Benign-by-design pharmaceuticals: Designing eco-friendly drugs to protect biodiversity

Posted: November 28, 2024

From 1992 to 2007, India’s resident vulture population fell by more than 97%-nearly a local extinction of three species of vulture. In the same span of time, the country witnessed a surge in rabies cases among dogs, which was particularly dire since India sees over 20,000 human deaths from rabies a year. Both crises shared the same root cause: a widely used anti-inflammatory drug given to cattle and water buffalo. The drug, diclofenac, which treats inflammation caused by trauma and infectious diseases, proved lethal to the vultures that scavenged the cattle carcasses.^[i]

As the vulture population nosedived, stray dogs began to eat the carcasses that the vultures would have consumed. Now, with an abundance of food, the dog population boomed, and with this boom came a surge in rabies cases, and later a rabies epidemic. The effects of the active pharmaceutical ingredients (APIs) in diclofenac worked their way through the ecosystem with deleterious and unpredictable consequences. In 2006, the Indian government banned the veterinary use of diclofenac.^[ii]

Pharmaceutical pollution in waterways

Pharmaceuticals make their way into ecosystems in a number of ways. A 2022 study of APIs in rivers around the world found that about 43.5% (461 sites of the 1052 surveyed) had concerning concentrations of APIs. The drugs detected included antidepressants, antimalarials, benzodiazepines, painkillers, antibiotics, antihistamines, beta blockers, and hormonal contraceptives, among others.^[iii]

Further studies substantiate the effect of APIs on the environment, even when found in low levels. In one seven-year study, fish exposed to low levels of estrogen from contraceptives in wastewater runoff experienced sex reversals, which led to a collapse of the population.^[iv] When exposed to antidepressants, European perch lose their fear of predators.^[v] Brown trout have become addicted to methamphetamines.^[vi] Pharmaceutical pollution is causing developmental, physiological, and behavioral alterations in wildlife at a time of rapid, global biodiversity loss.

The call for reform

APIs end up in waterways from manufacturing runoff, but also after human consumption. Waste treatment facilities are not currently set up to filter out APIs during treatment. What’s more, pharmaceuticals today are designed to have biological effects at low doses. Many industry experts are calling for pharmaceuticals that more easily and completely degrade in the environment. Another moniker for this: drugs that are “benign by design.”

In August of this year, a group of researchers released a paper in the journal Nature Sustainability calling on the pharmaceutical industry to design “greener” drugs that reduce the risk of environmental harm.^[vii]

Industry appetite for greener drugs

In 2023, the European Journal of Pharmaceutical Sciences published a survey of 30 R&D and environmental experts from seven global pharmaceutical companies.^[viii] The survey gauged the feasibility of including environmental criteria for APIs into the drug discovery and development process.

According to respondents, though potential environmental effects are not a part of the traditional R&D process, potential ecotoxicity could be incorporated earlier in the drug discovery and development process if it were mandated. Other researchers also recommend including environmental risks in the benefit-risk assessment when a medicinal product is considered for marketing authorization.

While greener drugs will require concerted R&D efforts to find alternatives in drug chemistry, collaboration among pharmaceutical companies, regulatory bodies, and academia can support the shift to more sustainable molecular design. Additionally, artificial intelligence models, such as AlphaFold, could accelerate the discovery of greener drugs. AlphaFold, developed by Google’s DeepMind, uses an artificial intelligence model to predict the three-dimensional structures of proteins. Researchers could use the tool to design enzymes that break down drugs after they fulfill their intended function, reducing their ecotoxicity and environmental impact.

Looking ahead, fast-tracking patents for “benign by design” drugs and increasing their patent lifetime exclusivity can incentivize their development. Similarly, a “green label” for “benign by design” drugs could encourage companies to invest in their development. Of course, regulations and mandates will also play a role in shifting the industry towards green chemistry, but some insiders feel the incentive already exists among medicinal chemists.

Citations:
 

^{[i] Green, R.E., Newton, I., Shultz, S., Cunningham, A.A., Gilbert, M., Pain, D.J. And Prakash, V. (2004), Diclofenac poisoning as a cause of vulture population declines across the Indian subcontinent. Journal of Applied Ecology, 41: 793-800. https://doi.org/10.1111/j.0021-8901.2004.00954.x
[ii] Aldred, Jessica. (2011, September 6). Diclofenac blamed for return of cattle killer to India. The Guardian. https://www.theguardian.com/environment/2011/sep/06/diclofenac-india-cattle-vultures
[iii] Bouzas-Monroy, A., Wilkinson, J.L., Melling, M. and Boxall, A.B.A. (2022), Assessment of the Potential Ecotoxicological Effects of Pharmaceuticals in the World's Rivers. Environ Toxicol Chem, 41: 2008-2020. https://doi.org/10.1002/etc.5355
[iv] Kidd KA, Blanchfield PJ, Mills KH, Palace VP, Evans RE, Lazorchak JM, Flick RW. (2007), Collapse of a fish population after exposure to a synthetic estrogen. Proceedings of the National Academy of Sciences of the United States of America. 2007 May 22; 104(21):8897-901. https://www.pnas.org/doi/full/10.1073/pnas.0609568104
[v] Johnson, C. J., Gibbs, J. P., & Simpson, S. G. (2016). Environmental exposure and ecological determinants of wildlife health. Environmental Pollution, 214, 123-130. https://doi.org/10.1016/j.envpol.2016.08.053
[vi] Pavel Horký, Roman Grabic, Kateřina Grabicová, Bryan W. Brooks, Karel Douda, Ondřej Slavík, Pavla Hubená, Eugenia M. Sancho Santos, Tomáš Randák. (2021) Methamphetamine pollution elicits addiction in wild fish. J Exp Biol 1 July 2021; 224 (13): jeb242145. doi: https://doi.org/10.1242/jeb.242145
[vii] Rogers, T., Bishop, T., … Orive, Gorka (2024). The urgent need for designing greener drugs. Nature Sustainability. https://www.nature.com/articles/s41893-024-01374-y.epdf
[viii] Puhlmann, N., Vidaurre, R., & Kümmerer, K. (2024). Designing greener active pharmaceutical ingredients: Insights from pharmaceutical industry into drug discovery and development. European Journal of Pharmaceutical Sciences, 192, 106614. https://doi.org/10.1016/j.ejps.2023.106614}