Riesgos medioambientales de los productos farmacéuticos y medicinales

    The pollution of water and soil with pharmaceutical residues is an emerging environmental concern. In August 2013, in the framework of the adoption of Directive 2013/39/EU as regards priority substances in the field of water policy, the Commission has been asked to develop a strategic approach to pollution of water by pharmaceutical substances by the end of 2015. In this report “medicinal products” will be used as the generic term for “pharmaceuticals” or “drugs”, which are administered to human and/or animals.

    Context and importance of the issue

      During the last two decades, there has been an increasing trend in the R&D, industrial production, sale, and consumption of medicinal products in the EU. In terms of market presence, around three thousand active pharmaceuticals ingredients (APIs) are currently authorised on the EU market as a whole, even if the APIs authorised at national level may vary significantly.

      Consumption of medicinal products is quite heterogeneous across the EU Member States. It ranges from 50 to 150 g/capita/year in the case of human medicinal products. Such heterogeneity is reflected by the nature of the associated waste streams, which vary strongly in terms of quantities and/or composition, Moreover, in the majority of EU Member States, a large share of unused human medicinal products (50% on average) is not collected.

      The issue is that we lack a global view in understanding what happens when these medicinal products are discharged into the environment, either through consumption, or as unused or expired products. Residues of various types of medicinal products (hormones, anti-cancer, antidepressants, antibiotics, etc.) have been detected in the different environmental compartments: surface water, groundwater, soil, air, and biota. The pollution of waters and soils with pharmaceutical residues is an emerging issue, as such widespread occurrence obviously begs the question whether a concentration of medicinal products in the environment poses a risk for exposed biota or humans.

      The objective of the report was to characterise the scale of the environmental effects of medicinal products, personal care products being excluded. Together with other relevant studies and reports, it should contribute to identify non-legislative and legislative causes of their presence in the environment, and the basis to develop a strategic approach by the end of 2015 for possible solutions across the entire EU legislative framework. The different aspects need to be further validated by the European Commission, based on the contributions from the European Medicines Agency, the European Environment Agency, Member States and stakeholders.

      There are of course uncertainties related to the availability of data concerning the quantity and nature of medicinal products reaching the environment from the different stages of the life cycle, and their behaviour in the environment. Due to knowledge gaps in their behavior in the environment, and/or detection issues, information is scarce on the environmental occurrence and fate of metabolites and transformation products. Data on environmental concentrations are scarce or even missing for some environmental compartments, notably for biota in the food web and marine ecosystems. Therefore further characterisation of possible exposure routes for humans and thus to the scientific knowledge is necessary to conduct a proper risk evaluation.

      How do medicinal products enter and behave in the environment?

        The consumption phase is considered to be the major contributor to the emissions of medicinal products into the environment, notably through excretions and incorrect disposal of unused medicines through sinks and toilets. Between 30 and 90% of the orally administered dose is generally excreted as active substance in the urine of animals and humans. However, the nature and amount of medicinal residues mainly depend on the volumes and nature of the administered substances, their modes of administration, and elimination (metabolisation) processes and rates. Medicinal products can also directly enter the environment through feed surplus, notably in the case of aquaculture. Although the use of medicinal products to meet needs for medication is hardly questionable, inappropriate and excessive consumption is at the origin of unnecessary emissions. The concept of “overconsumption”, i.e. consumption beyond actual needs, is an easy grasp but it is difficult to assess the scale of this phenomenon in practice, given the subjectivity of what is “needed”.

        In the EU, the contribution of manufacturing facilities to emissions of medicinal products and/or their residues is generally considered as negligible, even though pollution downstream of manufacturing plants has been sporadically observed while monitoring specific sites.

        Several medicinal products are detectable in the environment, and their concentration depends on the geographical location, season, local administration practices, and specific environmental factors (temperature, humidity, etc.). A large amount of information is now available, notably concerning the monitoring of certain active substances in surface and groundwater used for the production of drinking water, but the available data are not centralised and not in a standardised format. The detected concentrations could be in the range of sub-ng/L to more than several μg/L. For example, Carbamazepine (an anti-epileptic medicinal product) and its main metabolite, and Oxazepam (an anxiolytic of the benzodiazepines family) were detected in a freshwater monitoring programme in France. Highly lipid-soluble medicinal products may also have the ability to accumulate in the fat tissues of animals and can be thus introduced in the food chain.

        Once in the environment, medicinal products are transformed and can be transferred among different compartments, depending on the nature of the compounds and of the characteristics of the host compartment. These products can degrade biotically or abiotically in soils and water, a process that in general reduces their potency, even if some degradation products might be persistent and thus of concern. The residues remaining after wastewater treatment depend on the composition of the medicinal product, wastewater treatment process, and initial concentrations in the influent. As for landfills accepting medicinal products, sewage sludge can produce leachates containing concentrations similar to or even higher, than those found in wastewater treatment plant influents.

        What kind of hazards and risks do they represent for ecosystems?

          For a range of pharmaceuticals, environmental risks can be rather negligible, due to low environmental persistence and ecotoxicity of the compounds. It is becoming increasingly clear however that some medicinal products, in particular anti-parasiticides, anti-mycotics, antibiotics and (xeno)estrogens, pose environmental risks in specific exposure scenarios. Examples include the contraceptive ethinylestradiol, which impairs the reproduction of exposed fish populations, the effects of various antibiotics on environmental bacteria and algae, or of oxazepam on European perch. The decline of vulture populations on the Indian sub-continent due to poisoning with diclofenac, a non-steroidal painkiller, is a good example of how unexpected exposure pathways – feeding on carcasses – can lead to severe ecotoxicological effects.

          What are the potential impacts on human beings?

            For humans, the possible impacts are less clear than for the environment, but there are concerns notably regarding certain type of molecules that are especially intended to kill their target organism or target cells, even if to date there is no clear evidence of short-term health effects on humans. Chronic low-level exposure to medicinal products can occur through drinking water and through residues in leaf crops, root crops, fishery and dairy products, and meat. To date no legal limit exists for human medicinal products potentially present in animal derived food (e.g. due to bioaccumulation from contaminated soil) since this pathway of exposure is assumed as negligible although currently not well characterised.

            What are the limits of the present EU legislative framework regarding the presence of medicinal products in the environment?

              One of the key factors influencing the presence of the medicinal products in the environment is the current legislative framework for Environmental Risk Assessment (ERA), which is a part of the Market Authorisation (MA) process. For veterinary medicinal products, an ERA is required for all types of MA applications, including for new medicinal products, generics, variations and extensions, and is taken into account in a risk-benefit analysis in view of the authorisation.

              One of the limits is that there is a lack of ERA results for most ‘old’ human medicinal products currently consumed, as numerous active pharmaceutical ingredients contained in such medicinal products were authorised prior to October 2005, which is when a proper ERA became an obligation for human medicinal products. For several years, an ERA has also been required for a large number of human medicinal products on the market, but the ERA results in this specific case cannot lead to denying an authorisation, even if some Risk Mitigation Measures (RMM) can be required when considered necessary and in the current ERA process, not all medicinal products undergo a thorough environmental risk assessment.

              Due to the procedures in place, the ERA is anyway not based on the real active pharmaceutical ingredients (API’s) volumes emitted in the environment due to the sum of products, but only on a single product’s share, which does not necessary reflect the environmental reality. Meanwhile, a number of regulatory frameworks for chemicals marketed and used in Europe now include an assessment for Persistence, Bioaccumulation and Toxicity (PBT) potential but, regarding veterinary medicinal products, no specific guidance is available on how to include this PBT assessment in the risk-benefit analysis or on which risk management measures would be needed in order to grant the MA. As for human medicinal products, similarly to the rest of ERA results, the output of the PBT assessment have up to now no consequences on MA, since it is not considered in the risk benefit analysis.

              Furthermore, under the centralised EU procedure, only the Committee in charge of the evaluation of veterinary medicinal products (CVMP) has a member appointed specifically due to his expertise on environmental risk assessment, while the Committee dedicated to human medicinal products (CHMP) does not necessarily include an environmental expert when looking at the output of the evaluation process. The ERA for human medicinal products is often incomplete or altogether absent from some MA applications. In these cases, the MA is therefore often granted with “post-marketing commitments” which are de facto not mandatory, since these results are not considered for the risk-benefit analysis and thus have no weight to obtain an MA.

              Medicinal products are, for the most part, exempted from the EU REACH regulation on chemicals requirements. They are, however, not exempted from the REACH provisions regarding restrictions on the manufacturing, placing on the market and use of certain dangerous substances and preparations. However, Annex XVII to REACH does not currently impose restrictions regarding active pharmaceutical ingredients. There are derogations for medicinal products from certain restrictions applicable to the use and placing on the market of carcinogenic, mutagenic and reprotoxic (CMR) substances as single substances or in mixtures for supply to the general public.

              The issue of a soil contamination by medicinal products is not legally covered at EU level. The majority of the existing MS national soil legislation does not cover this specific issue either. Similarly, there is no obligation to monitor or regulate medicinal product residues present in sewage sludge originating from water treatment plants.

              Eventually, the EU food legislation, which requires the monitoring of veterinary medicinal products residues in foodstuffs of animal origin, does not refer to medicinal products for human use. As a consequence, EU food legislation does not address the issue of indirect transfer to humans, of residues of medicinal products for human use, which may be present and have accumulated in the natural environment and may be transferred to food animals including fish.

              What can be done to limit the limit of pharmaceuticals in the environment?

                A number of possible solutions have been identified, both legislative and non-legislative. However, the effectiveness of the proposed solutions to cope with the environmental impact of medicinal products would need to be further assessed, in light of their impacts on the use of medicinal products and the protection of public health.

                The key steps of legislative actions concern – but are not limited to – the strengthening of the ERA in the framework of MA. The ERA procedure could also equally target «old» pharmaceuticals through a «catching-up» procedure. The Water Framework Directive could also serve to facilitate the explicit consideration of ERA results for active pharmaceutical ingredients in the assessment of substances to be added to the priority substances list or watch list. Tailored legislative tools could also be implemented to limit emissions in the environment by establishing a specific label for green pharmacy.

                Major non-legislative solutions focus on consumption and waste management steps of the life cycle. The proposed solutions may help to reduce the uncertainties and to mitigate the issues, but will need a detailed evaluation in order to assess their relative weight and then to develop an action plan giving priority to the most appropriate ones. Better knowledge on the ecotoxicity of medicinal products and encouraging the recruitment in regulatory agencies of personnel with an eco-toxicology background, or developing European guidelines for the implementation of harmonised approaches for the environmental classification of medicinal products in MS, should contribute to manage the environmental risk assessment procedures (ERA).

                In parallel, training sections could be organised for medical doctors in order to increase awareness on the various environmental issues related to prescription strategies. Major steps forward in waste management could focus on the improvement of collection schemes for unused human and veterinary medicines, as well as on tracking their efficiency.

                Disclaimer: The views expressed in this study are those of the authors alone and do not necessarily represent those of the European Commission Directorate-General for Health and Consumers or the EAHC. The authors are fully responsible for any errors.

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