“A study explores meth addiction in brown trout, a common fish species found all over the world” (Image: Pavel Horký)

Trout Appear to Get Hooked on Meth
by Christie Wilcox / Jul 6, 2021

“According to a July 6 paper in Journal of Experimental Biology, brown trout (Salmo trutta) can get hooked on ecologically plausible amounts of meth. After prolonged exposure to concentrations seen in nature, the fish chose meth-laced water over water without the drug, a shift that could have ecological consequences if contamination with the drug similarly shifts habitat preference in the wild. Pavel Horký, a behavioral ecologist at Czech University of Life Sciences Prague and the first author on the paper, and his colleagues chose to look at methamphetamine specifically because its use is on the rise globally, he writes in an email to The Scientist, “and where methamphetamine users are, there is also methamphetamine pollution of freshwaters.”

“Drug reward cravings by fish, as was documented in our results, could overshadow natural rewards like foraging or mating that provide homeostatic and reproductive success,” he explains, adding that alterations to water chemistry preferences “could represent another example of unexpected evolutionary selection pressure for species living in urban environments.” “I think this paper is a really important contribution to our understanding of the effects of novel pollutants like illicit drugs on aquatic ecosystems and animals,” says Emma J. Rosi, an ecosystem ecologist at the Cary Institute of Ecosystem Studies in Millbrook, New York, who was not involved in the research. When Rosi and her colleagues set out to write a review of the ecotoxicological effects of illicit substances in the early 2010s, “there wasn’t much to write.” She says she’s thrilled to see more investigation in this area.

Randall Peterson, a chemical biologist at the University of Utah who helped develop a zebrafish model for opioid use disorders, urges caution in interpreting the study’s behavioral results. “I don’t think we need to run out and panic about fish being addicted to methamphetamines,” he says. “I don’t think that is necessarily warranted based on what’s in this paper.” Still, he applauds the experimental setup and use of wild-caught specimens, and says he is intrigued by the behavioral change seen in the fish, adding that the study is a step toward a broader goal of understanding how human waste may affect aquatic ecosystems. To examine the effects of meth exposure on trout, the team collected 120 wild fish from a local fish dealer in the Czech Republic and, after a two-week acclimation period, kept half of them in tanks that contained about one microgram of methamphetamine per liter of water for the next eight weeks. That amount is an order of magnitude less than levels in wastewater discharges in Australia, but 2.5 to 5 times the highest concentrations detected directly in rivers in the US and parts of Asia. The other half resided in untreated tanks.

Then, the researchers put all the fish in drug-free water, and every two days, they offered eight of each group a choice—meth or no meth—by placing them in a special tank where meth-laced and meth-free water flowed side-by-side. The previously exposed fish spent just over half of their time on the meth-laced side, roughly 10 percent more than the unexposed control fish did. This enhanced preference was especially pronounced during the first four days after the fish were removed from the drugged water, and correlated with the amount of methamphetamine detected in the animals’ brain tissue, which was collected shortly after the behavioral test, as determined by liquid chromatography with high resolution mass spectrometry.

“Fish were given the choice of spending time in waters with or without methamphetamine using the dual flow system depicted above (Figure 1B)”

Other studies have found that methamphetamines alter fish behavior, but most have involved water concentrations orders of magnitude higher than in the present study. One October 2020 study, which tested lower amounts, found that medaka (Oryzias latipes) activity levels changed in meth-laced water, but the research didn’t look at whether the fish displayed a preference for waters containing the drug afterward. Rosi applauds the new research: “It was a novel approach with really interesting questions,” she says, adding that she wasn’t exactly surprised by the results.

People use drugs such as methamphetamines because they’re very potent, so it tracks that they can have potent effects on other species, she explains. She says she’s especially excited by the paper because conducting studies with illicit substances is more difficult than with other potential wastewater pollutants. “You can’t just buy illicit drugs and have them in a lab, whereas you can very easily purchase acetaminophen or antibiotics, because those are not controlled substances,” she explains—which is why, in general, the effect of drugs in wastewaters on aquatic organisms is woefully understudied.

Peterson says he was impressed with the experimental setup. “From a technical perspective, their creation of this columnar flow system, where they can essentially create a tank with flowing water where one half has drug in it and the other does not, was really nicely executed,” he explains. He says he’d like to see research on even lower levels of methamphetamine, as based on his read of the literature cited by the authors, he finds it unlikely that a typical river would have a microgram of meth per liter of water, although wastewater discharge might. “When I go fly fishing this evening, which I plan to do, I don’t anticipate that I’ll be wading around in water with anywhere near that much.” Horký disagrees: “I would say that such concentrations are quite common worldwide.”

Peterson also says that while the fish’s preference to be in the drug is “meaningful and interesting . . . it doesn’t give us the whole picture about what’s going on.” Specifically, he notes that some researchers might quibble with the use of the term addiction, which the authors use in their paper, when the results could be explained by simple conditioning, because that’s the condition under which they had been fed and housed for eight weeks. “They’re just choosing to be in a place where there’s drug. That’s not exactly the same thing as self-administration.” The self-administration model Peterson helped develop for zebrafish involves a platform that the fish must swim over to receive a dose. The association between the platform and the narcotic substance is reinforced by a flash of light, and once the behavior is established, researchers can raise the effort required of the fish to get the drug.

“I don’t see any reason why you couldn’t do something like that with trout,” he says. Furthermore, addiction is a loaded word. “Many researchers try to be careful not to use that term. . . . We talk about being conditioned, or to animals self-administering the medication, and not necessarily anthropomorphizing to say that they’re addicted,” he says. Still, he says he found it “really cool that they were able to see this phenomenon in a wild species that might be exposed to these drugs,” and the overall question about how drugs in wastewater affect fish is “very important. . . . I view this [as] a really an interesting paper from that perspective.”

For Horký, the big, open question is how what he and his colleagues saw in the lab translates to ecological effects. He says he’d like to examine how the drug influences habitat choice or other behaviors in the wild. Rosi and Horký both note that illicit drugs are just some of the many pollutants aquatic organisms might encounter. “Fish that are living below wastewater treatment plants are going to be exposed to illicit drugs like methamphetamines and a whole host of other compounds,” says Rosi, including pharmaceuticals and the components of personal care products.

While there are numerous studies in this field, “when you consider the sheer number of compounds that are out there, the amount of research that we have done to understand the ecological effects is pretty small,” she notes. Even more importantly, she points out that ecotoxicology researchers have almost exclusively examined singular pollutants in one or a small number of species, while in the wild, entire ecosystems are exposed to dozens if not hundreds of compounds that may act additively, synergistically, or antagonistically. “We are really, really far behind in trying to understand how these mixtures might have ecological effects,” she says.”

Fish get addicted to meth in polluted rivers, go through withdrawal
by Nicoletta Lanese

“Fish can get hooked on meth that washes into their freshwater homes, to the point that they actively seek out the stimulant, a new study suggests. After being used by humans, methamphetamine enters waterways through sewage systems and discharges from wastewater treatment plants. “Where methamphetamine users are, there is also methamphetamine pollution of freshwaters,” first author Pavel Horký, an associate professor and behavioral ecologist at the Czech University of Life Sciences Prague, told Live Science in an email. Meth pollutes rivers all over the world, with concentrations of the drug ranging from a few nanograms to dozens of micrograms per liter of water, according to reports in the journals Chemosphere and Water. Given the global prevalence of meth in waterways, Horký and his colleagues wondered whether fish might get hooked on these small doses of the drug.

The team’s new laboratory study, published Tuesday (July 6) in the Journal of Experimental Biology, suggests that yes, even minuscule amounts of methamphetamine could be enough to cause addiction in freshwater fish, the team concluded. That said, an expert told Live Science that, even though the fish in the study sought out meth-tainted water, that may not be enough evidence to say they are truly addicted. “I’m not sure you can truly say these fish are addicted to methamphetamine, but they certainly show a preference for the compound … which they shouldn’t, really,” said Gabriel Bossé, a postdoctoral research fellow at the University of Utah who was not involved in the study; Bossé uses zebrafish as a model to study complex brain disorders and recently developed a technique to study opioid-seeking behaviors in the fish.

In regards to the new research, “it seems that the preference for meth dies down after just a few days,” whereas if the fish were truly addicted, he’d expect that preference to persist over a longer period of time, he said. “Whether you call it addiction or not, you can argue, but it’s clear that methamphetamine changed how these animals behave,” and those effects could potentially hinder their ability to find food, avoid predators and reproduce in the wild, Bossé noted. In the new study, the team specifically focused on brown trout (Salmo trutta), which are native to Europe, western Asia and northern Africa and have been introduced to every continent except Antarctica, Horký said. The researchers placed 60 trout in a drug-free holding tank and another 60 in a tank laced with 1 microgram of meth per liter of water.

The researchers had the latter group of fish soak in the meth-tainted water for two months — a step meant to simulate the effects of persistent drug exposure that might occur in a polluted river. The researchers then transferred the drugged fish into a clean tank for 10 days; if the trout had grown dependent on meth, they would begin to show symptoms of withdrawal after losing access to the drug, the team theorized.  To test for these withdrawal symptoms, the team devised an experiment where fish could choose between swimming in clean water or water with trace amounts of meth; the tank is designed such that the two streams of water don’t mix but the fish can still swim between them.

When previously exposed fish showed a preference for the meth-tainted water in the experiment, that was taken as a sign of addiction to the drug, Horký told Live Science. The team ran select fish through this experiment on the second, fourth, sixth, eighth and 10th days after they’d been moved to the drug-free tank; they also ran drug-free fish through the same experiment, as a point of comparison. They found that, in the first four days after the tank swap, the meth-exposed fish showed a stronger preference for drugged water, compared with the fish that had not been exposed to meth. This difference waned the more time the exposed fish spent in the drug-free tank. The researchers also noted that, in general, the meth-exposed fish became somewhat sedentary in these first four days of withdrawal, while the drug-free fish swam about as usual.

This lack of movement hinted that the fish were stressed out due to their meth withdrawal, the authors suggested; scientists have seen similar behavior in zebrafish that were experiencing withdrawal from opioids, according to a 2017 report by Bossé published in the journal Behavioural Brain Research. To get better insight into these behavioral changes, the team took samples of the fishes’ brain tissue and screened them for both methamphetamine and amphetamine, a metabolic byproduct of the drug.

They found that “there were differences in concentration of amphetamine and methamphetamine that were shown to be related to changes in behavior,” Horký said. The amount of amphetamine in the brain, which would indicate a past exposure to meth, correlated with the subdued swimming behavior seen in the trout experiencing withdrawal. Conversely, methamphetamine appeared in the brains of fish that chose to swim in the drugged water during the behavioral experiment; this acute exposure correlated with an uptick in swimming, again hinting that the meth offered relief from withdrawal in addicted fish.

Taken together, these results suggest that, in the wild, brown trout could become addicted to trace amounts of meth in rivers and potentially congregate in areas where the drug accumulates, the authors reported. Such “unnatural attraction to one area” could not only disrupt the fishes’ migratory patterns but also undermine their success in foraging for food or finding mates, they wrote. But again, while Bossé agrees that meth exposure could undermine the fishes’ survival, he’s not fully convinced the animals are addicted to the drug. The authors could strengthen their case with slight tweaks to their current experiment, he noted.

Firstly, they could allow the fish more time to explore the tank with a meth-tainted section; given hours, instead of minutes, as in the current study, the fish might learn where the meth can be accessed and show more persistant drug-seeking behavior. Their preference for the meth-tainted water could even be tested over several days, to see if they consistently gravitate to the contaminated water after being denied access to the drug, he said. In addition, the team could do additional tests to show the animals are truly in a stressed-out, withdrawal state; for example, they could measure the animals’ cortisol levels and run them through formal stress tests, Bossé said.

With zebrafish, these stress tests include observing what the fish do when placed in unfamiliar tanks or tanks with one darkened side, which the fish prefer, and one brightly-lit side. In any case, since the new study was conducted in a laboratory setting, the team still needs to investigate whether the observed patterns of addiction and withdrawal occur in wild fish populations, too, Horký said. There’s also the question of how meth mingles with other contaminants in the water, including other drugs, like antidepressants, and how all these substances collectively mess with fish behavior, he noted.  “There are a lot of contaminants of emerging concern — not only illicit drugs, but also standard prescription medicines, like antidepressants,” Horký said.”

Drugging the Environment
by Megan Scudellari  /  Aug 1, 2015

“In the fall of 2012, PhD student Hendrik Wolschke leaned over the side of a boat on the Elbe River in Northern Germany and lifted a stainless steel bucket from the water’s depths. Pulling it aboard, he set the sloshing bucket next to a pile of empty plastic bottles. Once he’d filled them with the river water, Wolschke packed the bottles into coolers for transport southeast to the chemistry laboratory of his doctoral advisor, Klaus Kümmerer, at Leuphana University of Lüneburg. There, the bottles joined water samples collected from all around Germany: the North Sea, drainage streams from wastewater treatment plants, even drinking water straight from municipal taps.

Each sample was tested for the most widely prescribed antidiabetic drug in the world—metformin, which treats high blood sugar by suppressing glucose production in the liver. Humans do not metabolize the drug, so within 24 hours of being swallowed, metformin is excreted from the body essentially unchanged. Because of its high prescription rate—the U.S. alone dispensed 76.9 million metformin prescriptions in 2014—it’s not surprising that the drug is abundant in the environment. Metformin was present in every water sample Kümmerer’s team tested, including tap water, at concentrations exceeding environmental safety levels proposed by an international Rhine River Basin agency by 50 percent. When publishing the results in 2014, Kümmerer and his coauthors concluded that the drug is likely “distributed over a large fraction of the world’s potable water sources and oceans.”1

That sounds melodramatic, but he may be right, and the problem is not limited to metformin. Rebecca Klaper and colleagues at the University of Wisconsin–Milwaukee recently measured concentrations of pharmaceuticals in Lake Michigan, where researchers had speculated that any drugs that were present would be highly dilute and not detectable. On the contrary, Klaper’s team found evidence of 32 pharmaceuticals and personal care products in the water and 30 in the lake’s sediment. Fourteen of these were measured at concentrations considered to be of medium or high risk to the ecosystem, based on data from the US Environmental Protection Agency (EPA) and other researchers.2 Metformin topped the list, at concentrations of concern even 3 kilometers off the shores of Milwaukee.

Ecologists have long recognized that pharmaceuticals, both unmetabolized drugs like metformin and others that break down into various metabolites, are polluting the environment, but researchers have traditionally focused on just two classes: antibiotics and endocrine-disrupting compounds such as the birth control hormone estradiol. Antibiotics in the environment promote antibiotic resistance in a range of bacterial species, and endocrine disruptors are known to affect development and reproduction in animals. Metformin was not thought to have either of those effects on animals. But in lab experiments conducted earlier this year, Klaper’s team discovered that male minnows exposed to metformin at concentrations comparable to those of wastewater treatment plants produce proteins typically found only in female fish, develop feminized gonads, weigh less, and have fewer offspring.3 The antidiabetic is now one of a growing list of drugs that researchers are realizing pose major ecological problems. “All [pharmaceuticals], by design, are meant to elicit a biological response,” says the US Geological Survey’s Dana Kolpin, chief of the organization’s Emerging Contaminants Project. “We need to know what the environmental consequences are.”

Pharmaceuticals are ubiquitous in wastewater, deposited primarily from human urine and feces. The active ingredients from leftover pills thrown in patients’ trash or even hospital waste also find their way to waterways, but the contribution of those sources pales in comparison to the share “from all of us,” says Kümmerer. Sewage treatment plants remove some pharmaceuticals from water during basic filtering processes, says Klaper, but many pass through unhindered. Metformin, for example, is stable against common water treatments such as UV light irradiation. And at this point, it is prohibitively expensive to add technologies that can filter out these chemicals. From sewage plants and landfills, drugs make their way into streams, rivers, lakes, seawater, and even into drinking water. Currently, however, the EPA does not regulate even a single human pharmaceutical in drinking water. An EPA list of pollutants that may make water unsafe, but are not regulated, includes eight hormones and one antibiotic. Metformin is not on the list. “Legislation is not protecting ecosystems at the moment,” says Kathryn Arnold, an ecologist at the University of York in the U.K., where there are also no regulations for pharmaceuticals in water.

Many ecologists believe that should change. Pharmaceutical use in the general population is growing, with sales expected to increase five percent annually for the next five years, so more and more drugs are likely to be entering the environment. Like so-called “legacy” pollutants that have been banned in many countries, including polychlorinated biphenyls (PCBs) and DDT, pharmaceuticals can persist for years, even decades. Pharmaceuticals are designed to maintain their strength and quality on the long route from manufacturer to pharmacy to medicine cabinet, and even sometimes inside the human body. That same stability, unfortunately, prevents many pharmaceuticals from degrading in the environment. Researchers at Umeå University in Sweden measured concentrations of the widely marketed antianxiety drug oxazepam in sediment cores from the same lake bed deposited over three decades.

Based on the sediment samples, they were able to identify the specific year that oxazepam first came on the market, and the amount of drug deposited in newer layers over the years correlated tightly with the numbers of prescriptions. Then, when the researchers measured concentrations in core samples extracted 30 years ago, they found that the older cores and more-recent samples had the same drug levels at the same time depths. Oxazepam hadn’t degraded at all over time, says study author Tomas Brodin, an ecologist at Umeå. To make matters worse, pharmaceuticals are hard to detect and measure in the environment. Detection methods are improving, however. Early methods used by the US Geological Survey required one liter of water and could identify 15 to 20 compounds, while the latest method measures more than 100 drugs in just a 20-milliliter sample. But scouring for individual agents isn’t enough. Our modern environment contains a swirling mixture of pharmaceuticals, pesticides, industrial by-products, and a plethora of other chemicals. “What’s happening in reality is an exceedingly complex cocktail of compounds,” says Kolpin.

“Estimated dietary intake of pharmaceuticals by two representative invertebrate predators compared to recommended human pharmaceutical doses.”

And within that chemical concoction, drugs interact with one another, with bacteria, and with basic environmental elements such as water. Chemical and biological reactions can result in a host of transformation products—new chemicals with new properties. Some bacteria break down metformin, for example, yielding a metabolite called guanylurea, which is also bioactive and stable in the environment. Similarly, the antidepressant enlafaxine (trade name Effexor) degrades into desvenlafaxine (Pristiq), another antidepressant. Such metabolites can sometimes be more toxic than their parent compounds. “Degradation expands that universe of potential chemicals exponentially,” says Kolpin. At high enough levels, pharmaceutical compounds can be lethal to wildlife. More often, however, drugs have subtle but significant effects on the behavior and development of organisms. Of the drugs that scientists test for in the environment, an emerging class of interest is selective serotonin re-uptake inhibitors (SSRIs), commonly prescribed for depression and anxiety disorders. “These chemicals are psychotropic. In humans they affect cognition, mood, and behavior,” says Melanie Hedgespeth, a graduate student at Lund University in Sweden. “So if they’re out there, they have potential to also affect behavior in aquatic organisms.”

“Proportions of pharmaceuticals in benthic aquatic invertebrates. Relative proportions of major classes of total pharmaceuticals (ng m−2 dry weight) in aquatic invertebrates at each site arranged by decreasing wastewater influence (indicated by δ15N in biofilms; Table 1). Each colour is representative of drug therapeutic class.”

Last year, Hedgespeth analyzed the effects of a popular SSRI, sertraline (trade name Zoloft), which had previously been detected in water samples and fish tissue in the U.S., Canada, and elsewhere. She spiked tanks full of juvenile perch with three concentrations of sertraline: 120 nanograms per liter (a level detected in wastewater), 89 micrograms per liter, and 300 micrograms per liter. After just eight days of exposure, the fish started eating less, even at high prey densities and at the lowest environmental drug concentration, though the effect at that level was “marginal.”4 Hedgespeth hypothesizes that the behavioral change is due to loss of appetite, a recorded side effect of the drug in humans. If such a decline in feeding occurs in the wild, it could impact the reproduction and life span of entire populations of fish, says Hedgespeth. “People tend to focus on mortality, but this could potentially impact fish in the longer term.”

Other research has shown how widespread the ecological effects of pharmaceutical pollutants can be. Every summer from 2001 to 2003, researchers in Canada poured a small amount of 17α-ethynylestradiol, the synthetic estrogen used in many birth control pills, into an experimental lake in northwestern Ontario. They then measured the effects of the hormone on a diversity of aquatic wildlife, including algae, microbes, zooplankton, minnows, trout, and other fish. Over the course of the experiment—the researchers collected data through 2005—the fathead minnow population in the lake nearly crashed due to reproductive failure. The lake trout and white suckers that relied on the minnows for food also suffered, declining in abundance due to lack of food. The minnow’s prey—zooplankton and insects—subsequently flourished.5 “Not only were there direct effects on one species, there were direct and indirect effects on multiple species at different trophic levels within the lake,” says Arnold, who edited the special issue of Philosophical Transactions of the Royal Society B in 2014 on pharmaceuticals in the environment that included the study. “It’s clear there are lots of knock-on effects that are difficult to predict with standard ecological risk assessments.”

Pharmaceuticals can also accumulate as they work their way up the food chain, exposing predators to higher levels than those found in the environment. Brodin and colleagues at Umeå found that while oxazepam had no effect on damselfly behavior, it did accumulate in the insects. And when perch ate oxazepam-riddled damselfly nymphs, the fish retained an average of 46 percent of the drug from the insects. The more damselflies they ate, the more the drug accumulated in the fish.6 In a separate experiment, the normally shy perch that hunt in schools became considerably bolder after exposure to oxazepam, eating more quickly and leaving their schools more often.7 “It was a drastic behavioral modification,” says Brodin. It may be that the drug reduced the perch’s tendency to seek safety in numbers from predation, Brodin speculates. “Perhaps they perceived their environment as less risky.” Interestingly, when no predators were around, the effect was positive for the fish, making them more efficient hunters. But testing such effects in the wild is a difficult thing to do, Brodin notes.

While it is easy to measure whether a chemical is deadly to a species, there is rarely an easy way to tell if it is promoting survival, which can also cause significant changes in an ecosystem. While most studies on the effects of environmental pharmaceuticals have focused on aquatic species, terrestrial organisms such as birds, worms, and insects can also be exposed to the drugs when they feed on sewage, on fields fertilized with human or animal waste, or on the flesh of livestock treated with drugs. In the late 1990s, for example, tens of millions of vultures began dropping dead around India and Pakistan. First, scientists assumed it was an infectious agent, then an environmental toxin. It was neither. In 2004, they pinpointed the cause: an anti-inflammatory drug named diclofenac. The birds had suffered acute kidney failure after ingesting diclofenac from the carcasses of livestock that had been given the drug to treat lameness and fever.8 “Vultures in that region were exceedingly sensitive to diclofenac,” says Kolpin. “That’s a classic example of unintended consequences.”

India, Nepal, and Pakistan banned veterinary use of diclofenac, but in 2013, Spain, home to 95 percent of Europe’s vultures, authorized the sale of the drug for use in animals. Wildlife groups immediately called for a full veterinary ban on the drug, and the European Commission asked the European Medicines Agency (EMA) to conduct a review of the risk of the drug. In December 2014, the EMA concluded that vultures and other carrion-eating birds were at risk from diclofenac, but the European Commission has not yet made a final decision on whether it will outlaw the drug. Meanwhile, many more terrestrial species are at risk from countless other pharmaceuticals polluting the environment. Some 10 to 30 percent of the antidepressant fluoxetine (trade name Prozac) is excreted unchanged by humans, and, like many other pharmaceuticals, fluoxetine is environmentally stable. The University of York’s Arnold estimated the concentration that would accumulate in earthworms living in sewage, and then how much of the drug would make it into a bird’s system if half its diet consisted of such worms. Adjusting for body mass, the total amount was equivalent to roughly 5 percent of a human dose of fluoxetine.9 Knowing that fluoxetine can cause reduced libido and decreased appetite in human patients, Arnold feared birds might suffer similar effects. “That could have big implications on survival,” she notes. Daily for four months, she and her team fed wild-caught starlings wax worms injected with low doses of fluoxetine. Sure enough, the birds that ingested the drug ate less and at all the wrong times: they snacked throughout the day rather than consuming large meals at sunrise and sunset, the optimal mealtimes for wintering birds.9 “If you have a harsh winter, [and] you have an animal not feeding heavily at the start and end of the day, they’re likely to starve,” says Arnold. With more and more examples of the effects of pharmaceuticals on wildlife, researchers are growing increasingly worried about potential effects of such pollutants on humans. “Human health is the million-dollar question,” says Kolpin. “All our environmental research, while maybe not a direct link to human health, certainly suggests that, as we start seeing things that affect aquatic and terrestrial organisms, we should be concerned about human health as well.”

Papers on the ecological impact of drugs have examined only a handful of the estimated 4,000 pharmaceuticals used around the globe in medicine and agriculture. Some scientists argue that we should spend less time identifying individual drugs in the environment and more time trying to prevent them from reaching it in the first place. “We have to think about preventative measures, not wait until the negative effects play out,” says Kümmerer. One option is to outfit wastewater treatment plants with equipment to remove pharmaceuticals. In Sweden, for example, Brodin and colleagues are rebuilding an entire wastewater plant to incorporate ozonation, a process that can remove some pharmaceuticals from water by bubbling ozone gas through it. The team of researchers will then monitor local streams to see how the plant upgrades affect organisms in the surrounding ecosystem. Technologies such as ozonation and nanofiltration are expensive, however, and no one method has been shown to remove all bioactive agents. Therefore, some researchers advocate measures to prevent pharmaceuticals from ever entering the water system, namely by designing drugs that quickly degrade in the environment—“benign by design,” as Kümmerer calls it. After giving a talk at a German cancer research center, Kümmerer was approached by scientists who had made a derivative of the anticancer drug ifosfamide. In the hopes of increasing absorption of the drug in the gut and reducing side effects in patients, the chemists replaced the part of the molecule known to keep the drug stable with a sugar. The chemists realized that the replacement might also make the drug more biodegradable in the environment, and they asked Kümmerer to test it. He found that the derivative, glufosfamide, was biodegradable and still as potent an anticancer agent as the original.10 Glufosfamide is currently in a Phase 3 clinical trial for metastatic pancreatic cancer.

Pharmaceutical companies can and should use such “green” chemical techniques to design drugs that biodegrade quickly in the environment, says Paul Anastas, director of the Center for Green Chemistry and Green Engineering at Yale University. “For not just pharmaceutical chemists, but for all chemists, whenever we know things are going into the environment, we have an obligation to make sure they are as least toxic as possible.” There is nothing inherently difficult about doing so, Anastas adds. “It’s all about just controlling properties to get the function you want. That is simply another design challenge.” And it shouldn’t be hard to convince companies to manufacture drugs to be greener, he says. “Nobody purposely designs a substance to be toxic in humans or the environment. There is just a lack of awareness of what’s possible.” But until drugs are truly environmentally friendly, research into their distribution and effects carries on, says Kolpin. “Over the next five years, we’re going to have a much better understanding of the bad actors out there.” 


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