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The urgent need for designing greener drugs

From Nature.com

The pervasive contamination of ecosystems with active pharmaceutical ingredients  poses a serious threat to biodiversity, ecosystem services and public health.  Urgent action is needed to design greener drugs that maintain efficacy but also minimize environmental impact.

We are living in an increasingly medicated world. Pharmaceuticals are indispensable in modern health care, having revolutionized the pre-vention and treatment of disease, and will remain crucial in the future. Nevertheless, our increasing dependency on pharmaceuticals comes at a major cost. Discharges to the environment during drug production, use and disposal have resulted in ecosystems around the globe being contaminated with mixtures of active pharmaceutical ingredients (APIs), as well as their metabolites, additives, adjuvants, excipients and transformation products. The extent of API pollution was recently demonstrated in a large-scale geographical study that measured  61 different drugs in river water taken from 1,052 locations across  104 countries, spanning all continents. Around 43% of the sites  sampled had levels of at least one drug that exceeded what is  considered safe for ecological health. Furthermore, at the more- contaminated sites, complex mixtures of many APIs were detected (a maximum of 34), including a wide variety of human and veterinary medications. Given their pervasive spread in ecosystems, as well as in groundwater used for drinking-water supply, several APIs were recently added as priority substances in the new proposal of the European Water Framework Directive. Moreover, it has recently been proposed that contamination of ecosystems with novel chemicals, including drug residues, has caused humanity to exceed the safe operating space of the planetary boundary for novel entities.

The threat of API pollution to wildlife

Evidence has been growing for decades that exposure to trace concen-trations of APIs and their mixtures can cause severe developmental, physiological, morphological and behavioural alterations in wild-life2. For instance, male fish exposed to the contraceptive oestrogen 17α-ethinyloestradiol were feminized and had associated reproduc-tive impairment, which precipitated a severe population collapse in a whole-lake experiment. Any such changes to the survival and repro-duction of API-exposed species will inevitably have cascading effects on the ecology and evolution of wildlife populations and communities, potentially driving population declines and local extinctions6. Even unexposed species may be impacted due to indirect effects such as reduced prey availability (for example, if prey reproduction is disrupted by APIs) or increased competition (for example, if APIs increase the feeding and/or aggressiveness of competitors)6. Furthermore, API pollution poses a threat to humans and wildlife alike, as seen in the case of antibiotics released into the environment that can act as a selection pressure promoting the mobilization and horizontal transfer of a wide range of antibiotic resistance genes.

API pollution in context

The problem of API pollution is occurring against a backdrop of mul-tiple other anthropogenic pressures on biodiversity and ecosystem services. These include a changing climate, habitat destruction and fragmentation, overexploitation of natural resources, and invasive species, together with the contamination of ecosystems with other pollutant classes, particularly in rapidly urbanizing areas. Interac-tions among chemical pollutants and secondary stressors can often be additive or even synergistic, where the combined effects are greater than the sum of individual effects. Some of this is due to the energetic cost of detoxification — that is, energy expended to metabolize and eliminate toxins from the body — which results in aquatic and terrestrial wildlife being more vulnerable to secondary stressors. In addition, APIs and their breakdown products pose a particular threat to biodiversity given that many have effects at extremely low exposures (for example, parts per billion to parts per trillion) and challenge existing regulatory determinations of chemical persistence, bioaccumulation and toxic-ity. Consequently, wildlife may not sense API residues and, therefore, may be unable to actively avoid contaminated habitats. Indeed, many aquatic species are attracted to wastewater outflows due to increased nutrient (and, hence, prey) availability and heightened temperatures, resulting in prolonged exposure to diverse cocktails of APIs, their break-down products and other contaminants.

Reforming the drug life cycle

To reduce drug pollution, the pharmaceutical industry and its custom-ers need to evaluate and reform many aspects of the complex life cycle of drugs. 

First, we need more informed and sustainable prescribing practices and usage, given that the most environmentally sustain-able pharmaceutical is one that is not required and not prescribed. This will necessitate training for health-care professionals, including pharmacists, physicians, nurses and veterinarians, and prescribing guidelines should be produced that consider the environmental impact of medicines.

Second, public awareness campaigns will be vital given that there is currently limited awareness of how prescribed and over-the-counter medicines can negatively impact the environment (for example, through incorrect disposal). Educational and sociological approaches intended to promote more informed and responsible purchasing and use of medicines are clearly a crucial component of an overall strategy but will not entirely eliminate the issue of API pollution.

Third, and key to reforming the drug life cycle, greener pharma-ceuticals need to be designed that are more easily and completely degraded in the environment, which is in alignment with the tenth prin-ciple of green chemistry (that is, design for degradation). In this regard, environmental persistence can be assessed according to standardized cut-off values set by regulatory agencies (for example, the European Chemicals Agency and the United States Environmental Protection Agency). Pharmaceutical manufacturing should also be optimized for greenness, including reducing waste generation and energy consump-tion. Embracing the production of green drugs is expected to have benefits for pharmaceutical manufacturers, both reputationally and economically, including by attracting more environmentally conscious customers and investors. However, stronger regulation and increased oversight are also needed to underpin and enforce these changes, such as through the polluter pays principle, where the polluter should bear the costs of pollution prevention and control measures.

Fourth, we need to improve and expand wastewater treatment pro-cesses to ideally prevent APIs entering the environment. In this regard, at least 48% of all wastewater globally currently flows into ecosystems without any treatment, underscoring the urgent need to increase the geographical extent of wastewater treatment infrastructure. Further, it is crucial to improve the efficacy of wastewater treatment, considering that conventional treatment plants are not designed to remove APIs and therefore commonly release these contaminants at trace levels. Technical solutions to remove APIs from wastewater exist (for exam-ple, activated carbon and ozonation) but, to date, only Switzerland has implemented advanced tertiary treatment of wastewater at the national level. Moreover, even advanced wastewater treatment is not capable of removing the majority of APIs and can even result in the formation of incompletely degraded by-products that are more toxic than the parent compounds. On top of these limitations, due to the relatively high price tag, trade-offs associated with energy use and resulting carbon emissions, and lack of regulatory implementation and enforcement, advanced treatment of wastewater is expected to remain uncommon on a global scale and is unlikely to solve the issue of API pollution without substantial additional innovation — for example, continued development of latest-generation catalysts for purifying micropollutants in wastewater.

More broadly, in seeking to reform the drug life cycle, it is impor-tant that we incorporate the One Health approach — that is, recogniz-ing the interconnection between humans, animals and their shared environment — within the rational use of all medicines, not only antimicrobials.

The key role of sustainable molecular design

Although the various sociological and technological interventions discussed above are important components of an overall strategy, molecular design of greener drugs is fundamental to reducing pollu-tion. Because drug design is the first step in the pharmaceutical pro-duction and consumption cycle, greener drugs lessen the potential for pollution throughout the entire cycle, reducing the need for other downstream mitigation measures. As such, pharmaceuticals — as well as their additives, adjuvants and excipients — should be designed not only to be efficacious and safe, but also to be quickly and fully miner-alized to carbon dioxide and water after excretion (for example, by environmental biodegradation). This approach, known as ‘benign by design’, is a key aspect of green pharmacy and has been successfully conducted with persistent APIs such as fluoroquinolone antibiotics14. Various benign-by-design workflows have already been developed to implement sustainable molecular design within the drug-design process15. Patent extensions or faster authorizations for more easily degradable pharmaceuticals might also be explored as incentives to design more easily environmentally biodegradable and mineralizing drugs. Furthermore, results of environmental risk assessments, par-ticularly when informed by mechanistic information that plausibly links to adverse outcomes, should be considered in the design and the risk–benefit analysis of medicines, considering the severity of the disease and the existing available alternatives.

Importantly, barriers exist along the path to designing greener drugs. This includes increased economic and time investment into research, development and manufacturing processes, although these costs will diminish over time due to technological advancements, increasing experience and expertise, and economies of scale. Fur-ther, some drug classes may be particularly challenging candidates for green redesign, such as those with especially high environmental persistence, bioaccumulation and/or toxicity attributes of concern. It is also important to appreciate that pharmaceuticals can challenge existing persistence, bioaccumulation and toxicity cut-off values, which were developed for conventional contaminants by regulatory agencies as part of common chemicals management strategies around the world. However, many pharmaceuticals are already on the market that have not been intentionally designed with environmental sus-tainability in mind but are nevertheless readily biodegradable in the environment (for example, β-lactams such as penicillin V, valproic acid and acetylsalicylic acid), and it is well established that adding various molecular elements (for example, esters) to drugs can reduce their environmental persistence.

The evidence is clear that APIs in the environment pose a major and escalating risk to biodiversity, ecosystem services and public health. The same trait that makes these drugs so effective in human and animal patients makes them particularly concerning as environ-mental pollutants: rationally and intrinsically designed attributes to exert a range of biological effects even at low dosages. Moreover, API contamination of ecosystems is co-occurring with other widespread environmental changes, which can magnify the detrimental effects of drugs. While various sociological and technological approaches exist to reduce the environmental burden of APIs, all of which should be leveraged, development of greener drugs that fully degrade in the environment is critical to a truly sustainable solution. Appreciating that patient access to pharmaceuticals will remain vital into the future, we urge drug designers and manufacturers, scientists and policymakers to recognize the growing environmental threat posed by APIs and to urgently prioritize the sustainable molecular design of greener drugs to prevent further environmental harm.