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When Covid-19 started spreading in 2020, humans across the world ran through 4.5 trillion doses of myriad pharmaceuticals. In 2021, India alone sold 3.5 billion pills of just one drug – paracetamol, a pain reliever used to treat some Covid-19 symptoms. Big pharma went into overdrive as companies raced to develop successful vaccines and hit the market, dispensing more than 12.6 billion doses in record time.

But long before Covid-19 struck, new and existing medicinal drugs were being churned out at a cracking pace, a trend sure to surge in the future. Over the next five years, drugmakers could unveil 300 new drugs, health research firm IQVIA predicted.

Yet, medicines, even life-saving ones, in the wrong place and in the wrong doses can be pollutants.

These chemical concoctions that enter the human bloodstream and alleviate much human suffering also often end up seeping into the Earth’s veins – into rivers, lakes and estuaries – with scientists remaining largely in the dark regarding the ills potentially bred in this wider wild world.

In the next five years, drugmakers could unveil 300 new drugs, a health research firm predicted. While these new drugs will likely be tested vigorously for their human side effects, their impacts on the environment are far less evaluated. Credit: Mongabay.

Taking stock of pharmaceutical pollution

A global study published this year found that rivers everywhere, including in Antarctica, are tainted by pharmaceuticals. Alistair Boxall and his colleagues analysed samples from 1,000 sites in more than 100 countries, looking for 61 active pharmaceutical ingredients, the core components that turn mundane compounds into medicines.

There are more than 4,000 active pharmaceutical ingredients in use today. All are compounds designed to evoke a biological response, to manipulate the functioning of living organisms. That fact alone means that active pharmaceutical ingredients released into waterways have the potential to do environmental harm.

Initial findings by Boxall’s team indicated that concentrations of at least one active pharmaceutical ingredient breached safe levels for aquatic life at a quarter of sites studied. A follow-up study published in June suggests this number could be higher, closer to 40%, if a wider range of impacts is considered.

These statistics point to a stunning scientific oversight, says Boxall, a professor of environmental science at the UK’s University of York. He says he is irked that now, decades after many medicinal drugs first came into wide use, they continue to be labelled “emerging pollutants”.

“Only in the last 10 to 20 years have we started to recognise that pharmaceuticals can harm the environment,” he said.

Pollution in the Hindon River near Delhi. Less industrialised countries are rapidly increasing their use of pharmaceuticals, while often lacking advanced waste processing systems to control those contaminants. Such systems are expensive to install, and are often even lacking in sewage treatment facilities in more industrialised nations. Credit: Hridayesh Joshi/Mongabay.

The metformin example

Of the 61 active pharmaceutical ingredients evaluated, some kept popping up repeatedly. Among the most ubiquitous in the world’s waterways were carbamazepine, employed to treat epilepsy, as well as the everyday stimulant caffeine, and metformin, a first-line medication for type 2 diabetes prescribed by doctors and used by patients the world over.

Mongabay decided to look at just one of those three, picking metformin, not because it stands out as a particularly dangerous pollutant, but because its environmental pathways and our poor understanding of its ecological impacts exemplify other highly prescribed pharmaceuticals.

Roughly 90% of people diagnosed with diabetes suffer from type 2 diabetes, where the body progressively loses its ability to use insulin, a hormone produced by the pancreas. Insulin normally helps cells absorb sugar in the form of glucose from the blood. But insulin resistance results in high blood glucose levels. Over time, too much sugar in the blood can damage vital organs like the kidneys, weaken nerves, and in extreme cases, lead to blindness or loss of limbs.

Metformin hydrochloride – or 1,1-Dimethylbiguanide hydrochloride – is the most prescribed diabetes drug today. The exact mechanism by which it lowers glucose levels is unknown. The latest research suggests it works by triggering enzymes in the liver that limit glucose formation, and increasing glucose absorption in the intestine. Like many drugs, it has a litany of side effects that vary from patient to patient.

A bubble pack of metformin hydrochloride tablets. Metformin is just one of many pharmaceuticals entering the world’s waterways, largely with unknown impacts. Credit: Mongabay.

Metformin was synthesised in a lab in Dublin, Ireland, in 1922, but it was only in 1957 when French physician Jean Sterne first reported its glucose-lowering properties. The 1940s to ’60s saw a surge in its medicinal use globally, corresponding with an explosion in new drugs coming on the market, including the mass distribution of antibiotics.

While other nations approved metformin for diabetes treatment, the US did not do so until the mid-1990s. Regulatory authorities moved with caution there following a debacle with another diabetes drug: phenformin. Phenformin was linked to severe lactic acidosis, or acid build-up in the bloodstream, leading to thousands of deaths in the US in the 1960s and ’70s.

Concerns about human safety have understandably remained central to drug development. But ecological concerns didn’t feature significantly in the approval of metformin globally, and environmental harm is rarely a block today to new drug approvals in most nations.

That reality now leaves scientists asking the question: How much of any one pharmaceutical, or a combination of these pollutants, might result in an overdose for a river system?

The answer is, we just do not know and data remain woefully lacking.

Despite its global scope, the original investigation by Boxall’s team captured the active pharmaceutical ingredients footprint for just 471 million people, without evaluating any specific harms. The planet is home to nearly eight billion humans, with new drugs streaming into the market – and waterways – every year.

A late-19th century advertisement for “sugar coated” pills during a period when drugs were virtually unregulated. Today, while concerns about human safety have understandably become central to pharmaceutical development, potential ecological impacts still do not figure significantly into approvals. Credit: Miami University Libraries-Digital Collections via Flickr.

On the trail of pharmaceuticals in India

Soaring human population since World War II has translated into higher demand for medications worldwide, especially in countries where incomes rose more recently. That has led to increased pharmaceutical pollution, including in newly urbanised, once pristine areas. Other common denominators of growing contamination include easy access to, and broad acceptance of, medicines across the planet.

India, for example, is now the world’s third-biggest pharmaceutical manufacturer by volume, earning it the moniker “the world’s pharmacy”. In particular, it serves as a hub for generic drug production (versions of which replace more expensive formulations that are no longer patent-protected). The resulting cheaper medicines are readily available on India’s domestic market, while also being shipped worldwide. Around 40% of generic formulations sold in the US are supplied by India, according to one estimate.

While most people link medical waste to hospitals, medical facilities are not, in fact, the most significant source of pharmaceutical pollution. Though drug manufacturing plants do generate waste containing active pharmaceutical ingredients, it is households that are by far the biggest source of pharma contaminants.

Which brings us back to metformin. India is home to the second-largest number of people with diabetes after China: 80 million in total, which is greater than the entire population of France. In Delhi, a city of nearly 20 million, an estimated 25%-33% of residents have diabetes, and many are certainly metformin users.

Those taking the ubiquitous diabetes drug unwittingly pollute their vital water source, the Yamuna river, which irrigates much of north India’s crops.

“Any change in the use of medicines by a society will influence what we see in a river,” Boxall explained. That’s because many pharmaceutical compounds, including metformin, pass through the human body without losing their potency, and are not metabolised fully. In fact, more than two-thirds of a metformin dose can end up in the urine or feces intact.

And most of it passes right through sewage treatment plants.

Domestic sewage being discharged into the Yamuna River. Researchers detected a cocktail of 22 APIs, including metformin, in river water samples collected in India’s Delhi national capital region through which the Yamuna flows. Credit: Kathuria Films Production/Mongabay.

According to India’s primary pollution control agency, sewage is the main contaminant of India’s waterways. The country struggles to ensure even primary treatment of household wastewater. Bigger cities and towns generate about 30 billion litres of sewage daily. Only about a fifth of it gets treated.

Delhi is an outlier in this respect, with the ability to treat 80% of its waste. Yet, according to government data, 24 of the 34 capital sewage treatment plants did not meet standards for wastewater treatment as of 2021. The Yamuna receives most of the mega city’s wastewater.

Despite being among India’s best-equipped facilities for tackling waste, the capital’s sewage treatment plants are not designed for extracting pharmaceutical contaminants. Researchers detected a cocktail of 22 active pharmaceutical ingredients, including metformin, in river water samples collected in the capital region. In the new study, Delhi had some of the world’s highest average concentrations of active pharmaceutical ingredients, alongside Addis Ababa in Ethiopia, La Paz in Bolivia and Lahore in Pakistan.

Studies like those published by Boxall’s team are closing an important gap. The swaths of the planet that have, until now, received the least attention in mapping pharmaceutical pollution – South America, sub-Saharan Africa and parts of southern Asia – turn out to be some of the most affected.

Lagos in Nigeria, the most populous city in sub-Saharan Africa, is another pollution hotspot, with 26 pharmaceutical compounds detected in the Odo-Iya Alaro River. “There are no restrictions on who can open a pharmacy,” explained Charles Obinwanne Okoye, an environmental biologist at the University of Nigeria, “and people can easily buy medicines without a prescription.”

“It is first and foremost a problem of waste management,” Okoye asserted, with sewage treatment systems woefully inadequate in countries where pharmaceutical use is galloping ahead.

A sewage treatment plant in Mumbai, India. Credit: Mongabay.

Early evidence

The same properties that make medications so useful in the targeted organism – humans or livestock – can turn them into dangerous ecological pollutants, especially in waterways where other water users are exposed to them.

Downstream from the Yamuna River in Delhi, people from informal settlements use the water for their everyday needs, including, in some cases, for drinking. They also use the river water to irrigate crops, with pharmaceuticals potentially contaminating the food supply.

Direct exposure can be dangerous for wildlife too. In clinical studies, brown trout (Salmo trutta) display addiction-like behaviour to methamphetamine, commonly known as meth. But fish addiction to illicit drugs is not the only problem.

Certain pharmaceuticals are a subset of a broader class of chemicals called endocrine disruptors, which mimic hormones and interfere with the endocrine system. These chemicals are found in everything from plastic bottles to pesticides, and are used in pharmaceuticals too.

Metformin may also fall into this category. Although the diabetes drug does not structurally resemble classical endocrine disruptors, there is an increasing recognition “that endocrine disruption may occur by mechanisms other than classical endocrine receptor binding.” According to some studies, metformin is capable of producing “wide and unknown changes in fish, mammals and invertebrates.

Scientists found that when the fathead minnow (Pimephales promelas) was exposed to metformin levels equivalent to those occurring in wastewater, male fish showed signs of feminisation, some males were abnormally small, and the drug also impacted fish reproduction. However, other studies did not capture similar effects in the species.

Low dose effects

Some experts maintain that when it comes to endocrine disruptors, larger doses do not equal larger effects. There is no simple one-to-one correlation, they say, between dose size and impacts. Hence, the conventional rationale for determining safe limits for environmental pollutants may not apply to endocrine disruptors. In some instances, lower doses can produce vastly different effects than concentrations studied in lab experiments.

This low-dose effect also manifests in another class of pharmaceuticals linked to antimicrobial resistance. Disease-causing pathogens including bacteria, viruses and fungi can evolve in the human body, and in the wild, to resist antibiotic drugs designed to target them. This chiefly happens via their exposure to medical compounds developed to kill them, with a subset of the surviving pathogen population more likely to be immune to the antibiotic, an evolved trait passed to offspring.

Sulfamethoxazole is an antibiotic and growth promoter for livestock. It’s also a common pollutant. Today, its efficacy is being vastly undermined, with bacterial targets becoming increasingly resistant.

Importantly, toxic levels of antibiotics are not required to produce significant antimicrobial resistance. Even lower doses – like those potentially found in waterways – can give rise to resistance by allowing the microbes a chance to familiarise with and adapt to a threat.

This “silent pandemic” of super bugs is stealthily hollowing out the medical armory of antibiotics built up over decades. A study commissioned by the UK government estimated the death toll from antimicrobial resistance infections could reach 10 million annually by 2050. Antimicrobial resistance is already exacting a devastating toll in India, where health care access is poor. More than 50,000 newborns die every year there from drug-resistant infections.

Livestock are often given sulfamethoxazole as an antibiotic and as a growth promoter. But it’s also a common pollutant. Credit: LHOON via Flickr.

Flying blind

Despite their potential for harm, active pharmaceutical ingredients have thus far remained understudied and underregulated.

“Pharmaceutical pollutants are one example of chemicals of concern that fall outside the scope of existing international treaties that apply to chemicals and waste,” said Mirella Miettinen, a specialist in environmental law at the University of Eastern Finland.

Miettinen is a lead investigator for the SUDDEN project, aimed at curbing ecological risks arising across the life cycle of pharmaceuticals.

Despite the growing awareness of scientists, there is no systematic reporting about the impacts of drugs on ecological health. This is especially true in countries where there is steady growth in pharmaceutical use, combined with poor waste management. But it is not a lapse limited to “pharmerging” economies, as countries like India, China and Brazil are known in the industry lingo.

Boxall says that of the roughly 2,000 pharmaceuticals in use in Europe, ecological effects data are available for less than a fifth. Sweden is a pioneer on this front. The Scandinavian nation set up an environmental classification system for pharmaceutical products in 2005.

The risk-benefit analysis done by EU regulatory bodies during the authorisation of a new medicinal product does not consider environmental risk, Miettinen noted. The US FDA, on the other hand, is empowered to refuse applicants who do not furnish sufficient information about the environmental effects of a new medicine. However, a plethora of approval exceptions means environmental assessments are not the norm for new drug applications.

Experts like Miettinen argue that regulators should always consider environmental impacts when authorising new pharmaceuticals and restrict the use of a medicine that carries with it the greatest environmental risk.

Likewise, excessive prescribing and improper pharmaceutical use needs to be checked. Far more research is also needed into the impacts of individual drugs, and multiple drug interactions, on waterways around the globe.

But even knowing what those impacts are won’t be enough. Take metformin, for example. It’s an essential front-line drug; consumers and health care providers can’t easily substitute a “greener” version for it. To do so, a company would need to find it financially beneficial to produce one that is just as efficacious, safely test it, and make it available – an expensive, lengthy process.

“We need various actions at different levels to tackle the problem,” Miettinen said, including “creating incentives for the development of compounds with improved biodegradability.”

Once medicines enter the market and our bodies, keeping track grows far more complicated.

Regulating pollution at manufacturing sites is low-hanging fruit, and frameworks for controlling industrial waste often include pharmaceutical manufacturers. “The pharmaceutical industry is a heavily polluting industry which is under the Red category,” said Gopal Krishna, an environmental activist based in India. “These are industries which generate hazardous waste.”

Hospitals are well-placed to undertake treatment of active pharmaceutical ingredients before they enter the public wastewater stream. Several active pharmaceutical ingredients removal technologies are currently being tested at hospitals, many in Europe.

But household waste is far trickier to tackle. For more industrialised countries, this means wholesale upgrades to wastewater infrastructure. For less industrialised nations, the process would need to start with waste treatment facility construction – with builders leapfrogging to install cutting-edge water treatment technologies, some now considered too expensive even for richer nations.

Untreated sewage entering a waterway in Mumbai, India. Credit: Mongabay.

Metformin again provides a good example of inherent problems. It is already ubiquitous in the water supply, even in industrialised countries like the UK and US, because conventional treatment methods cannot remove it.

Radboud University Medical Center in the Netherlands partnered with Dutch company VitalFluid to test methods to extract pharmaceutical residues from hospital wastewater. They relied on an advanced oxidation process that increased reactive oxygen and nitrogen. Even then, metformin proved to be a stubborn pollutant to extract.

“Solutions like activated carbon filters or ozone treatments will degrade a lot more pharmaceuticals,” Boxall explained. “The problem is that they are costly.”

Installing such systems at scale will greatly burden taxpayers. More than a decade ago, an upgrade at a single Canadian treatment plant to deal with organic waste and pharmaceuticals cost more than Rs 2,440 crore. This July, the Delhi government approved a Rs 1,855 crore plan to clean up the Yamuna River. Authorities envision using this money to lay down new sewer lines, build 10 new sewage treatment units, and upgrade six existing sewage treatment plants.

Clearly, achieving the goal of fully evaluating and effectively managing the world’s pharmaceutical pollution lies far in the future. Mongabay reached out to pharma majors who market metformin globally, including Pfizer, Johnson & Johnson, Merck & Co and Bristol Myers Squib, but did not receive any responses by the time of publication.

This article was first published on Mongabay.

Also read: Why India must urgently tackle the challenge of multidrug resistant pathogens