Transcription

• Adam Elwan - Host, ECHA

  Safer Chemicals podcast. Sound science on harmful chemicals.

• Tomasz Sobanski - ECHA

  All three partners are very well integrated with various European projects, which are aiming at developing the methodologies related to phasing out animal testing. So having them, it's like having almost European community working for us.

• Sylvia Escher - Fraunhofer Institute

  We discussed a lot about pragmatic solutions, so we are not aiming to have the one and only most sophisticated model in the end that nobody can actually fill in this data because it's so over-complex. We are aiming at something very pragmatic.

• Adam Elwan - Host, ECHA

  In today's episode, we're exploring how new approach methods are shaping the future of chemical hazard assessment and regulation, especially in light of growing commitments to replace animal testing. This shift away from animal testing has been making waves in the regulatory landscape for years. Recently, the European Chemicals Agency took a significant step by commissioning a project of 4.2 million euros aimed at developing advanced NAM-based tools. The project aims to improve the way we identify and assess hazards, particularly for complex chemicals like polymers and nanomaterials. This and other similar EU-level initiatives reflect a growing focus on combining scientific innovation with regulatory advancement, ultimately to ensure the safer use of chemicals across Europe. Now, today's discussions will be focusing on how ECHA and the research community can support and contribute to this work. I'm joined by Sylvia Escher from Fraunhofer Institute and coordinator of the project. Also with me is Tomasz Sobanski from ECHA, who will guide us through the goals, challenges, and we'll be also talking about potential impacts of this important work. Now, I know there's a workshop ongoing as we speak on laying the groundwork for this project. So first of all, I'd like to start by thanking you both for taking the time to join me here in the studio. Maybe if we then start with you, Sylvia, could you briefly introduce yourself and the consortium?

• Sylvia Escher - Fraunhofer Institute

  Yeah, thanks a lot. So my name is Sylvia Escher. I'm working for Fraunhofer Institute for Toxicology and Experimental Medicine. And it's my pleasure to coordinate this project in which we teamed up with two other partners. One is Michabo Health Science from the UK led by Mark Weyand and the other partner is BASF Metabolome Solutions from Germany led by Henneke Kamp. And in this project, we are actually interested to promote the integration of new approach methods into risk assessment and therefore we are very glad to work together with ECHA on this exciting topic. And here we have all three different complementary expertises. So Mark and Henneke, they are mainly working on the integration of metabolome and transcriptome data, which means we are integrating data that tell us something about mechanisms leading to toxicological findings. And ETEM is also working on these transcriptome data, so gene changes, actually. And we are also interested into learning more about the kinetics, which means the absorption, distribution, metabolism, and excretion of compounds into the human organism.

• Adam Elwan - Host, ECHA

  Thanks for that, Sylvia. So it sounds like there's a really strong collaboration between your team and the partners from the UK and Germany that you mentioned, with kind of each group bringing a unique perspective to the table. It's interesting also that you're focusing on both the molecular data and the kinetics side of things. So understanding how these compounds are absorbed and processed in the body is definitely a big challenge, but a necessary one. Could you tell me a little bit more about the importance of collaboration and how you manage it between such a diverse set of partners?

• Tomasz Sobanski - ECHA

  So basically what we set up is the so-called scientific framework contract, which basically set up the time that for the six years, we have the possibility to define small projects and through those projects we can tackle some specific issues which are of regulatory relevance or scientific relevance from our perspective. And then the consortium is meant to work on it. And actually the first three projects, which we already started December last year, are very good example of this kind of issues which are of high regulatory concern. From our perspective, we are very happy to have this consortium with our main contractors because they are not only great scientists, not only with complementary skills, but as well they are very nicely representing the European scientific society with whom we want to have a dialogue. So basically all three partners are very well integrated with various European projects which are aiming at developing the methodologies related to phasing out animal testing. So having them, it's like having almost European community working for us.

• Adam Elwan - Host, ECHA

  I mean, you've got these experts who are deeply involved in European initiatives. So I guess that must give the project quite a solid foundation and also make sure that what you're doing is relevant not just to ECHA, but to the broader regulatory landscape, which I think is important. So what is the work involved so far and what are the first topics the project will be working on?

• Sylvia Escher - Fraunhofer Institute

  We have three projects to work on. And the first topic is that we would like to develop a guidance document for omics sampling from in vivo animal studies and Mark is leading this activity. And the aim is to introduce possibility for measuring molecular biomarkers to a wide range of tox tests, which are already planned and requested by the regulator. So we are not aiming to do any extra animal studies, but we are, so to say, making the best out of already existing approaches. So this is also in the benefit of the reduction of animal testing.

• Adam Elwan - Host, ECHA

  That guidance document you're working on, I guess, will be... very important for ensuring that researchers know, first of all, how to collect and then, second of all, handle these new types of molecular data. So it's really about making the current tests more efficient, more insightful, and without adding to the testing burden.

• Tomasz Sobanski - ECHA

  Yes. So basically, the guidance is to allow CROs, so the contract research organisations, which are normally the place when you are conducting the animal studies, or any other studies, because actually we are not only limited to in vivo studies we are as well aiming and introducing those measurements to the other regulatory testing also in vitro. And basically the idea is to give them clear instruction how they should collect and preserve the samples to make them suitable for different type of omics analysis, so to generate properly the molecular data, because that's the starting point for any further discussion on how you can use them in the regulatory context.

• Adam Elwan - Host, ECHA

  That makes a lot of sense. So the idea of giving organisations kind of clear instructions on how to handle and store samples for omics analysis really speaks to the kind of practical side of this work. So it's not just about the science, but actually really making sure that people on the ground, those running the tests, can actually then implement these methods in a way that regulators can also use. Now, you mentioned the three first projects, but I suppose there's also some kind of prioritisation going on and you're looking at certain focus areas that you think will have high impact. In terms of what areas research should be focusing on, can you talk a little bit more about these projects and any future ones that you've already considered as being of high relevance?

• Tomasz Sobanski - ECHA

  First of all, all of those three topics were the topics which we already discussed last year during our NAM workshop. If you remember, we had those discussions of how to demonstrate that what we can already achieve with different new approach methodologies already now without changing anything. And we identify that basically there are certain elements which we have to cover to have this more successful demonstration of those methodologies, which is exactly the ability to generate this omics data from the normal regulatory testing. This is what we already discussed about the omics sampling project. The second is about using molecular data. So applying, basically utilising those data in read-across and category buildings because read-across is the most common adaptation used by our registrants. At the same time it is the which is most often failed by us during the compliance check because basically there is no strong... basis for building the hypothesis for those read acrosses. So we want to really use this molecular data to strengthen those hypotheses. And the third one is about toxicokinetics and especially the role of the toxicokinetics in doing in vitro to in vivo extrapolation. So then how you can extrapolate the results from the in vitro test to the in vivo situation that you know it can inform the hazards for the general population or for environment later on.

• Adam Elwan - Host, ECHA

  Just for the benefit of our listeners, can you explain briefly read-across adaptations? So what does that involve exactly?

• Sylvia Escher - Fraunhofer Institute

  So read-across means that you want to avoid animal testing and you use existing data from other compounds to predict the toxicity of a compound that you don't yet know. So you predict or infer its toxicological properties. And now with the new approach methods, we have the opportunity to also support this reading across by showing some evidence on a shared mode of action. And here we need the new approach methods because they are generating this mechanistic understanding. And this is, so to say, our chance to really get this read across better. And also with the kinetics in the third project, we can also not only show a shared mode of action, but we can also show shared kinetic properties. So the compound is actually Having the same bioavailability or show a similar trend when it's absorbed and then you have taken it in, like you have already ingested it or you have inhaled it, it was on your skin and somehow it penetrates into your organism.

• Adam Elwan - Host, ECHA

  Thanks for breaking that down, Sylvia. So essentially, Read Across lets you predict the effects of one chemical based on data from another similar one, right? And these new methods are helping you add more confidence to those predictions, by understanding the biological mechanisms that are involved. So that's quite a big step forward. You mentioned the NAM, or new approach methodologies workshop that we organised here at ECHA last year. And I think one thing that came out clearly from there is that there are challenges and we may well be quite far actually from the ultimate goal of fully, I mean, fully replacing animal tests. So let's focus on the challenges for a while. So especially in terms of the work of the consortium, what do you expect to be the main challenges for the projects that you've identified?

• Sylvia Escher - Fraunhofer Institute

  So in the first phase, actually the work that we are doing in this first year, we are relying mainly on existing data and later on we can also define more experimental data. But here we are facing the situation that not all data are standardised and it's a kind of issue that we have to work on this to make them comparable. And also the quality and validity of these assays needs to be assessed to be integrated in the end into a concept to integrate them into risk assessment. That's one challenge that we are facing.

• Adam Elwan - Host, ECHA

  I can imagine that the lack of standardised data would be a real hurdle. I guess without consistency, how can you make accurate comparisons or conclusions? So I think it's clear that tackling this from the start is probably going to be crucial in making sure these methods can be trusted and then ultimately used more widely.

• Tomasz Sobanski - ECHA

  I think the other challenge is that many of those approaches were applied primarily for pharmaceuticals. The compounds which are meant to be bioactive, which are meant to be bioavailable because basically they need to do some certain work in the organism. While now we are extrapolating those approaches to industrial chemicals which were not designed having in mind any interaction with human body or any organism. So we will face some difficulties in how to test them, how to dissolve them. To which extent they are bioavailable. And then we will need to cover this complexity and try to come up with the solution which can be understood by our registrants and by the contract lab research organisations to perform those. So I think that this is an extension of the standardisation because this is the standardisation of the quite complex solution, how to approach the technical difficulties.

• Adam Elwan - Host, ECHA

  That's a really important point. So unlike pharmaceuticals, many industrial chemicals weren't designed with the expectation that they interact with the body in a specific way. So you're not just dealing with scientific complexity, but also with kind of practical challenges around how to even test them. It's almost like you're building the plane while flying it, which is never a good idea.

• Sylvia Escher - Fraunhofer Institute

  And I think to add to that, I think today we discussed a lot about pragmatic solutions. So we are not aiming to have the one and only most sophisticated model in the end that nobody can actually fill in this data because it's so over complex. We are aiming at something very pragmatic. We want to make this alive. And therefore, we are, so to say, coming with something which is soluble also by applicants.

• Adam Elwan - Host, ECHA

  Exactly. It seems like you're aiming for something that strikes a kind of balance between being first and foremost scientifically robust, but then also, you know, importantly doable in the real world. How do you ensure that the solutions you're developing are both scientifically valid and practical for regulatory use?

• Tomasz Sobanski - ECHA

  We've seen already some attempts to integrate those data into the read-across attempts, so basically to justify that substance which is used as a source of the information is indeed very similar to the substance for which you want to cover, you want to generate this toxicological information. So this is probably the first most obvious application of those technologies. Although we have to remember that even this is not so straightforward, because what we are trying to do, we are trying to use molecular data. So data which are measured at the quite basic level of biological organisation and associated with the adverse outcome, which is at the end of the biological process. So there is a lot of steps in between which we have to tackle and we need to come up with a pragmatic solution, not overcomplicating it, but making it as well accessible for our registrants.

• Adam Elwan - Host, ECHA

  Right. And regulatory acceptance is key here. So even if you've got the science nailed down, it doesn't really matter if it doesn't fit within the strict framework of regulations. But starting with read-across as an entry point for these new methods seems like a logical place. Could you talk a bit about how you're working towards regulatory acceptance for these methods, particularly when it comes to read-across?

• Sylvia Escher - Fraunhofer Institute

  Yeah, I agree fully that read across is probably the obvious thing to do because also we can compare new approach methods to anchoring in vivo animal data, so traditional data that we always used for risk assessment. So that's a kind of nice way to learn also about, to gain some more confidence about these new approach methods and how they are performing. So that's a very nice way to learn it. And then I think the next midterm achievement will be that we can probably use it for screening and prioritisation of compounds. So just identifying those compounds that are a little bit more hazardous and those that are non-hazardous. And this is a challenge on its own, but we are working on that. And I think the long-term goal is still the refinement and reduction of animal testing. And here this is something that we all would like to achieve. But I think here we have a lot of more steps to do and we will probably not solve this in the next six years, I think.

• Tomasz Sobanski - ECHA

  As well, a very critical element for the regulatory acceptance is actually exposing our risk assessors, our experts, to this kind of data. In the scientific literature, there is a lot of evidence and a lot of discussions, but actually almost none of this evidence was phasing out when, for example, Risk Assessment Committee is deciding about classifying substances. So what we are aiming at is that by now introducing those molecular measurements as routine techniques within the toxicity testing, we will by nature start to expose our experts to this data more often. So they will be able to build their own confidence and their own understanding how it can work. And then it will be much easier in the future to change the system because people will already have some experience in using this data in the practical decision-making.

• Adam Elwan - Host, ECHA

  That's a great point. Getting risk assessors familiar with these new types of data is so important. It sounds like by integrating omics data into routine testing, you're not only advancing the science, but also easing its way, one could say, into regulatory acceptance by making it a part of the everyday decision-making process. Could you talk a little bit about the kind of cooperation between other EU institutions and how this feeds into your work?

• Tomasz Sobanski - ECHA

  Of course. Silvia, would you like to start?

• Sylvia Escher - Fraunhofer Institute

  Yeah, I'd like to start. So at the moment there are several initiatives around. So we have the huge cluster of three European projects, which is called ASPIS. And here we are working on the integration of new approach methods for different endpoints like systemic toxicity. So when you have, so to say, an exposure to a compound over a long time and it causes some type of toxicity, that's our question. And we want to develop an... it's called integrated approaches to testing and assessment. So we want to develop an in vitro and in silico testing battery. So we want to use cell lines and cell models to infer toxicological properties in the end, probably also to predict them. And we integrate them together because not only one cell line can tell us everything, but you have to have different bits and pieces to make this happen. So this is one huge activity. And here we are already working together with three different projects. And then we have the PARC consortium. This is another huge European initiative. And here we are working on an international level together with authorities and academia and we have different types of toxicological properties that we want to work on. But it's the same idea. We also want to use NAM data to do risk assessment in the end and also these two are already collaborating. And then we also have EFSA. And EFSA has also funded some interesting projects about how to best use NAMs for food and feed safety. And we are also working on the same types of questions. So what is the minimal scope? What do we have to do as a minimal type of testing to come to a conclusion? And is this safe enough in the end?

• Tomasz Sobanski - ECHA

  And maybe as well to add, of course, being realistic, we will never reach the full 100% percent alignment between different agencies or different member states simply because our legal frameworks are working slightly different, that there is slightly different logic behind the system and slightly different need. However what we already identified last year and what we are now working quite hard with EFSA is to really agree what are the commonalities for example how and there are commonalities for example how we are characterising hazard is common, regardless whether we are talking about biocides, pesticides or REACH chemicals, we need to characterise hazard and we are doing it more or less in the same way. We are already aligning our views on how it should be done in the future and in addition we are already looking for how we can use our initiatives to combine them, to use the synergies. And just to give you an example, EFSA was working for many years to develop toxicokinetics platforms, toxicokinetic solutions and different models because they're needed in many different applications. We've been not so active with toxicokinetics, but now we have as well very concrete needs regarding the toxicokinetics. So we basically now will use the EFSA platform to develop REACH specific solutions. And the same, we started this initiative about the sampling, so the guidance of best practices for sampling for omics, and then now we are as well introducing it to the test guideline development programme to endorse it. And then EFSA will as well directly benefit from that, and they are already investigating how they can already request certain extension of the traditional study to use it directly in their decision-making system. So... we are already identifying those synergies and we are trying to really work together towards this.

• Sylvia Escher - Fraunhofer Institute

  I think there's another example where you can collaborate a lot. So I think also on data sharing, I think you started collaboration and it would be really brilliant if we could share all the available data on a European level, not only in IUCLID, but in a really standardised database to develop better models for risk assessment.

• Tomasz Sobanski - ECHA

  And then of course there is another dimension because whenever we are talking about regulatory hazard and risk assessment we have to remember the OECD level which means basically you know mutual acceptance of data. This is the concept that if you will do the toxicity testing in any of the OECD member states it will be accepted in others in the same regulatory context. So basically if we really want to move forward this animal-free approaches, we need to do it as well at the OECD level together with our partners from US, Canada, Japan. Because otherwise we will end up with different solutions in different jurisdictions and again registrants will be very confused what to follow, how to do it. And so that's another very important layer of collaboration and even here majority of those projects have as well the OECD components already. So we want to fit outcomes from those collaborations into the OECD discussions which we're having at the moment.

• Adam Elwan - Host, ECHA

  That's really encouraging to hear. So the fact that these efforts are being mirrored across these different projects and organisations shows how widespread the commitment is. The collaboration between agencies like the European Food Safety Authority and us at ECHA, and even on a broader international scale, I guess is key to making sure these new methods aren't just developed in silos, but can then be applied across the board and globally, on a global level. Before we end, in one sentence, what would you say will be different after the consortium has carried out its work? What will concretely change?

• Sylvia Escher - Fraunhofer Institute

  In one sentence? Okay.

• Adam Elwan - Host, ECHA

  Well, it doesn't have to be one sentence, but as shortly as possible. What's the vision, basically, for when the work is over?

• Sylvia Escher - Fraunhofer Institute

  Yeah, the vision is that we gain more confidence in the new approach methods and we also work on concrete steps to implement them in regulatory risk assessment. And I think this is a fruitful way to do this in this close cooperation between industrial partners, academia partners and authority.

• Tomasz Sobanski - ECHA

  Yeah. And for me, I think what I see, what can happen by the end of the six years is that we will really build the foundation for the new system. It will be not yet new system. It will be not even the beginning of the new system, but we will have a strong fundament to start thinking about the new system.

• Adam Elwan - Host, ECHA

  And that brings us to the end of our episode. It's been a pleasure having you all here. Very heavy stuff, but very interesting, I'm sure, especially to our scientific audiences. To conclude, I'd say that it's clear that the work being done by this consortium through this project could very well help lay the groundwork for a future where new approach methodologies are both widely accepted and actually implemented then in regulatory settings. Of course, then hopefully reducing animal testing and enhancing safety assessments. So as Sylvia and Tomasz highlighted, while we're not there yet, the foundation that is being built is vital and a key part in this whole picture. Thanks again to both of you for sharing your expertise. And thank you to you for listening. Safer Chemicals Podcast. Sound science on harmful chemicals.