Pharmaceuticals in the environment

29 April 2017 - By: Caroline Wood

Pharmaceuticals in the environment

Mummichog group
Mummichog group. Photo: Bent Christensen


By Caroline Wood

These days we seem to have a ‘pill for every ill’ and most of us happily take them or administer them to pets without a second thought. But once released into the environment, these powerful drugs can start to have effects beyond their target consumers.

Unlike some forms of pollution, the issue of pharmaceutical waste has had a low profile up to now – hampered by the limited dialogue between ecologists and ecotoxicologists. At our Annual Meeting this year in Gothenburg, the symposium ‘Effects of pharmaceuticals on wildlife – bridging the gap between ecotoxicology and ecology’ will bring together researchers from traditionally unrelated fields to tackle this. By generating new theoretical knowledge and increasing the evidence base, we can start to make governments and the public aware of the impact our clinical waste is having on wildlife.

A catastrophe in the pipeline?

Toxic effects of pharmaceuticals on wildlife can pass largely unnoticed – until they cause a spectacular population crash. The sudden devastation in Gyps vultures in India certainly brought the issue to the public’s attention: between 1990 and 2007, their population fell by over 97%1 due to lethal ingestion of diclofenac, a non-steroidal anti-inflammatory drug administered to cattle. The drug came into widespread use in 1994, after the Novartis patent on the active molecule ended. Suddenly millions of veterinary doses were being administered each year, including treatments to ease the suffering of dying cattle (due to their religious significance, cattle cannot be euthanized in India). Diclofenactainted cattle carcasses were thus the route by which many vultures were exposed to the drug. “Gyps vultures are particularly susceptible to diclofenac, as it causes necrosis of the kidney tubules and disrupts secretion of uric acid, the main component of birds’ urine,” says Rhys Green (University of Cambridge, UK), whose research helped establish the link between diclofenac use and vulture declines. “Most vultures die within two to three days of exposure and post-mortem analyses typically show deposition of uric acid crystals in the majority of the tissues.” 

Tragedies like these demonstrate the critical need for tighter controls on pharmaceuticals, yet governments and pharmaceutical companies are resistant to introducing changes. No government currently requires pharmaceutical companies to conduct environmental risk assessments for their products. In the case of the Gyps vultures, whilst veterinary use of diclofenac was outlawed in India, the drug is still approved for humans – meaning that it remains readily available to buy. Furthermore, the pro-drug aceclofenac is still available for veterinary use, despite the fact that it is rapidly metabolised to diclofenac in cattle2.

Something in the water

Even when the effects aren’t lethal, pharmaceuticals can still have severe repercussions at the population or even ecosystem level. Aquatic species are particularly vulnerable as they are exposed to drug residues in urine and sewage from humans and treated livestock. Perhaps the most well known are the effects of estrogenic compounds, such as ethynylestradiol containing contraceptives. These alter the normal reproductive endocrine signalling pathways in fish, shutting down egg production in females and causing ovarian tissue to develop in males (known as ‘intersex’ fish). The molecular mechanisms driving this remain unclear, but it is thought that receptormediated estrogen-responsive pathways, as exemplified by abnormal secretion of the egg yolk protein vitellogenin in male fish, play a role. Nevertheless, the problem is clearly increasing: in key areas, such as the Potomoc River basin in the USA, up to 100% of sampled male smallmouth bass can be intersex3. At the Gothenburg meeting, Deborah MacLatchy (Wilfrid Laurier University, Canada) will be  presenting her work on a curious fish that seems unusually resistant to estrogens: “The mummichog or Atlantic killifish (Fundulus heteroclitus) is often the ‘last standing’ fish in case studies of contaminated environments,” she explains. “They can withstand large extremes of temperature and salinity, and also conditions of low dissolved oxygen.” Interestingly, whilst these fish share some responses to estrogens similar to that of other species, such as feminisation of developing fish, the adults are remarkably resistant to the drug’s effects on ceasing egg production, even at much greater concentrations. It’s currently a mystery why this is the case, and one which Deborah and her students are tackling: “It’s been like a mini-detective story!” she says. “We are using an integrated approach linking mechanisms of action at the molecular and physiological levels to whole-organism and population-level outcomes.” So far, her studies have eliminated the possibility that estrogen uptake itself is reduced by the high-saline environments where killifish are found, compared to freshwater environments: “We now feel that a difference in the physiology of the ovarian tissue may be contributing to the exogenous estrogen resistance and we’re planning to present the findings in Sweden.”

Depressing bird populations

The effects of pharmaceuticals are not limited to the physiological, as Kathryn Arnold (University of York) will demonstrate at Gothenburg during her talk ‘Sex, stress and food: Impacts of antidepressants in the environment on birds.’ Although much of the work on pharmaceutical pollution has focused on aquatic organisms, birds are also vulnerable when they feed off contaminated invertebrates. “Every bird watcher will tell you that sewage treatment plants are very good places to watch birds,” Kathryn says. “These tanks teem with maggots, earthworms and invertebrates that feed off pharmaceutical-tainted waste material, making them a reliable food source for wild birds, particularly in winter. We wanted to see the effects of the chemicals they are being exposed to,” says Kathryn. Antidepressants were a prime candidate: in England and Wales, roughly 50 million antidepressant prescriptions are written each year, and around 30% of these drugs pass through the human body completely unchanged. One of the most heavily prescribed, Prozac (also called fluoxetine), is even more active once metabolised. 

Kathryn and her colleagues devised a study to mimic what happens when the birds obtain 50% of their daily food from sewage treatment plants. Wild-caught starlings were kept in outdoor aviaries and fed daily with a waxworm, some of which had been injected with the equivalent amount of Prozac to that estimated in worms from sewage plants. After 16 weeks, the birds exposed to Prozac showed marked changes in behaviour, including a significant reduction in boldness and exploratory activity. More worryingly, the exposed birds also showed disrupted foraging activity. “Humans on fluoxetine often have appetite changes and the drug is even used to aid weight-loss,” says Kathryn. “We found analogous changes in the Prozac-exposed starlings.” In winter, birds follow a general foraging pattern where they have a hearty breakfast first thing to replenish energy reserves, then snack lightly throughout the day to cover their energy needs, without becoming too heavy to escape predators. Then at twilight, another heavy meal helps them survive the long, cold night. Whilst the control group kept to this pattern, the Prozacexposed group did not show any peaks in feeding activity at the start and end of the day. “Under harsh conditions, this could impact whether these birds are able to survive the night,” says Kathryn. At Gothenburg, Kathryn will present her latest results, which indicate that antidepressants can also affect courtship behaviour. “Females in particular seem negatively affected by exposure to fluoxetine,” she says. “They become less interested in the opposite sex and we have evidence that males find females on Prozac less attractive.”

Reality shows

Whilst lab experiments are useful for investigating drug mechanisms, “to get to the core of the ecological effect, we need to validate our findings in more complex realworld situations,” says Tomas Brodin (Umeå University, Sweden), who will describe this further in his talk ‘Ecological effects of pharmaceuticals in the environment – from lab experiments to field studies.’ His research on the behavioural effects of the sedative benzodiazepine on fish demonstrates all too clearly how conclusions made in the laboratory don’t always translate into the field. When young salmon were exposed to the drugs in a controlled indoor environment, their migration speed increased by approximately 50% – potentially a real benefit for survival of young salmon travelling downstream to reach the ocean. But when Tomas and his colleagues released tagged salmon into rivers and followed their progress, they found that the opposite was the case. “We discovered that the control fish actually survived much better than the benzodiazepine-exposed fish, which were eaten by predators such as pike,” says Tomas. “What appeared to be a real benefit in the lab was actually a big drawback in the field.” Tomas has also made use of acoustic telemetry to study the effects of benzodiazepine exposure on schools of wild perch. In this technique, the fish are fitted with unique electronic tags which emit sound waves into the surrounding water. “This gives very high resolution data, and tracks the position of each fish three times a second down to 10 cm accuracy, even in a large lake,” he says. “This means we can follow 200 fish at the same time, and see their relative positions to each other.” In this study, benzodiazepine caused these normally social fish to venture away from their conspecifics and instead spend more time in high-risk areas of the lake that contained predatory pike4. In humans, benzodiazepine binds to GABA-A receptors, changing their conformation to make them more receptive to the neuroinhibitory ligand GABA (γ-aminobutyric acid). As this receptor is present in all vertebrate species studied so far, it’s likely that these drugs act in the same way in fish, inducing anti-anxiety effects. “In some ways, the drug did what it is supposed to do – the salmon became less anxious and their fear of risk was removed,” says Tomas. “But in nature, if you are not scared, you had better be big, or you will end up dead!”

A growing problem

Most pharmaceutical-related research focuses on animals, but evidence is emerging that they also affect plants, particularly during the crucial phase of early development. A study led by the European Centre for Environmental and Human Health at the University of Exeter Medical School and the Petroleum and Environmental Geochemistry Group at the University of Plymouth found that environmental exposure to non-steroidal anti-inflammatory drugs (NSAIDs) significantly affected root and shoot growth in lettuce and radish5. Due to their pain-relieving effects, NSAIDs are prescribed widely for conditions such as arthritis, menstrual pains and migraines. These can enter the environment when they are excreted out of the body, or when surplus pills are disposed of at landfill. “We investigated a range of different common NSAIDs including ibuprofen, diclofenac and naproxen,” says Wiebke Schmidt (University of Exeter), who was involved in the study. “The results showed that NSAIDs can affect various parameters of plant development – including root and shoot development and water uptake.” Strikingly, different compounds had contrasting effects even when their chemical structures were very similar, suggesting that the presence of certain functional groups can be very significant. The addition of methylchlorine groups, for instance, was found to be associated with enhanced root length. The drugs also had drastically different effects depending on the crop species. Diclofenac sodium, for example, suppressed cotyledon opening in radish, but accelerated it in lettuce. Certain NSAIDs even appeared to affect the allocation of photosynthate, resulting in a smaller root: shoot ratio in the plant. “The long-term consequences of pharmaceutical pollution on agriculture and plants in the natural environment is not yet understood. However, as pharmaceutical usage increases, and therefore levels of these persistent compounds build in the environment, this remains a growing concern for the future of food security and sustainability,” Wiebke concludes.

Cleaning up our act

Despite this growing body of evidence, governments and pharmaceutical companies have so far been reluctant to take responsibility to do more to prevent drugs from entering the environment. “We already have the technology to remove at least 90% of pharmaceuticals from wastewater – the real problem is the cost,” says Tomas Brodin. However, there are some notable exceptions: in January 2016, new legislation was passed in Switzerland requiring wastewater treatment plants to implement an additional treatment process to remove micropollutants such as pharmaceutical residues. Many plants are now being equipped with ozone generators to allow ozone-oxidation of wastewater that can remove up to 80% of these harmful chemicals.

Lake Tosktjarn
Lake Tosktjarn



Another approach is to reduce the amounts of pharmaceuticals that get released into the environment. Kathryn Arnold is an advocate of ‘Green Pharmacy,’ where the environmental impact of drugs is taken into account during the decision-making process. “If there are two drugs that are equally effective and no difference in price, the one that is less environmentally harmful should be selected over the other,” she suggests. However, according to Lina Nikoleris (Lund University, Sweden), whose PhD examined the effects of 17α-ethinylestradiol contraceptives on fish, many practitioners are unaware of the environmental effects of the treatments they prescribe. “Most of the nurse midwives I interviewed during the course of my research were unaware that there are environmental issues with all of the hormonal contraceptives, believing that estrogen-free contraceptives, such as those based on progesterone, were environmental friendly,” she explains. “Relying on information from pharmaceutical companies, they also felt constrained because often only certain contraceptives are subsidised by the government, and these tend to be traditional hormonal contraceptives and not the new generation contraceptives which contain natural estrogen and the more easily broken down molecule progesterone.” Of course, some of the burden rests with the public and the need to raise awareness of the continuing powerful effects of pharma drugs after they exit our own bodies. Tomas Brodin offers one suggestion, to take unused drugs back to the pharmacist for proper disposal to avoid them ending up in land-fill, and Deborah MacLatchy agrees: “Pharmaceuticals are amazing products of human ingenuity, and we need to apply that same ingenuity to ensure they don’t make it into the environment and cause more problems than they solve in medicine.”

References:

1. Prakash V, Green RE, Pain DJ, et al. (2007) Recent changes in populations of resident Gyps vultures in India. Journal of the Bombay Natural History Society 104, 129–135.

2. Galligan TH, Taggart MA, Cuthbert RJ, et al. (2016) Metabolism of aceclofenac in cattle to vulture-killing diclofenac. Conservation Biology 30, 1122–1127.

3. Blazer VS, Iwanowicz LR, Iwanowicz DD, et al. (2007) Intersex (testicular oocytes) in smallmouth bass from the Potomac River and selected nearby drainages. Journal of Aquatic Animal Health 19, 242–253.

4. Klaminder J, Hellström G, Fahlman J, et al. (2016) Druginduced behavioral changes: Using laboratory observations to predict field observations. Frontiers in Environmental Science 4, 81.

5. Schmidt W, Redshaw CH (2005) Evaluation of biological endpoints in crop plants after exposure to nonsteroidal anti-inflammatory drugs (NSAIDs): Implications for phytotoxicological assessment of novel contaminants. Ecotoxicology and Environmental Safety 112, 212–222.

 

 

 
Category: Animal Biology
Share
Caroline Wood

Caroline Wood

Caroline Wood was the SEB’s 2014 science communication intern. Since then, Caroline has been a regular contributor the SEB, reporting on events and writing insightful features for our members.Caroline has an undergraduate degree from Durham University in Cell Biology and is currently a PHD student at Sheffield University studying parasitic Striga weeds that infect food crops. You can read her blog here.