Environment International 36, 403-409.

Van der Aa, N.G.F.M., Kommer, G.J., van Montfoort, J.E., Versteegh, J.F.M. (2011). Demographic projections of future pharmaceutical consumption in the Netherlands. Water Science and Technology 63, 825-832.

Williams, M., Backhaus, T., Bowe, C., Choi, K., Connors, K., Hickmann, S., Hunter, W., Kookana, R., Marfil-Vega, R., Verslycke, T. (2016). Pharmaceuticals in the environment: An introduction to the ET&C special issue. Environmental Toxicology and Chemistry 35, 763-766.