Front. Environ. Sci. Frontiers in Environmental Science Front. Environ. Sci. 2296-665X Frontiers Media S.A. 1077974 10.3389/fenvs.2022.1077974 Environmental Science Mini Review Minimizing the environmental impact of unused pharmaceuticals: Review focused on prevention Paut Kusturica et al. 10.3389/fenvs.2022.1077974 Paut Kusturica Milica 1 * Jevtic Marija 1 2 Ristovski Jovana Trifunovic 1 1 Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia 2 School of Public Health, Research Center on Environmental Health and Occupational Health, Université libre de Bruxelles (ULB), Bruxells, Belgium

Edited by: Xiaohu Wen, Northwest Institute of Eco-Environment and Resources (CAS), China

Reviewed by: Miguel Machado Santos, University of Porto, Portugal

Haile Kassahun, Wollo University, Ethiopia

 *Correspondence: Milica Paut Kusturica, milica.paut-kusturica@mf.uns.ac.rs

This article was submitted to Toxicology, Pollution and the Environment, a section of the journal Frontiers in Environmental Science

 16 12 2022 2022 10 1077974 23 10 2022 08 12 2022 Copyright © 2022 Paut Kusturica, Jevtic and Ristovski. 2022 Paut Kusturica, Jevtic and Ristovski

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Pharmaceuticals are essential for human health, but they become an environmental concern when entering the environment which occurs when residues are excreted after consumption or when unused pharmaceuticals are discarded improperly. Although there are no developed detection methods for all pharmaceuticals that reach the ecosystem, certain groups have been proven to cause adverse effects on ecosystems, including increased mortality in aquatic species and changes in physiology, behavior, or reproduction. Particular attention is devoted to these groups of pharmaceuticals and their environmental impact. In this review, the authors suggest measures for the reduction of unused pharmaceuticals in the environment, with a strong emphasis on prevention. Various policy interventions are recommended across the lifecycle including source-directed, user-orientated, and waste management measures, to prevent the creation of household pharmaceutical waste and to ensure environmentally friendly ways of pharmaceutical household waste disposal. Preventive measures include rational pharmaceutical consumption, prescribing greener drugs, or designing pharmaceuticals that are benign and easily biodegradable, improved disease prevention, personalized medicine, enhanced dimensioning of pack sizes, and marketplaces for redistribution of unused pharmaceuticals. The next step is to prevent unavoidable waste to reach the environment, so proper collection and disposal of unused pharmaceuticals is of utmost importance. Finally, educating health professionals and the public and partnership between environmental and healthcare scientists are of vital significance in all stages of the pharmaceuticals’ lifecycle. Minimalization of the level of pharmaceuticals in the environment will benefit human life.

 unused pharmaceuticals environmental impact waste prevention waste reduction pharmaceutical waste disposal Ministarstvo Prosvete, Nauke i Tehnološkog Razvoja10.13039/501100004564 1 Introduction

Demographic, epidemiological and lifestyle changes such as aging population, the increase of chronic diseases, the availability of inexpensive generic treatments and ease of access to vast amounts of over-the-counter drugs have been key drivers for increased pharmaceutical consumption (González Pena et al., 2021; European Commission, 2019). The global increase in pharmaceutical consumption has led to an enhanced international awareness of the issue of unused pharmaceuticals (UPs) in households and the harmful environmental and health effects of their improper disposal (Paut Kusturica et al., 2016; Mitkidis et al., 2022). Pharmaceuticals in the environment are a challenge to manage as they are designed to interact with a living system and produce a pharmacological response at low doses, which makes them of environmental concern even at low concentrations. Secondly, pharmaceuticals are designed to be stable in order to reach and interact with target molecules, meaning that either they are very slow to degrade or their constant use leads to continuous release into the environment at rates above degradation rates. Also, conventional wastewater treatment plants are not designed to fully remove pharmaceuticals from wastewater (OECD, 2019).

There are two main ways by which pharmaceuticals enter the environment: excretion and improper disposal (OECD, 2022). In both cases, pharmaceuticals end up in sewage treatment plants that are generally not designed to remove such pollutants from wastewater (Thomas,Felicity and WHO, 2017). Pharmaceuticals have been detected primarily in surface waters, but also in groundwater, soil, manure and even drinking water. The presence of pharmaceuticals in freshwater and terrestrial ecosystems can result in the uptake of pharmaceuticals into wildlife with the potential to bioaccumulate (Zenker et al., 2014). Humans are subsequently exposed to pharmaceuticals via drinking water, and ingestion of its residues in plant crops, fish, dairy products and meat. The consequences of pharmaceuticals in the aquatic environment are an issue of rising concern, with impacts that can range from molecular alterations to effects at the population level (Queirós et al., 2021). Given that this is a growing environmental and health concern globally, this review pursues to answer the following questions: 1) which pharmaceuticals have been proven to cause detrimental effects on the environment 2) what are the options to reduce detrimental environmental impact of UPs before they reach the environment.

 2 Effect of pharmaceuticals on the environment and human health

Human pharmaceuticals are listed as emerging contaminants by UNESCO. Their detection and elimination represent the crucial step according to the “2030 Agenda for Sustainable Development” Goal Targets (UNESCO 2020). The concentrations of drugs found in the environment are under therapeutic levels. In water surfaces that receive treated wastewater, pharmaceuticals are detected in concentrations less than 100 ng/L (Vumazonke et al., 2020; Björklund and Svahn, 2021; Li et al., 2021). These low concentrations are the reason for the difficult assessment of their toxic effects on the ecosystem and human health. The vast majority of pharmaceuticals have not been sufficiently explored for their long-term toxic effects, presence and fate in the environment (aus der Beek et al., 2016). However, certain pharmaceutical groups such as beta-blockers, antibiotics, anticancer drugs and endocrine disruptors (Nie et al., 2013; Kovács et al., 2015; Godlewska et al., 2021; Ortuzar et al., 2022) have been shown to cause devastating effects on the ecosystem including increased mortality, and impairment of the physiological and reproductive functions of aquatic species. Also, devastating effects are reflected on human health because it is impossible to separate humans from nature. Still, the scale of the problem remains highly unknown, due to the huge number of pharmaceuticals and the challenges of evaluating risks related to multi-compound exposure at low doses and over long periods of time (Kümmerer, 2019). The German Environment Agency (UBA) announced that 10% of medicines on the market represent potential environmental risk. Even though there are no developed detection methods for all pharmaceutics that reach the ecosystem some of them are predominantly present and proven to cause negative adverse effects on ecosystems (Küster et al., 2010). These groups include hormones, antibiotics, antidepressants, anti-inflammatories and analgesics, beta-blockers and anticancer pharmaceuticals (Monteiro and Boxall, 2010).

The presence of estrogens in the environment represents a serious contamination problem (Bilal and Igbal, 2019). The world’s human population discharges approximately 30,000 kg/yr of natural steroidal estrogens and an additional 700 kg/yr of synthetic estrogens only from birth control pill practices. However, the abundance of these hormones in the environment mostly originates from the livestock industry due to the wide usage of a variety of growth-regulating steroids to enhance the production rate of meat. Undoubtedly, estrogens are essential for normal human physiology but can have serious adverse effects if accumulate in the environment and enter the human food chain (Adeel et al., 2017). These types of hormones are capable to perturb human and animal physiology and affect normal reproduction. Estrogens as pollutants are also linked with a higher incidence of breast cancer in women and prostate cancer in men (Nelles et al., 2011; Trevino et al., 2015).

Antimicrobial resistance represents a global public health issue, especially considering the increased use of antibiotics during the COVID-19 pandemic which led to the depletion of the last line of antibiotics (Lai et al., 2021). It has been noted that the application of antibiotics in human medicine, veterinary medicine and agriculture is related to the contamination of the different parts of the environment which contributed to an increase in antibiotic resistance and the occurrence of ecotoxicological effects (Zainaba et al., 2020). A lack of proper antibiotic disposal practices among patients by discharging them into the sewage systems represents also a growing environmental threat to public health (Anwar et al., 2020). Also, the strong impact of antibiotic pollution after long-term exposure can affect human health, especially in patients with chronic diseases including obesity, diabetes, and asthma (Ianiro et al., 2016).

The worldwide contamination with antidepressants significantly increased during the COVID-19 pandemic (Rabeea et al., 2021). To this day antidepressants have been detected in urban and non-urban water systems. Many different types of aquatic animals bioaccumulate different antidepressants in their tissues which leads to cytotoxicity, genotoxicity, stress response alteration, increase/decrease in weight and length, and liver and kidney damage (Castillo-Zacarías et al., 2021). Considering that the human and animal environments significantly overlap, antidepressant pollution (sertraline, fluoxetine) has also impacted human neurodevelopment and different psychiatric conditions (Abbey-Lee et al., 2018; Li et al., 2020). Although psychopharmaceuticals are generally present in wastewaters at subtherapeutic levels they are capable to induce biological effects at low doses, particularly in an environment is often presents a combination of several psychopharmaceuticals which increases the risk of their toxic effects (Chan et al., 2021).

Large amounts of non-steroidal anti-inflammatory drugs, including acetaminophen, acetylsalicylic acid, ibuprofen, diclofenac and naproxen significantly contribute to the pollution of the environment, particularly as they have been found in nanograms and micrograms in soil, wastewater, surface water, drinking water, groundwater (Tyumina et al., 2020). These drugs have chronic ecotoxic effects as they are very resistant to biological transformation in the environment due to their stable chemical structure. It is known so far that they mostly cause disorders in the organs of invertebrates and vertebrates by inducing oxidative stress and disrupting activity of detoxification enzymes (Hodkovicova et al., 2022). These pharmaceuticals can also cause cardiovascular abnormalities, and hepatotoxicity and disrupt oocyte maturation by an unknown mechanism (Lister and Van Der Kraak, 2009; Xia et al., 2017).

Beta-blockers represent pharmaceutical compounds that show the potential to be highly persistent and toxic in the environment (Kuster et al., 2010). While some data about their environmental adsorption are lacking, it is known that these pharmaceuticals demonstrate moderately high solubility in water and have been detected in surface waters at concentrations of μg/L. These compounds are very resistant to hydrolysis, bioavailable and mobile in the environment. Therefore, their accumulation in the environment can cause unexpected consequences to different living organisms. In accordance with European Union Directive 93/67EEC, metoprolol and propranolol represent adverse compounds to aquatic species. This indicates results from tests performed on green alga (S. vacuolatus) (Maszkowska et al., 2014).

Anticancer drugs stop the growth and division of cells and by their release into the environment, these pharmaceuticals affect the ecosystem through disruption of fertility and significant genetic alteration of living organisms. Anticancer drugs are prescribed in lower quantities but their effects even in ng/l concentrations are devastating, including mutagenic, carcinogenic, and teratogenic consequences to aquatic species. Due to their application and inappropriate disposal, cytostatic drugs are often detected in wastewater from pharmaceutical manufactories and hospitals. The detection frequency of anticancer drugs in hospital wastewater is 58% and cisplatin is marked as one of the most hazardous pharmaceuticals (Dan et al., 2021). The presence of cisplatin in waterbodies even at ng/l concentrations can cause toxic effects on aquatic species (Roque-Diaz et al., 2021) The surface water Watch List (WL) includes information about emerging pollutants that can cause a significant risk to aquatic organisms and humans upon consumption of contaminated drinking water. This list contains all the above-mentioned groups of pharmaceuticals (Gomez Cortes et al., 2022).

 3 Measures to mitigate environmental impacts of UPs from households

Prior to seeking ways to improve the elimination processes of pharmaceuticals once they reach the environment, it is apparently more rational to act at source(Table 1). Considering that pharmaceuticals provide an unquestionable benefit to the health of humanity, great care must be taken not to restrict access to those pharmaceuticals that are necessary but to prevent their negative environmental impact (Argaluza et al., 2021).

Measures to mitigate impacts of UPs.

UPs mitigation Measure Description
UPs avoidance Disease prevention Communication and education activities and policy interventions aimed at reducing the development and severity of chronic diseases and other morbidities can reduce pharmaceutical consumption and UPs creation
Personalized medicine Fewer and more effective treatments can be achieved by using pharmaceuticals that are better targeted to patients’ needs
Dimensioning Reducing packaging sizes for new drug treatments and starter packs can reduce risk of accumulation of UPs in households
Marketplace for UPs A marketplace for UFs that are close-to-expiry-date, unopened and undamaged provides better matching of supply and demand
Collection and safe final disposal of UPs Collection in mixed municipal solid waste and controlled final disposal Collection in mixed municipal solid waste and incineration in state-of-the-art incinerators
Drug take-back programs Take-back programs can prevent improper disposal of UPs from households
EPR schemes EPR implements the “producer pays principle”, moving waste management costs from tax payers to pharmaceutical industry
“Eco-prescription” Change prescriptions to more environmentally-friendly drugs The “Wise List” incorporate environmental aspects to recommend drugs in ambulatory care prescribing
“Green pharmacy” Development of more “environmentally friendly” pharmaceuticals Designing more biodegradable pharmaceuticals that are less harmful for the environment (“benign by design”)
Increase awareness and induce behaviour change Information campaigns They can be financed and managed by public authorities, the private sector, NGOs or be an accompanying requirement in the design of EPR schemes
Incentives for returning UPs to pharmacies Refunds or other rewards to nudge consumers for returning UFs to collection points
Pharmaceutical ecolabelling A mandatory information in EU countries
Environmental classification schemes Environmental classifications schemes allow doctors to make informed prescription choices
3.1 Prevention of pharmaceutical waste

The findings from a recent study showed that more than one-third of UPs were classified as preventable pharmaceutical waste (Bekker et al., 2018). Given that ‘prevention is better than cure’ the priority is avoidance of pharmaceutical waste. Prevention of pharmaceutical waste could be performed through various measures such as improved disease prevention, personalized and precision medicine, and improved dimensioning of packaging sizes (Straub, 2016; Klatte et al., 2017; OECD, 2022).

Where the dose of pharmaceuticals must be calculated on a per-patient basis there exists a degree of wastage. The medication that is dosed based on the patient’s weight or body size is often wasted due to the required dose not matching the vial size. Therefore, to encounter medication waste, manufacturers ought to facilitate more variety in package sizes and avoid large packages. Policymakers can urge manufacturers to stimulate a reasonable set of size options by requiring a maximum percentage of waste (Bach et al., 2016). Furthermore, the risk of accumulation of UPs in households can be reduced by reducing packaging sizes, particularly for new drug treatments and starter packs. Also, the appropriate range of pack sizes should be in line with the treatment duration and the posology in the summary of product characteristics (European Commission, 2021; OECD, 2022).

Pharmaceutical waste is only partially preventable, and should therefore be accompanied by other waste-minimizing approaches. Throughout society, recycling programs for the sustainable use of different resources have been implemented. A similar approach could be implemented for pharmaceutical waste, such as the redispensing of UPs that are within the expiration date (Bekker et al., 2018). Bekker et al. estimated that one-fifth of the returned medications were potentially suitable for redispensing. Returned UPs were considered eligible for redispensing if the package was unopened, undamaged and the period between the return and the expiry date was at least 6 months. One of the possible solutions for unused close-to-expiry-date pharmaceuticals is marketplaces that offer better matching of supply and demand. Although redispensing has the potential to contribute to waste minimization and monetary savings, it is still not applied in the practice due to concerns regarding counterfeits, quality assurance, and following legal restraints. However, some initiatives occur. In the Netherlands, there is a platform under the name PharmaSwap that allows certified pharmacists to sell undamaged UPs before their expiration date to other pharmacies, often at reduced prices. Likewise, two US start-ups are founded with the aim to collect and redistribute UPs to patients with low income (OECD, 2022). Redispensing is a promising way of UPs minimization, but requires a thoughtful implementation strategy with comprehensive communication with all stakeholders, paying particular attention to product quality assurance, financial handling, and legal aspects.

 3.2 Collection schemes and take-back systems for household pharmaceutical waste

The practice of improper disposal of UPs from households represents a global phenomenon. Thus, effective collection schemes and take-back programs with the main purpose to offer an easy method for disposal of UPs represent an important measure to protect the environment (Paut Kusturica et al., 2016). Separate collection systems help avoid environmental leakage caused by flushing pharmaceuticals via drain or by mixing them with solid household waste that is destined for landfills without leachate collection (Masoner et al., 2016). The approaches used for collection differ among countries, but in general, pharmacies play an essential role. One-day collection events or mail-back envelopes are also available in some countries (e.g., United States). Some programs rely only on government funding (e.g., Australia) while others are financed by the pharmaceutical industry or pharmacies that provide support voluntarily or driven by extended producer responsibility (EPR) legislation (OECD, 2022).

Given that financial moment plays a significant role in UPs disposal systems, one of the valuable solutions is an implementation of the EPR laws which require that pharmaceutical manufacturers manage their products in all phases of their life cycle, including end-of-life treatment and waste management. Countries that have pursued an EPR approach shift the financial and organizational burden of UPs collection and disposal from the government to the pharmaceutical industry (Paut Kusturica et al., 2020). As a result, EPR implements the “producer pays principle”, moving waste management costs from taxpayers to manufacturers. Companies can incorporate these costs in the price and provide services more cost-efficiently. European waste legislation currently provides a global framework for the implementation of EPR law in Europe and its policies have been designed and implemented in a very heterogeneous manner across Europe (OECD, 2022).

 3.3 “Eco-prescription”

“Eco-prescription” or “green prescription” implies that the prescriber should consider the characteristics and environmental behavior of pharmaceuticals when prescribing (Daughton and Ruhoy, 2011). For instance, although oxazepam is considered a good option for the elderly due to its suitable pharmacokinetic profile, it is excreted unchanged via urine and accumulates for decades without biodegrading. From an environmental perspective, pharmaceuticals that are metabolized to inactive metabolites prior to elimination are preferable (Daughton, 2014). Incorporating environmental criteria in the use of pharmaceuticals is crucial, and it may represent a true revolution in pharmacology (Lertxundi et al., 2020).

The Stockholm County Council possesses an environmental classification of pharmaceuticals, created from a joint initiative between producers, authorities, and public health professionals. The classification indicates the risk and environmental hazards of pharmaceuticals determined based on the active pharmaceutical ingredient’s persistence, bioaccumulation potential and toxicity. The risk refers to the likelihood that a pharmaceutical is toxic to aquatic organisms. Prescribers may incorporate this information when using pharmaceuticals for individual patients and choose those that are environmentally friendly. To date, the “Wise List” (Kloka Listan) is the only multifaceted approach incorporating environmental aspects to recommend drugs in ambulatory care (Gustafsson et al., 2011).

 3.4 New development or redesign of pharmaceuticals

To follow the concept of environmental protection, the pharmaceutical industry should develop promising concepts to minimize the content in excretion while ensuring sufficient pharmacologically active concentrations in the patient. “Green pharmacy” recognizes the potential for designing new more biodegradable pharmaceuticals that are less harmful to the environment (Daughton and Ruhoy, 2011). “Greener drugs” also contribute to the Sustainable Development Goals 6 (Clean Water), 3 (Health), 9 (Sustainable industries), 11 (Sustainable cities) and 12 (Responsible production and consumption) of the United Nations (Kummerer, 2019). There are already some examples of the development of more “environmentally friendly” pharmaceuticals, such as glufosfamide and green drug delivery systems (Dai et al., 2016; Banik, 2020). Scientists are currently developing an effective and environmentally friendly variant of the antibiotic ciprofloxacin which is a very stable pharmaceutical. Through computer modeling, the existing active substance is analyzed and changed theoretically for improved biological degradability and lower toxicological effects. The most promising candidates will be synthesized and tested in vitro (Kummerer, 2019).

 3.5 Education and information campaigns

The limited consumers’ awareness of proper disposal practices weakens their impact on disposal practices in many countries (Paut Kusturica et al., 2016). Information campaigns can increase the awareness and use of environmentally friendly ways of pharmaceutical waste from households. A good example is The #Medsdisposal campaign, a European initiative jointly coordinated by several European supply chain and healthcare organizations and supported by media campaigns in different languages. The initiative aimed to combat the detrimental impacts of mishandled pharmaceuticals on the environment by educating consumers about proper disposal routes and available take-back systems in different European countries. The German campaign entitled: “No pharmaceuticals down the toilet or sink!” is also considered a cost-efficient and effective educational campaign (OECD, 2022).

Furthermore, awareness and behavioral change can be achieved with special instructions for disposal that appear on the outer packaging or in the information leaflet of the drug, which is mandatory in EU countries. Incentives for returning UPs to collection points, such as various rewards to encourage consumers to adopt proper disposal practices are also useful approaches. For example, in Sweden, most pharmacy chains offer bonus credit points to consumers who return UPs to collection points. Furthermore, eco-labels on the environmental impact of different pharmaceuticals can influence consumer choice and awareness and help doctors make a decision while prescribing medications. The aforementioned environmental classification schemes include about 200 pharmaceuticals that are available online for consumers and prescribers (Stockholm County Council, 2014). The advice on proper drug disposal should also routinely follow drug dispensing. Pharmacists can play a key role in educating their customers on proper medication disposal methods (Paut Kusturica et al., 2016).

 4 Conclusion

Environmental pollution with pharmaceuticals is a complex public health challenge that entails scientific doubts and involves a great number of stakeholders with various interests and at different organizational levels: governments, non-governmental organizations, scientific institutions, manufacturers, industry and households.

Various policy interventions should be implemented across the pharmaceutical lifecycle including source-directed, user-orientated and waste-management activities. The most valuable solutions should be implemented at source before pharmaceuticals reach the environment. These measures include rational pharmaceutical consumption, prescribing greener drugs, or designing pharmaceuticals that are benign and easily biodegradable. Improved disease prevention, personalized medicine, enhanced dimensioning of packaging sizes, and marketplaces for redistribution of UPs can to some extent prevent pharmaceutical waste creation. The next step is to prevent unavoidable waste to reach the environment, thus appropriate collection and disposal of UPs is essential and needs to be tailored to the national context and local challenges. Finally, educating health professionals and the public and partnership between environmental and healthcare scientists are of crucial importance in all phases of the pharmaceuticals’ lifecycle. The heart of all joint efforts should be the “One Health” approach to tackle pharmaceutical waste and enhance human, animal, and environmental health that are strongly interconnected.

 Author contributions

MPK: conceptualization. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

This work was supported by the Ministry of Education and Science of the Republic of Serbia through the Project of the Faculty of Medicine University of Novi Sad (Science Research Organization 200114) 451-03-68/2022-14/200114.

 Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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