Environmental risk assessment for the serotonin re-uptake inhibitor fluoxetine: Case study using the European risk assessment framework.

The serotonin re-uptake inhibitor fluoxetine was selected for an environmental risk assessment, using the most recent European guideline (EMEA 2006) within the European Union (EU)-funded Environmental Risk Assessment of Pharmaceuticals (ERAPharm) project due to its environmental persistence, acute toxicity to nontarget organisms, and unique pharmacokinetics associated with a readily ionizable compound. As a widely prescribed psychotropic drug, fluoxetine is frequently detected in surface waters adjacent to urban areas because municipal wastewater effluents are the primary route of entry to aquatic environments. In Phase I of the assessment, the initial predicted environmental concentration of fluoxetine in surface water (initial PEC(SW)) reached or exceeded the action limit of 10 ng/L, when using both a default market penetration factor and prescription data for Sweden, Germany, and the United Kingdom. Consequently, a Phase II risk assessment was conducted in which green algae were identified as the most sensitive species with a NOEC of <0.6 microg/L. From this value, a predicted no effect concentration for surface waters (PNEC(SW)) of 0.012 microg/L was derived. The PEC/PNEC ratio was above the trigger value of 1 in worst-case exposure scenarios indicating a potential risk to the aquatic compartment. Similarly, risks of fluoxetine for sediment-dwelling organisms could not be excluded. No risk assessment was conducted for the terrestrial compartment due to a lack of data on effects of fluoxetine on soil organisms. The need for a separate risk assessment for the main metabolite of fluoxetine, norfluoxetine, was not conducted because of a lack of fate and effect studies. Based on published data, fluoxetine and norfluoxetine appeared to have a low to moderate bioaccumulation potential, which should be confirmed in formal studies according to OECD guidelines. Exposure assessments for fluoxetine according to the current framework rely heavily on K(OC) and K(OW) values. This approach is problematic, because fluoxetine is predominantly a cationic substance at environmental pH values. Consequently, the fate of fluoxetine (and other ionic substances) cannot be predicted using partition coefficients established for nonionic compounds. Further, published estimates for partition coefficients of fluoxetine vary, resulting in considerable uncertainties in both the exposure and environmental risk assessments of fluoxetine.

Environmental risk assessment of ivermectin: A case study.

The veterinary parasiticide ivermectin was selected as a case study compound within the project ERAPharm (Environmental Risk Assessment of Pharmaceuticals). Based on experimental data generated within ERAPharm and additional literature data, an environmental risk assessment (ERA) was performed mainly according to international and European guidelines. For the environmental compartments surface water, sediment, and dung, a risk was indicated at all levels of the tiered assessment approach. Only for soil was no risk indicated after the lower tier assessment. However, the use of effects data from additional 2-species and multispecies studies resulted in a risk indication for collembolans. Although previously performed ERAs for ivermectin revealed no concern for the aquatic compartment, and transient effects on dung-insect populations were not considered as relevant, the present ERA clearly demonstrates unacceptable risks for all investigated environmental compartments and hence suggests the necessity of reassessing ivermectin-containing products. Based on this case study, several gaps in the existing guidelines for ERA of pharmaceuticals were shown and improvements have been suggested. The action limit at the start of the ERA, for example, is not protective for substances such as ivermectin when used on intensively reared animals. Furthermore, initial predicted environmental concentrations (PECs) of ivermectin in soil were estimated to be lower than refined PECs, indicating that the currently used tiered approach for exposure assessment is not appropriate for substances with potential for accumulation in soil. In addition, guidance is lacking for the assessment of effects at higher tiers of the ERA, e.g., for field studies or a tiered effects assessment in the dung compartment.

Environmental effect assessment for sexual endocrine-disrupting chemicals: Fish testing strategy.

Current standard testing and assessment tools are not designed to identify specific and biologically highly sensitive modes of action of chemicals, such as endocrine disruption. This information, however, can be important to define the relevant endpoints for an assessment and to characterize thresholds of their sublethal, population-relevant effects. Starting a decade ago, compound-specific risk assessment procedures were amended by specifically addressing endocrine-disrupting properties of substances. In 2002, the Conceptual Framework, agreed upon by OECD's Task Force on Endocrine Disrupters Testing and Assessment, did not propose specific testing strategies, and appropriate testing methods had not yet been developed and approved. In the meantime, the OECD Test Guidelines Programme has undertaken important steps to revise established and to develop new test methods, which can be used to identify and quantify effects of endocrine-disrupting chemicals on mammals, birds, amphibians, fish, and invertebrates. For fish testing of endocrine-disrupting chemicals, the first Test Guidelines have recently been adopted by the OECD and validation of further test systems is under progress. Based on these test systems and the experience gained during their validation procedures, we propose a 3-step fish testing strategy: 1) Weight-of-evidence approach for identifying potential sexual endocrine-disrupting chemicals; even after advanced specification of systematic criteria, this step of establishing initial suspicion will still require expert judgment; 2) in vivo evaluation of sexual endocrine-disrupting activity in fish by applying in vivo fish screening assays; sufficient data are available to diagnose the aromatase-inhibition and estrogen-receptor agonist mechanisms of action by indicative endpoints (biomarkers), whereas the ability of the respective biomarkers in the screening assay to identify the estrogen-receptor antagonists and androgen-receptor agonists and antagonists requires further validation; 3) characterization of sexual endocrine-mediated adverse effects including threshold concentrations; in cases when the most sensitive population-relevant endpoints and the most sensitive time window for exposure are known for the mechanisms of action, the fish full life-cycle or 2-generation test, which are the normal definitive tests, might be abbreviated to, e.g., the fish sexual development test. In the European Union, the measurement of indicative endpoints in the definitive test might be crucial for the authorization procedure under REACH and plant-protection products. The results of the definitive tests can be used in existing schemes of compound-specific environmental risk assessments.

A water-sediment screening tool for measuring biodegradation of organic chemicals.

A water-sediment screening tool (WSST) was developed based on OECD guideline 301 C (MITI I; Ministry of International Trade and Industry, Japan) to generate biodegradation data. The WSST and experimental procedures were tested and validated using aniline (CAS No. 62-53-3) and benzoic acid (CAS No. 65-85-0) as reference substances. In the presence of sediment components a higher endogenous respiration rate in the control vessels without test substance was measured compared to the water-only MITI test system, particularly due to organic constituents. However, it could be demonstrated that a distinct biodegradation in the presence of sediment can be determined and that there is no influence of the sediment pre-treatment on the biological oxygen demand in the WSST. Experiments resulted in biodegradation rates >60% after approximately six days for both compounds. However, degradation of benzoic acid resulted in a shorter lag-phase and a higher degree of degradation compared to aniline. Differences in results between the MITI test system and the WSST observed for aniline can be explained by adsorption to constituents of the sediment and assimilation by activated sludge. In comparison with literature data the results obtained for aniline in the MITI test system and the WSST showed reproducibility and were within the expected range. In conclusion, the WSST is a suitable screening tool to determine kinetic biodegradation data required to predict the biodegradation behaviour of organic chemicals in water-sediment systems and the data might be used to improve quantitative structure-property relationships (QSPRs).

Toxication or detoxication? In vivo toxicity assessment of ozonation as advanced wastewater treatment with the rainbow trout.

Ozonation as advanced wastewater treatment method is an effective technique for micropollutant removal. However, the application of this method carries the inherent danger to produce toxic oxidation byproducts. For an ecotoxicological assessment conventionally treated wastewater, wastewater after ozonation and ozonated wastewater after sand filtration were evaluated in parallel at an operating treatment plant via the fish early life stage toxicity test (FELST) using rainbow trout (Oncorhynchus mykiss). The FELST revealed a considerable developmental retardation of test organisms exposed to ozonated WW. This was accompanied by a significant decrease in body weight and length compared to reference water, to the conventionally treated WW and to the ozonated water after sand filtration. Hence sand filtration obviously prevents from adverse ecotoxicological effects of ozonation. An additional test with yolk-sac larvae resulted in a significant reduction of vitellogenin levels in fish exposed to ozonated wastewater compared to fish reared in conventionally treated wastewater. This demonstrates the effective removal of estrogenic activity by ozonation. Adverse ozonation effects may have been a result of the conversion of chemicals into more toxic metabolites. However, sand filtration reduced toxication effects indicating that these oxidation byproducts are readily degradable or adsorbable. The results indicate that in any case ozonation should not be applied without subsequent post treatment appropriate for oxidation byproducts removal (e.g. sand filtration).

Environmental risk assessment of human pharmaceuticals in the European Union: A case study with the ß-blocker atenolol.

ß-Adrenergic receptor blockers (ß-blockers) are applied to treat high blood pressure, ischemic heart disease, and heart rhythm disturbances. Due to their widespread use and limited human metabolism, ß-blockers are widely detected in sewage effluents and surface waters. ß-Adrenergic receptors have been characterized in fish and other aquatic animals, so it can be expected that physiological processes regulated by these receptors in wild animals may be affected by the presence of ß-blockers. Because ecotoxicological data on ß-blockers are scarce, it was decided to choose the ß-blocker atenolol as a case study pharmaceutical within the project ERAPharm. A starting point for the assessment of potential environmental risks was the European guideline on the environmental risk assessment of medicinal products for human use. In Phase I of the risk assessment, the initial predicted environmental concentration (PEC) of atenolol in surface water (500 ng L−1) exceeded the action limit of 10 ng L−1. Thus, a Phase II risk assessment was conducted showing acceptable risks for surface water, for groundwater, and for aquatic microorganisms. Furthermore, atenolol showed a low potential for bioaccumulation as indicated by its low lipophilicity (log KOW = 0.16), a low potential for exposure of the terrestrial compartment via sludge (log KOC = 2.17), and a low affinity for sorption to the sediment. Thus, the risk assessment according to Phase II-Tier A did not reveal any unacceptable risk for atenolol. Beyond the requirements of the guideline, additional data on effects and fate were generated within ERAPharm. A 2-generation reproduction test with the waterflea Daphnia magna resulted in the most sensitive no-observed-effect concentration (NOEC) of 1.8 mg L−1. However, even with this NOEC, a risk quotient of 0.003 was calculated, which is still well below the risk threshold limit of 1. Additional studies confirm the outcome of the environmental risk assessment according to EMEA/CHMP (2006). However, atenolol should not be considered as representative for other ß-blockers, such as metoprolol, oxprenolol, and propranolol, some of which show significantly different physicochemical characteristics and varying toxicological profiles in mammalian studies.

Targeting the environmental risk assessment of pharmaceuticals: Facts and fantasies.

In contrast to industrial chemicals, pharmaceuticals and pesticides are designed to show specific pharmacological actions or biocidal activities. Despite this difference, the same principles for environmental risk assessment, e.g., risk characterization by comparing compartment-specific exposure and effect, are applied to both nonspecifically and specifically acting substances. In addition, many pharmaceuticals are relatively hydrophilic, polar, or charged compounds. However, standardized guidelines for generating fate and effects data have been developed predominantly for neutral substances. For these reasons, the risk characterization of biologically active pharmaceuticals might contain a considerable degree of uncertainty. In this paper, we propose a conceptual approach for a targeted environmental risk assessment to reduce the uncertainties of risk characterization for pharmaceuticals by using the information provided in the nonenvironmental part of the regulatory dossier. Three steps have been defined for this purpose: 1) The first is collation of specific information contained in regulatory dossiers for pharmaceuticals, e.g., data produced to understand the interaction of the active substance with biological structures, 2) Based on this information, conclusions might be drawn with regard to environmental compartments likely to be exposed and organisms likely to be affected, and 3) Selection can be made of single-species or multispecies tests to generate additional information for the ecotoxicological risk characterization of pharmaceuticals. Furthermore, some thoughts will be presented on the integration of targeted testing strategies into conceptual regulatory guidance.

A ranking of European veterinary medicines based on environmental risks.

The most likely entry pathways of veterinary pharmaceuticals to the environment are via slurry or manure from intensively reared animals to soil and via dung or urine from animals grazing on pasture. These pathways may result in contamination of surface water via runoff or leaching and drainage. Direct entry into water may occur by defecation by pasture animals or by Scompanion animals. In addition, application of medicines for aquaculture is important for a limited number of veterinary medicinal products. For a large number of veterinary medicinal products, consistent data on the environmental risk have never been generated. In this project, a simple risk-based ranking procedure was developed that should allow assessing the potential for environmental risks of active substances of veterinary medicinal products. In the European Union approximately 2000 products containing 741 active substances were identified. In the prescreening step and in agreement with the technical guidelines released by the European Medicines Agency, 294 natural substances, complex mixtures, and substances with low expected exposure were exempted from the ranking procedure. For 233 active substances, sufficient information was collated on 4 exposure scenarios: Intensively reared animals, pasture animals, companion animals, and aquaculture. The ranking approach was performed in 4 phases: (1) usage estimation; (2) characterization of exposure to soil, dung, surface water, and aquatic organisms depending on exposure scenarios; (3) characterization of effects based on therapeutical doses; and (4) risk characterization, which is the ratio of exposure to effects (risk index), and ranking. Generally, the top-ranked substances were from the antibiotic and parasiticide groups of veterinary medicines. Differences occurred in the ranking of substances in soil via application to either intensively reared or pasture animals. In intensive rearing, anticoccidia, for example, are used as feed-administered medicines (feed additives) in comparatively large doses over a long time. For pasture animals, these substances are used less, if at all, and therefore receive lower ranks. Besides that, the risk indices for the aquatic compartment are large for substances used in aquaculture or applied to companion animals. In conclusion, the ranking scheme developed for this project provided a scientifically based and pragmatic means of assessing the relative priority of veterinary medicines for further detailed risk assessment. The outcome of this project will support pharmaceutical industries and competent authorities when seeking authorization for market applications of veterinary pharmaceutical products.

Direct and indirect effects of pollutants on algae and algivorous ciliates in an aquatic indoor microcosm.

An aquatic indoor microcosm was used to study effects of the pesticides parathion-methyl and prometryn on phototrophic flagellates (Cryptomonas sp.) and predatory ciliates (Urotricha furcata). Parathion-methyl caused effects to flagellates and ciliates at the range of low mg L(-1), regardless of whether the organisms were exposed separately or combined in the multi-species test system. Prometryn caused effects on the flagellates at low microg L(-1) concentrations, resulting in a NOEC of 6.9 microg L(-1) in the single-species test and a NOEC of 15.2 microg L(-1) in the multi-species microcosm. For ciliates the NOEC decreased by factor 145 in the multi-species test compared to the NOEC of 2.2 mg L(-1) in the single-species test when exposed to prometryn. The lower NOEC for ciliates exposed to prometryn in the microcosm was most likely caused by an indirect effect due to reduced availability of flagellates as food. The measurement of nutrient concentrations in the test media and organisms facilitated the modelling of effects. The presented aquatic indoor microcosm is considered as a tool which could be standardised and applied as an instrument to provide data for higher tier risk assessment.

ECOSAR model performance with a large test set of industrial chemicals.

The widely used ECOSAR computer programme for QSAR prediction of chemical toxicity towards aquatic organisms was evaluated by using large data sets of industrial chemicals with varying molecular structures. Experimentally derived toxicity data covering acute effects on fish, Daphnia and green algae growth inhibition of in total more than 1,000 randomly selected substances were compared to the prediction results of the ECOSAR programme in order (1) to assess the capability of ECOSAR to correctly classify the chemicals into defined classes of aquatic toxicity according to rules of EU regulation and (2) to determine the number of correct predictions within tolerance factors from 2 to 1,000. Regarding ecotoxicity classification, 65% (fish), 52% (Daphnia) and 49% (algae) of the substances were correctly predicted into the classes "not harmful", "harmful", "toxic" and "very toxic". At all trophic levels about 20% of the chemicals were underestimated in their toxicity. The class of "not harmful" substances (experimental LC/EC(50)>100 mg l(-1)) represents nearly half of the whole data set. The percentages for correct predictions of toxic effects on fish, Daphnia and algae growth inhibition were 69%, 64% and 60%, respectively, when a tolerance factor of 10 was allowed. Focussing on those experimental results which were verified by analytically measured concentrations, the predictability for Daphnia and algae toxicity was improved by approximately three percentage points, whereas for fish no improvement was determined. The calculated correlation coefficients demonstrated poor correlation when the complete data set was taken, but showed good results for some of the ECOSAR chemical classes. The results are discussed in the context of literature data on the performance of ECOSAR and other QSAR models.

Estimating the use of veterinary medicines in the European union.

Risk-based ranking is a procedure that ranks active substances according to their potential environmental risk, which can be used to prioritise effort in environmental risk assessment procedures. An important aspect in this procedure is the extent of use of the active substance. However, use volume data for veterinary pharmaceuticals are generally not publicly available. Therefore, the use of several groups of pharmaceuticals was estimated. For this, available data were collected from different sources and used to calculate the average use, related with the total meat production in the respective countries. Then, an extrapolation, based on food-stuff production data, yields a rough estimate of the use volume for all European countries, largely based on 2004 data. The estimated use was 5393 tons antibiotics, 194 tons antiparasitics and 4.6 tons hormones, 221 tons to treat the alimentary tract and metabolism related disorders, 120 tons CNS active substances, 60 tons of substances used for blood and blood forming organs and 52 tons for muscles and skeleton related disorders. In total, an estimated 6051 tons of active substances in veterinary medicines were used in the European Union. We discuss available data sources and quality, our method and possible refinement of our approach. Environmental risk-based ranking procedures of veterinary substances would benefit from more detailed use data.

Eco-labelling of shampoos, shower gels and foam baths.

GOAL, SCOPE AND BACKGROUND: Environmental issues of personal care products have been met with little attention in the past. Monitoring data as well as preliminary environmental risk assessments indicate that some ingredients in personal care products might be relevant pollutants in the environment. Following the precautionary principle, eco-labelling is proposed as an effective tool for source control of one major group of personal care products, shampoos, shower gels and foam baths (SSBs). Eco-labelling is a soft, but effective market driven and product specific approach to lower discharge of environmentally detrimental substances. Products that fulfil the criteria proposed help to minimise the impact of SSBs on the environment. METHODS: Available assessment tools for dangerous substances (e.g. current legislation on environmental risk assessments and classification, and labelling, eco-labelling criteria for similar products, the calculation of the critical dilution volume) were adapted and integrated into the criteria for the eco-labelling of SSBs. RESULTS AND DISCUSSION: A short outline of the eco-labelling criteria developed for SSBs is provided. The basic criteria concern the effects of the substances discharged into the waste water during and after use. Products with an eco-label award may exclusively contain substances for which basic information about their effects on the environment is available. They may not contain persistent, bioaccumulating, toxic or ecotoxicological substances. In addition, the basic criteria include requirements for the container and consumer information. CONCLUSION: The basic criteria for eco-labelling SSBs are based on the actual state of science and are at the same time as simple and transparent as possible to ensure the best applicability. SSBs that comply with the described basic criteria can contribute to a lower chemical burden of waste water treatment plants and surface water. RECOMMENDATION AND OUTLOOK: The proposal for basic criteria described should stimulate discussion on eco-labelling of SSBs. It should help to pass valid criteria supported by authorities, producers and consumer groups for a national or international eco-label, e.g. for the European Flower or the German Blue Angel. In future, the successful introduction of labelled SSBs into the market will raise the awareness of the general public about the environmental effects of personal care products and it will help to promote environmentally compatible products.

Evaluation of measured and predicted environmental concentrations of selected human pharmaceuticals and personal care products.

GOAL, SCOPE AND BACKGROUND: In the past few years, there was an increasing awareness of the occurrence of pharmaceuticals and personal care products (PPCPs) in surface water and drinking water resources, and measurements in surface water, sediment or waste water were done for a number of PPCPs. In the regulatory context, an environmental risk assessment (ERA) has become essential for new PPCPs. Reliably predicted or measured environmental concentrations (PECs or MECs) of chemicals are essential for the exposure assessment, which is one of the two main pillars of environmental risk assessment (ERA). This paper reports on measured data of selected PPCPs in surface waters and compares the measured values with predicted environmental concentrations from exposure models. Such models have been proposed by the European Agency for the Evaluation of Medicinal Products (EMEA) and the Technical Guidance Document on Risk Assessment for New Notified and Existing Chemical Substances (TGD). METHODS: Four pharmaceuticals and one personal care product were in the scope of the investigation reported here: 17alpha-ethinylestradiol, carbamazepine, sulfamethoxazole and iopromide as well as tonalide. Measured environmental concentrations in surface waters for these PPCPs were reviewed in the scientific literature. The appropriateness of these data was evaluated according to criteria for monitoring data recommended by the TGD. A total of 38 references were evaluated with emphasis on the adequacy of chemical analysis and the representativeness of sampling. Measurements of concentrations in surface water (MECsw), which were found to be adequate for use in exposure assessment according to the monitoring quality criteria, were averaged and compared with respective PECs in surface water (PECsw) derived from exposure modelling (cf. EMEA and TGD). RESULTS AND DISCUSSION: Measured environmental concentrations adequate for use in exposure assessment were found in 20 out of 38 references. Several of the measurements from Germany could be used for a comparison with calculated PECs. Average MECs(sw) in Germany were < 0.58 ng/L for 17alpha-ethinylestradiol, 454 ng/L for carbamazepine, 126 ng/L for sulfamethoxazole, 1105 ng/L for iopromide and 311 ng/L for tonalide. In comparison to the measured concentrations, PECs calculated with the model proposed by the EMEA in 2001 were in the same range, but slightly higher than the MECs. The EMEA model from 2001 is based on a production/use volume of the PPCPs. The more recent EMEA model (2003/2005) overestimated the PECs by more than one order of magnitude for carbamazepine and sulfamethoxazole, but underestimated the concentration of 17alpha-ethinylestradiol by a factor of almost 5 compared to the MECs. This model is based on maximum daily doses and the assumption that 1% of the population is consuming the pharmaceutical (default value). Calculations with the European Union System for the Evaluation of Substances (EUSES), which is part of the TGD describing the risk assessment of chemicals and biocides, resulted for the investigated pharmaceuticals in almost the same PECs as derived by the older EMEA model (2001). For the PCP tonalide, to which the recent EMEA model (2003/ 2005) cannot be applied, the PEC was overestimated by a factor of 3 with the older EMEA model (2001), but underestimated with EUSES by a factor of 5 compared to the averaged MECsw in Germany. Conclusions. It was shown that PEC calculations with exposure models provided by EMEA and the TGD, resulted in PECs very close to the corresponding MECs in most cases. However, environmental concentrations can be underestimated by models in cases, where, e.g. due to high lipophilicity, sorption to sewage sludge is assumed which does not occur to that extent under real conditions. Thus, it appears that the exposure models do not come up to the complexity of the real environment. However, the main factor with the highest impact on predicted environmental concentrations and a high degree of uncertainty is the production volume. Recommendations and Outlook. References and their data evaluated as not adequate for use in exposure assessment were mainly rejected due to missing or insufficient specifications related to the sampling procedure and/or representativeness of the samples. Several of the evaluated studies aimed at the introduction and establishment of a new analytical methodology. A detailed description of sampling frequency and pattern, for example, was therefore neglected. Often, a more accurate description of analytical procedure, sampling pattern and statistical analysis of data would be sufficient to provide an adequate basis for exposure assessment and hence establish confidence in environmental risk assessment procedures. For new substances, an exposure assessment is solely based on estimations using environmental fate models. To avoid unacceptable risks for the environment, PECs should not underestimate actual environmental concentrations. Since it was shown that under specific conditions the models applied in this study underestimated measured environmental concentrations, further development of the calculation models appears to be necessary.

Biodegradability of 14C-labeled antibiotics in a modified laboratory scale sewage treatment plant at environmentally relevant concentrations.

For all new pharmaceuticals, an environmental risk assessment (ERA) has to be performed according to guidelines developed by the European Medicines Evaluation Agency. An important factor of this procedure is the assessment of the predicted environmental concentration in the aquatic environment, which is significantly influenced by the biodegradability of pharmaceuticals in sewage treatment plants. Established standardized methods for determining biodegradation under laboratory conditions apply to substance concentrations, which are much higherthan those expected in reality. Against this background, the laboratory scale sewage treatment plant (LSSTP), as described by the Organisation for Economic Cooperation and Development (OECD) Guideline No. 303A, was modified to construct a lossless system, which allows laboratory testing at realistic concentrations. To verify the experimental setup, the antibiotics benzylpenicillin, ceftriaxone, and trimethoprim were tested at low concentrations (microg/L) using 14C-labeled compounds. The results show that approximately 25% of benzylpenicillin was mineralized, whereas ceftriaxone and trimethoprim were not mineralized at all. Due to the high total recoveries of added radioactivity (> or =95%) and the fact that the findings comply with available literature data, the lossless operation of the test system could be proved. Consequently, the modified LSSTP is a suitable tool to determine more realistic biodegradation data required for the exposure assessment within the scope of an ERA for pharmaceuticals.

The EU-project ERAPharm. Incentives for the further development of guidance documents?

Triggered by the detection of a large variety of pharmaceuticals in surface waters, soils and groundwaters across the world (e.g. Halling-Sørensen et al. 1998, Daughton & Ternes 1999, Jones et al. 2001, Heberer 2002) and the widespread occurrence of endocrine active compounds and related effects in the environment (e.g. Purdom et al. 1994, Tyler et al. 1998, Vethaak et al. 2002), pharmaceuticals in the environment have become an issue for both the scientific and the public community. During the last few years, our understanding of the fate and effects of pharmaceuticals in the environment has progressed significantly. However, there are still a number of uncertainties concerning the effects of pharmaceuticals on the environment and the assessment of potential exposure (e.g. Hanisch et al. 2004, Salomon 2005). These uncertainties will be addressed by the EU-project 'Environmental risk assessment of pharmaceuticals' (ERAPharm). This project, a specific targeted research project, is carried out within the priority 'Global change and ecosystems' of the 6th framework programme of the European Union. ERAPharm has started on 1st October 2004; the project duration is three years.

The use of terrestrial and aquatic microcosms and mesocosms for the ecological risk assessment of veterinary medicinal products.

In this paper, we investigate the applicability of experimental model ecosystems (microcosms and mesocosms) for the ecological risk assessment of veterinary medicinal products (VMPs). VMPs are used in large quantities, but the assessment of associated risks to the environment is limited, although they are continually infused into the environment via a number of routes. It is argued that the experience obtained by pesticide research largely can be used when evaluating VMPs, although there are several major differences between pesticides and pharmaceuticals (e.g., knowledge of their mechanisms of action on nontarget organisms). Also, because microorganisms are often the target organisms of VMPs, risk assessment should focus more on endpoints describing functional processes. This paper provides a review of the current risk assessment schemes of Europe and North America along with examples of experiments already performed with veterinary medicinal products in aquatic and terrestrial ecosystem models. We suggest that some of the approaches developed for pesticide risk assessment can be used for VMPs and offer suggestions for the development of a framework for ecological risk assessment of VMPs.

Bioaccumulation of 14C-17alpha-ethinylestradiol by the aquatic oligochaete Lumbriculus variegatus in spiked artificial sediment.

A bioaccumulation study was performed with the endobenthic freshwater oligochaete Lumbriculus variegatus MULLER exposed to the radiolabelled synthetic steroid 17alpha-ethinylestradiol (14C-EE2) in a spiked artificial sediment. Concentration of total radioactivity increased constantly and almost linearly during 35 days of exposure. The accumulation factor normalised to worm lipid content and sediment TOC (AFlipid/OC) was 75 at the end of the uptake period, but a steady state was not reached. Uptake kinetics were calculated fitting the measured AFs to a kinetic rate equation for constant uptake from sediment using iterative non-linear regression analysis. After 10 days of elimination in contaminant-free sediment 50% of the accumulated total radioactivity was excreted by the worms. Extracts from L. variegatus sampled at the end of the uptake phase were analysed by thin layer chromatography (TLC). The results showed that 6% of the total radioactivity incorporated by the worms was 14C-EE2. After treatment of extracts with beta-glucuronidase the amount of 14C-EE2 increased to 84%. These results suggest that L. variegatus has the potency to accumulate high amounts of conjugated EE2. Hence, a transfer of EE2 to benthivores and subsequent secondary poisoning of predators might be possible.

A rapid method to measure the solid-water distribution coefficient (Kd) for pharmaceuticals and musk fragrances in sewage sludge.

Pharmaceuticals and personal care products are omnipresent in wastewater world-wide. In order to predict their sorption quantities onto sludge in wastewater treatment plants (WWTPs), the solid-water distribution coefficients (Kd values) of selected pharmaceuticals (antiphlogistics, estrogens, lipid regulators, anti-epileptic and cytostatic agents) and polycyclic musk fragrances (HHCB, AHTN) were determined in primary and secondary sludges taken from a German municipal WWTP. For the Kd determination, batches of primary and secondary sludge slurries were spiked with the respective target compounds and slowly stirred under defined conditions (e.g. an argon atmosphere). Finally, the water and solid sludge phases were analysed. The Kd values of pharmaceuticals ranged from <1 to 500 L kg(-1), while those for the polycyclic musk fragrances AHTN and HHCB proved to be up to 5300 and 4900 L kg(-1), respectively. The primary and secondary sludge showed significant differences for some pharmaceuticals such as Diclofenac and Cyclophosphamide due to the different pH and composition of the two sludges. The removal rate from the water phase caused by sorption in a WWTP can be reasonably predicted on the basis of the Kd values.

Ring-testing and field-validation of a terrestrial model ecosystem (TME)--an instrument for testing potentially harmful substances: effects of carbendazim on organic matter breakdown and soil fauna feeding activity.

Organic matter (OM) decomposition and soil fauna feeding activity were integrated as functional endpoints into ecotoxicological tests with intact-soil-core Terrestrial Model Ecosystems (TMEs). Cellulose filter paper served as standardized OM and was either inserted into the top soil or placed on the soil surface for a period of up to 16 weeks. Faunal feeding activity was assessed by the bait-lamina method. The fungicide carbendazim, applied at six dosages ranging from 0.36 kg/ha to 87.5 kg a.i./ha, served as a model chemical. To validate the results from the TME test, a field study was run in parallel. In TMEs the cellulose paper inserted into the soil was decomposed faster than under field conditions. The carbendazim-induced effects on OM decomposition in TMEs and in the field were comparable and followed a clear dose-response relationship. The calculated EC50 values after 8 weeks of incubation were 9.5, 7.1 and 2.1 kg carbendazim/ha for grassland TMEs, grassland field and arable TMEs, respectively. The feeding activity of the soil fauna showed a large variability. The EC50 values for the effect of carbendazim on bait-lamina consumption ranged between 2.0 and 56 kg a.i./ha. Effects on decomposition were correlated with effects on enchytraeids and earthworms but not with effects on bait-lamina consumption.