Concerns regarding the fate and effect of pharmaceuticals in the environment have been increasing following the detection
of pharmaceuticals in sewage treatment plant (STP) effluents, surface waters, seawater, groundwater and even drinking water.1,2 Monitoring studies have demonstrated that drug residues in treated wastewater and surface waters are widespread,2 and concerns have further strengthened after residues of the analgesic and anti-inflammatory drug substance diclofenac were
held responsible for the unusually high death rate among three species of vulture in India and Pakistan in 2004.3 In response, regulatory agencies have issued detailed guidance on how pharmaceuticals should be assessed for possible adverse
effects in the environment and have introduced the requirement for a environmental risk assessment (ERA). An ERA is required
for all new marketing authorisation applications for a medicinal product; for type II variations, an ERA should be submitted
if there is an increase in environmental exposure; for type IA/IB variations and renewal applications, an ERA is not required.
An assessment of potential risks to the environment of medicinal products is a step-wise, phased procedure that may be terminated
when sufficient information/data is available to either indicate that the medicinal product is unlikely to pose a risk to
the environment, or to identify and sufficiently characterise the potential risks.
(RADIUS IMAGES/GETTY IMAGES)
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,
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.
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
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.