## 6.5.4. Environmental Risk Assessment of Pharmaceuticals in Europe

Author: Gerd Maack

Reviewers: Ad Ragas, Julia Fabrega, Rhys Whomsley

Learning objectives:

You should be able to

- Explain the philosophy and objective of the environmental risk assessment of pharmaceuticals.
- mention the key aspects of the tiered approach of the assessment
- identify the exposure routes for human and veterinary medicinal products and should know the respective consequences in the assessment

Keywords: Human pharmaceuticals, veterinary pharmaceuticals, environmental impact, tiered approach

Introduction

Pharmaceuticals are a crucial element of modern medicine and confer significant benefits to society. About 4,000 active pharmaceutical ingredients are being administered worldwide in prescription medicines, over-the-counter medicines, and veterinary medicines. They are designed to be efficacious and stable, as they need to pass different barriers i.e. skin, the gastrointestinal system (GIT), or even the blood-brain barrier before reaching the target cells. Each target system has a different pH and different lipophilicity and the GIT is in addition colonised with specific bacteria, specialized to digest, dissolve and disintegrate organic molecules. As a consequence of this stability, most of the pharmaceutical ingredients are stable in the environment as well and could cause effects on non-target organisms.

The active ingredients comprise a variety of synthetic chemicals produced by pharmaceutical companies in both the industrialized and the developing world at a rate of 100,000 tons per year.

While pharmaceuticals are stringently regulated in terms of efficacy and safety for patients, as well as for target animal safety, user and consumer safety, the potential effects on non-target organisms and environmental effects are regulated comparably weakly.

The authorisation procedure requires an environmental risk assessment (ERA) to be submitted by the applicants for each new human and veterinary medicinal product. The assessment encompasses the fate and behaviour of the active ingredient in the environment and its ecotoxicity based on a catalogue of standardised test guidelines.

In the case of veterinary pharmaceuticals, constraints to reduce risk and thus ensure safe usage can be stipulated in most cases. In the case of human pharmaceuticals, it is far more difficult to ensure risk reduction through restriction of the drug's use due to practical and ethical reasons. Because of their unique benefits, a restriction is not reasonable. This is reflected in the legal framework, as a potential effect on the environment is not included in the final benefit risk assessment for a marketing authorisation.

Exposure pathways

Human pharmaceuticals

Human pharmaceuticals enter the environment mainly via surface waters through sewage systems and sewage treatment plants. The main exposure pathways are excretion and non-appropriate disposal. Typically only a fraction of the medicinal product taken is metabolised by the patients, meaning that the main share of the active ingredient is excreted unchanged into the wastewater system. Furthermore, sometimes the metabolites themselves are pharmacologically active. Yet, no wastewater treatment plant is able to degrade all active ingredients. So medicinal products are commonly found in surface water, to some extent in ground water, and sometimes even in drinking water. However, the concentrations in drinking water are orders of magnitude lower than therapeutic concentrations. An additional exposure pathway for human pharmaceuticals is the spreading of sewage sludge on soil, if the sludge is used as fertilizer on farmland. See for more details the Link “The Drugs We Wash Away: Pharmaceuticals, Drinking Water and the Environment”.

Veterinary pharmaceuticals

Veterinary pharmaceuticals on the other hand enter the environment mainly via soil, either indirectly, if the slurry and manure from mass livestock production is spread onto agricultural land as fertiliser, or directly from pasture animals. Moreover, pasture animals might additionally excrete directly into surface water. Pharmaceuticals can also enter the environment via the detour of manure used in biogas plants.

Figure 1: Entry path paths of human and veterinary medicinal products. See text for more details (reproduced with permission from the German Environmental Agency).

Assessment schemes

Despite the differences mentioned above, the general scheme of the environmental risk assessment of human and veterinary pharmaceuticals is similar. Both assessments start with an exposure assessment. Only if specific trigger values are reached an in-depth assessment of fate, behaviour and effects of the active ingredient is necessary.

Environmental risk assessment of human pharmaceuticals

In Europe, an ERA for human pharmaceuticals has to be conducted according to the Guideline on Environmental Risk Assessment of Medicinal Products for Human Use (EMA 2006). This ERA consists of two phases. Phase I is a pre-screening for estimating the exposure in surface water, and if this Predicted Environmental Exposure Concentration (PEC) does not reach the action limit of 0.01 µg/L, in most cases, the ERA can stop. In case this action limit is reached or exceeded, a base set of aquatic toxicology, and fate and behaviour data need to be supplied in phase II Tier A. A risk assessment, comparing the PEC with the Predicted No Effect Concentration (PNEC), needs to be conducted. If in this step a risk is still identified for a specific compartment, a substance and compartment-specific refinement and risk assessment in Phase II Tier B needs to be conducted (Figure 2).

Phase I: Estimation of Exposure

In Phase I, the PEC calculation is restricted to the aquatic compartment. The estimation should be based on the drug substance only, irrespective of its route of administration, pharmaceutical form, metabolism and excretion. The initial calculation of the PEC in surface water assumes:

- The predicted amount used per capita per year is evenly distributed over the year and throughout the geographic area (Doseai);
- A fraction of the overall market penetration (Fpen), in other words ‘how many people will take the medicinal product? Normally a default value of 1% is used;
- The sewage system is the drug’s main route of entry into surface water.

The following formula is used to estimate the PEC in surface water:

PECsurfacewater = mg/l

DOSEai = Maximum daily dose consumed per capita [mg.inh-1.d-1]

Fpen = Fraction of market penetration (= 1% by default)

WASTEinhab = Amount of wastewater per inhabitant per day (= 200 l by default)

DILUTION = Dilution Factor (= 10 by default)

Three factors of this formula, i.e. Fpen, Wasteinhab and the Dilution Factor, are default values, meaning that the PECsurfacewater in Phase I entirely depends on the dose of the active ingredient. The Fpen can be refined by providing reasonably justified market penetration data, e.g. based on published epidemiological data.

If the PECsurfacewater value is equal to or above 0.01 μg/l (mean dose ≥ 2 mg cap-1 d-1), a Phase II environmental fate and effect analysis should be performed. Otherwise, the ERA can stop. However, in some cases, the action limit may not be applicable. For instance, medicinal substances with a log Kow > 4.5 are potential PBT candidates and should be screened for persistence (P), bioaccumulation potential (B), and toxicity (T) independently of the PEC value. Furthermore, some substances may affect vertebrates or lower animals at concentrations lower than 0.01 μg/L. These substances should always enter Phase II and a tailored risk assessment strategy should be followed which addresses the specific mechanism of action of the substance. This is often true for e.g. hormone active substances (see section on Endocrine disruption). The required tests in a Phase II assessment (see below) need to cover the most sensitive life stage, and the most sensitive endpoint needs to be assessed. This means for instance that for substances affecting reproduction, the organism needs to be exposed to the substance during gonad development and the reproductive output needs to be assessed.

Phase II: Environmental Fate and Effects Analysis

A Phase II assessment is conducted by evaluating the PEC/PNEC ratio based on a base set of data and the predicted environmental concentration from Tier A. If a potential environmental impact is indicated, further testing might be needed to refine PEC and PNEC values in Tier B.

Under certain circumstances, effects on sediment-dwelling organisms and terrestrial environmental fate and effects analysis are also required. Experimental studies should follow standard test protocols, e.g. OECD guidelines. It is not acceptable to use QSAR estimation, modelling and extrapolation from e.g. a substance with a similar mode of action and molecular structure (read across). This is in clear contrast to other regulations like e.g. REACH.

Human pharmaceuticals are used all year round without any major fluctuations and peaks. The only exemption are substances used against cold and influenza. These substances have a clear peak in the consumption in autumn and winter times. In developed countries in Europe and North America, antibiotics display a similar peak as they are prescribed to support the substances used against viral infections. The guideline reflects this exposure scenario and asks explicitly for long-term effect tests for all three trophic levels: algae, aquatic invertebrates and vertebrates (i.e., fish).

In order to assess the physio chemical fate, amongst other tests the sorption behaviour and fate in a water/sediment system should be determined.

Figure 2: Scheme of conducting an ERA for Human Medicinal Products according to the EMA guideline

If, after refinement, the possibility of environmental risks cannot be excluded, precautionary and safety measures may consist of:

- An indication of potential risks presented by the medicinal product for the environment.
- Product labelling, Summary Product Characteristics (SPC), Package Leaflet (PL) for patient use, product storage and disposal.

Labelling should generally aim at minimising the quantity discharged into the environment by appropriate mitigation measures

Environmental risk assessment of veterinary pharmaceuticals

In the EU, the Environmental Risk Assessment (ERA) is conducted for all veterinary medicinal products. The structure of an ERA for Veterinary Medicinal Products (VMPs) is quite similar to the ERA for Human Medicinal Products. It is also tier based and starts with an exposure assessment in Phase I. Here, the potential for environmental exposure is assessed based on the intended use of the product. It is assumed that products with limited environmental exposure will have negligible environmental effects and thus can stop in Phase I. Some VMPs that might otherwise stop in Phase I as a result of their low environmental exposure, may require additional hazard information to address particular concerns associated with their intrinsic properties and use. This approach is comparable to the assessment of Human Pharmaceutical Products, see above.

Phase I: Estimation of Environmental Exposure

For the exposure assessment, a decision tree was developed (Figure 3). The decision tree consists of a number of questions, and the answers of the individual questions will conclude in the extent of the environmental exposure of the product. The goal is to determine if environmental exposure is sufficiently significant to consider if data on hazard properties are needed for characterizing a risk. Products with a low environmental exposure are considered not to pose a risk to the environment and hence these products do not need further assessment. However, if the outcome of Phase I assessment is that the use of the product leads to significant environmental exposure, then additional environmental fate and effect data are required. Examples for products with a low environmental exposure are, among others are products for companion animals only and products that result in a Predicted Environmental Concentration in soil (PECsoil) of less than 100 µg/kg, based on a worst-case estimation.

Figure 3: Phase I Decision Tree for Veterinary Medicinal Products (VMPs); (VICH 2000)

Phase II: Environmental Fate and Effects Analysis

A Phase II assessment is necessary if either the trigger of 100 µg/kg in the terrestrial branch or the trigger of 1 µg/L in the aquatic branch is reached. It is also necessary, if the substance is a parasiticide for food producing animals. A Phase II is also required for substances that would in principle stop in Phase I, but there are indications that an environmental risk at very low concentrations is likely due to their hazardous profile (e.g., endocrine active medicinal products). This is comparable to the assessment for Human Pharmaceutical Products.

For Veterinary Pharmaceutical Products also the Phase II assessment is sub-divided into several Tiers, see Figure 4. For Tier A, a base set of studies assessing the physical-chemical properties, the environmental fate, and effects of the active ingredient is necessary. For Tier A, acute effect tests are suggested, assuming a more peak like exposure scenario due to e.g. applying manure and dung on fields and meadows, in contrast to the permanent exposure of human pharmaceuticals. If for a specific trophic level, e.g. dung fauna or algae, a risk is identified (PEC/PNEC ≥1) (see Introduction to Chapter 6), long-term tests for this level have to be conducted in Tier B. For the trophic levels, without an identified risk, the assessment can stop. If the risk still applies with these long-term studies, a further refinement with field studies in Tier C can be conducted. Here a co-operation with a competent authority is strongly recommended, as these tests are tailored, reflected by the individual design of these field studies. In addition, and independent of this, risk mitigation measures can be imposed to reduce the exposure concentration (PEC). These can be, beside others, that animals must remain stabled for a certain amount of time after the treatment, to ensure that the concentration of active ingredient in excreta is low enough to avoid adverse effects on dung fauna and their predators. Alternatively, the treated animals are denied access to water as the active ingredient has harmful effects on aquatic organisms.

Figure 4: Scheme for conducting an ERA for Veterinary Medicinal Products (VMPs) according to the EMA guidelines (VICH 2000; VICH 2004).

Conclusion

The Environmental Risk Assessment of Human and Veterinary Medicinal Products is a straightforward, tiered-based process with the possibility to exit at several steps in the assessment procedure. Depending on the dose, the physico-chemical properties, and the anticipated use, this can be quite early in the procedure. On the other hand, for very potent substances with specific modes of action the guidelines are flexible enough to allow specific assessments covering these modes of action.

The ERA guideline for human medicinal products entered into application 2006 and many data gaps exist for products approved prior to 2006. Although there is a legal requirement for an ERA dossier for all marketing authorisation applications, new applications for pharmaceuticals on the market before 2006 are only required to submit ERA data under certain circumstances (e.g. significant increase in usage). Even for some of the blockbusters, like Ibuprofen, Diclofenac, and Metformin, full information on fate, behaviour and effects on non-target organisms is currently lacking.

Furthermore, systematic post-authorisation monitoring and evaluation of potential unintended ecotoxicological effects does not exist. The market authorisation for pharmaceuticals does not expire, in contrast to e.g. an authorisation of pesticides, which needs to be renewed every 10 years.

For Veterinary Medicinal Products, an in-depth ERA is necessary for food producing animals only. An ERA for non-food animals can stop with question 3 in Phase I (Figure 3) as it is considered that the use of products for companion animals leads to negligible environmental concentrations, which might not be necessarily the case. Here, the guideline does not reflect the state of the art of scientific and regulatory knowledge. For example, the market authorisation, as a pesticide or biocide, has been withdrawn or strongly restricted for some potent insecticides like imidacloprid and fipronil which both are authorised for use in companion animals.

Further Reading

Pharmaceuticals in the Environment:https://www.umweltbundesamt.de/en/publikationen/pharmaceuticals-in-the-environment-the-global
Recommendations for reducing micro-pollutants in waters: https://www.umweltbundesamt.de/publikationen/recommendations-for-reducing-micropollutants-in