**4. Environmental risk assessment of veterinary pharmaceuticals (VPCs) in soil ecosystems**

Guidelines describing how the environmental risks of veterinary products should be assessed for a range of countries have been published [22]. The approach used in Europe is based on the recommendations of the International Co-operation on Harmonization of Technical Requirements for Registration of Veterinary Products (VICH), which has attempted to harmonize the environmental risk assessment requirements of veterinary products in the USA, Europe and Japan. The approach is a two-phase process [19-20,22]. According to these guidelines for the environmental risk assessment (ERA) of VPCs, the ERA process starts with an initial exposure assessment (Phase I). With some exceptions, a fate and effects analysis (Phase II) is only required when exposure-based thresholds, the so-called action limits, are exceeded in different environmental compartments. Thus, risk assessment, described by the Risk Quotient (RQ), is carried out by calculating the ratio of the predicted (or measured) environmental concentration (PEC or MEC respectively) and the predicted biological noneffective concentrations (PNEC) on non-target organisms. The PNEC is ultimately derived from the toxicity data by applying an assessment factor (AF), usually calculated as the ratio of EC50 or NOEC to AF. The assessment factor (in the range from 10 to 1000) takes into account interspecies variation, acute/subchronic to chronic extrapolation and laboratory data to field impact extrapolation. For example, for acute toxicity tests its value is 1000. Nevertheless, if RQ is less than one, no further testing is recommended. Calculations of environmental concentra‐ tions rely 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 assumptions. No fate and effects analysis is required for VPCs if the predicted environmental concentration in soil (PECsoil) is < 100 µg/kg dry weight of soil. In this case the ERA is brought to a close. However, if PECsoil is higher than the action limit, then Phase II, divided into two parts, comes into play: 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 (when RQ > 1 or in the case of soil microorganisms an effect > 25 %); no further guidance on Tier B testing is provided. There are no requirements regarding the species of organisms that should be used at this stage apart from the statement that the study using terrestrial plants should be repeated on two additional species from the most sensitive species category in the Tier A study, in addition to repeating the study on the most sensitive species. However, if after Tier B testing RQ is still > 1, more studies may be needed in order to further elucidate the effects on terrestrial ecosystems [19-23].

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 [124]. Moreover, the (eco)toxicity tests in Phase II are carried out only for single compounds and on a limited range of species. As these compounds occur in natural media not as single, isolated drugs but usually together with other compounds of the same family or the same type, accumulated concentrations or synergistic-antagonistic effects need to be considered. For these reasons, Schmitt et al. suggested checking whether the current action limits are sufficiently protective for aquatic and terrestrial organisms by at least performing limit tests to confirm the absence of effects due to pharmaceuticals with PECs below the action limits [125]. Therefore, it seems to very important to check whether other pharmaceuticals do not also pose a threat to such organisms. In addition, it must be highlighted that contaminants in ecosystems can cause adverse effects, and that the severity of such effects is not dependent on the total substance concentration but on the bioavailable concentration of the xenobiotics. Therefore, the central concept for an assessment of soils should be the bioavailability representing the link between exposure and effect of contaminants. As a consequence a "bioavailability concept" was developed, which links environmental chemistry and ecotoxicology. According to Frische et al. [126] "bioavail‐ ability describes the complex processes of mass transfer and uptake of contaminants into soilliving organisms which are determined by substance properties, soil properties, the biology of organisms and climatic influence. The bioavailable contaminant fraction in soil represents the relevant exposure concentration for soil organisms". For these reasons, risk assessments and subsequent regulatory measures (permission to use chemicals, threshold values and redemption goals in soils) are particularly subject to considerable uncertainties as long as nominal and measured total concentrations are the basis of exposure assessment [126]. Owing to necessary extrapolations, the present non-consideration of bioavailability in practice can result in both over- and underestimating the risks posed by chemicals to soils, which is why it should be included in such an ecotoxicological test. To date, only a few authors have investigated the ecotoxicity potential of pharmaceuticals with respect to their bioavailability in soil samples (e.g. [127]).

**4. Environmental risk assessment of veterinary pharmaceuticals (VPCs) in**

Guidelines describing how the environmental risks of veterinary products should be assessed for a range of countries have been published [22]. The approach used in Europe is based on the recommendations of the International Co-operation on Harmonization of Technical Requirements for Registration of Veterinary Products (VICH), which has attempted to harmonize the environmental risk assessment requirements of veterinary products in the USA, Europe and Japan. The approach is a two-phase process [19-20,22]. According to these guidelines for the environmental risk assessment (ERA) of VPCs, the ERA process starts with an initial exposure assessment (Phase I). With some exceptions, a fate and effects analysis (Phase II) is only required when exposure-based thresholds, the so-called action limits, are exceeded in different environmental compartments. Thus, risk assessment, described by the Risk Quotient (RQ), is carried out by calculating the ratio of the predicted (or measured) environmental concentration (PEC or MEC respectively) and the predicted biological noneffective concentrations (PNEC) on non-target organisms. The PNEC is ultimately derived from the toxicity data by applying an assessment factor (AF), usually calculated as the ratio of EC50 or NOEC to AF. The assessment factor (in the range from 10 to 1000) takes into account interspecies variation, acute/subchronic to chronic extrapolation and laboratory data to field impact extrapolation. For example, for acute toxicity tests its value is 1000. Nevertheless, if RQ is less than one, no further testing is recommended. Calculations of environmental concentra‐ tions rely 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 assumptions. No fate and effects analysis is required for VPCs if the predicted environmental concentration in soil (PECsoil) is < 100 µg/kg dry weight of soil. In this case the ERA is brought to a close. However, if PECsoil is higher than the action limit, then Phase II, divided into two parts, comes into play: 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 (when RQ > 1 or in the case of soil microorganisms an effect > 25 %); no further guidance on Tier B testing is provided. There are no requirements regarding the species of organisms that should be used at this stage apart from the statement that the study using terrestrial plants should be repeated on two additional species from the most sensitive species category in the Tier A study, in addition to repeating the study on the most sensitive species. However, if after Tier B testing RQ is still > 1, more studies may be needed in order to further elucidate the effects on terrestrial

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 [124]. Moreover, the (eco)toxicity tests in Phase II are carried out only for single compounds and on a limited range of species. As these compounds occur in natural media not as single, isolated drugs but usually together with

**soil ecosystems**

678 Environmental Risk Assessment of Soil Contamination

ecosystems [19-23].
