Welcome & Introduction

Alexandra 0:15

Pharmacovigilance scientists are primarily concerned with the safety of medicines and vaccines in treating a patient. But what of the medicines that end up in our environment through other means? My name is Alexandra Coutinho, and this is Drug Safety Matters, a podcast by Uppsala Monitoring Centre where we explore current issues in pharmacovigilance and patient safety. Joining me today are Valentina Giunchi, a biostatistician at Uppsala Monitoring Centre, and Joe Mitchell, affiliated researcher at Karolinska Institute and lead safety surveillance advisor at ALK Abello. Our discussion centres around the One Health approach, which recognises that environmental, animal, and human health are inextricably linked. So inextricably, in fact, that pharmacovigilance scientists can no longer afford to overlook it. I hope you enjoy listening.

Alexandra 1:08

Hi Valentina and Joe, and welcome to Drug Safety Matters. Before we get started with the questions, how did you both become involved in ecopharmacovigilance research, and what is your particular focus?

Valentina 1:32

Actually, it was a bit by chance. After my master's in biostatistics, I wanted to go on with a PhD in the health medical area, applied to statistics. And I found a PhD position back in Italy using statistical methods to study the concentration of medicines in surface water, that are rivers and lakes. And I found it interesting and I applied for that PhD position. So let's say that uh before the PhD, I was not aware that medicine could have caused harm to the environment and so on. I just read a PhD ad and applied for that and became passionate about that.

Alexandra 2:19

Fantastic. Okay. And how about you, Joe?

Joe 2:22

My interest in this world started when I started with my master's in global health and I did a course on antibiotic resistance. And then my thesis was also on the topic and more specifically looking at the interlinkedness between humans, animals, and the environment when it comes to antibiotic resistance. And then when I moved to work in PV, it sort of felt natural that I would take that sort of, okay, how does this affect the environment when looking at PV in general?

Alexandra 2:52

And this serves as a great introduction to a number of topics that we're going to cover a little bit today in our interview.

Where medicines show up in nature and why it matters

Alexandra 2:58

Pharmacovigilance is usually concerned with side effects we may experience because of taking or being administered a medicine or vaccine. However, we are exposed to medicines every day through our environment, just as you both were mentioning. Where in the environment have traces of medicines been found, and why should this be a concern for pharmacovigilance scientists? Why don't we start off with you, Joe?

Joe 3:23

More or less, medicines can be found everywhere. Traditionally, people would think about groundwater, which is freshwater sources within the land, or it could also be within seawater, drinking water, it's even found concentrations within soil, and then also that when we grow crops or grow animals that interact with that soil as well, they can also be uptaken and accumulate within those crops and animals that are exposed there too. And similarly, it can have the same effect with us.

Valentina 3:51

I would like to add that usually in the environment like the exposure of wildlife to medicine is not something accidental or rare, but it's something continuous and widespread that occurs at low concentration over a really long period of time. And if I have to think about pharmacovigilance perspective, I think that this challenges a bit the focus we have in traditional pharmacovigilance because it's shifted from individual patients to a broad environment, a broad ecosystem, that needs us to broaden a bit the perspective.

Diclofenac and vulture population collapse

Alexandra 4:30

The impact of medicines on the environment really gained traction after the collapse of the vulture population in India and Pakistan, I think, in the early 2000s. So, what exactly happened and how are the two linked, Valentina?

Valentina 4:46

So in the early 2000s, researchers observed a dramatic and rapid collapse of vulture population in India, with some species declining up to 90% of the population. It was discovered that vultures feeding on carcasses of cattle were exposed to diclofenac, that is a non-steroidal anti-inflammatory drug, administered to livestock for veterinary purposes, so to treat them. So this exposure caused acute kidney failure in vultures that led to their death. This case was quite a turning point because it showed that medicine designed for one species and considered safe and effective for them could have had a negative impact on another species, another ecosystem when released to the environment. So, as a consequence, this also led to regulatory action, like for example, in India or other countries, diclofenac for animal use was restricted and alternative of medicine were proposed.

Alexandra 5:54

And the story is such a striking example of how human, animal, and environmental health are linked. Joe, are there any other examples of such connections?

Joe 6:06

Yeah, I'm gonna come back to antibiotic resistance, antimicrobial resistance, as I'm sure I will do several times. But here we can see that the actual antibiotic resistance itself and the antibiotic resistance genes can travel not only in between the different bacteria that are within these different areas, but they can also spread between humans, animals, and the environment itself. So you can see that there is a similarity between the antibiotic resistance patterns between these three areas, but there's been cases where you've traced the gene itself moving, and you've been able to attribute it from one of these sources to the human, for example. It's been proven that it can move between all of them, humans, animals, and environment, freely.

What is ecopharmacovigilance?

Alexandra 6:49

So we move on to one of the first terms that we perhaps need a definition for, and that defines this particular area of research. That is ecopharmacovigilance. So, what is ecopharmacovigilance and what are the similarities and differences between this and pharmacovigilance? What are your thoughts, Joe?

Joe 7:08

Ecopharmacovigilance is a twist on traditional pharmacovigilance, in so much as when we think of pharmacovigilance, I'm not gonna do a full quote, but it's along the lines of the science of adverse events, and it's intuitively looking at humans as the subject, and then when we look at veterinary, it's looking at animals, but then for ecopharmacovigilance, there is a twist added there that we are looking at the impact on the environment and those who come in contact with the environment. So it differs in lots of ways from pharmacovigilance. Pharmacovigilance would typically rely on a patient and a healthcare professional interaction, and this occurs due to a monitoring of the use of a medicine. So the patient knows they're taking the medicine, the healthcare provider knows they're taking the medicine, but when it comes to exposure within the environment itself, it's unlikely that either the patient who's experienced the adverse event, or the healthcare professional that they are in contact with, would know that they've been exposed. So it requires a very high level of suspicion from either to be able to put these two together. It feels quite disparate. And then also on top of that, when people are exposed to medicines in the environment, you typically say that they could be exposed to not just one medicine, but to several medicines, or it's been quoted as a cocktail of medicines. And so, how do you then differentiate which one of these medicines may be causing these adverse events if you have that suspicion in the first place, which is a difficult step to take. Rather than having a well-regulated known exposure, you end up having an unknown exposure, a lack of suspicion from both parties. And then even if there is a suspicion, you still are going to find it hard to narrow it down to what may be the causative agent.

One Health and its connection to ecopharmacovigilance

Alexandra 8:53

So, understanding now the interconnectedness of seemingly unrelated health sectors, what is the One Health approach and how can it be used to help us with exactly these problems?

Joe 9:06

One Health is the recognition that human, animal, and environmental health are interlinked and interdependent on each other. So it's a recognition that if you wish to address one concern within animal or human health that you also need to consider and act in accordance with the other parts as well. And so it sort of inherently requires this multi-sectorial collaboration and interventions to ensure that you can fully address the problems, or else you just push the problem to one side and then it can re-enter from another path.

Alexandra 9:37

How is ecopharmacovigilance then connected to the One Health approach framework, Valentina?

Valentina 9:43

Eco pharmacovigilance fits into the one health approach framework by acting as a bridge between medicine use and its unintended effect on human, animal, and environmental system. While One Health approach provides an overall perspective that these domains are interconnected with each other, ecopharmacovigilance contributes with concrete methods and evidence to understand how medicine used in one sector can have an impact or can lead to an exposure and effects in another sector. So, in other words, I think that ecopharmacovigilance helps to operationalise the One Health approach in the context of medicine by monitoring, anticipating, and informing decision around the risk that otherwise could remain outside the traditional pharmacovigilance approach.

Alexandra 10:40

So bringing some of that pharmacovigilance regulation to such an unregulated research area, I guess. Yeah.

The One Health approach and AMR

Alexandra 10:48

And the One Health approach has already been applied to address antimicrobial resistance, which is your forte, Joe. So how was it applied and what was the outcome?

Joe 10:57

I think antimicrobial resistance is really one of the main areas where One Health has gained traction. So dating back to 2015, there was a joint global action plan from the World Health Organization, the Food and Agricultural Organization, and the World Organization for Animal Health. They came up with a plan as to how we can combat and try contain antimicrobial resistance. As a part of that, they've stated that they see antimicrobial resistance as a One Health problem that requires One Health intervention. It requires One Health and integrated surveillance. And as part of that, they've actually expanded this tripartite to a quadripartate. And now the United Nations Environmental Program is also sitting on this collaborative board together and coming up with future plans and future surveillance methods. But these integrated surveillance programs where they used antimicrobial resistance in these different fields and then interplay and work together to try and come up with a plan to reduce the exposure and the need for antibiotics and try and make sure the antibiotics don't overlap between these groups. They've shown that it can play an important role in reducing or at least stopping the increase in antibiotic resistance. It's not universal, in so much as not every country is able to have an integrated surveillance program as it is. And there is a tendency still that human health will take up most of the role here, most of the research and headlines. But then it does require, and having this in paper from these organisations shows that there does need to be a recognition that you need to invest and you need to spend time looking at animal and environmental health too.

Alexandra 12:35

I think I had read somewhere about, so in terms of antimicrobial resistance and pharmacovigilance at the very least, incorporating better terminology in databases, right? Or creating a AMR database, is that correct? Or did I misread that, Joe?

Joe 12:52

That is not something I've come across.

Alexandra 12:54

Okay.

Joe 12:55

I mean, there's a, in terms of not a new database, but there is a way of searching for antimicrobial resistance cases or potential cases within these databases, and then using that as a trigger to stimulate further intervention if required. Again, this is usually going to be very location dependent and it's not tested out within many locations, if any locations, and it does require using data beyond pharmacovigilance as well. It's not a solution pharmacovigilance can solve by itself. It needs to be integrated with these other data sources, such as the laboratory data and the usage data as well, which is traditionally missing from PV data.

Alexandra 13:35

Okay, great. Thank you for clarifying.

The One Health approach to drug utilisation and other therapeutic groups

Alexandra 13:38

Valentina, last year you co-wrote a paper on environmental sustainability as an essential component of rational drug use. How can the One Health approach help solve issues with drug utilisation and the increasing concentration of drugs in surface water?

Valentina 13:55

In the paper, we argue that environmental sustainability should be considered an integral part of the rational drug use. This is where the One Health approach becomes particularly useful. From a One Health perspective, decision about which medicine are prescribed, in what quantities, and for how long they are prescribed, are not only clinical decisions, but also decisions with downstream environmental consequences, especially for surface water, where many pharmaceuticals end up after their use. So applying the One Health approach helps to shift the focus upstream toward a more appropriate prescribing, avoiding unnecessary treatment, optimising doses, and considering environmental impact alongside the effectiveness and safety whenever possible. At the same time, applying the One Health approach to rational drug use encourages better integration across sectors. So it could allow to link drug utilisation data, environmental monitoring, and regulatory decision making, so that increasing concentration of medicine in surface water are not seen as an isolated problem, but as an outcome of practices across human, animal, and the environmental health system.

Alexandra 15:19

And coming up with a more rational use of drugs will also help address antimicrobial resistance within pharmacovigilance as well, right? Not only will it have an impact on the environment and animals as well, but a problem that is quite inherently big in pharmacovigilance too. So it has been suggested that One Health be broadened beyond antimicrobials to include other therapeutic groups. What are they and how will they help counteract the negative effects of pharmaceuticals in the environment?

Valentina 15:50

Yeah, yeah, that's true, because traditionally the One Health approach discussion around medicine have focused mainly on antimicrobials because of antimicrobial resistance. However, there is a growing recognition that this perspective should include other therapeutic groups that are widely used, environmentally persistent, or biologically active at low concentrations. That are like main key points when you evaluate the environmental harms. Because if a substance is really persistent in water, it means that it cannot be degraded in a short time, but it stays in the water for a longer period of time. And so it's more concerning than others.

Alexandra 16:32

So having more of like a routine monitoring of groundwater and water.

Valentina 16:36

Yeah, yeah, that's that's a possible action that you can do. But coming back to your question about some examples of therapeutic groups, I think one is hormones, such as estrogens, that can disrupt the reproduction in aquatic species. Especially, it has been observed that estrogens can lead to the feminisation of male fish, altering the biological chain. Another therapeutic class of environmental concern are non-steroidal anti-inflammatory drugs, like has been illustrated by the diclofenac vulture case. There are also antiparasitic drugs that are mainly used in animal vet medicine, which can affect the organism and the ecosystem functioning in general. But we can also consider medicine with climate impacts, which contribute indirectly to environmental and public health risk through greenhouse gases emissions.

Alexandra 17:39

Right. And that is something that Joe will speak a little bit more about later in our interview.

Challenges to studying long-term environmental effects of drugs

Alexandra 17:44

From your experience, what are the main data and methodological challenges in studying the long-term environmental effects of medicines, especially compared with traditional pharmacovigilance? Let's start with you, Joe.

Joe 17:57

For me, I think from the work I've done is how to identify the adverse event. So when you're looking at an adverse event when it comes to ecopharmacovigilance, you're thinking either something that's occurred to a person or an animal due to their exposure to these products in the environment. As I've said earlier, it's very difficult to establish this relationship. And then on top of that, there's no uniform way of reporting that or where to report to. So how and where do you collect that data? But then on top of that as well, is that a sufficient end point that we want to be looking at? Should we also be looking at how are these medicines impacting the environment itself? I know that is within some people's definition of ecopharmacovigilance, and again, how do we monitor that? How do we collect data on that in a way similar to what we do in pharmacovigilance? Because there is no way currently, if we want to, then we need to think of new and novel ways to find and store these information so the data can be analyzed.

Valentina 18:55

Completely agree on that. And maybe I can share another corner of ecopharmacovigilance, since my PhD was actually focused on surface water. When I started the PhD, so working both on eco pharmacovigilance, on surface water, and on pharmacovigilance, so the traditional one, I understood that they were quite different topics, and also the data source and the methods to use were substantially different. So in classical pharmacovigilance, we usually rely on well-defined data sources, such as adverse event reports or clinical data, and we can often link an exposure to an individual outcome. Instead, when we look at the effect of medicine in surface water and on aquatic wildlife, exposure was much more diffuse because it's a chronic exposure, widespread, and that typically occurs at very low concentration over a long period of time. So in eco pharmacovigilance on the water perspective, we often have information from laboratory study on toxicity threshold. They are usually synthesized in a measure that is the predicted no -effect concentration, shortened as PNEC, that basically says that these thresholds are the specific threshold for some aquatic species. However, translating this threshold into the understanding of what is actually happening in the real aquatic environment is not very easy. One major challenge is the data availability, because to assess the risk, we need to know how concentration of medicine in surface water change over time and over space. And for doing this, we need environmental monitoring. So someone that sample the water and say, "oh, there is this concentration of this medicine". However, the problem here is that this environmental monitoring of rivers and lakes is often limited by the feasibility and the cost, because it's pretty expensive to do a lot of monitoring, and results in few location monitored and also not so frequently, and also the number of substances to be limited. So certain areas of the world are usually not monitored or with really few sampling, but also if we go, let's say, to Western country, we don't have many frequent sampling and also for a limited set of substances. So these limitations create the need for an indirect estimation approach. For example, drug utilisation data can be used to predict environmental concentration, but these require completely different methodologies compared to traditional pharmacovigilance. These include geospatial and temporal models that account for river network, water flow, and the location and performance of wastewater treatment plants. Because human consumption is basically the major source of pharmaceutical entering into surface weather, and so it becomes essential to understand how wastewater systems are organised, how they connect to surface water, and how effectively substances are removed in a wastewater treatment plant. Let's say that the additional complexity in this estimation model framework comes from other sources of emission because drugs traditionally can be the major one, but not the only one. Like, for example, animal use, but also industrial discharges, like for example, of industry producing medicine.

Alexandra 22:53

I was curious when you spoke about how it can be hard to do routine monitoring of water and surface water, groundwater. It got me thinking about wastewater treatment plants. I would imagine that as part of the filtering process, surely wastewater treatment plants are measuring levels of different additives in water to ensure that they are appropriately filtering out what we don't want, right?

Valentina 23:23

Not exactly. Let's say that the most common wastewater treatment plant, at least in Europe right now, are not targeted to remove medicine. So they are done for removing some chemical substances, but not for medicine. They can filter out medicine, but they were not projected to do them. There are some case studies that are developing medicine-targeted filters, and they are mainly focused on oncological drugs. I think we never mentioned them before. Oncological drugs also have disrupting effects on the ecosystem. They are less used than other types of drugs, and they are often used in hospital settings. Not necessarily, also at home, but some of them in hospital settings. So they have a high disrupting effect in the environment, but they have a lower consumption rate because of the disease. There are some really interesting studies that are trying to apply these removal filters in the hospital wastewater treatment plant, so targeting some oncological structure, cancer structure, and they actually can remove. What's limiting the widespread adoption is that they are really expensive. To project them, to apply them, requires a lot of funding, a lot of investment. But yeah, we are going towards that.

Alexandra 24:51

Yeah. Yeah, exactly. It takes us actually quite smoothly into what can be done to reduce the effects of medicines in the environment on animal, human, and environmental health.

Solutions for reducing the impact of medicines on the environment

Alexandra 25:02

In my foray into ecopharmacoviligence research, I encountered the term green pharmaceuticals. What are they and how do they reduce the concentration of medicines in the environment?

Joe 25:14

So green pharmaceuticals or green pharmacy is a term that is generally applied to the methods for the production of medicines or the use of medicines to reduce their environmental impact. So specifically, when we're talking about the impact of these products within the environment itself after use or after production, then you would be looking at how long do these medicines and their products stick around, do they degrade readily into harmless products or they environmentally persistent particles, which is a larger concern, of course. But the term green pharmaceuticals actually includes right from the design of these medicines to the manufacturing packaging and use of these medicines to sort of what can be done to reduce the environmental impact. It also includes green prescribing. So as we've mentioned earlier, inhalers cause the release of greenhouse gases when they're used. This is also true for other medicines too, and there are often other usable solutions that can be done instead of using these medicines that have this greater impact. For example, if you look at an aesthetic agent, sevoflurane is known to have a higher carbon footprint compared to other medicines. One way of reducing that is that you can use machinery and tools to recapture the medicines, but also there can be prescribing practices where you choose not to prescribe sevoflurane if there are other medicines that will work. sevoflurane medications can be used instead, which have a lower carbon footprint, and it's led to examples of sevoflurane being less used and actually banned in some instances if we look at NHS Scotland to not be used if possible.

Alexandra 26:57

Yeah, I read about that incident. I had no idea that inhalers contributed to greenhouse gases. So which other solutions would have the most impact on reducing environmental exposure to medicines?

Valentina 27:10

Beyond individual behavior, the solution with the greatest impact are those that act upstream across the full life cycle of medicine. While a key area is prescribing and drug utilisation, so reducing unnecessary prescription, optimising doses, and choosing alternatives with a lower environmental impact when clinically appropriate, can reduce the amount of medicine in entering into the environment. As discussed before, another important solution is wastewater management. Conventional wastewater treatment plants are not designed to remove pharmaceuticals, so targeted upgrades combined with prioritisation of substances can make a difference. I think another topic that can lead to solution is also broadening the regulatory and research perspective. So to integrate the environmental consideration more systematically into drug development and approval processes, but also improving environmental risk assessment and encouraging the development of medicines that are degradable in the environment. Finally, I think that better data are essential, so strengthening ecopharmacovigilance by combining data utilisation data, predictive models, and environmental monitoring, and possibly many other sources can help identify priority and guide intervention where they could have the greatest impact.

How the public can help

Alexandra 28:47

You mentioned what as experts can do and as pharmacovigilance scientists can do to reduce the concentration of medicines in the environment. The public can also help address this issue by knowing how to dispose of medicines properly. So, how can I, as a taker of medicine, dispose of expired medication so that it doesn't end up in the environment? How about we start with you, Joe?

Joe 29:11

So I think this depends more or less on your location. So different countries have different ways of dealing with this. So perhaps the safest catch-all answer would be to take the medicines back to your pharmacy and talk to your pharmacist about what can be done in your location and how can they safely be removed. In general, don't throw medicines down the sink. If you've applied cream, it's more effective to wipe off the cream and then put the wipe in the bin as opposed to wash your hands directly to wash off the cream. But as I say, it is trying to avoid direct release of these pharmaceuticals into the water systems primarily, but it depends a little bit on where you are as to what more can be done.

Valentina 29:53

Yeah, yeah, I agree. I think the main important point is that medicines should never be disposed by flushing down the toilet or pouring them into the sink, unless this is explicitly stated in the product information. Because these also lead directly to the wastewater system that often they don't remove the medicine and so they go in the water. So I think if you or someone is unsure what is the correct option where they live, because they can change by country or by area sometimes. The safest advice is to ask the pharmacist who can explain the disposal pathway available locally. Beyond disposal, the public can also help not stockpile medicine, following prescription carefully, and discussing with their healthcare professional whether a medicine is still needed. So, in my opinion, a small individual action may seem modest, but at scale they can contribute to reducing environmental exposure.

Alexandra 31:01

Definitely.

One key takeaway from the guests

Alexandra 31:04

So that brings us to the end of the episode. So before we do finish, if you could emphasise one key takeaway for listeners regarding ecopharmacovigilance and One Health, what would it be?

Joe 31:17

 Mine would be to reiterate what One Health is and what it means. And it's just a recognition that humans, animals, and environmental health are all interlinked, and we need to work together to ensure that we all experience the best health we can.

Valentina 31:33

I think for me is that the effect of medicine don't stop with the patients. But eco pharmacovigilance and the One Health approach remind us that medicine can move through the environment and affect ecosystem, animal, and ultimately human health. Addressing these requires looking beyond individual use and adopting a more preventive system-level perspective across the entire life cycle of medicines.

Alexandra 32:04

Yeah, and in all my research into this episode, I really came to think about the One Health approach and this interlinking between animal, humans, and environmental health as a health ecosystem. So much like we have an ecosystem, you know, in the environment, we have an ecosystem regarding the use of medicines, the disposal of medicines, and how every different health sector is impacted by medicines. With that, I want to thank you both for making yourselves available to talk to me today and for shedding light on such an important topic. Thank you both very much.

Valentina 32:38

Thank you very much for organising this.

Joe 32:41

Yeah thank you for having us.

Closing, resources, and credits

Alexandra 32:47

That's all for now. But if you want to know more about One Health and ecopharmacovigilance, we've collected some useful links in the show notes. If you enjoy this podcast, don't forget to subscribe in your favorite player. And if you have an idea or any other feedback for the show, you can now send us a text by clicking the top link in the show notes. It's anonymous and we'd love to hear from you. We'll be back soon with another episode. But until then, visit our new site Uppsala Reports at UppsalaReports.org for more pharmacovigilance stories. And if you want to learn more about Uppsala Monitoring Centre and how we promote safer use of medicines and vaccines globally, then visit our website or follow us on social media. You'll find us on Facebook, LinkedIn, X, and Blue Sky. For Drug Safety Matters, I'm Alexandra Coutinho. I'd like to thank Federica Santoro and Frederick Bronus for production and post-production support, and of course, you for tuning in. Till next time.