3. Emerging policy instruments for the control of pharmaceuticals in water

The chapter documents existing policy approaches to manage pharmaceutical residues in freshwater. The chapter draws inspiration from a range of OECD country case studies using various policy approaches - source-directed, use-orientated and end-of-pipe.

    

3.1. Key messages

While pharmaceuticals have undeniable benefits, countries struggle to address their potential impacts on drinking water quality, and ecosystem and human health. Pharmaceutical pollution challenges traditional water quality management, requiring new technologies in wastewater treatment and behavioural changes in industry, agriculture and health care sectors and society at large.

Current policy approaches to water quality protection are typically reactive; measures are adopted only when routine monitoring is in place and risks can be proven. Many country responses to the pharmaceutical problem have focussed on monitoring and end-of pipe measures (e.g. upgrading wastewater treatment plants and implementing public take-back programmes for unused and expired medicines). However, upstream, source-directed and use-orientated approaches are emerging, such as restrictions on the use of antibiotics in agriculture, green pharmacy and public environmental health campaigns.

3.2. Introduction

As the identification and understanding of pharmaceuticals in the environment improves, and attention from both the scientific community and public media increases, so does the need for policy intervention to reduce human and environmental risks. Various possibilities for the abatement of pharmaceuticals in the environment have received relatively little attention; many OECD countries and research institutions have focused on monitoring programmes, problem diagnosis, risk analysis and prioritisation of problematic pharmaceuticals.

This chapter looks at policy responses to address the challenge, beyond just monitoring, reporting and risk assessment (see chapter 2). Ongoing national policy responses and country case studies are documented, and categorised as: i) source-directed approaches (section 3.3), ii) use-orientated approaches (section 3.4), and iii) end-of-pipe measures (section 3.5) to managing pharmaceuticals in the environment.

3.3. Source-directed approaches

Source-directed policy approaches include different types of policy instruments, which impose, incentivise, or encourage measures in order to prevent the release of harmful substances to water bodies and their adverse effects on aquatic ecosystems. They are primarily targeted towards pharmaceutical companies and manufacturing facilities, however regulatory bodies, companies that purchase bulk drugs, international investment companies, pharmacies and healthcare organisations that buy and distribute final pharmaceutical products have the potential to influence and create incentives to manage their release (Larsson, 2014[1]). Table 3.1 summarises various source-directed regulatory, economic and voluntary policy instruments, which concern diverse, intersecting policy sectors, such as health, water, agriculture, industry and environmental protection. The following sections describe some of these policy instruments in more detail and provide case study examples of their implementation.

Source-directed approaches have the added advantages of reducing the need for, and cost of, end-of-pipe wastewater treatment upgrades and solid waste disposal, and supporting drinking water safety. Examples include green pharmacy, good manufacturing practices, EQNs and water quality standards, and water safety planning. Substance bans are another source-directed policy approach. For instance, diclofenac has been banned for veterinary use in India, Nepal and Pakistan as a result of the decline of vulture populations in the Indian subcontinent (Box 1.5). The German Environment Agency proposes that veterinary pharmaceuticals containing active substances with PBT or vPvB properties should be banned to protect the environment (UBA, 2018[2]). Where a substance ban is in the political discussion, one has to consider that such a restriction comes at the cost of employing them for what may be valuable human and animal health benefits, in comparison to the cost of damages if use is continued. It also requires consideration (alternatives assessment) that a substitute pharmaceutical is available with lower environmental risk (i.e. does not simply result in pollution-swapping).

Table 3.1. Source-directed policy instruments to prevent the release of pharmaceutical residues to water bodies
Policy instrument type	Policy instrument	Description
Regulatory	Substance bans	Complete prohibition of non-essential use of problematic pharmaceuticals
	Marketing authorisation	Evaluation-dependent authorisation of pharmaceuticals based on their predicted risks to human health and the environment. Such evaluations can also take into account principles of green chemistry such as "rational design" or "benign by design”. Incentives can be used for green pharmaceuticals, such as fast-track marketing authorisation, reimbursement for greener APIs or longer exclusivity.
	Environmental quality norms and water quality standards	EQNs and water quality standards for harmful substances in water bodies. Detection above safe levels (or PNEC) can require action upstream to protect water bodies from harmful effects.
	Green public procurement	Clear and shared environmental criteria (and performance indicators) to pre-qualify pharmaceuticals for public procurement. Added advantage of impacting trade of pharmaceutical products across country borders.
	Good manufacturing practices and audits	Mandatory codes of conduct to reduce emissions from pharmaceutical manufacturing plants, as part of good manufacturing practice audits. Alternatively, environmental criteria for green public procurement could incorporate good manufacturing practices.
	Effluent discharge permits	Effluent discharge permits issued to pharmaceutical manufacturing plants with conditions for protection of drinking water sources and freshwater ecosystems. Non-compliance may lead to fines or withdrawal of operation permits.
	Best available techniques	Guidance documents that assist industrial operators with the design, operation, maintenance and decommission of manufacturing plants in compliance with environmental quality standards and discharge permit conditions (i.e. based on the PNEC or safe level of discharge). A BAT-based approach can be used to help set emission limit values as part of discharge permit conditions.
	Drinking water quality standards and water safety planning	Preventive measures to identify and address the source of risks to drinking water.
Economic	Subsidies for “green” action	Financial support from governments in return for environmental commitments by the private sector, such as reduced pollution from pharmaceutical manufacturing facilities.
	Subsidies for green pharmacy innovation	Subsidies or tax incentives for innovations green pharmacy, biological therapies, personalised or precision medicines to improve the business case for industry.
	Pollution charges	Charges to pharmaceutical manufacturing plants for discharging toxic effluent to water bodies.
Voluntary	Information campaigns	Transfer of knowledge or persuasive reasoning to industry on how to avoid water pollution.
	Voluntary agreements between private and public sectors	Non-legally binding agreements negotiated on a case-by-case basis between industry and public authorities fixing environmental targets or specific mitigation measures (e.g. changes in the production chain).
Source: Author

3.3.1. Environmental quality norms and water quality standards

It remains to be seen if environment quality norms (EQNs; also commonly known as environmental quality standards) are a feasible option to address pharmaceuticals given the number of APIs and the time taken to develop quality norms. Existing EQNs aim to control residual compounds, but there is a need to account for the impact of a mixture of pharmaceuticals and chemicals that ecosystems and humans are exposed to. There can also be a long time lag between the identification of a substance as having potentially negative impacts and the introduction of the associated EQN in legislation. As a consequence, the current control management of pharmaceutical pollution is often reactive i.e., it is in response to problems with water quality. This is demonstrated through the case of the detection of pyrazole in drinking water and the development of an EQN in the Netherlands (Box 3.1). The Netherlands has recognised the limitations of such an approach and have subsequently established other precautionary measures, such as: i) issuing wastewater discharge permits conditional to the protection of drinking water sources from pharmaceuticals and other emerging pollutants, ii) formation and use of a protocol for risk-based monitoring of pharmaceuticals and other emerging pollutants for drinking water quality by all drinking water companies (Box 3.1), and iii) improved stakeholder engagement and action across the pharmaceutical life cycle (section 4.2).

In 2012, the European Commission proposed the setting of EQNs for four pharmaceuticals of emerging concern: diclofenac, estrone (E1), 17-β -estradiol (E2) and 17-α-ethinylestradiol (EE2). In the UK, estimates made in 2013 by the water industry and regulators tentatively put the cost of “end of pipe” treatment for these chemicals at GBP 27-31 billion over a 20-year period (see section 4.4.4). Ultimately, the evidence base for regulating these pharmaceuticals in the EU was felt to not be strong enough in the light of potential costs; they were however placed on the WFD’s “watch list” for ongoing monitoring (see Box 2.4).

Box 3.1. Deriving a water quality standard for Pyrazole, Netherlands

In the Netherlands, drinking water suppliers and national government agencies control drinking water quality by monitoring different parameters, either enforced by legislation or as part of non-binding efforts. In addition to this, non-target screenings are performed with the aim to identify new potential hazardous substances in drinking water supplies. A threshold value (or signalling parameter) of 1 µg/L is used to identify unregulated substances in drinking or groundwater. Exceedance of this threshold value does not indicate an immediate threat to humans, but triggers the investigation of possible human health effects.

In 2015, this threshold value was exceeded in the River Meuse (an important drinking water source) by an unknown compound (concentration detected at 100 µg/L). This compound was later identified as Pyrazole. The cause of the elevated concentrations of Pyrazole was due to a malfunctioning WWTP. At the time, little was known about the human health impact of pyrazole. Given the potential threat to drinking water quality, it was decided that precautionary action should be taken. As a consequence, three drinking water companies were required to temporarily use alternative water sources for drinking water supply.

The incident triggered the development of a water quality standard (WQS) for Pyrazole, implemented in the national Dutch Drinking Water Directive on July 2017 (IENM/BSK-2017/160338). Toxicity testing and existing data were used to help determine the WQS. In addition, the following four factors were taken into account when determining the standard: i) the ability of treatment systems in place to remove pyrazole; ii) the precautionary principle to take into account possible risks where scientific understanding was not yet complete, including for mixture toxicity; iii) maintaining consumer’s trust in drinking water; and iv) water quality standards from neighbouring transboundary country Germany.

The Pyrazole incident also initiated The Structural Approach Programme – a programme designed to improve the long-term risk prevention of CECs in drinking water. The programme was developed by the Ministry of Infrastructure and Water Management, together with relevant stakeholders from regional and local government agencies, industry, and knowledge institutes. Taking into account lessons learned in the Pryazole case, stakeholders recommended the following points for improvement:

• The implementation of a systematic assessment of the potential effects of the emission of anthropogenic substances, specifically on drinking water quality, in the issuing process of wastewater discharge/emission permits. In response, the relevant wastewater guidelines was modified to mandate the inclusion of the potential effects of CECs from effluent on drinking water production.

• The formation and use of a protocol for risk-based monitoring of drinking water quality by all drinking water companies by 2019. It is anticipated that this recommendation will be implemented in federal law.

• The formalisation of the procedure for setting drinking water quality values and making them available to all stakeholders.

At the same time, a step-by-step-guide was created with the purpose of improving the management of incidents of CECs in drinking water in the short-term.

The guide has been designed to improve information exchange between stakeholders at an early stage of an incident. These policy responses have increased the level of cooperation between, and commitment amongst, stakeholders, and created a mutual understanding as well as mandatory requirements.

Source: Summary of case study provided Julia Hartmann, Ana Versteegh and Tialling Vlieg, Ministry of Infrastructure and the Environment, Netherlands.

3.3.2. Green pharmacy

Ultimately the use of pharmaceuticals which are biodegradable and have a low intrinsic toxicity would be the most ‘eco-effective’ and sustainable in a circular economy. However, potency and stability are often important properties of effective pharmaceuticals for human and animal health. A potential long-term approach to reducing the environmental risks of pharmaceuticals, and possible health risks at source, is the rational design and manufacture of new green pharmaceuticals (or 'benign by design’ (Kümmerer, 2007[3])). ‘Green pharmacy’, ‘green chemistry’ or ‘sustainable chemistry’ is often referred to as: i) the development of new substances that are more efficiently biodegraded but retain their effective pharmaceutical properties (Van Wezel et al., 2017[4]; Anastas and Warner, 1998[5]) (Leder, Rastogi and Kümmerer, 2015[6]), or ii) the re-design of existing pharmaceuticals for environmental biodegradability (Rastogi, Leder and Kümmerer, 2015[7]) (although a definition is not agreed upon). The expected outcome is better biodegradable and pharmacologically active drug molecules that do not accumulate in, or cause adverse effects to, the environment. An example is the development of glufosfamide - a green alternative to ifosfamide (chemotherapy medication) - that is 70% biodegradeable and has the added benefit of improved uptake in the human gut (Kümmerer, 2007[3]; Daughton, 2003[8]). Biologics - any pharmaceutical drug product manufactured in, extracted from, or semi-synthesised from biological sources – also have shorter half-lives.

Although research on green pharmacy has expanded in recent years, the share of green pharmaceuticals on the market is still low. Green pharmacy is expected to bring positive environmental results in the medium to long-term. The 2018 Nobel Prize in Chemistry, for example, was awarded for path-breaking research on how chemists produce new enzymes, leading to new pharmaceuticals and cancer treatments and less waste (UN Environment, 2019[9]). A new generation of biodegradable antibiotics (which would rapidly degrade in WWTPs) together with targeted delivery mechanisms, could reduce accumulation in freshwater ecosystems and subsequently to the promotion of resistance development.

Barriers delaying immediate progress of green pharmacy include (Matus et al., 2012[10]):

• An agreed definition. An agreed definition of green pharmacy is required between environmental chemists, clinical chemists, drug discovery scientists and other relevant stakeholders. The definition must be realistic and risk-based, with the aim of achieving a balance between patient/animal health and environmental protection.

• Regulatory barriers. Pharmaceutical manufacturers have little incentive to invest in pollution prevention and green pharmacy; most environmental, health, and safety regulations focus instead on controlling risk through reductions in exposure with end-of-pipe technologies. For example, in 2005 in the U.S., chemical manufacturing spent more than any other industrial sector on pollution abatement (U.S. Census Bureau, 2008[11]), a partial reflection of a regulatory focus on risk control, rather than risk prevention.

• Economic and financial barriers: costs, incentives, and markets. A green pharmaceutical must not only represent an improvement for health and the environment, but it must also be profitable, without sacrificing efficacy or quality. In the case of an existing pharmaceutical, changes in the formulation must represent enough of a potential cost savings to outweigh upfront costs.

• Technical barriers: uncertainties, expertise and metrics. The science behind green chemistry is often complex and multidisciplinary, and there are significant uncertainties. The novel field of green pharmacy requires combinations of innovative methods, and linkages between environmental science and green chemistry, with other existing pharmaceutical research fields in pharmacology, drug development, organic chemistry, computational chemistry and analytical chemistry (Leder, Rastogi and Kümmerer, 2015[6]). There are many reactions and processes for which greener substitutes remain unknown. New formulations and degradation products should be tested with the same rigor (and vigor) as conventional products for toxicity; parent compound toxicity must be considered, as well as the toxicity of degradation products. An absence of clear definitions and metrics for use by researchers and decision makers also pose barriers. Finally, advances in green pharmacy may not be shared by pharmaceutical companies in order to retain their competitive advantage.

Policy can help to reduce these barriers and provide incentives to make green pharmacy more attractive to pharmaceutical companies. For instance, governments can:

• Facilitate knowledge creation and accessibility, through R&D spending and access to data (including testing) to avoid costly replication of work.

• Demonstrate the feasibility of new green pharmaceuticals as new business opportunities for industry.

• Create tax incentives, access to inexpensive capital and technical assistance for implementation to drive innovation (OECD, 2012[12]). A return on public investments in new pharmaceuticals should be considered when assessing subsidies for the private sector in pharmaceutical development.

• Implement ERA-dependent authorisation of new pharmaceuticals based on their predicted risks to the environment to incentivise investment in green pharmacy. Such evaluations could take into account principles of green chemistry such as "rational design" or "benign by design”, and allow for an easy or fast-track authorisation process based on the biodegradability of APIs and their transformation products after use. Other options for incentives for green pharmacy may include reimbursement for greener APIs or longer exclusivity.

• Develop and implement evidence-based technical guidelines on sustainable procurement of pharmaceuticals. Integrate environmental criteria into good manufacturing practices utilised by authorities to pre-qualify pharmaceuticals for procurement. There are initiatives to advance sustainable procurement of pharmaceuticals in order to create an incentive for manufacturers to strive towards production of more green products, as well as to integrate environmental criteria into manufacturing practices (SAICM, 2015[13]). For example, the interdisciplinary research project “PharmCycle” aims to reduce the contamination of the aquatic environment with antibiotics by developing sustainable antibiotics, improving the ERA of antibiotics (and increasing data availability), and reducing the discharge of antibiotics in wastewater (Andrä et al., 2018[14]).

3.3.3. Water safety planning

As outlined in the WHO 2011 Guidelines for Drinking Water Quality, the water safety plan (WSP) approach is “the most effective means of consistently ensuring the safety of a drinking-water supply […] through the use of a comprehensive risk assessment and risk management approach that encompasses all steps in the water supply from catchment to consumer”. Water safety plans highlight the importance of considering risk assessment and risk management comprehensively from source to tap, and adopting preventive measures to address the source of risks (WHO, 2012[15]).

The primary objectives of a WSP in ensuring good drinking-water supply practice are: i) the prevention or minimisation of contamination of source waters; ii) the reduction or removal of contamination through treatment processes; and iii) the prevention of contamination during storage, distribution and handling of drinking-water. For more information on water safety planning, refer to the WHO Water Safety Plan Manual (Bartram et al., 2009[16]).

Adapting the water safety plan approach to the context of pharmaceuticals in drinking water means that preventing pharmaceuticals from entering the water supply cycle during their production, consumption (i.e. excretion) and disposal is a pragmatic and effective means of risk management. Preventive measures need to be applied as close as possible to the source of the risk and hazard (WHO, 2012[15]).

3.3.4. Good manufacturing practices, best available techniques and green public procurement

Good manufacturing practices (GMP) and Best Available Techniques (BAT) are one policy tool to prevent and control the emission of industrial pollutants, and thus to improve the protection of human health and the environment (OECD, 2018[17]).

BAT are guidance documents that assist industrial operators with the design, operation, maintenance and decommission of manufacturing plants in compliance with environmental quality standards and discharge permit conditions (which are legally binding) to prevent or control emissions to air, soil and water. A BAT-based approach can also be used to help set emission limit values as part of discharge permit conditions. One of the advantages of BAT is that it gives industrial facilities the freedom to choose their preferred means to achieve environmental quality standards and discharge permit conditions, using BAT as a guiding – rather than prescriptive – policy tool.

Determination of BAT is often done in consultation with stakeholders (OECD, 2018[17]). Technical and environmental aspects are taken into account as part of the evaluation of techniques, and in most cases also economic aspects. The EU operates with a hierarchy of techniques, giving priority to preventive techniques, over end-of-pipe measures when selecting BAT. The EU and the U.S. both have BAT for pollution prevention and control during the manufacturing of pharmaceutical products (EU, 2010[18]) (EC, 2006[19]; US EPA, 2006[20]).

GMP focus on quality assurance to ensure that medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the product specification (WHO, 2014[21]). Although GMP do not currently focus on environmental protection, there is potential to integrate environmental criteria, such as effluent discharge standards, into GMP utilised by the WHO to pre-qualify pharmaceuticals for procurement. Because any company that exports pharmaceuticals must follow GMP, such criteria have the potential for a wider impact (Larsson, 2014[1]). The process of incorporating environmental criteria into GMP would need to be carefully managed to ensure buy-in and prevent withdrawal of GMP agreements by countries.

GMP, sustainability reporting and green public procurement may be particularly relevant to OECD pharmaceutical companies operating in developing economies. For example, in Sweden, about one-third of antibiotics on the market are produced in other regions where the environmental requirements and enforcement are in general weaker (e.g. India, China and Puerto Rico) (Bengtsson-Palme, Gunnarsson and Larsson, 2018[22]). The Swedish government has proposed a revised system in which pollution control during manufacturing is considered when companies compete to obtain product subsidies for state healthcare. Swedish county councils have also started to request monitoring of emissions during manufacturing when procuring medicines (Larsson, 2014[1]). Environmental criteria and performance indicators to pre-qualify pharmaceuticals for public procurement has the added advantage of impacting trade of pharmaceutical products across country borders.

Connecting control of emissions to the existing regulatory framework of GMP would allow for control of the production chain, thus taking advantage of a system of control and action that is already in place. Additional benefits include preserving a level playing field regarding effects on competition between companies or countries within and outside Europe. Sweden have recently proposed that within the EU GMP framework, requirements limiting emissions of APIs into the water environment be included in the EU Directives on Medicinal Products for Human Use and Medicinal Products for Veterinary Use (Swedish Medical Products Agency, 2018[23]).

3.4. Use-orientated approaches

Use-orientated policy approaches include policy instruments which impose, incentivise, or encourage a reduction in the use of pharmaceuticals and their release to the environment. They are designed to inform and change the behaviours and practices of physicians, veterinarians, pharmacists, patients and farmers. For example, a reduction of inappropriate and excessive consumption of pharmaceuticals can be achieved through: i) regulatory instruments, such as restrictions on over-the-counter sale of environmentally harmful pharmaceuticals, and mandatory codes of conduct for health practitioners, veterinarians and farmers; ii) economic instruments, such as subsidies from governments in return for environmental commitments by the private sector; and iii) voluntary measures, such as public environmental health campaigns on the sustainable use and disposal of pharmaceuticals.

Use-orientated policy instruments for pharmaceuticals have not long been considered; in general they involve the modification of long-established norms in the practice of clinical prescribing, and human and animal health practices. However, as excretion and release through WWTPs is one of the most important routes of pharmaceuticals into the environment, use-orientated approaches have the potential of being more effective and less-costly in comparison to end-of-pipe solutions (Daughton, 2014[24]). There are opportunities for alternative business models in the health care and agriculture sectors based on increased service and education, instead of resorting to pharmaceuticals only.

Table 3.2 summarises various use-orientated-directed policy instruments, most of which are aimed at health practitioners, pharmacists, veterinarians, farmers and the general public. The following sections describe some of these policy instruments, targeting health-care practices, and veterinary and agriculture practices. A number of case studies are provided as examples of policy implementation.

Table 3.2. Use-orientated policy instruments to reduce release of pharmaceutical residues to water bodies
Policy instrument type	Policy instrument	Description
Regulatory	Substance bans	Prohibition of non-essential use of pharmaceuticals
	Substance restrictions	Restrictions on the prescription of non-essential use of pharmaceuticals Restrictions on over-the-counter sale and purchase of environmentally harmful pharmaceuticals Constraints to the placement on the market or the use of a substance at specific points in time (e.g. before rainfall events) or locations (e.g. sensitive areas). This is particularly relevant to farming practices.
	Best environmental practices (BEP) for health care practices	Mandatory codes of conduct for health practitioners to promote sustainable use (e.g. improved diagnostics, rationale use and targeted drug regiments) and responsible disposal of pharmaceuticals
	Best environmental practices (BEP) for veterinary and agriculture practices	Mandatory codes of conduct for veterinarians and farmers to promote improved diagnostics, sustainable use and disposal of pharmaceuticals, and reduce emissions from veterinary and agriculture practices
Economic	Product charges	Tax levied on products high-risk APIs in order to incentivise consumers to reduce or change consumption behaviours. Pharmaceuticals that are of high-risk to the environment and difficult to remove with conventional wastewater treatment could be priced accordingly.
	Substance charges	Tax levied on hazardous compounds in order to incentivise producers to change production processes or substitute chemicals with less hazardous alternatives (e.g. green pharmacy)
	Subsidies for “green” action	Financial support from governments in return for environmental commitments by the private sector
Voluntary	Public environmental health campaigns and disease prevention	Transfer of knowledge or persuasive reasoning on sustainable use, consumption and disposal of pharmaceuticals, and how to prevent illness and the need for pharmaceuticals (e.g. through effective hand washing to prevent spread of infection)
	Eco-labelling of green pharmaceuticals	Products that meet certain environmental standards can be marketed and sold at a premium and/or subsidised (n.b. regulatory changes would be required to set up such schemes)
Source: Author

3.4.1. Health-care practices and consumer choices

It is explicitly understood that pharmaceuticals exert an indispensable factor in modern healthcare and that the general public should have access to the best available pharmaceuticals. The challenge is to establish pharmaceutical management that combines the best possible treatment of the patient with a sustainable environmental cautiousness.

Health practitioners and pharmacists play an important role in influencing and changing citizen’s behaviour on the sustainable use and disposal of pharmaceuticals. One of the most important aspects is to stress the importance of avoiding prescription of unnecessary medicines. Alterations to prescribing and dispensing practices may include:

• Avoiding prescription of unnecessary medicines with improved diagnostics and increased service and education focusing on prevention rather than cure (e.g. hand-washing, diet/nutrition, well-being and therapy). Antibiotics, for example, should be prescribed only when there is an evidence-based need in order to reduce the risk of resistant strains. A successful response to AMR will address not only antimicrobials and the over- and mis-use of antibiotics, but also diagnostics, vaccines and alternatives to antibiotics for human and animal health (WHO, 2015[25]).

• Lower, optimised and more targeted dose prescribing (including shorter regimens and refill schedules) tailored to patients needs can minimise release of pharmaceuticals to the environment. Personalised adjustment of drug dose holds the potential for also enhancing therapeutic outcomes while simultaneously reducing the incidence of drug side-effects, optimising use of resources and lowering patient healthcare costs (Daughton and Ruhoy, 2013[26]). Genomics enables patients to receive therapy individually customised to their genetic makeup. Much of the cost of DNA sequencing is dropping, and in the future, may change the whole concept of prescribing medication (UN Environment, 2019[9]).

• Prescribing smaller packages, to deliver the exact dosage of medicine required, rather than standard universal packaging. However, this may increase costs for pharmacists.

• Substitution to green pharmaceuticals with less environmental impact but equivalent medicinal benefits (see section 3.3.2).

Education and information campaigns play a major role in the adoption of use-orientated approaches. Environmental issues can be introduced in already existing information schemes to increase awareness that, in addition to the desired health effects, certain pharmaceuticals may have significant environmental impacts. In Germany, a two-year training and education campaign on the sustainable consumption and responsible disposal of pharmaceuticals in the town of Dülmen (population circa 46,000) was particularly effective. Results from the campaign - involving 13 schools, all pharmacists, and many doctors, sports clubs and local stakeholders – increased awareness of the environmental issues to 77% of the population, increased appropriate disposal of unused pharmaceuticals by 20%, and reduced the number of people using painkillers between medical treatments by 10% (noPILLS, 2015[27]). Information received via trustworthy avenues, such as the doctors’ waiting room and the annual pharmaceutical garbage collection calendar were particularly effective (noPILLS, 2015[27]). Health insurers are another stakeholder that should be involved in the discussion. They may play a role in the reimbursement of environmentally friendly alternatives such as health education, non-medicine treatments and green pharmaceuticals.

Action on pharmaceuticals in the environment is much more likely to be extended and sustained if it is mainstreamed into broader health, agricultural and environmental projects. The WHO One Health approach provides such a framework, and recognises that putting resources into AMR containment now is one of the highest-yield investments a country can make to mitigate the impact of AMR (IACG, 2018[28]) (WHO, 2015[25]). Providing access to safe clean drinking water and sanitation services, in line with Sustainable Development Goal 6, will be critical to reducing AMR, and improving human health and well-being. Given the scale of the AMR crisis (Box 1.7, chapter 1), the OECD (2018[29]) has undertaken analysis of five simple policy interventions to reduce AMR targeting different stakeholders. The analysis has demonstrated their high impact on population health, affordability to implement and favourable cost-effectiveness ratio (Box 3.2). Furthermore, when such policies are implemented together as part of a coherent strategy, they produce a more beneficial impact.

Box 3.2. OECD cost-effective policy actions to combat antimicrobial resistance

OECD analysis demonstrates that governments could counter the AMR problem with five affordable policies as part of a coherent package. The policies align with the WHO’s Global Action Plan on AMR.

1. 1. Improve hygiene in healthcare facilities, including promotion of hand-washing and better hospital hygiene.

2. 2. Introduce stewardship programmes promoting more prudent use of antibiotics to end their over-prescription and over-use.

3. 3. Utilise rapid diagnostic tests to detect whether an infection is bacterial or viral before issuing prescription antibiotics.

4. 4. Delay prescription of antibiotics when they are not immediately required.

5. 5. Establish public awareness campaigns on the impacts of AMR and the importance of: hand-washing, completing a full treatment of antibiotics as prescribed (to avoid re-infection) and the safe disposal of unused antibiotics to avoid their entry into the environment.

It is projected that investment in these measures could pay for themselves within one year and produce savings of about USD 1.5 for every dollar invested thereafter. Simple measures, such as promoting hand washing and better hygiene in healthcare facilities, more than halve the risk of death and decrease the health burden of AMR (measured in DALYs1) by about 40%. Mass media campaigns, delayed prescriptions and the use of rapid diagnostic tests also produce a positive health impact, albeit more limited.

Public health actions to tackle AMR are affordable. Implementing such policies varies from as little as USD PPP2 0.3 per capita for mass media campaigns to a few hundred USD PPP per hospitalised patient in the case of enhanced hygiene in healthcare.

← 1. DALYs = Disability Adjusted Life Years. DALYs is the sum of years of potential life lost due to premature mortality and the years of productive life lost due to disability.

← 2. PPP = Purchasing power parity.

Source: (OECD, 2018[29]).

Classification and labelling approaches may help to minimise risks. A good example is found in Stockholm, Sweden, where pharmaceuticals are classified according to their environmental risks and this information is distributed to doctors and made publicly available to facilitate the prescription and use of pharmaceuticals with lower environmental risk (Box 3.3). The extension of a model similar to the Swedish scheme could potentially be desirable on a European level or to other OECD countries. Key issues for developing and implementing classification and labelling schemes include: necessary improvements to ERAs (see section 2.2), and the standardisation of the information used, the criteria applied, who provides the information and the mode of communication (Clark et al., 2008). It also requires careful consideration (an alternatives assessment) that a substitute pharmaceutical is available with lower environmental risk (i.e. does not simply result in pollution-swapping).

Box 3.3. Environmentally Classified Pharmaceuticals: Allowing doctors to make informed prescription choices, Sweden

Reducing pharmaceuticals in water is an environmental priority of the Stockholm County Council. Essential Drug Recommendations were issued and launched as a 'Wise List' by the regional Drug and Therapeutics Committee in Stockholm, on the basis of environmental hazard assessments initiated in 2003 by the Environmental Department of the Stockholm County Council. The Wise List is a list of recommended pharmaceuticals for the treatment of common diseases that takes into account cost-effectiveness and environmental impact when comparing medications that are equally safe and equally suitable for the medical purpose.

The acute risk to the aquatic environment was one of the assessment criteria of pharmaceuticals on the Wise List, with pharmaceuticals scored as insignificant, low, moderate or high risk according to environmental persistence, bioaccumulation and toxicity. These scores are used to assist with decision-making by doctors when prescribing medications to their patients. In 2009, 77% of doctors in Stockholm were reported to have adhered to the Essential Drug Recommendations and the Wise List.

A 2014-2015 leaflet of Environmentally Classified Pharmaceuticals was issued to all prescribers with the following information: i) a brief summary of the impact of pharmaceuticals on the environment, ii) the ‘Wise List’, including details on how the substances are classified according to their environmental risk and how to interpret the classification of pharmaceuticals (including which pharmaceuticals are exempt), iii) the role of the precautionary principle, and iv) advice for doctors and patients to reduce environmental impacts.

Sources: (Gustafsson et al., 2011[30]; Stockholm County Council, 2014[31]).

Pharmacists can also play an important role in educating the public on the environmental effects of pharmaceuticals. For example, Swedish pharmacies are required to educate consumers on the environmental effects of diclofenac, for which there is a water quality standard governed by the Marine and Water Authority's regulations on specific pollutants (Box 3.4). Viable, ‘greener’ substitutes for diclofenac is something that is questioned; there is concern of pollution swapping with substitutes such as naproxen and ibuprofen, which may have similar environmental impacts to diclofenac (limited data).

Box 3.4. Swedish pharmacies required to educate consumers on the environmental effects of Diclofenac

In 2015, Sweden introduced legislation on how much diclofenac may be released into water, under the Marine and Water Authority's regulations on specific pollutants. This value was often exceeded. Diclofenac is a popular analgesic drug but can have negative environmental impacts (see section 1.4) which Sweden believes customers should be aware of.

In 2018, the Swedish Association of Pharmacy agreed that all pharmacies must start to inform consumers about diclofenac's adverse effects on the environment. Shelf signs inform consumers that the substance has a negative impact on the environment and should be used with reflection. The agreement applies to both store and e-commerce sales.

Many Swedish county councils have removed diclofenac from their recommended lists of prescription drugs because of its environmental impact. In addition, the Swedish Medical Products Agency, which authorises pharmaceuticals in Sweden wants a regulatory change requiring environmental effects be considered in the authorisation and approval of human pharmaceuticals.

Swedish pharmacies also take other steps to reduce pharmaceuticals in the environment. For example, in 2017, Swedish pharmacies collected 1 200 tonnes of unused drugs as part of a public collection scheme. Several pharmacies have introduced their own eco-labels for over-the-counter pharmaceuticals.

Sources: (Swedish Association of Pharmacy, 2018[32]) (Ringbom, 2017[33]) (Sweco, 2016[34]).

3.4.2. Veterinary and agricultural practices

The overuse of veterinary pharmaceuticals, such as antibiotics and hormones used as growth promoters in industrial farming, results in the release of their residues into soil, groundwater and surface waters via leakage from animal waste storage and disposal tanks, and the use of animal manure and slurry as fertiliser and irrigation water. Agriculture is not only a source of pharmaceutical pollutants, but also contributes to the spread and introduction of these pollutants into aquatic environments through municipal wastewater reuse for irrigation and the application of biosolids onto the land as fertiliser (Muñoz et al., 2009[35]). Use of veterinary pharmaceuticals in aquaculture directly enter water bodies

Regulations specifically addressing these sources of pharmaceutical pollutants are lacking at national and international levels. The overuse and misuse of antibiotics and parasiticides (e.g. as a preventive measure) and hormones (e.g. as growth promoters) of are of particular concern because of their contribution to AMR (see Box 1.5), their PBT properties, and endocrine disrupting effects (see Box 1.9), respectively.

Changes in agricultural practices may minimise the risks of pharmaceuticals in the environment. A range of approaches can be used, including (Pope et al., 2008[36]; Boxall, 2012[37]):

• Minimising the use of veterinary medicinal products

• Preventive measures for improving animal health

• Requiring more targeted treatment of sick animals, rather than treating a whole herd

• Changes in treatment timings and intensities

• Development of best practices on manure storage and treatment to increase biodegradation of APIs before land application

• Changes in manure/sludge application rates and timings (i.e. to avoid/minimise overland runoff and leaching). For example, injection application of manure has been shown to reduce overland runoff of pharmaceuticals when compared to a broadcast application (Topp et al., 2008[38]). And the application of sewage sludge during dry periods would minimise the potential for some substances to be transported to surface waters (Boxall, 2012[37]).

• Development of recommendations on where not to apply manure and biosolids (e.g. where slopes or soil types are unsuitable) and

• Specification of riparian buffer zones to protect water bodies.

Recently, several effective and alternative means of treating and controlling livestock disease caused by microorganisms have been developed. This includes new gene editing technology; effective immunoglobulins, which can act in the body as defence molecules against infections; and peptides, which help the host system in its defence against pathogens, partly by delaying the establishment of infection. The production of peptides can be induced in the host animal, or can be used to create vaccines, and thereby prevent illness and reduce the need for antibiotics (Marquardt and Li, 2018[39]; van Dijk et al., 2018[40]). In Norway, the development of a vaccine to prevent furunculosis (a highly-contagious bacterial fish disease) has significantly reduced the need for antibiotics in salmon farming (WHO, 2015[41]). Improved DNA technology has also greatly facilitated the selection of livestock that have genetic resistance to pathogenic microorganisms (Marquardt and Li, 2018[39]).

The use of veterinary pharmaceuticals can be optimised and reduced through information campaigns. For example, Germany has developed an environmental checklist for the use of pharmaceuticals in veterinary medicine and livestock farming (Box 3.5).

Box 3.5. Environmental checklist for the use of veterinary medicines

In 2017, the German Environment Agency (UBA) developed an environmental checklist for the use of veterinary pharmaceuticals, with the aim of reducing pharmaceutical residues in the environment. The checklist is targeted to veterinarians and farmers. A summary translation of the checklist is outlined below.

Veterinary Medicine

• Operate sufficient animal health diagnostics

• Confirm a medical indication

• Consider whether avoiding drug treatment is possible

• Consider alternative remedies to avoid input of pharmaceuticals to the environment, and to reduce resistance formation (i.e. contribution to AMR)

• Inform the pet owner about the correct administration of the prescribed medication

• Inform the pet owner about the correct storage and disposal of the veterinary drug.

Livestock Farming

• Question whether preventative measures, such as vaccinations, are necessary

• Ensure the veterinarian and farmer have considered alternative treatment methods

• Follow the veterinarian instructions regarding administration of the correct dosage, duration and frequency of the medicine.

• Keep a record of veterinary medicines to avoid unnecessary treatment and entry of pharmaceutical restudies to the environment

• Dispose of used medicines, leftovers and packaging properly

• Ensure a rest period of several months before the spreading of manure, which may contain traces of veterinary medicinal products

• Assess what prevention measures could be taken at the farm scale to avoid or reduce future drug treatments.

Source: (Kemper, Hein and Lehmann, 2017[42]).

Restrictions on the unnecessary use of veterinary pharmaceuticals have proven to be effective. Since 2006, antibiotics used as growth promoters in feed additives within the EU have been banned (European Commission, 2005[43]). In addition, veterinary prescriptions are required to use antibiotics (i.e. they cannot be purchased over-the-counter, with exemptions in certain cases). Implementation of these EU policies has resulted in a decreased detection of antibiotic resistant genes and pathogens in Germany, the Netherlands, Sweden and Denmark. In Germany, since the introduction of the German Antimicrobial Resistance Strategy and the 16th amendment to the German Medicines Act, the consumption of antibiotics for livestock farming has reduced by over 32% between 2014 and 2017 (BMEL, 2019[44]). In the UK, the poultry industry has successfully reduced unnecessary antibiotic use – whilst increasing meat production – with a voluntary antibiotic stewardship programme (Box 3.6). Canada has implemented a similar policy to the EU, requiring that antibiotics for animal use be sold by prescription only. Further actions to promote responsible use in Canada include: i) removal of growth promotion claims from pharmaceutical labels; and ii) labelling all antibiotics to be used as additives in livestock feed and water with responsible use statements (Government of Canada, 2018[45]).

Box 3.6. Voluntary reductions in the use of veterinary antibiotics: The British Poultry Council Antibiotic Stewardship

In the UK, the British Poultry Council Antibiotic Stewardship aims to ensure the sustainable use of antibiotics throughout the supply chain, based on three measures: i) review and replace antibiotics used where effective alternatives are available; ii) reduce the number of birds receiving treatment, through systems based on risk assessments; and iii) continue to refine existing strategies, using data collection. More specifically, it was agreed to: i) cease preventative use of antibiotics; ii) restrict the use of antibiotics classified as critically important by the WHO; and iii) ban the use of third and fourth generation cephalosporins (a class of antibiotics).

As a result of the Stewardship, over the period 2012-2017, total antibiotic use in the British poultry industry reduced by 82% and the use of Fluoroquinolones (a Critically Important Antibiotic for human health) reduced by 91%. During the same period, poultry meat production increased by 10 %.

Source: (British Poultry Council, 2018[46]).

In Denmark, strict biosecurity measures and the Specific Pathogen Free system have kept the country free from many pig diseases and helped contain infected animals so that the spread between farms is limited (FAO and Denmark Ministry of Environment and Food, 2019[47]). The focus on keeping diseases out of farms is the most important step to lower antimicrobial consumption. The phasing out of antimicrobial growth promoters in the year 2000 in Denmark has showed that it is feasible to reduce the use of antimicrobials for pigs, and sustain low usage, whilst: i) maintaining high productivity; ii) resulting in no detrimental effects on pig health or welfare; and iii) and at low cost to the farmer. One of the reasons for Denmark’s success was the stepwise phasing out of antimicrobial growth promoters over several years that gave farmers sufficient time to adjust (FAO and Denmark Ministry of Environment and Food, 2019[47]).

3.5. End-of-pipe measures

End-of-pipe measures focus on removing or eliminating pharmaceuticals after their use or release into water. End-of-pipe policies involve different types of instruments that impose, incentivise, or encourage improved wastewater treatment and solid waste disposal. One policy option for the reduction of pharmaceuticals in water is to provide incentives for the upgrade of WWTPs with new removal technologies; conventional WWTPs are not designed to, nor do they fully, remove pharmaceuticals. Another option involves improvement of solid waste collection and disposal to prevent unused pharmaceuticals from entering the water cycle.

End-of-pipe measures will not solely solve the problem of pharmaceuticals in water. They are limited by their removal efficiencies, high capital investment and operation costs and increased energy consumption. Furthermore, end-of-pipe measures do not capture diffuse sources of pharmaceutical pollution (e.g. from agriculture and aquaculture). However, end-of-pipe measures will remain a policy option due to the continued need of pharmaceuticals for human health and wellbeing.

Table 3.3 summarises end-of-pipe regulatory, economic and voluntary policy instruments, which concern a diverse set of stakeholders including consumers, wastewater utilities, solid waste collectors, pharmaceutical industry, and health and environment officials. The following sub-sections describe some of these policy instruments in more detail and provide case study examples of their implementation. Much of this section focuses on the removal of pharmaceutical residues through advanced wastewater treatment, the cost-efficiency of such a measure, and potential financing mechanisms to fund WWTP upgrades.

Table 3.3. End-of- pipe policy instruments to remove pharmaceuticals after their use and release into water bodies
Policy instrument type	Policy instrument	Description
Regulatory	Best available technique (BAT)	Definition of the best technology options for improved wastewater treatment
	Wastewater treatment standards	Definition of performance standards for wastewater treatment (e.g. treatment capacity or effluent load) without requiring a specific technology
	Pharmaceutical disposal requirements	Standards on correct waste disposal, e.g. mandatory consumer-level “take-back” programmes for unused pharmaceuticals
Economic	Effluent/ emission charges	Tax on discharging wastewater to water bodies, in order to incentivise emission reduction
	Wastewater tariffs or taxes for WWTP upgrades	Tariffs or taxes designed to signal the cost of wastewater treatment to remove pharmaceuticals to the public and consumers
	Subsidies for improved wastewater treatment	Financial support from governments to incentivise operators to invest in advanced wastewater treatment; or to promote research on improved wastewater treatment
	Extended producer responsibility (EPR) schemes	Instead of consumers being responsible for the cost of wastewater and waste management, producers, to some extent, become responsible for financing the end-of-life costs (wastewater treatment and solid waste disposal). In principle, companies can internalise these costs and are incentivised to produce pharmaceuticals more cost-efficiently and sustainably
Voluntary	Advisory services	Support from governments in the form of information, advice, and consultancy about improved wastewater treatment or solid waste management
	Voluntary agreements on wastewater treatment	Non-legally binding agreements negotiated on a case-by-case basis between wastewater treatment operators and a public authority to improve wastewater treatment practices
	Waste collection/ take-back schemes	Voluntary schemes designed to collect and appropriately dispose of unused pharmaceuticals, thereby reducing their release to water bodies.
Source: Author

3.5.1. Upgrading wastewater treatment plants with advanced removal technologies

Removal effectiveness and cost efficiency

Advanced wastewater treatment processes, such as reverse osmosis, ozonation, activated carbon, membranes and advanced oxidation technologies, can achieve higher removal rates for pharmaceuticals in comparison to conventional secondary wastewater treatment (activated sludge processes, or other forms of biological treatment such as biofiltration).

The removal efficiencies of the different wastewater treatment processes depend on the various physico-chemical properties of APIs (and their metabolites), such as hydrophobicity, reactivity, molecular size and charge and biodegradability. Table 3.4 summarises advanced wastewater treatment options, and their advantages and disadvantages. Activated carbon adsorption (with both powered activated carbon (PAC) and granular activated carbon (GAC)), ozonation and filtration by nanofiltration or reverse osmosis membranes, have been demonstrated to effectively remove most pharmaceuticals. Switzerland and Germany have upgraded some WWTPs with activated carbon adsorption and ozonation. However, filtration with nanofiltration or reverse osmosis are found to be more cost-intensive. Nevertheless, reverse osmosis membranes have been implemented in potable reuse schemes in the U.S., Singapore and Australia because of the additional benefit of reducing salinity and metal reduction (Rizzo et al., 2019[48]). Ozonation generates toxic transformation products that will need to (and can) be removed post-treatment (Völker et al., 2019[49]).

Table 3.4. Advantages and disadvantages of advanced wastewater treatment options to remove pharmaceuticals
Advanced treatment	Advantages	Drawbacks
UV light with hydrogen peroxide (UV / H2O2)	• Moderate-good pharmaceutical removal at lab/pilot scale • Also effective as disinfection process	• Formation of oxidation transformation products • No full-scale evidences on removal • Higher energy consumption compared to ozonation, specifically when high organic matter concentration acts as inner filter for UV radiation.
Photo-Fenton	• High pharmaceutical removal • Use of solar irradiation • Also effective as disinfection process	• Formation of oxidation transformation products • No full-scale evidences on pharmaceutical removal • At neutral pH 7 addition of chelating agents necessary. • Large space requirements for solar collectors
UV light with titanium dioxide (UV / TiO2)	• High pharmaceutical removal • Use of solar irradiation • Also effective as disinfection process	• Low kinetics • Formation of oxidation transformation products • Catalyst removal • Large space requirements for solar collectors
Ozonation	• High pharmaceutical removal • Full scale evidence on practicability • Partial disinfection • Lower energy demand compared to UV/H2O2 and membranes	• Formation of by-products and other unknown oxidation transformation products • Need for a subsequent biological treatment (e.g., slow sand filtration) to remove organic by-products
Powdered activated carbon (PAC)	• High pharmaceutical removal • Full scale evidence on practicability • Additional dissolved organic carbon removal • No formation of by-products • Partial disinfection possible by the combination with membrane filtration (UF)	• PAC must be disposed • Post-treatment required (membrane, textile or sand filter) to prevent discharge of PAC • Production of PAC needs high energy • Adsorption capacity may fluctuate with each batch
Granular activated carbon (GAC)	• High pharmaceutical removal • Full scale evidence on practicability • Additional dissolved organic carbon removal • No formation • An existing sand filtration can relatively easily be replaced by GAC • GAC can be regenerated	• Production of GAC needs high energy • Still under investigation if more activated carbon is needed compared to PAC • Less flexible in operation than PAC and ozonation to react to changes in wastewater composition • Adsorption capacity may fluctuate with each batch
Nanofiltration (NF) and Reverse Osmosis (RO)	• High pharmaceutical removal • RO can reduce salinity • Effective disinfection • Full rejection of particles and particle-bound substances	• High energy requirements • High investment and re-investment costs • Disposal of concentrated waste stream • Need for pre-treatment to remove solids
Source: (Rizzo et al., 2019[48]).

Figure 3.1 provides a rough estimation of the relative effectiveness and cost of different advanced wastewater treatment methods, based on a four-year study in Stockholm on the presence and effects of pharmaceuticals in the aquatic environment, and preventive measures and possible treatment methods (Wahlberg, Björlenius and Paxéus, 2010[50]). From Figure 3.1, the most economical and effective advanced treatment options are ozonation and activated carbon adsorption. This fining aligns well with published literature but It is worth noting that there is a lack of standardisation in the tests being used to determine removal efficiencies, which complicates the comparison of different studies.

Figure 3.1. Relative reduction efficiency to remove pharmaceuticals and cost comparison between different advanced wastewater treatment methods

Note: Results presented are based on a four-year study in Stockholm on possible treatment methods to mitigate pharmaceuticals in wastewater.

Source: (Bui et al., 2016[51]), adapted from (Wahlberg, Björlenius and Paxéus, 2010[50]).

For removal of pharmaceuticals and complex mixtures, one single optimal wastewater treatment technology does not exist; several technologies are usually combined to try and cover the chemical profiles of different substances (Undeman and McLachlan, 2011[52]). Combinations of methods are often based on ozone and adsorption treatment (Cimbritz et al., 2016[53]; Bui et al., 2016[51]); adsorption processes (such as activated carbon) typically result in higher removal rates of hydrophobic and biodegradable chemicals, and oxidation processes (including ozone) typically result in high removal rates of reactive chemicals (Van Wezel et al., 2017[4]). Ozonation and activated carbon adsorption have a longer history as advanced technologies to upgrade traditional WWTPs in relation to other technologies (Bui et al., 2016[51]). In Switzerland, it was decided to implement advanced wastewater treatment at a large scale using ozonation and granulated activated carbon technologies.

Besides the efficiency (and cost) of removal of APIs and metabolites from wastewater, other environmental factors to consider in the selection of advanced wastewater treatment technologies include: potential formation of toxic transformation products, energy efficiency and carbon emissions, and disposal of any concentrate or sludge containing pharmaceutical residues (Bui et al., 2016[51]). Entec (2011[54]) provide an indication of these costs for a WWTP upgrade with GAC servicing 200,000 p.e. Other technical considerations include flexibility to deal with a range of pollutants and influent flows (accounting for demographic changes and increased rainfall variability with climate change), reliability and the quality of effluent, and ease of operation and maintenance requirements (Bui et al., 2016[51]).

Table 3.5. Estimated costs to the environment from WWTP upgrades
Environment impact	Estimated unit cost	Impact based on WWTP upgrade with GAC for p.e. 200,000	Total estimated annual cost per WWTP servicing 200,000 p.e.
Carbon emissions	EUR 59.8 / tonne	2,277 tonnes / yr	EUR 136,164 / yr
Additional sludge production	EUR 126-411 / tonne	394 tonnes / yr	EUR 49,644 – 161,934 / yr
Damage costs associated with additional energy use	EUR 0.018-0.059 / kWh	5,297,136 kWh / yr	EUR 95,348 – 312,531 / yr
Source: (Entec, 2011[54]).

An informed risk assessment and cost-benefit analysis is essential before scarce resources are allocated to upgrade or invest in additional advanced treatment processes to reduce concentrations of pharmaceuticals in wastewater. Advanced and costly wastewater treatment technology will not be able to completely remove all pharmaceuticals, at all times, to concentrations less than the detection limits of the most sensitive analytical procedures. Therefore, it is imperative that the toxicological relevance of various compounds be considered in the context of appreciable risks to human and ecosystem health, and the selection of wastewater treatment technology.

Whilst conclusive evaluation of the most suitable and cost effective solution/s is not yet possible (Rizzo et al., 2019[48]), there are a number of factors that be considered in decision-making:

• The allocation of advanced treatment techniques at WWTPs can be optimised with the aim to protect susceptible functions of the water system (such as protected areas or the provision of drinking water), or the upgrade of existing WWTPs as they reach the end of their life. For example, the Netherlands is performing a hotspot analysis to evaluate which WWTPs might deserve an extra purification step from the viewpoint of aquatic ecology and protection of drinking water. It is expected that this will be limited to a relatively small number of WWTPs.

• Opportunities to centralise treatment and close smaller, marginal WWTPs which are less cost-effective to upgrade (Table 3.6). Box 3.7 further illustrates the importance of economy of scale (centralisation of WWTPs) for improved cost-effectiveness, even for pollution hotspots such as hospitals; evidence shows that decentralised wastewater treatment at hospitals would not have a substantial impact on pharmaceutical loads entering centralised WWTPs, and finally the environment (Le Corre et al., 2012[55]).

• Site-specific limitations (e.g., availability of space and solar energy, cost of electricity) may lead to different conclusions for two different sites.

• Opportunities for co-benefits, such as the removal of other wastewater contaminants and expanding the possibilities of wastewater reuse. With these co-benefits may come additional market demands and revenue streams for infrastructure investment.

• Different relevant endpoints for a safe effluent discharge or reuse, such as CECs abatement, effluent toxicity, bacteria inactivation, by-products minimisation or abatement, antibiotic resistance control and treatment cost (Völker et al., 2019[49]) (Rizzo et al., 2019[48]).

Table 3.6. Cost comparison for removal of pharmaceuticals at different scales in Germany, Switzerland and the Netherlands
Euros per cubic metre
	Germany	Switzerland	Netherlands	Sweden
Small-scale WWTPs	€0.21 ± 0.08	€0.15–0.30	€0.22–€ 0.26 ± 0.05
Medium-scale WWTPs	€0.19 ± 0.08		€0.18–€ 0.20 ± 0.05	€0.15–0.30
Large-scale WWTPs	€0.14 ± 0.08	€0.05–0.11	€0.16–€ 0.18 ± 0.05
Note: Cost estimates include the following advanced wastewater treatment technologies: ozone + sand filtration, powered activated carbon + sand filtration, and activated carbon filtration.
Source: (Bui et al., 2016[51]).

Box 3.7. Decentralised advanced wastewater treatment at hospitals is less cost-effective than centralised municipal WWTP upgrades

Despite, the fraction of pharmaceuticals in wastewater discharged from hospitals being relatively low (15-20%) in comparison to the total load of municipalities, hospitals are a pollution hotspot for specialised pharmaceuticals with high environmental risks (e.g. X-ray contrast media, cytostatics, cancer treatments and some antibiotics) (PILLS, 2012[56]; Le Corre et al., 2012[55]). This offers the opportunity to eliminate high amounts of these specific pharmaceuticals from the environment with decentralised hospital wastewater treatment plants (PILLS, 2012[56]).

The early separation and on-site treatment of CECs (including pharmaceuticals) in wastewater from hospitals was investigated in Winterthur, Switzerland (Eawag, 2007[57]). While the study concluded that decentralised measures were capable of lowering emissions of CECs to the environment, it was also concluded that these approaches are not yet sufficiently developed to be cost-competitive with centralised end-of-the-pipe approaches (i.e. large-scale WWTP upgrades). The annual operation costs of a dedicated wastewater treatment with ozonation at the hospital would be as high as 40% of the annual operating costs of an additional ozonation stage at the central WWTP, while decreasing the overall CEC mass flow in the domestic effluent by only 20% (Eawag, 2007[57]).

The results of this study support more recent studies (e.g. (Le Corre et al., 2012[55])) which suggest that the risks of human exposure to the pharmaceuticals exclusively administered in hospitals are limited, and decentralised wastewater treatment at hospitals would not have a substantial impact on pharmaceutical loads entering centralised WWTPs, and finally the environment.

Other alternative methods to reducing the release of specialised pharmaceuticals used in hospitals to the water cycle include hospital protocols to safely dispose of pharmaceutical waste. For example, a pilot project in a Dutch hospital showed that patients are often willing to use disposable urine-bags during the time it takes for X-ray contrast media to leave their body (typically one day). Contrast media is often used in highly concentrated dosages, and they are inert and mobile which makes them hard to remove from wastewater (PILLS, 2012[56]).

Sources: (PILLS, 2012[56]; Le Corre et al., 2012[55]; Le Corre et al., 2012[55]).

The Swedish Government has recognised the adverse effects of certain pharmaceuticals on the aquatic environment and has mandated an evaluation of the cost-effectiveness of upgrading WWTPs. A summary of the evaluation results is presented in Box 3.8.

Box 3.8. The cost-effectiveness of end-of pipe removal of CECs, Sweden

In 2013, Swedish Parliament introduced a bill mandating the evaluation of advanced wastewater treatment technologies for the removal of pharmaceutical residues and other CECs by 2018. Because future impacts on the environment and human health are difficult to predict, the introduction of advanced wastewater treatment can be justified on the basis of the precautionary principle, as per the general rules in the Swedish Environmental Code.

The advanced wastewater treatment technologies examined included different treatment processes focusing on those sufficiently accessible and realistic to implement today, including ultra-filtration, ozonation, biologically active filtration, adsorption (pulverised activated carbon and granulated activated carbon) or combinations thereof.

The main results of the evaluation are as follows:

• A combination of different advanced wastewater treatment technologies result in >80% removal of pharmaceuticals. However, installation and operation of combined technologies result in higher costs compared to individual ones. Individual treatments can be justified depending on site-specific conditions or budget.

• Ozonation is the least expensive additional treatment step; however, in contrast to the Stockholm study by (Wahlberg, Björlenius and Paxéus, 2010[50]) (Figure 3.1), ozonation showed lower removal compared to biological and adsorptive methods. Adsorptive and biological technologies were the most energy-efficient technologies, with approximately 2-10% increased consumption. Technologies using oxidative treatments (e.g. ozonation) increase energy consumption by 20-60% and may also give rise to formation of residues with potential ecotoxicological effects.

• The costs of advanced treatment vary widely regarding the different capacities and size of WWTPs. Economies of scale and cost effectiveness can be achieved for advanced treatment upgrades at larger WWTPs. In general, larger facilities have more resources to ensure follow-up, process optimisation, and operation and maintenance of the facility.

• The cost of upgrading large WWTPs (>100,000 population equivalents) is estimated to be approximately 1 SEK/m³. Upgrades of smaller facilities (2,000- 20,000 PE) can reach up to 5 SEK/m³.

• The cost for upgrading each of the medium-large 431 WWTPs in Sweden (>2,000 PE) was estimated at between SEK 241 million to 2.1 billion per year, corresponding to SEK 55-480 per household per year. The cost estimates do not include costs associated with policy instruments, such as taxes, subsidies, fees, discharge allowances, permits and regulations.

The Swedish EPA identified five main factors for prioritising WWTP upgrades, including:

• The amount of pharmaceutical residues and other persistent pollutants released into receiving waters.

• The presence of several WWTPs that discharge to the same receiving water body.

• The water recharge rate of the receiving waters, where the receiving waters with low initial dilution and a low water recharge rate risk reaching the threshold values stated in the assessment criteria for river-basin-specific pollutants and effect levels.

• Fluctuations in water recharge rate over the year in the receiving waters, and variations in effluent volumes from the WWTP.

• The receiving water body’s sensitivity, such as ecological sensitivity.

Source: (Swedish EPA, 2017[58]).

There are a number of considerations to be made when prioritising WWTPs for upgrade to advanced treatment that have the ability to maximise benefits and lower costs (including capital, operation and maintenance, opportunity and environmental costs). Firstly, it is important to invest in wastewater connection and treatment services where access is lacking, or treatment is limited (e.g. primary or secondary treatment only, and combined sewer overflow systems). Secondly, prioritisation should primarily be based on the concentration and volume of pharmaceutical residues entering water bodies, and their effects on ecological and human health. In relation to this, there are number of factors to consider for prioritisation of upgrades:

• WWTPs servicing a large population, or where urban population is projected to expand rapidly in the near future

• Age and state of WWTPs (i.e. WWTPs that are due for a refurbishment)

• Potential for amalgamating existing small WWTPs to one large centralised WWTP to achieve economy of scale

• WWTPs operating in basins where pharmaceutical manufacturing occurs

• Basins where several WWTPs and other sources of pharmaceutical pollution (e.g. pollution hotspots: aquaculture, intensive livestock agriculture, pharmaceutical manufacturing, hospitals) discharge to the same receiving water body.

• WWTPs upstream of drinking water supply sources

• WWTPs operating in basins where certain industries operate that require very high quality water sources, such as pharmaceutical and electronics industries

• WWTPs operating in basins under high water stress where wastewater reuse is a valuable resource (e.g. for irrigation on arable land)

• WWTPs operating in basins where the water recharge rate and dilution potential of the receiving waters is low

• WWTPs discharging to ecologically sensitivity water bodies

• WWTPs which discharge other persistent pollutants which may be effectively removed with advanced wastewater treatment (e.g. co-benefits of removing dissolved organic carbon, nutrient and pesticides, which are very costly to remove from raw drinking water supplies).

Modelling the impact of WWTPs on susceptible functions of water bodies can assist with decision making and allow for spatially smart implementation of WWTP upgrades. At the same time, trade-offs and associated costs should be considered and managed when deciding to upgrade WWTPs, including the aforementioned trade-offs such as: incomplete removal of pharmaceutical residues to varying degrees, depending on the treatment technology selected; the generation of toxic transformation products and sludge; increased use of energy and chemicals for treatment; increased carbon emissions; and increased capital and operating and maintenance costs, and potential affordability issues of sanitation bills.

Financing WWTP upgrades

The cost of WWTP upgrades, and the ability to finance them, is a concern for wastewater utilities. Table 3.7 provides a summary of the cost estimates of WWTP upgrades found in literature. Whilst these costs are high, it is helpful to understand how they compare to the cost of inaction, including the loss of ecosystem services. Section 1.4, chapter 1 highlights some of the impacts and costs of pharmaceuticals in the environment.

Table 3.7. Summary of the cost estimates for upgrading WWTPs to remove CECs
Region / country and source	Cost estimates and description
EU (Civity, 2018[59])	Cost of fourth treatment stage to remove pharmaceuticals: EUR 6.5 billion per year.
Finland (FIWA, 2016[60])	Pharmaceuticals and hazardous substances removal costs: EUR 700-1,400 million, with increase in operational by EUR 100–220 million. This corresponds to an increase of 20–30% of current wastewater fees. In addition, energy needs would increase by 30–80% from the current level
Germany (Entec, 2011[54])	Cost of removal of diclofenac: EUR 5-11 million per WWTP, with added energy and CO2 costs. Additional sludge disposal costs totalling EUR 86 million – 256 billion per year. Average NPV capital and operating costs are EUR 398 per p.e. and 295 per p.e. for diclofenac removal using either GAC (99% removal) or UV (57% removal). Case study for WWTP in Ulm, with 440,000 population, cost: EUR 40 million.
Germany (Civity, 2018[59])	Cost of fourth treatment stage to remove pharmaceuticals: EUR 1.2 billion per year, or EUR 15.20 per person per year. Represents an average wastewater fee increase of 14-17%. Total cost over 30 years: EUR 36 billion.
Switzerland (Entec, 2011[54])	Diclofenac removal costs in 756 WWTPs: EUR 495 – 591 million capital costs, plus EUR 56-76m operational costs. Total costs EUR 0.03-0.3/year per m3 treated. Cost per person ranges from EUR 14,000 – 590,000.
Switzerland (Logar et al., 2014[61])	Estimated annual cost of upgrading 123 WWTP to remove CECs: CHF 133 million or CHF 86 per household connected. Discounted total costs over the 33 years life span of the investment: CHF 3.3 billion.
UK (Comber et al., 2007[62])	Cost of removal of pharmaceuticals for UK as a whole: EUR 10 billion, or potentially EUR 1.5 million per WWTP on average. This assumes all 6800 WWTPs need to be upgraded. Added costs for pharmaceutical removal per WWTP was EUR 0.8 – 25 million capital and EUR 0.02 – 4.1 million operational costs per year.
UK (Haigh, 2018[63])	Cost estimate to remove diclofenac, E1, E2 and EE2: GBP 27-31 billion over 20 years.
UK (Entec, 2011[54])	Cost of upgrading 48 WWTPs in Yorkshire Region: EUR 725 million, with operational costs of EUR 45 million per year. Discounted costs are EUR 1,020 million, discounted over 25 years. Scaling these figures up to England and Wales: EUR 12 – 14 billion.
Notes: WWTP: wastewater treatment plant; NPV: net present value; p.e.: population equivalent.
Source: Adapted from Ashley et al. (2018[64]), Financing water in 28 European countries: Challenges and responses. Background paper drafted for the OECD.

There are several options to finance WWTP upgrades, including: public taxes, wastewater tariffs, charges passed onto the pharmaceutical industry, or a combination thereof. Switzerland - the first country to tackle the CECs challenge at the national level – has introduced a wastewater tax to partially (75%) fund the upgrade of approximately 120 WWTPs to remove 80% of CECs (including pharmaceuticals) from wastewater by 2040 (Box 3.9). The drivers mentioned for the decision to upgrade WWTPs nationwide were: endocrine effects on the aquatic environment, risk of contamination of drinking water, the removal efficiency of new technology, societal acceptance and cost-efficiency of attributing advanced treatment techniques to upgrade WWTPs - although uncertainty remains (Eggen et al., 2014[65]; Logar et al., 2014[61]; Stamm et al., 2015[66]).

Box 3.9. Tax to update wastewater treatment plants to treat CECs, Switzerland

Switzerland has committed to remove 80% of CECs from wastewater by 2040. The Swiss Waters Protection Act requires polluted wastewater produced by households, businesses or industry to be treated before being discharged into water bodies. In 2014, the Waters Protection Act was revised, following agreement by Parliament, to further improve wastewater treatment for the removal of CECs (including pharmaceuticals). The revised Act involved three policy instruments: i) a new technical wastewater treatment standard, and ii) a nationwide wastewater tax, and iii) public subsidies to fund technical upgrades of WWTPs. The technical standard requires selected WWTPs to remove 80% of CECs from raw sewage, measured on the basis of 12 indicator substances, by 2040. The standard applies only to WWTPs that meet one of the following three selection criteria, which aim to achieve environmental improvements at acceptable costs:

• Large WWTP servicing > 80,000 population equivalents (p.e.);

• Medium-size WWTP (24,000-80,000 p.e.) that discharge into small rivers with low dilution ratio; and/or

• Medium-size WWTP (24,000-80,000 p.e) that discharge into water bodies used for drinking-water purposes.

In total, approximately 120 out of 700 WWTPs met one of the above three criteria for upgrade. It is projected that this will result in a 50% overall load reduction of CECs in surface water. In addition, several WWTPs will be closed and wastewater transferred to larger facilities where the treatment is considered to be more cost effective.

Pilot- and full-scale facilities assessed the effectiveness of various advanced wastewater treatment technologies, including ozonation, powered activated carbon, granular activated carbon, high-pressure membranes and advanced oxidation processes. Ozonation and powdered activated carbon showed the best applicability for Switzerland with the two techniques combined capable of removing 80% of detected CECs in wastewater.

The total investment cost to equip 100 WWTPs with advanced treatment technology was estimated to be CHF 1.2 b. Operation and maintenance costs were estimated to be an additional CHF 130 m per year, equivalent to 6% of the total current cost of wastewater treatment in Switzerland annually. The majority of the costs (75%) are financed by a new nationwide wastewater tax of CHF 9 per person per year, which is earmarked in a federal fund to upgrade WWTPs. The remaining 25% of costs are covered by the municipalities. As WWTPs are upgraded and become operational, the municipalities are exempted from the tax.

Despite having higher estimated costs than preventative source-directed measures, the end-of-pipe approach was selected because it was more predictable, measurable and feasible, and received support from industry, business, farmers, the research community and international actors. Furthermore, a national online survey indicated that the public were willing to pay the tax for reducing the potential environmental risk of pharmaceuticals; the average willingness to pay per household was CHF 100 per year, generating a total annual economic value of CHF 155 m per year.

Source: Summary of case study provided by Florian Thevenon, WaterLex International Secretariat, Switzerland. Additional source: (Logar et al., 2014[61]).

In Germany, the costs of nationwide WWTP upgrades to remove pharmaceuticals are estimated to amount to approximately EUR 1.2 billion per year, and in Europe, about EUR 6.5 billion per year (Civity, 2018[59]). In an investigation by Civity Consultants (2018[59]), preventive (source-directed and use-orientated) measures were deemed more cost-effective. However, if WWTP upgrades were to be considered, the researchers proposed that pharmaceutical companies should bear some of the cost and thus indirectly be incentivised to reduce entry of pharmaceutical residues to the wastewater system (Box 3.10).

Box 3.10. Proposed tax on pharmaceutical products as a financing mechanism for WWTP upgrades, Germany

The question of how to finance the installation of advanced treatment at selected WWTPs in Germany needs to be resolved, unless capital, operation and maintenance costs are to be paid for by wastewater tariffs and/or public taxes. A recent report by the Helmholtz Centre for Environmental Research (UFZ) advocates for the introduction of a regulatory tax on pharmaceutical products as an effective financing mechanism to upgrade WWTPs and to pass on some responsibility for the cost to industry.

A three-tier tax on pharmaceutical products was proposed:

1. 1. High tax if it is clear that a pharmaceutical product causes damage to freshwater ecosystems.

2. 2. Low tax if it is unclear whether a pharmaceutical product causes damage to freshwater ecosystems. Either the manufacturer or its delivery point (e.g. pharmacy) must pay a charge for the product's potential effect on water, as a precaution.

3. 3. Zero tax if it can be proven that the pharmaceutical product does not result in any adverse environmental effects.

In theory, in order to qualify for zero tax, pharmaceutical companies would have to prove that their products were not harmful to the environment. Strict legal requirements would apply to assess the testing processes used by the manufacturers.

From a legal point of view, introducing such a regulatory tax on pharmaceutical products in Germany would not be an issue and may make good economic sense; tax revenue raised could provide adequate finance for WWTP upgrades, and the tax would act as an incentive for industry to develop green pharmaceuticals.

Source: (Gawel et al., 2017[67])

3.5.2. Pharmaceutical waste management and collection programmes

It is estimated that 10-50% of prescription medications are not taken as per the doctors’ orders and unused or expired medicinal waste may be disposed of via the toilet - therefore offering zero therapeutic benefit and resulting in water pollution. Although the contribution of improper disposal of pharmaceuticals to the overall environmental burden is generally believed to be minor (Daughton and Ruhoy, 2009[68]), pharmaceutical collection schemes are still considered to be important.

Various systems have been developed around the world to recover and manage waste pharmaceuticals from households. Drug take-back programmes provide the public with a convenient way to safely dispose of leftover medications. In Europe, collection schemes of unused/expired medication are an obligatory post-pharmacy stewardship approach that reduces the discharge of pharmaceuticals into environmental waters (via WWTPs) and minimises the amounts of pharmaceuticals entering landfill sites.

High levels of public awareness and education on the environmental consequences of the disposal of unused/expired drugs are key for the success of collection programmes. Increased awareness and a change in consumer behaviour regarding disposal practices can be a cost-effective measure to help reduce environmental exposure to pharmaceuticals. The German education campaign: “No pharmaceuticals down the toilet or sink!” is considered a cost-efficient and effective reduction measure (UBA, 2018[2]). In the EU, the annual cost of pharmaceutical collection schemes range from EUR 250,000 in Belgium, up to EUR 15 million in Denmark (Entec, 2011[54]). Pharmacy on-site receptacles are considered the most common collection system.

Public collection schemes of unused pharmaceuticals are established in several OECD countries either as voluntary schemes or mandated by legislation (Table 3.8). Collection programmes are funded either by the government (e.g. Sweden, Australia) or by Extended Producer Responsibility (EPR) in line with the Polluters-Pays principle (e.g. in Canada, Belgium, Spain and France) (Barnett-Itzhaki et al., 2016[69]). Through EPR legislation, pharmaceutical companies are required to collect and dispose of the unused pharmaceuticals their companies put on the market. The advantage of EPR systems is that it takes the burden off the government and requires industry to finance and manage the collection and safe disposal (usually through incineration) of unused drugs. Companies can internalise these costs in the price of pharmaceuticals and can, in theory, provide services more cost-efficiently (for more on EPR see (OECD, 2016[70])).

Table 3.8. Household pharmaceutical collection and disposal programmes, select OECD countries
Country	Programme coverage	Method	Funding
U.S	28 local EPR laws in the US; 5 at state-level, 23 at local government level	Either voluntary programs by firms or governments, or mandatory programs through EPR	Governmental, Industry
Canada	Several regional programs across the country. Four EPR programs regulated under different jurisdictions	Retail pharmacies commonly act as collection sites	Brand-owners and contributions are based on market share.
Australia	National programme	Mandatory, Retail pharmacies commonly act as collection sites	Federal government
France	National programme	Mandatory EPR-scheme, Retail pharmacies commonly act as collection sites	Industry
Sweden	National programme	Mandatory EPR-scheme , Retail pharmacies commonly act as collection sites	Pharmacies
Source: Author

Key factors determining the success of public collection schemes include if the scheme is implemented by legislation (i.e. obligation to collect), and the level of public awareness (communication effectiveness). In Israel, there is no legislation regarding household medical waste collection and disposal; correspondingly, less than 14 % of Israelis return unused pharmaceuticals (Barnett-Itzhaki et al., 2016[69]). In Sweden, public collection schemes are mandatory and 75% of unused drugs are estimated to be returned (Larsson and Löf, 2015). Some Swedish pharmacies go as far as providing reward schemes and discounts when customers return unused drugs. One Swedish pharmacy chain has an annual 4 week- campaign to increase awareness that they collect pharmaceuticals. During the period after the campaign, the number of customers who returned old medicines tripled (Apoteket AB, 2018[71]). In the U.S., one of the biggest barriers to implementing pharmaceutical collection schemes is the need to change federal law and Drug Enforcement Administration regulations to allow pharmacies (the most convenient collection location) to collect from residents. This can be a very long process.

Regulations can also be designed to manage pharmaceutical waste from health care facilities Box 3.11 provides an example of such regulation in the U.S.

Box 3.11. Regulations on the disposal of hazardous pharmaceutical waste in the health sector, U.S.

In the U.S., the Management Standards for Hazardous Waste Pharmaceuticals (US EPA, 2019[72]) establishes a new rule for the healthcare sector (i.e. hospitals, veterinarian clinics, pharmacies) regarding the disposal of hazardous waste pharmaceuticals to protect human health and the environment. It aims to eliminate the intentional disposal of hazardous waste pharmaceuticals (both prescription and over-the-counter, non-credible and evaluated hazardous) to sewer systems. Hazardous waste pharmaceuticals must be disposed of in permitted hazardous waste facilities for combustion or incineration.

The new rule is in response to a growing body of studies documenting the presence of pharmaceuticals in drinking and surface waters, as well as their negative impacts to aquatic and riparian ecosystems. It is expected to reduce hazardous waste pharmaceuticals entering US waterways by up to 2,300 tonne per year.

A guidance document on managing hazardous pharmaceuticals waste, as well as best practices to minimise pharmaceutical waste, is provided for the healthcare sector (Practice Greenhealth, 2008[73]). It advocates, that “when in doubt, apply the Precautionary Principle”; when an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically.

Sources: (Practice Greenhealth, 2008[73]) (US EPA, 2019[72]).

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3. Emerging policy instruments for the control of pharmaceuticals in water