An ERA was first required for veterinary pharmaceuticals in accordance with EU Directive 92/18/EEC and the corresponding note for guidance was issued by the European Medicines Agency (EMA) in 1998. In 2001, the requirement for an ERA was described for human pharmaceuticals in Directive 2001/83/EC. A guidance document was first issued in January 2005 (first draft) and finalised in June 2006.4 In comparison, in the US ERAs for veterinary and human pharmaceuticals have been required by the FDA since 1980 and 1998, respectively.
This article will describe the ERA for human pharmaceuticals in Europe and will present the steps to be taken during the phased procedure of assessing environmental risk.Background
The main route of entry of human pharmaceuticals into the environment is through uptake in the patient followed by excretion and disposal via wastewater. Hospital wastewater, wastewater from manufacturing sites and landfill leachates may also contain significant concentrations of pharmaceuticals.1 Pharmaceuticals that are not degraded or bound in the sewage treatment plant are released in treatment effluents, subsequently contaminating surface water and possibly ground water. Pharmaceuticals that bind to sewage sludge may also end up in the environment when sludge is spread on land, after which soil, groundwater and surface water may be contaminated.
Existing literature about the ecotoxicological effects of human pharmaceuticals deals predominantly with acute toxicity in standardised tests with aquatic organisms; however, because of continuous, low level exposure, chronic effects are considered more relevant. Therefore, the guidance for environmental risk assessment prepared by the EMA contains the requirement of chronic ecotoxicity studies.4
The guidance document on environmental risk assessment contains the data requirements that should be fulfilled in an ERA,4 but the specific data requirements are not as straightforward as they seem because the choice of the appropriate test is subject to expert judgement. Moreover, certain types of chemicals are, in principle, exempt (e.g., electrolytes, vitamins, amino acids, peptides, proteins, carbohydrates and lipids, vaccines and herbal medicinal products), but these exemptions may be overruled by the specific mode of action (e.g., when the substance has an intended endocrine mode of action).
An ERA consists of two phases: Phase I, which is a screening phase, and Phase II, which may be triggered by the results of Phase I, and in turn consists of two tiers. Phase I is generally thought to be a nontesting phase (with testing taking place in Phase II), but this is not necessarily the case. The non-testing data collected in Phase I include a calculation of the predicted environmental concentration in surface water (PECsurfacewater) of the active substance (based on the maximum daily dose), as well as an assessment of the mode of action and observations extracted from the toxicology database on the active substance. In addition, the logPow of the active substance should be made available. If the logPow value passes the trigger value of 4.5, an assessment is needed to determine whether the substance is Persistent, Bioaccumulative and Toxic (PBT); this is where testing may be necessary. The different steps taken in Phase I and the considered triggers are outlined below.