Pharmacology beyond the patient - The environmental risks of human drugs.

BACKGROUND: The presence of pharmaceuticals in the environment is a growing global concern and although environmental risk assessment is required for approval of new drugs in Europe and the USA, the adequacy of the current triggers and the effects-based assessments has been questioned. OBJECTIVE: To provide a comprehensive analysis of all regulatory compliant aquatic ecotoxicity data and evaluate the current triggers and effects-based environmental assessments to facilitate the development of more efficient approaches for pharmaceuticals toxicity testing. METHODS: Publicly-available regulatory compliant ecotoxicity data for drugs targeting human proteins was compiled together with pharmacological information including drug targets, Cmax and lipophilicity. Possible links between these factors and the ecotoxicity data for effects on, growth, mortality and/or reproduction, were evaluated. The environmental risks were then assessed based on a combined analysis of drug toxicity and predicted environmental concentrations based on European patient consumption data. RESULTS: For most (88%) of the of 975 approved small molecule drugs targeting human proteins a complete set of regulatory compliant ecotoxicity data in the public domain was lacking, highlighting the need for both intelligent approaches to prioritize legacy human drugs for a tailored environmental risk assessment and a transparent database that captures environmental data. We show that presence/absence of drug-target orthologues are predictive of susceptible species for the more potent drugs. Drugs that target the endocrine system represent the highest potency and greatest risk. However, for most drugs (>80%) with a full set of ecotoxicity data, risk quotients assuming worst-case exposure assessments were below one in all European countries indicating low environmental risks for the endpoints assessed. CONCLUSION: We believe that the presented analysis can guide improvements to current testing procedures, and provide valuable approaches for prioritising legacy drugs (i.e. those registered before 2006) for further ecotoxicity testing. For drugs where effects of possible concern (e.g. behaviour) are not captured in regulatory tests, additional mechanistic testing may be required to provide the highest confidence for avoiding environmental impacts.

Aquatic environmental risk assessment of manganese processing industries.

An environmental risk assessment (ERA) has been conducted for sites producing and processing manganese and its inorganic compounds, focussing on potential risks to freshwater. A site specific questionnaire was used to collect information. Sites fall into three broad categories: mining sites, refining sites, and sites producing chemicals and pigments. Waste disposal is principally carried out by the treatment of liquid wastes to separate solids for disposal off-site with a consented wastewater discharge, or disposal on-site using evaporation or settlement ponds in order to maintain the waste materials in a suitable manner following site closure. The main source of emissions from refining and alloying sites is from the treatment of emissions to air using wet scrubber air filters. There is also the potential for fugitive environmental emissions of manganese from stockpiles of raw material held on-site. Data provided from the questionnaires were both site-specific and also commercially sensitive. Therefore, this paper has undertaken the manganese exposure assessment, using a probabilistic approach to reflect the distribution of emissions of manganese and also to maintain the confidentiality of site specific data. An inverse correlation was observed between the total annual tonnage of manganese processed at the site and the emission factor, such that sites processing larger quantities resulted in lower emissions of manganese per tonne processed. The hazard assessment determined a Predicted No Effect Concentration (PNEC) for freshwater using a species sensitivity distribution approach, resulting in a freshwater PNEC of 0.075mgL-1 for soluble manganese. Based on the exposure data and the freshwater PNEC derived for this study, the distributions of risk characterisation ratios using the probabilistic approach indicates that two thirds of manganese processing sites would not be expected to pose a potential risk to the local aquatic environment due to wastewater emissions, although local risks are possible at some sites.