**2. Environmental risk assessment of pharmaceuticals vs. chronic and mixture toxicity of pharmaceuticals**

The approaches currently being used to assess the potential environmental effects of human and veterinary drugs in the U.S. and in the European Union are in some respects dissimilar [34-39]. The Environmental Risk Assessment (ERA) process usually starts with an initial exposure assessment (Phase I). But with some exceptions, a fate and effects analysis (Phase II) is only required when exposure-based threshold values, the so-called action limits, are exceeded in different environmental compartments. Thus risk assessment, described by Risk Quotient (RQ), is performed by the calculation the ratio of the predicted (or measured) environmental concentration (PEC or MEC respectively) and predicted biological noneffective concentrations (PNEC) on non-target organisms. If RQ is less than one it indicates that no further testing is recommended. Calculations of environmental concentrations rely e.g. on information on treatment dosage and intensity along with default values for standard husbandry practices, and are based on a total residue approach reflecting worst-case assump‐ tions. For example, the recently introduced European guidance on assessing the risks of human drugs excludes the testing of pharmaceuticals whose PECsurface water is below an action limit of 0.01 μg L-1; in the U.S. this threshold value is 0.1 μg L-1. Moreover, there are two different action limits for veterinary pharmaceuticals, one each for the terrestrial and the aquatic compart‐ ments. No fate and effect analysis is required for veterinary pharmaceuticals used to treat animals if the PECsoil is < 100 μg kg-1 dry weight of soil. However, a Phase II assessment is not required for veterinary medicines used in an aquaculture facility if the estimated concentration of the compound is < 1 μg L-1 [40-41]. If the PECsurface water of a pharmaceutical is above the action limit, effects on algae, crustaceans and fish are investigated. However, if PECsoil is higher than the action limit, then Phase II, divided into two parts: Tier A, in which the possible fate of the pharmaceutical or its metabolites and its effects on earthworms (mortality) and plants (germination and growth) as well as the effects of the test compound on the rate of nitrate mineralization in soil are determined; and Tier B in which only effect studies are recommended for affected taxonomic levels [34-39].

The main problem associated with this approach is the fact that the no actual sales figures or measured environmental concentrations are at hand when a risk assessment is conducted. Therefore, only crude PEC calculations are performed [42]. Moreover, the (eco)toxicity tests included in Phase II focus on acute toxicity of only single compounds. Chronic and mixture toxicity is not obligatory. As the risk of an acute toxic effect from pharmaceuticals in the environment is unlikely and organisms in the environment are exposed to mixtures of pharmaceuticals, such limited focus results in important uncertainties. Additionally, same drugs (like sulfonamides) are used to treat both humans and animals. Although the exposures may differ, their potential effects on non-target organisms will be the same, and so the effecttesting approaches should be similar. For these reasons, many scientists have already pointed out the need for more reliable PEC and PNEC calculations for more realistic ERA of pharma‐ ceutical [40-42].
