Sunday, 8 September 2024
08h00
Congress Registration opens
09h30 – 16h00
Workshop: Ellegaard Göttingen Minipigs
00h00 – 09h30 | Departure by bus from Tivoli Hotel & Congress Center, Copenhagen
00h00 – 11h00 | Arrival at Ellegaard Göttingen Minipigs A/S
11h10 – 11h30 | Introduction to Ellegaard Göttingen Minipigs and the model, by Martin Velin, CEO, Ellegaard Göttingen Minipigs A/S
11h30 – 12h30 | Tour of the Ellegaard Göttingen Minipigs facility
12h30 – 13h15 | Lunch and networking
13h15 – 13h45 | Göttingen Minipigs in toxicology, by Andy Makin, Andrew Makin Preclinical Consulting
13h45 – 14h15 | Spontaneous histopathological findings in Göttingen Minipigs in toxicity studies, by Nanna Grand, Scantox A/S
14h15 – 14h30 | Future of Göttingen Minipigs, by Kirsten Rosenmay Jacobsen, Ellegaard Göttingen Minipigs A/S
00h00 – 14h30 | Departure by bus from Ellegaard Göttingen Minipigs
00h00 – 16h00 | Arrival at Tivoli Hotel & Congress Center
Please read this visitor information carefully in order to be allowed to participate in the workshop.
10h00
Welcome Coffee
10h30 – 16h00
Continuing Education Courses (CECs)
CEC01: Adverse Outcome Pathways: Systematic methods for AOP development & utilization of new technologies and tools
Session Chair(s): Alexandra Schaffert (Medical University Innsbruck, AT), Bette Meek (University of Ottawa, CA)
By establishing biologically plausible and empirically supported links between molecular-level perturbation and an adverse outcome, Adverse Outcome Pwathways (AOPs) serve as an invaluable tool for researchers and regulators alike. The Organisation for Economic Co-operation and Development (OECD) supports the development, documentation, and assessment of AOPs through their program. In this educational course, participants will have the opportunity to learn from members of the OECD subgroup for Education, Training, and Communications (ETC) about the latest developments in AOP methodology and tools, and how to integrate Omics data for a more comprehensive understanding of chemical-induced adverse effects. As we delve into the need for consistent and transparent systematic approaches for evidence identification and assessment within AOP development, we will also examine specific available tools and concrete workflows for integrating these approaches. Moreover, with advances in system-level data analysis, Omics data can be utilized on different levels within the AOP framework. Participants will be introduced to different applications of Omics for data-driven AOP development and beyond, as well as the challenges associated with the use of these technologies in risk assessment. Additionally, successful regulatory applications of AOPs will be presented to showcase their effectiveness in real-world scenarios. To prepare participants for their own AOP development journey, a practical exercise (2h) will cover the fundamentals of AOP development, the AOP wiki, and Weight of Evidence assessment. With this comprehensive training, attendees will be equipped with the knowledge and tools necessary to apply the AOP framework in their own work.
Alexandra Schaffert (Medical University Innsbruck, AT)
Introduction into the AOP framework/ Practical exercise
Sivakumar Murgadoss (Sciensano, BE)
AOP development, the AOP wiki & the way to OECD endorsement/ Practical exercise/ Flash talks on the regulatory use of AOPs
Bette Meek (University of Ottawa, CA)
The path to a more systematic approach in the OECD AOP Development program: Integration of systematic evidence identification and assessment
Barbara Viviani (University of Milan, IT)
Example of a stepwise approach to systematic development of AOPs including available tools/Flash talks on the regulatory use of AOPs
Ksenia Groh (Eawag, CH)
From de novo development and AOP refinement to biomarkers of effect – Utilizing Omics for AOPs /Flash talks on the regulatory use of AOPs
Martin Paparella (Medical University Innsbruck, AT)
Flash talks on the regulatory use of AOPs
CEC02: Developmental and Reproductive Toxicology (DART)
Session Chair(s): Steven Van Cruchten (University of Antwerp, BE)
This Continuous Education Course (CEC) on developmental and reproductive toxicity (DART) testing is designed to provide a basic understanding of DART testing, including the regulatory requirements, but also to create in-depth knowledge on epigenetic mechanisms and new insights in alternative approaches for risk assessment in developmental toxicology. Special attention is given to the interpretation of DART studies using group discussions on case studies. The intended audience for this CEC includes industrial and regulatory scientists, graduate students, and postdoctoral fellows.
Steven Van Cruchten (University of Antwerp, BE)
Introduction to developmental and reproductive toxicity (DART) testing
Joëlle Ruegg (Uppsala University, SE)
Epigenetic changes as biomarkers for developmental neurotoxicity
Daphne Van Den Oetelaar (Charles River Laboratories, NL)
Current regulatory DART testing
Aldert Piersma (National Institute for Public Health and the Environment, NL)
The Virtual Human approach to animal-free chemical hazard and risk assessment in developmental toxicology
CEC03: Therapeutic Vaccines: how to assess their safety from a toxicology perspective, including species selection
Session Chair(s): Sarah Gould (Charles River Labs, FR), Marc Pallady (Université Paris-Saclay, FR)
Therapeutic Vaccines: how to assess their safety from a toxicology perspective, including species selection and there are no specific regulatory guidelines.
Introduction
Vaccines are not just for infectious diseases. They also have the potential to treat diseases, such as Cancer, Autoimmune Disease and Allergies. To assess their safety, they can pose a challenge for a toxicologist. Not only are there no guidelines but defining a relevant species may depend on the vaccine’s target, the expression pattern (including if endogenous it’s expression in disease state only or and/or healthy animals), the mechanism of action and the immune system. In many cases, an animal species may not be able to mimic or predict the immune response of humans (Matsumoto et al., 2014).
Understanding the pharmacology and the nuances of the immune system relating to antigen presentation and the activation of the adaptive immune system is key to determining any toxicology program. As well as understanding the target specificity of the selected antigens and/or epitopes, the technology (e.g., a protein-based vaccine versus an RNA based or DNA vector vaccine (FDA)), the route of administration, the addition of adjuvants or use of specific delivery agents, including DNA plasmids, Vectors and/or Lipid Nanoparticles, are an important consideration in any non-clinical testing strategy.
This session will consider what constitutes as a therapeutic vaccine (and name), the mode of action and the key principles of the immune system that need to be considered when putting together the toxicology strategy, including selecting the species. The panel will present various case studies that highlight and discuss the challenges, issues and considerations for selecting a species and what to do in the case that there is no relevant species.
Sarah Gould (Charles River Labs, FR)
Introduction to vaccines
Patricia Londono Hayes (Simbios Innovation ltd, IE)
Pharmacology/Immunology
Paul Desert (Sanofi Pasteur, FR)
Toxicology
Marc Pallady (Université Paris-Saclay, FR)
Clinical Safety issues
CEC04: Toxicology – Environmental Pollutants
Session Chair(s):
This continuing education course is offered through the EUROTOX rolling program and provides the participants with a comprehensive understanding of the current state of knowledge regarding classical and emerging environmental pollutants. The course content is designed to impart knowledge and understanding of the toxicity of pollutants found in the air, dust, water, and food, including their potential to cause cellular disturbances and resulting health effects on a variety of organ systems, such as the respiratory and reproductive organs. The course will explore the various routes and sources of exposure to toxic pollutants, including the emerging issue of how pollutants can interact with female reproduction. It will also delve into international and national guidelines and regulations that can be used to assess and characterize the risks associated with these pollutants. The program culminates in a group assignment that focuses on the complexity and burning issues associated with one of the most discussed groups of environmental pollutants: per- and polyfluoroalkyl substances (PFAS). Overall, this program is a valuable opportunity for professionals to deepen their understanding of the toxicology and risk assessment of environmental pollutants and stay up-to-date with the latest research and regulatory developments in this rapidly evolving field.
Dorte Herzke (Norwegian Institute of Public Health, NO)
Introduction to Environmental Pollution
Swapna Upadhyay (Karolinska Institutet, SE)
Mechanisms and health
Marco Corvaro (Corteva Agriscience, IT)
Exposure and risk assessment of plant protection products
Pauliina Damdimopoulou (Karolinska Institutet, SE)
Pollutants and female reproduction
Antero Vieira Silva (Karolinska Institutet, SE)
Group assignment about PFAS
CEC05: The open science movement: challenges and opportunities for toxicology
Session Chair(s): Paul Whaley (Lancaster University, UK)
“Open science” is a broad movement that seeks to make research more reproducible, ethical, rewarding, and useful. It covers a wide range of issues, including: making research data FAIR (Findable, Accessible, Interoperable, and Reusable); open peer review, where reviewer comments are made public and may even be signed; and even reform to the fundamental infrastructures and processes of research, such as the preregistration and peer-review of study protocols, the self-publication of preprints, and novel publishing models where journals view themselves as curators rather than gatekeepers of research.
Advocates of open science initiatives in toxicology believe they will benefit the research community and help in the quest for safer chemicals and medicines. However, these initiatives also bring many challenges and questions, such as: Isn’t it risky for early-career researchers to sign their peer-reviews? Doesn’t preregistration of study protocols take a lot of effort and time, and risk other scientists gazumping the investigators? Won’t preprints confuse the public and policymakers about what is known about the results of a study? Won’t FAIR data requirements just create more work for under-funded scientists while taking away control of their data?
This continuing education course will give participants a comprehensive introduction to open science, answering the questions of what it is, why it is so relevant to modern toxicological research, and what practical tools and strategies are available to researchers to help meet funder, publisher, and community expectations that science should be increasingly open. The course will be delivered by a mix of early-career and senior researchers with a breadth of expertise from regulatory science, tool development, publishing, and funding, all of whose work directly involves developing, using, or encouraging open science practices in research.
Maria Shatz (US National Institute of Environmental Health Sciences, US)
What is “open science” and why does it matter?
Anne Scheel (Utrecht University, NL)
How things can go wrng with sharing data – and how they can go right
Kaitlyn Hair (University of Edinburgh, UK)
Hands-on with open data – a practical exercise
Paul Whaley (Lancaster University, UK)
What funders want, and how journals can help
Antony Williams (US Environmental Protection Agency, US)
Practical tips on preparing open data
17h00 – 19h00
EUROTOX CONGRESS OPENING CEREMONY
EUROTOX MERIT AWARD PRESENTATION
KEYNOTE LECTURE: Overview of PFAS, toxicology, historical levels in EU vs. health effects and EU risk assessments
Tina Kold Jensen, University of Southern Denmark, DK
19h00
Welcome Reception & Opening of Exhibition
Monday, 9 September 2024
08h30 – 09h30
EUROTOX LECTURE AWARD: Endocrine disruptors and microplastics: facing complexity with connection
Juliette Legler, Utrecht University, NL
09h30 – 10h00
Coffee Break and Poster Viewing 1
10h00 – 12h00
S01: Complex chemical mixtures: Assessment of chemical mixture drivers and adverse human health and environmental effects
Session Chair(s): Beate Escher (Helmholz Center for Environmental Research, DE)
The toxicological impact of exposure to chemical mixtures is a matter of undisputed concern, but mixtures are only slowly making their way into regulatory risk assessment. Critical knowledge gaps are which and how many chemicals that drive mixture effects in the environment and in humans. Moreover, scientific uncertainty remains on the validity of the dose addition principle for complex mixtures of large numbers of chemicals at low concentrations as they occur in our bodies. This symposium will address these challenges by showcasing a novel experimental path based on whole mixture assessments for identifying and quantifying the risk of chemical mixtures extracted from real-life samples representing the environment and food as well as humans. The applied methodologies, including a panel of in vitro assays coupled with effect-directed analyses and large-scale suspect and non-targeted chemical profiling are innovative in their combinatorial approach. Specifically, attention will be directed towards a well-studied human cohort of new-borns, in whom chemical mixture drivers are determined in cord blood and related to known adverse health outcomes such as reproductive toxicity (e.g., shortened anogenital distance) and developmental neurotoxicity (e.g., IQ levels or ADHD symptoms). In this symposium, state-of-the-art for risk assessment of chemical mixtures will be presented together with an overview of the various approaches used for mixture modelling, for performing case studies and for calculating effect-based trigger values for in vitro effects that can be directly measured in water, food, and blood to identify when mixture exposure is posing a health threat. By taking part in the Green Deal project, PANORAMIX, and by involving regulatory and scientific stakeholders throughout the project, we will support the implementation of existing mixture risk assessment and management approaches to reduce the most critical exposures and assist in optimizing regulatory approaches to yield evidence-based policies, contributing to EU’s zero-pollution ambition for a toxic free environment in the future.
Anne Marie Vinggaard (National Food Institute, DK)
Risk assessment of complex chemical mixtures – an overview of approaches and recent developments
Beate Escher (Helmholz Center for Environmental Research, DE)
Whole mixture assessments of water, food and human blood
Marja Lamoree (Vrije University Amsterdam, NL)
Effect-directed analysis for determination of chemical mixture drivers in environmental and human samples
Bruno Dujardin (European Food Safety Authority (EFSA), IT)
Mixture risk assessment from a regulatory point of view
S02: Data Science in Drug Discovery and Development
Session Chair(s): Tong Weida (US FDA National Centre for Toxicological Research, US)
Data science is a discipline that has eolved from big data and is key to understanding and interpreting data to make it available and impactful to everyone from researchers to policy makers, especially those working in drug discovery and development. There are many ways to extract useful information, and these approaches are evolving rapidly, especially given the rise of artificial intelligence (AI) and machine learning (ML). This session will start with an overview of drug discovery and development, including two recent case studies of how data science is being used to mitigate safety issues associated both with the drug target and with the molecule. This will be followed by an overview of the state-of-the-art methods in AI/ML being developed to assist in drug discovery. Specifically, molecular representation learning has advanced drug discovery applications by facilitating efficient predictions of bioactivity and toxicology profiles. In this presentation, we will demonstrate how these techniques enable researchers to effectively identify promising drug candidates and evaluate their safety profiles, surpassing traditional methodologies in both accuracy and efficiency. Next, we will hear about the FDALabel database, a web-based application that allows us to take advantage of data accumulated in the regulatory setting via customizable searches of over 140,000 human prescription, biological, over-the-counter (OTC), and animal drug labeling documents. Finally, we hear about where the field of data science is evolving. Computational toxicology remain unchanged for many years but has seen big changes recently. This session gives an insight into what has changed and how it is impacting drug discovery and development. This session will be of great interest to academics, industry and government participants that wish to understand how data science has evolved and how it can be used in research and decision making.
Ruth Roberts (ApconiX, UK)
Data Science in derisking drug target and chemistry
Djork-Arne Clevert (Pfizer, DE)
Molecular Representation Learning for Drug Discovery
Hong Fang (US FDA National Centre Toxicological Research, US)
FDA Label: Enabling Full Text Searching of Drug Labels
Igor Tetko (Helmholtz Institute, DE)
Computational Toxicology in Drug Safety
S03: PFAS compounds and Immunotoxicity
Session Chair(s): Katja Merches (Bavarian Health and Food Safety Authority (LGL), DE), Charlotte Esser (Leibniz Research Institute for Environmental Medicine , DE)
Per- and polyfluoroalkyl substances (PFAS) are widely dispersed and persistent in the environment and pose a serious threat to the health of people and other organisms. All in all, this compound category comprises more than 4700 substances, but only few have already been studied in terms of their toxicological profile and with regard to human exposure. In particular, extensive immunotoxicological evaluations including the comprehension of molecular pathways, key events, and adverse outcome pathways (AOPs) are still lacking and render difficult a comprehensive risk assessment of the different PFAS . In 2020, with respect to PFAS immunotoxicity, the European Food Safety Authority (EFSA) established a tolerable weekly intake (TWI) level of 4,4 ng/kg bodyweight for the sum of the four PFAS substances perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS). This TWI was based on epidemiologic data, which identified that reduced antibody titers following infants‘ routine immunizations were associated with higher serum concentration levels of PFOA. As a result, the presumed immunotoxic impact of PFAS is now considered the most sensitive endpoint for toxicological risk assessment. How PFAS are affecting the production of antibodies – their mode of action- is still under investigation. Using new approach methods (NAMs) may assist in answering this question and in determining the relative potency factors of other PFAS as well, thus improving the accuracy and acceptability of PFAS risk assessment.
Thus, we here propose a EUROTOX symposium on “PFAS and immunotoxicity”. We will highlight recent studies on the immunotoxic characteristics of PFAS looked upon from two different points of view, the epidemiological and the mechanistic standpoint. The topics will be presented by experts from three European nations that are actively engaged in PFAS immunotoxicity research. They will present their data and together, this will give an up-to-date overview of the named issues as well as on current methods and perspectives.
Our goal is to bring the widely debated issue of PFAS immunotoxicity to the EUROTOX audience, to present cutting-edge research, and to trigger an in-depth discussion about causalities and ongoing research requirements.
Martina Iulini (University of Milan, IT)
Using NAMs to address PFAS immunotoxicity: in vitro and in silico approach
Amalie Timmermann (University of Southern Denmark, DK)
PFAS exposure, vaccine antibody concentrations, and risk of infection among West African infants.
Charlotte Esser (Leibniz Research Institute for Environmental Medicine , DE)
Effects of PFAS on T cell membrane fluidity and its immuntoxic consequences
Jamie C DeWitt (Oregon State University, US)
Effects of PFAS exposure on B cell functions
S04: New developments in micro- and nanoplastics research
Session Chair(s): Raymond Pieters (Utrecht University, NL)
Plastics are versatile materials with a myriad of applications in daily life and degrade in the environment to smaller fragments called microplastics and nanoplastics. Microplastics and nanoplastics can enter the human body via the oral, dermal and inhalatory way, and may be considered a potential human health hazard. This symposium will inform on the most recent developments in the microplastics and nanoplastics field. The first presentation will cover recently acquired knowledge on immunotoxicology-related effects of microplastics and nanoplastics on epithelial cells and innate immune cells, such as macrophages, both from in vitro and real-world human studies. The second presentation will discuss the effects of nanoplastics on predeveloped liver cancer using in vitro human liver cancer spheroids. The third presentation will describe a systematic study of the sorption behavior and carrier effects of various types of microplastics. The fourth presentation will discuss a study using in-house fabricated microplastic, in which it was found that material composition strongly influences toxicity in macrophage-like and alveolar cell models. This mode of action appeared different to that of ambient PM2.5 and, when combined as a mixture, microplastic augmented PM2.5 toxicity.
Raymond Pieters (Utrecht University, NL)
Inflammation-related key events stimulated by micro- and nanoplastics
Nelly Saenen (Universiteit Hasselt-Belgium, BE)
Redox-mediated toxicity of micro- and nanoplastics in intestinal models
Andrea Haase (German Federal Institute for Risk Assessment, DE)
A systematic investigation of the carrier hypothesis for microplastics and its possible impact on human health
Stephanie Wright (Imperial College London, UK)
The differential toxicity of inhaled microplastic particles in human in vitro models
12h00 – 13h00
Lunch Break, Poster Viewing 1 and Industry Hosted Sessions
12h00 – 13h00
Speciality Section Meetings
13h00 – 14h00
EUROTOX – SOT DEBATE: Can the microbiome mediate the toxicity of environmental chemicals?
SOT Speaker: Tamara Tal, Centre for Environmental Research, DE
EUROTOX Speaker: Karsten Beekmann, Wageningen Food Safety Research, NL
14h00 – 15h30
S05: Young scientist session: emerging researchers in the field of in vitro and in silico toxicology
Session Chair(s): Theo de Kok (Department of Toxicogenomics, GROW School for Oncology and Reproduction, Maastricht University, NL)
The EUROTOX Executive Committee recently decided to more intensively involve young researchers in the EUROTOX activities. The present symposium is a first step into this direction by providing a platform to young scientists, in casu active in the area of in vitro and/or in silico toxicology, to present their work. The first presentation will describe the generation of a qualitative adverse outcome pathway network focused on decreased cognition in children. To assess the impairment of selected important key events in the network, an animal-free in vitro battery is proposed, which was scientifically validated and characterized. The second presentation will introduce the development of new quantitative structure-activity relationship models and their implementation in a user-friendly web platform followed by some examples to illustrate their use for toxicological purposes. The third presentation will present an integrated testing strategy utilizing an ontology-based approach toward the development of adverse outcome pathways and a battery of in vitro assays for the improved assessment of chemical safety with regard to human nephrotoxicity.
Eliska Kuchovska (IUF-Leibniz Research Institute for Environmental Medicine, DE)
In vitro new approach methodologies for predicting effects of chemicals on the developing brain
Simón Perera del Rosario (ProtoQSAR and Institute of Evolutionary Biology, ES)
In silico toxicology from a deep tech’s perspective
Anouk Verhoeven (Vrije Universiteit Brussel, BE)
The development of a human liver-based in vitro test battery to detect liver steatotic potential of chemicals from various applicability domains
Devon Barnes (Utrecht University, NL)
Development of adverse outcome pathways and in vitro assay batteries as predictors of nephrotoxicity
S06: Consideration of dose-response in the assessment of genotoxic carcinogens
Session Chair(s): Angela Mally (University of Würzburg, DE)
Based on the „one-hit“ hypothesis that even one or a few DNA lesions may induce mutations and increase tumor risk, current approaches to risk assessment and regulation of genotoxic substances are mainly hazard driven, resulting in binary classification.
While the concept of linear, no-threshold dose-response in chemical risk has been challenged for some time by accumulating evidence for non-linear, thresholded dose-response curves for key events involved in the mechanisms of chemical carcinogens, there is also increasing discussion to move away from primarily qualitative analysis to quantitative interpretation of genetic toxicity dose-response data, including derivation of a point of departure for risk assessment.
This workshop aims to bring together researchers and regulators to discuss critical key events that drive dose-response relationships in chemical carcinogenesis, to highlight opportunities and challenges involved in quantitative interpretation of genotoxicity data, and to provide future perspectives for assessing the risk of genomic damage.
Andrea Hartwig (Karlsruhe Institute of Technology (KIT) / University of Karlsruhe (TH), DE)
Mechanisms driving non-linear dose-response relationships in genotoxicity
George Johnson (Swansea University Medical School, UK)
Opportunities and challenges involved in quantitative interpretation of genotoxicity data
Mirjam Luijten (National Institute for Public Health and the Environment (RIVM), NL)
Next generation strategies for quantitative assessment of genomic damage
S07: Emerging Technologies in Pharmaceutical Preclinical Testing
Session Chair(s): Peter Theunissen (Dutch Medicines Evaluation Board, NL), Jeffrey Brown (PETA Science Consortium International e.V., DE)
The modern pharmaceutical industry must use the most protective and human-relevant preclinical tests, rather than defaulting to animal models. Many new drugs—such as Advanced Therapy Medicinal Products—are more individualized and human-specific than ever before, and both developers and regulatory bodies are agreeing that drugs such as these cannot always be adequately tested with animal models. Of note, two sponsors have published their experience gaining regulatory approval to start first-in-human (FIH) clinical trials exclusively on the basis of in vitro studies. Even more developers have published examples of using in vitro data to support safety or dose selection prior to human tests without animal data alongside it. The current preclinical testing standard, however, usually means exhausting all possible animal-based methods before considering non-animal techniques. Developers often investigate surrogate molecules or transgenic animals for their human-specific drugs, then evaluate non-animal methods only if all animal-based options are deemed insufficient.
The proposed workshop will center around the theme of “when to use emerging technologies rather than defaulting to animal models for pharmaceutical safety testing.” Presentations and discussion will focus on shifting the current paradigm away from a default mindset, towards rational selection of the most relevant, state-of-the-art methods available. One speaker has been providing expert consultant services in the biopharmaceutical space for over 15 years and will share his perspective on the current state of non-animal methods in new drug preclinical assessment. A second speaker is the CEO and Scientific Director of a company offering organ-on-chip technologies to drug developer clients. She will discuss her recent experience using these in vitro models to improve preclinical decision-making and reduce drug development costs. The final speaker will talk about his organization’s experience bringing a non-animal preclinical safety testing package before worldwide regulators (including the US Food and Drug Administration and the European Medicines Agency), as the strategy applies to the organization’s sponsored candidate monoclonal antibody therapeutic.
Leander Grode (Serum Life Science Europe GmbH (SLS), DE)
The current landscape of non-animal preclinical assessment for biopharmaceuticals
Nina Hobi (AlveoliX AG, CH)
CRO perspective of emerging technology use for preclinical decision-making
Jeffrey Brown (PETA Science Consortium International e.V., DE)
Non-animal preclinical safety testing strategy
S08: Innovative in vitro screening tools for assessing the risk of immunotoxic chemicals
Session Chair(s): Marija Sollner Dolenc (University of Ljubljana, SI), Erica Buoso (University of Pavia, IT)
Man-made and natural chemicals can represent a significant public health issue since they can have adverse effects on the immune system due to their potency, constant and universal human interaction. Indeed, immunotoxic chemicals exposure can occur via ingestion (food, dust and water), via inhalation (gases and particles in the air) and through the skin. They can also be found in food contact materials, cosmetics, consumer goods (including furnishings, cleaning products), toys, as well as in drinking water. Moreover, the effects of certain chemicals, pollutants, and other environmental toxins can affect the endocrine system functions thus weakening the immune system and make individuals more susceptible to infectious diseases, autoimmune and metabolic disorders, and various cancers (i.e. breast and prostate cancer).
These immunotoxic chemicals can act on similar or different pathways displaying cumulative or synergistic effects, which can be observed in different temporal windows (i.e., pre- and postnatal life, puberty and adulthood) with adverse effects in both the short- and long-term. Hence, a strict regulation is crucial. Accordingly, it is important to identify and assess the potential risks of immunotoxic chemicals in order to protect public health and prevent adverse outcomes. Innovative in vitro screening tools appears to be a useful tool to capture their immunotoxicity and the complex interplay of transcriptional and non-transcriptional events associated with their exposure and the resulting biological consequences.
Mirco Masi (Istituto Italiano di Tecnologia (IIT), IT)
Immunological implications of EDCs: RACK1 as a bridge between the endocrine and the immune systems
Raymond Pieters (University of Applied Sciences, Utrecht University, NL)
The importance and recent development of screening tools in the immunotoxic context
Dori Germolec (National Institute of Environmental Health Sciences (NIEHS) – National Toxicology Program (NTP), US)
Exploring applicability domain and predictive value across in vitro platforms to detect potential dermal sensitizers
15h30 – 16h00
Coffee Break and Poster Viewing 1
16h00 – 18h00
S09: Advances in class-based and grouping approaches to chemical assessment
Session Chair(s): Andrew Rooney (National Institute of Environmental Health Sciences (NIEHS)/NIH, US), Richard Brown (World Health Organization, CH)
Health assessors and regulatory agencies typically assess hazard or risk from environmental exposures on a chemical-by-chemical basis that is time and resource-intensive. However, many commercial chemicals are structurally related compounds that may have similar toxicological effects. As such, there is a growing need for class-based assessment methods. Class-based approaches, a term used to describe methods that group multiple chemicals in relation to physiochemical, environmental, and toxicological properties, can be used for the purposes of more efficient decision making. How classes are defined vary based on the decision context (e.g., prioritization for research or hazard/risk assessment). Leading groups such as the European Chemicals Agency (ECHA), the Organisation for Economic Co-operation and Development (OECD), and the US National Academies of Sciences (NAS) outline class methods based on common functional groups (e.g., aldehyde, ester, or specific metal ion), shared mechanisms, common precursors or metabolites, or other aspects of chemical classes. This session will showcase the application of emerging technologies to the evaluation of chemicals by category or class. Session speakers represent a range of perspectives and expertise, from international health organizations, government agencies, and academic institutions. Presentations will cover the role that harmonization of methods can play in optimizing the use of resources and the importance of evidence-based methods. Several highly relevant and topical case-examples with diverse chemicals comprising a given class will be featured, including organohalogenated flame retardants (OFRs), endocrine disrupting chemicals, and per- and polyfluorinated substances (PFAS). Finally, the speakers will focus on different aspects of hazard and risk assessment process from overall methods or framework to informatics and evidence mapping and adverse outcome pathways.
Richard Brown (World Health Organization, CH)
Introduction: The role of methods harmonization in grouping chemicals for hazard and risk assessment
Andrew Rooney (US National Institute of Environmental Health Sciences (NIEHS), US)
Informatics approaches and evidence mapping to establish the foundation for class-based research and risk assessments
Xenia Trier (University of Copenhagen, DK)
Risk governance of per- and polyfluroalkyl substances (PFAS) as a chemical class
Martin Olwen (University College London, UK)
Evidence-Based Approaches to Develop Endocrine-Mediated Adverse Outcome pathways
S10: Practical Application of New Approach Methodologies (NAMs) for human health risk assessment
Session Chair(s): Maria Baltazar (Unilever, UK), Sandra Coecke (JRC, IT)
Next Generation Risk Assessment (NGRA) is an exposure-led, hypothesis-driven approach that uses new approach methodologies (NAMs) to ensure the safety of chemicals without the use of animal data. Testing strategies that combine exposure characterisation and mechanistic approaches, such as in vitro methods and computational modelling are advancing at a rapid pace. Whilst some NAMs have been validated and adopted by regulators (e.g. OECD test methods for skin sensitization) there is a need amongst both industry and regulatory risk assessors for more examples that can demonstrate the utility of NAMs for decision-making on potential systemic effects that are associated with chronic systemic exposure to a chemical. This symposium aims to increase awareness and confidence in the use of NAMs in such decision making by presenting end to end case studies for the safety assessment of chemicals in different contexts of use/exposure ranging from cosmetic ingredients to residues in foods. In every talk, the goal is to highlight the practical application of the NAMs, strengths and limitations as well as future research needs. The first talk will briefly introduce the state of play of non-animal approaches for the safety of new chemicals and the application of a NAM toolbox for a UV filter of regulatory interest due to concerns of potential endocrine activity; the second talk will demonstrate the application of a combined in vitro-in silico approach for the screening, prioritisation and potentially risk assessment of four perfluorinated compounds (PFOA, PFNA, PFHxS and PFOS from dietary exposure); in the third talk, an Adverse Outcome Pathway (AOP)-informed Integrated Approach to Testing and Assessment (IATA) for the safety assessment of a pesticide residue in food will be presented. Lastly, this symposium will end with three case studies (cosmetic ingredient and industrial chemicals) where a mixture of existent data (animal data) and newly generated NAMs are used to demonstrate the application of an overall pragmatic framework. Even though each talk will use different NAMs and approaches for their case studies, we will aim to discuss what are those common framework components across all talks, the areas where flexibility is required and where do we still need to build consensus to achieve regulatory acceptance.
Maria Baltazar (Unilever, UK)
Making Safety Decisions for a Sunscreen Active Ingredient Using Next-Generation Risk Assessment: Benzophenone-4 Case Study
Styliani Fragki (esqLABS, DE)
New approach methodologies (NAMs): A quantitative in vitro to in vivo extrapolation case study with perfluorinated compounds
Marcel Leist (University of Konstanz, DE)
Use of NAMs within an IATA for potential mitotoxicants: Tebufenpyrad case study
Sandra Coecke (JRC, IT)
Pragmatic One Health frameworks based on new approach methodologies to assess risks of human disease following exposure to chemicals and pathogens.
S11: New era of cardiotoxicity risk assessment. Where we are, challenges and opportunities
Session Chair(s): Jean-Lou Dorne (European Food Safety Authority (EFSA), IT)
New era of risk assessment moves away from reliance on animal studies to new-approach methodologies (NAMs) and when animal studies are required for fulfilling regulatory needs, then to be conducted in line with the 3Rs of reduction, refinement, and replacement.
The replacement of animal studies presents opportunities for:
- More human relevant risk assessment,
- Human relevant models,
- Mechanistic data to inform adverse outcome pathways (AOPs), key characteristics (KCs) and modes of action (MoA),
- Human disease-relevant models Fast and cheap.
However, at the same time faces challenges in standardisation, reproducibility, validation, acceptance and confidence.
The development of NAMs requires expertise from different fields such as computational modelling, chemistry and toxicology. A multi-disciplinary panel will summarise the current situation in cardiotoxicity assessment, will present where we are with the application of NAMs and will address the areas where more scientific input is needed in order to promote the use of NAMs in the new era of cardiotoxicity risk assessment.
This symposium will pick up examples of how NAMs can contribute to decision-making in risk assessment. Then, four recent examples will be described. More specifically, A roadmap to integration of NAMS and available in vivo studies in a weight of evidence framework for the assessment of cardiotoxicity for regulatory purposes. An example of key of how key characteristics of cardiotoxicants facilitate integration of data for improved safety assessment of chemicals will be presented
Nikolaos Georgiadis (European Chemical Agency (ECHA), FI)
Cardiotoxicity risk assessment: an example of how the weight of Evidence approach can be used for promoting NAMs and 3Rs.
Brian R. Berridge (B2 Pathology Solutions LLC, US)
Key characteristics of cardiovascular toxicants
Federico Vozzi (CNR, IT)
New Approach Methodologies for cardiac toxicity assessment: the ALTERNATIVE perspective
Jean-Pierre Valentin (UCB Biopharma, BE)
Cardiotoxicity in drug development
S12: Skills for Early Career Toxicologists
Session Chair(s): Heather Wallace (University of Aberdeen, UK ), Ruth Roberts (Apconix, UK)
The aim of this session is to highlight areas where early career scientists can gain useful knowledge and understanding of the softer skills that are that are integral to the success of being a fully rounded scientist. There will be 3 areas covered: communication, career building and finding funding. These areas is crucial to a successful career as a scientist and are often neglected in the excitement of scientific research. The session aims are to raise awareness in each area and provide some tips and suggestions to improve your skills or to provide information to help you plan your future.
Heather Wallace (University of Aberdeen, UK )
Skills for Early Career Toxicologists
Ruth Roberts (Apconix, UK)
Career Development Industry
Heather Wallace (University of Aberdeen, UK)
Career Development Academia
Manon Beekhuijzen (Charles River, NL)
Career Development CRO
Georges Kass (European Food Safety Authority (EFSA), IT)
Career Development Regulatory
Mathieu Vinken (Vrije Universiteit Brussel, BE)
Finding Funding: Finding European research funding and writing a competitive research proposal
OS01: Oral Session 1
18h30 – 21h15
EUROTOX Early Career Networking Event (sponsored by Danish Society of Engineers IDA)
19h00 – 21h00
Reception at the Copenhagen City Hall
Tuesday, 10 September 2024
08h30 – 09h30
SOT MERIT AWARD LECTUR: Are Humans REALLY Just Big Rats and Mice? Using the Mode of Action of Aflatoxins, Nitrosamines and Dioxin-like Chemicals for More Relevant Human-Based Risk Assessments
David L. Eaton (University of Washington, US)
09h30 – 10h00
Coffee Break and Poster Viewing 2
10h00 – 12h00
S13: Integrating Exposome and Risk Assessment Approaches: A Joint Strategy for Chemical Mixture Assessment
Session Chair(s): Jacob van Klaveren (National Institute for Public Health and the Environment, NL), Georges Kass (European Food Safety Authority (EFSA), IT)
Risk assessment of exposure to multiple chemicals, also referred to as chemical mixtures, as observed in human biomonitoring studies (HBM studies) is crucial in determining potential health problems. The mixture concerns have been given paramount consideration in the Chemical Strategy for Sustainability and other European Policy documents and consequently it is ranked as a top priority for research in the Partnership for the Risk Assessment of Chemicals (PARC). The PARC “Real-life mixtures” project aims to establish a common strategy for conducting human risk assessment of chemical mixtures by integrating exposure from HBM studies all over Europe.
EFSA will present an update of their Roadmap of Combined Exposure to Multiple Chemicals, EFSA projects and guidelines on mixture risk assessment.
Following principles described in EFSA guidelines to risk assessment based on HBM data, exposure assessors, toxicologists, epidemiologists and kinetic modellers are collaborating on the interpretation of the risk of co-exposure of prioritized case studies. These are chemical mixtures of heavy metals potentially affecting the kidney, mixtures of PFAS with an impact on the immune system, mixtures of pesticides affecting the nervous system or the thyroid and mixtures of chemicals associated with an effect on IQ loss. More realistic mixtures crossing regulatory silos will be identified from co-exposure of several European HBM surveys. The link between biomarkers of exposure and potential health effects will also be studied. The project will also develop knowledge and tools for identifying sources of exposure and chemicals or food items with a high contribution to the combined risk. The risk assessment of the prioritized mixtures will be performed with the Monte Carlo Risk Assessment (MCRA) software open with training to all the different stakeholders. The integration of toxicological, epidemiological and exposure data is imperative for acquiring a comprehensive understanding of the health effects of exposure to chemical mixtures, and for offering risk management options to reduce the risk when the exposure exceeding effect specific health limits.
Amelie Crepet (ANSES, FR)
Strategy for real-life mixture risk assessment using HBM data
Sara Levorato (European Food Safety Authority (EFSA), IT)
EFSA’s Roadmap RACEMiC Risk Assessment of Combined Exposure to Multiple Chemicals
Kiki Machera (BPI, GR)
Case studies showing the applicability of the strategy
Jasper Engel (Wageningen Research, NL)
Software for mixture risk assessment using HBM data
S14: New insight into mechanisms of food-borne chemical carcinogens
Session Chair(s): Doris Marko (University of Vienna, AT)
Exposure to chemical carcinogens present or formed in foods and beverages may pose a risk to human health. Understanding the mechanisms underlying the carcinogenic effects of food-borne carcinogens is critical to inform human risk assessment. This symposium will provide new insight into the mechanisms of a range of important food-borne carcinogens, including natural food constituents (alkenylbenzenes as secondary plant metabolites and heme iron from red meat) as well as chemical contaminants (inorganic arsenic and mycotoxins). The first speaker will present recent computational approaches to obtain mechanistic insight into the bioactivation of alkyenylbenzenes, including possible species differences. The second talk will focus on the role of heme iron and subsequent chronic intestinal inflammation in colorectal carcinogenesis associated with the consumption of red meat. The third speaker will discuss direct and indirect mechanisms of how inorganic arsenic may modify the epigenome, and how this leads to arsenic-mediated carcinogenesis. In the final talk, new evidence indicating replication stress as an underlying cause in the genotoxicity and carcinogenicity of the mycotoxin ochratoxin A will be presented.
Luca Dellafiora (Department of Food and Drug, University of Parma, IT)
Mechanistic insight into the bioactivation of alkylbenzenes from computational studies
Jörg Fahrer (Technical University of Kaiserslautern, DE)
Mechanism of colorectal carcinogenesis triggered by heme iron from red meat
Yvonne Fondufe-Mittendorf (Van Andel Institute, US)
Epigenomic reprogramming in iAs-mediated carcinogenesis
Christina Klotz (Department of Toxicology, University of Würzburg, DE)
Role of replication stress in ochratoxin A carcinogenicity
S15: Ontology-driven and artificial intelligence-based repeated dose toxicity testing of chemicals for next generation risk assessment
Session Chair(s): Nynke Kramer (Wageningen University & Research , NL)
The goal of the European ONTOX project (1 May 2021-30 April 2026) is to provide a functional and sustainable solution for advancing human risk assessment of chemicals without the use of animals in line with the principles of 21st century toxicity testing and next generation risk assessment. The conceptual cornerstone of ONTOX revolves around ontologies, which allow to gather, structure and integrate data. The methodological cornerstone of ONTOX fully relies on artificial intelligence, which is used for a number of purposes, including data collection. This symposium will illustrate how ontologies and artificial intelligence are the drivers of the building blocks of the ONTOX risk assessment strategy. The first presentation will give a short overview of ONTOX and will discuss tools and strategies for hazard identification, including physiological maps, qAOPS and in vitro test batteries. The second talk will present biokinetic modelling frameworks for refined hazard characterization, and how these can aid in the extrapolation from in vitro to in vivo with respect to specific toxicological endpoints. The third presentation will describe the concept of probabilistic exposure assessment as part of probabilistic risk assessment with the example of PFOA. The fourth presentation will show how to use artificial intelligence to carry out risk characterization through probabilistic risk assessment.
Mathieu Vinken (Vrije Universiteit Brussel, BE)
ONTOX: overview and hazard identification strategy
Susana Proença (esqLABS GmbH, DE)
Biokinetic frameworks for hazard characterization
Trine Husøy (Norwegian Institute of Public Health, NO)
Probabilistic exposure assessment from food and cosmetics
Thomas Hartung (Johns Hopkins University, US)
The use of artificial intelligence in risk characterization through probabilistic risk assessment
OS02: Oral Session 2
12h00 – 13h00
Lunch Break, Poster Viewing 2 and Industry Hosted Sessions
13h00 – 14h00
HESI CITE LECTURE
14h00 – 15h30
S16: PFAS and health: state-of-the-art in some areas of controversy
Session Chair(s): Greet Schoeters (University of Antwerp, BE)
Per- and polyfluoroalkyl substances (PFAS) are abundantly used in a plethora of products with applications in daily life. PFAS are of concern due to their ubiquitous environmental distribution and their potential to accumulate in humans. PFAS research is gaining momentum, yet is still surrounded by quite some controversy. This symposium intends to focus on some of these controversial areas in the PFAS research field. The first presentation will cover exposure of the general population and of residents from hot spot areas assessed by exposure and effect biomarkers to elucidate the PFAS-related exposome. The second presentation will present the latest evidence on PFAS-lipid association, shown in multiple different study designs, considering evidence for confounding, especially in cross-sectional epidemiological studies. The third presentation will highlight the recent advances in the methodology to assess the risk of combined exposure to multiple PFAS, integrating human biomonitoring data and NAMs in risk assessment.
Greet Schoeters (University of Antwerp, BE)
Human exposure to PFAS: what did we learn?
Tony Fletcher (London School of Hygiene & Tropical Medicine, UK)
PFAS and lipids: epidemiological evidence of causal associations
Wieneke Bil (National Institute for Public Health and the Environment, NL)
Recent advances in the risk assessment methodology for PFAS mixtures
S17: Toxicology – a quest for safer firefighting
Session Chair(s): Anne Thoustrup Saber (National Research Centre for the Working Enviroment, DK), Jefferey L. Burgess (University of Arizona, US)
Firefighting activities include a combination of exposures, involving a highly complex mix of hazards such as smoke, soot, heat and strenuous work, use of chemicals, night work and stress. Firefighting exposures have been associated with cancer in humans, with sufficient evidence for causality (recently re-evaluated by the International Agency for Research on Cancer in 2022). From studies around the globe, firefighters have also been reported to suffer more from cardiovascular disease than other worker forces and some studies have reported affected reproductive and neurotoxic endpoints among firefighters. The differences of firefighting realities around the globe, the different fires, the different roles and tasks performed at fire scenes, the changes of used protection equipment and processes, the historical differences within building, electronic and furnish materials and chemicals, contribute to the challenges and complexity of studying mechanisms of toxicity from firefighting.
With this proposal, we intend to raise attention to working evidence from mechanistic pathways, and future paths needed, promoting interdisciplinary discussion among specialists, in order to continue to work on improving the occupational conditions of firefighters.
Jefferey L. Burgess (University of Arizona, US)
Use of biomarkers of effect in evaluating toxicity in firefighters: Results from the US Fire Fighter Cancer Cohort Study
Maria Helena G. Andersen (The National Research Centre for the Working Environment, DK)
Exposure and effect markers during firefighting activities – Danish intervention studies
Anna A. Stec (University of Central Lancashire, UK)
Fire Toxicity- Elephant in the Room?
S18: Advances and Applications in Quantitative Systems Toxicology to Support Chemical Safety Assessment
Session Chair(s): Mark Cronin (Liverpool John Moores University, UK), Huan Yang (esqLABS GmbH, DE)
Quantitative Systems Toxicology (QST) involves the synthesis of toxicodynamic and toxicokinetic information, offering a holistic and mechanism-based solution to predict and understand exposure-response relationship. It provides an opportunity to integrate New Approach Methodology (NAM) data to perform chemical safety assessment. It can be seen as an extension of quantitative Adverse Outcome Pathway (qAOP) modelling utilising and applying information from exposure and toxicokinetics.
This session will explore the state-of-the-art of QST to support chemical safety assessment. It will draw upon the experiences and findings of the EU ASPIS cluster. Specifically, this session will provide examples of the types of models that underpin QST, as well as illustrations of how these technologies are applied to make decisions in industry and a regulatory perspective.
The presentations will illustrate how QST can support next generation risk assessment (NGRA). The first presentation will define and describe how QST models are developed, their purpose and role in animal free chemical safety assessment. This will include an illustrative case study which will explore how to improve the applicability of qAOP toxicodynamic (TD) models by linking them to chemical-specific physiologically-based kinetic (PBK) models. Two approaches for linked PBK-TD modelling: (1) a linear approach applied to a generic AOP describing the mitochondrial toxicity (AOP #3), and (2) a more complex hybrid approach for liver injury will be presented. The use of QST will be exemplified in an industrial setting with a description of how it can be applied to support safety decisions. Lastly, a perspective describing the regulatory perspective, opportunities and expectations of QST will be provided.
Elias Zgheib (Certara France Ltd., FR)
Mathematical and Computational Approaches for Linked qAOP PBK-TD Modelling in a Quantitative Systems Toxicology Context
Andrew White (UnIlever Research, UK)
Application of Quantitative Systems Toxicology to Support Chemical Safety Assessment in the Cosmetics Industry
Georges Kass (European Food Safety Authority (EFSA), IT)
Regulatory Perspective for the Opportunities Afforded by by Quantitative Systems Toxicology in Chemical Safety Assessment
S19: Getting scientific confidence for NAM-based regulatory assessments
Session Chair(s): Suzanne Fitzpatrick (US Food and Drug Administration, US), Jose V Tarazona (Spanish National Environmental Health Centre, ES)
Although development of New Approach Methods (NAMS) has accelerated in recent years, validation and acceptance strategies have not followed at the same pace. Until recently, concordant animal data was considered the “gold standard” for determining whether a NAM was as “good or better” than the traditional test. But discussions have been ongoing that data derived from animal studies has questionable or limited value in characterizing the biological relevance of data on chemical effects on humans. And often there are endpoints where no comparable animal test exists. A modern, more flexible framework to establish scientific confidence in NAMS for regulatory assessment of chemicals for human health effects is needed. But what information are needed to move away from using concordant animal data? And what is needed to establish confidence in this new more mechanistic framework to ensure it will be accepted by both regulators and end-users of NAMs?
This workshop will present the views of different experts, representing a broad spectrum of stakeholders covering scientific, political and societal views, followed by a panel discussion aiming at setting the foundations for generating the required confidence in NAM-based risk assessments.
Philip Marx-Stölting (German Federal Institute for Risk Assessment, DE)
PARC and other current EU scientific initiatives
Donna Macmillan (ICCS – International Collaboration on Cosmetics Safety, USA)
The societal needs
Jutta Paulus (European Parliament Group of the Greens/European Free Alliance, BE)
The political and regulatory needs
15h30 – 16h00
Coffee Break and Poster Viewing 2
16h00 – 18h00
S20: Opportunities and challenges for PB(P)K models to uncover the role of maternal transfer in developmental toxicity
Session Chair(s): Nynke Kramer (Wageningen University & Research , NL), Alicia Paini (EFSA, IT)
Physiologically based (pharmaco)kinetic (PB(P)K) models have been used to aid study design, dose adjustments and risk assessment interpretation. Usually, these models describe the average human adult; however, they can also be developed to represent paediatrics and pregnancy life stages. More than 200 models have been developed for maternal-fetal chemical disposition. In line with the recently published OECD DNT guidance document (release date May2023), more of these models will be needed to extrapolate from in vitro concentration to in vivo. The present session will provide a state-of-the-art of PB(P)K model for pregnancy already developed. The first speaker will briefly introduce the OECD DNT Guidance document with insight into the In Vitro to In Vivo Extrapolation (IVIVE) approach proposed and the application of PB(P)K modelling (M. Sachana). The session will continue with a presentation on PB(P)K models principles and applying them for maternal-fetal drug disposition for therapeutics and safety (K. Fairman). While the third talk will present a high-level overview and selected case examples of maternal-fetal PB(P)K modeling in the field of clinical pharmacology, discuss recent learnings gained from modeling placental transfer and fetal exposure to pharmaceutical drugs, and how these learnings can be leveraged in crop sciences and human health risk assessment (A. Dallmann). The session will conclude with a talk on Generic Pharmacokinetic Models for Mother-to-Offspring Transfer of environmental Chemicals (D. Kapraun).
Alicia Paini (EFSA, IT)
Guidance on Evaluation of Data from the Developmental Neurotoxicity (DNT) In-Vitro Testing Battery – Annex In Vitro in Vivo Extrapolation
Kiara Fairman (US Food and Drug Administration (FDA), US)
Maternal and Maternal-Fetal PBPK Models for Estimating Therapeutic Efficacy and Safety in Pregnancy
André Dallmann (Bayer, DE)
Maternal-fetal PBK modeling in the field of clinical pharmacology: Insights and future directions
Dustin Kapraun (US EPA, US)
Generic Pharmacokinetic Models for Mother-to-Offspring Transfer of environmental Chemicals
S21: Microphysiological systems as emerging tools in predictive toxicology
Session Chair(s): Lena Smirnova (Johns Hopkins University Bloomberg School of Public Health, US)
The symposium will revolve around microphysiological systems, which are gaining momentum in the field of toxicology. The first presentation will provide some examples of using microphysiological systems for developmental neurotoxicity testing and gene environmental interactions in the context of neurodevelopmental disorders. Furthermore, a historical perspective on how the MPS society was established and promotes the use of microphysiological systems towards regulatory safety testing will be given. The second presentation will discuss the combination of pluripotent stem cell technology with microfluidic devices tailored to create physiological micro-environments and recapitulate 3D tissue structure and function with focus on the heart. The third presentation will focus on kidney in vitro models that incorporate flow. Specific emphasis will be put on the possibilities offered by microphysiological systems to generate multi-organ cultures combining liver and kidney. In addition, the use of miRNAs and proteins as extracellular biomarkers of nephrotoxicity will be discussed.. The fourth presentation will show how microphysiological systems can be used while retaining screening compatibility. This will be demonstrated by a high-throughput liver toxicity screening platform with unparalleled physiological complexity.
Lena Smirnova (Johns Hopkins University Bloomberg School of Public Health, US)
From microphysiological system research to international society
Peter Loskill (Eberhard Karls University of Tübingen, DE)
Heart-on-chip systems: next-generation microphysiological in vitro models for pharmacology and toxicology
Laura Suter-Dick (University of Applied Sciences and Arts Northwestern Switzerland, CH)
Kidney models and nephrotoxicity: microfluidics and biomarkers
Vincent van Duinen (MIMETAS, NL)
High-throughput screening for liver toxicity: a new era of complexity with organ-on-chip technology
S22: What’s new for addressing safety: a multi stakeholders’ perspective
Session Chair(s): Maria Baltazar (SEAC Unilever, UK), Arianna Giusti (Cosmetics Europe, BE)
Recently, several European and international multi-stakeholder projects were initiated to address existing gaps in environmental and human health safety assessment. They address scientific and technical gaps together with needs for building capacity, education, and training as well as regulatory engagement. This session will feature the cutting-edge global programs led by different stakeholders from industry, academia, regulatory and global harmonisation bodies. The International Collaboration on Cosmetic Safety was created with the desire to develop robust and human relevant non animal approaches for the safety of cosmetic ingredients, which could be applied worldwide. In this first talk, the speaker will give an update of the scientific ambition of the research program and lessons learnt from previous next generation risk assessment (NGRA) case studies. In the second talk, progress on the PARC initiative will provide insights to the ways in which the regulatory community is developing new strategies to address current and future challenges in chemical safety. The third talk will focus on the European Project Ontox which aims at developing physiological maps, qAOP networks and ontology frameworks by integrating biological and kinetic information aided by artificial intelligence. Finally, there is a need to evaluate and build confidence in these new technologies if regulatory acceptance is to be achieved. Therefore, the last talk will provide an overview of efforts by the OECD to develop a new regulatory paradigm for increased robustness in chemical testing global harmonization program. A Q&A session will close this symposium.
Gladys Ouédraogo (L’Oréal Research & Innovation, FR)
Update on the science program of the International Collaboration on Cosmetics Safety
Matthias Herzler (German Federal Institute for Risk Assessment (BfR), DE)
Perspectives from regulators: progress from the EU PARC initiative
Erwin L Roggen (3Rs Management and consulting ApS, DK)
Where science meets technology: probabilistic risk assessment
Magdalini Sachana (Environment Health and Safety Division, OECD, FR)
Building confidence in 21st first century approaches: perspective from the OECD
S23: Bringing NGRA to life – A global joint effort for putting Next-Generation Risk Assessment into practice
Session Chair(s): Hennicke Kamp (BASF Metabolome Solutions GmbH, DE), Georges Kass (European Food Safety Authority (EFSA), IT)
In recent years, global efforts have advanced the risk assessment of chemical substances, integrating exposure and hazard assessment models and implementing new approach methodologies (NAMs). Next-generation risk assessment (NGRA) has emerged as a viable approach, benefiting from scientific and technological advancements. This includes the development of models for rapid exposure predictions, high-throughput toxicokinetic modeling, and innovative in vitro approaches for toxicity testing. However, while some case studies have demonstrated the applicability of NGRA, its full integration into regulatory risk assessment remains limited.
This session aims to address this issue by presenting relevant initiatives that facilitate the faster implementation of NGRA for chemical risk assessment. One of the most relevant initiatives is the ASPA (ASPIS Safety Profiling Algorithm) workflow, developed under the Horizon 2020-funded ASPIS cluster. ASPA follows a tiered approach, guiding the selection of NAMs for data generation and assessment, and evaluating associated uncertainties. The session will introduce the general concept and key aspects of ASPA. It will also share initial insights gained from applying ASPA to case studies that tackle specific regulatory problems. The first case study will focus on using a NAM-based testing strategy to characterize the hazards of compounds that form shared metabolites, which could raise regulatory concerns. The second case study demonstrates a tiered assessment strategy that employs NAMs for prioritization and screening approaches. Around 100 chemicals, classified as toxic or low toxic based on studies primarily extracted from the ECHA CHEM database, have been tested using a high-throughput NAMs battery.
Since ASPA is continuously refined and improved in collaboration with related initiatives, this session will finally explore synergies with other projects, such as the European initiative PARC (Partnership for the Assessment of Risks from Chemicals) and the US EPA (Environmental Protection Agency). Presentations will outline the development of roadmaps, including the PARCtour, and platforms like RapidTox, a workflow suite that utilizes available NAM-based data for deriving human health assessment values. The session aims to highlight synergies and complementary aspects among these initiatives and foster collaborations.
Mirjam Luijten (RIVM, NL)
The ASPIS Safety Profiling Algorithm (ASPA): setting the stage for NGRA
Barira Islam (Certara, UK)
Assessment and modelling of metabolites – the Conazole case study
Sylvia Escher (Fraunhofer ITEM, DE)
Prioritization and screening – which testing scope is sufficient?
Jason Lambert (U.S. EPA, US)
RapidTox: Decision-based workflow environment to advance human health assessment
Matthias Herzler (BfR, DE)
PARCroute: a road from innovative science to regulatory risk assessment practice
19h30 – 24h00
Congress Dinner
Wednesday, 11 September 2024
08h30 – 09h30
KEYNOTE LECTURE: The Toxicology of Inhaled Nanomaterials and Examples of Risk Assessment and Regulation
Ulla Birgitte Vogel, National Research Centre for the Working Environment, DK
09h30 – 11h30
S24: New approach methods for risk assessment of thyroid disrupting chemicals
Session Chair(s): Stephanie Melching-Kollmuss (BASF SE, DE), Martin Wilks (University of Basel, CH)
More than 5 years after the introduction of criteria for endocrine disruption and the publication of an ECHA/EFSA Guidance, the investigation and assessment of thyroid hormone disruptors remains challenging. From a regulatory perspective the most relevant adverse human health outcomes are cognitive learning and memory deficits. However, there are uncertainties regarding the sensitivity of neurodevelopmental parameters investigated in rat in vivo studies, the accuracy and predictivity of thyroid hormone and/or thyroid histopathological effects for neurodevelopmental toxicity, and how any identified effects may translate to humans. Validated in vitro assays investigating thyroid molecular initiating events (MIE) are not available; in addition, there are numerous possible MIEs, leading to thyroid hormone changes in vivo which results in a complex adverse outcome pathway (AOP) network, with insufficiently described key events. This symposium will demonstrate how new approach methods (NAMs) can form the basis for a human-relevant testing strategy based on mechanistic understanding in an AOP-based testing strategy, including quantitative elements. The first presentation will cover the scientific framework. This includes, how substances that cause thyroid effects in rodents can be tested using human-relevant NAMs, and how key event relationships will need to be established. The second presentation investigates if biomarkers of thyroid hormone action in the rat brain could serve as predictive readouts of developmental neurotoxicity. Promising early results have shown that targeted gene expression and histopathology assays hold great promise as biomarkers of effects, and could be incorporated into in vivo guideline studies to reduce uncertainty in chemical evaluation. The third presentation explores the quantitative relationships between thyroid hormone levels and thyroid toxicity by means of a Quantitative Systems Toxicology (QST) modelling, developed to support thyroid toxicity assessment in rat and human for next generation risk assessment (NGRA). The TH QST platform comprises physiologically based kinetic (PBK) models for T3, T4 and TSH. Finally, results will be presented from experiments with multiorgan on a chip technology to aid on the mechanistic understanding of thyroid disruptors in rats and to actually compare the rat with the human system. In total, this session summarizes innovative approaches to improve the evaluation of thyroid disrupting chemicals.
Ellen Hessel (Dutch National Institute for Public Health and the Environment, NL)
Building an IATA-based testing strategy for thyroid-mediated developmental neurotoxicity
Katie O’Shaughnessy (US-EPA, US)
Biomarkers of Neurodevelopmental Effect Can Reduce Uncertainty When Assessing the Risks of Thyroid Disrupting Chemicals
Stefan Schaller (esqLABS, DE)
Thyroid Hormones Quantitative Systems Toxicology Platform (TH QST Platform) in Rat and Human for cross-species NGRA
Julia Kuehnlenz (Bayer Cropscience France, FR)
3D thyroid and liver models: a holistic in vitro approach for mechanistic investigations of agrochemicals
S25: Towards the Implementation of Virtual Control Groups – Regulatory and Scientific Challenges
Session Chair(s): Peter Hald Brinck (NovoNordisk, DK)
The concept of Virtual Control Groups (ViCoG) has been developed in the Innovative Medicine Initiative (IMI) consortium, eTRANSAFE (https://etransafe.eu/, Steger-Hartmann et al. ALTEX 2020). The ViCoG aims at replacing concurrent control animals in toxicity studies with historical data indicating that up to 25% of the animals can be replaced in most in vivo studies.
The symposium will outline the current status and the perspectives on the development of the ViCoG and its roadmap for qualification and implementation.
An overview will be provided on the establishment of a control group repository, the challenges associated to data harmonization and curation. To date, EFPIA companies started to share single animal data from control groups using standardized SEND format. The repository currently contains data for more than 70.000 animals including rat, mouse, dog, and non-human primates as major species. First use cases on statistical evaluation of the performance of virtual controls compared to current controls will be provided.
Applying the VCG concept to regulatory toxicity studies is currently the ultimate challenge. Therefore, a perspective will be provided on hurdles and opportunities of ViCoGs in a regulatory context.
Thomas Hartung (Center for Alternative to Animal Testing, US)
Virtual Control Groups – Roadmap into 3R
Frank Bringezu (Merck HealthCare KGaA, DE)
ViCoG DB – a cross company control repository
Sylvia Escher (Fraunhofer ITEM, DE)
Analytical approaches to build and evaluate ViCoGs
Kevin Snyder (US Food and Drug Administration (FDA), US)
ViCoG – a regulatory perspective
S26: Risk assessment under the real-life risk simulation (RLRS) approach – new technologies and mechanistic data
Session Chair(s): Aristidis Tsatsakis (University of Crete, GR)
In real life, where individuals are exposed to a multiplicity of chemicals from diferent routes in low doses, exposure assessment becomes a complex task, even with biomonitoring techniques, and makes it hard to identify causal associations with long-term adverse effects evidenced by epidemiological studies. The current regulatory risk assessment approach is based on studies administering single chemicals at unrealistically high doses, followed by the identification of the dose which is associated with no observable adverse effects. This approach does not provide an integrated assessment of the potential multiple risks associated with complex exposures inherent to real-life scenarios. Hence, the impact of combined and intermittent exposures at variable realistic doses of diverse environmental stressors is not properly addressed, which may lead to an underestimation of risk. Evidence from studies addressing simulation of real-life exposures has shown that long-term exposure to low-doses of chemicals used daily, which are presumed to be safe for human health, can impair biological processes. Novel assessment methodologies, such as in chemico, in silico, in vitro, and high-throughput multi-omics techniques can detect or predict changes in genes, mRNA, proteins, or metabolites in biological samples in response to chemical exposures. While these techniques can be useful in examining MoA, for using them in hazard assessment a strong link needs to be biologically plausible between their results and apical effects observed in in vivo or epidemiological studies. Of particular concern are complex diseases, which are not properly captured by in vivo experimental toxicological studies. However, multidimensional datasets integrating various data streams can be used to develop systems-biology levels of understanding of chemical effects. In this regard, the definition of signatures of toxicity based on molecular endpoints represents a novel development to define adversity. The development of various computational methods can facilitate integration of these datasets into biological networks. This symposium will address and discuss how different models and methodologies can be integrated to increase the reliability and confidence in chemical risk assessment by considering multiple streams of evidence that are heterogeneous in nature.
Docea Anca Oana (University of Medicine and Pharmacy Craiova, RO)
Evidenced from experimental studies on real-life risk simulation supporting the need of new risk assessment evaluations
Dimosthenis Sarigiannis (Hellenic Society of Toxicology, GR)
The exposome approach to real-life risk assessment
Antonio F. Hernández Jerez (University of Granada Spain/Spanish Society of Toxicology, ES)
Challenges posed by real-life exposure scenarios – A Systems Toxicology approach to integrated assessment of multiple risks
Aristidis Tsatsakis (University of Crete, GR)
The concept of risk assessment evaluations in 21 century
OS03: Oral Session 3
11h30 – 12h00
Coffee Break
12h00 – 13h30
S27: Interindividual variability in toxicokinetics and toxicodynamics in chemical safety assessment
Session Chair(s): Jean-Lou Dorne (European Food Safety Authority (EFSA), IT)
Current chemical risk assessment involves safety factors that consider interindividual variability in the human population. The rationale is based on variability related to absorption, distribution, metabolism and excretion that drive the toxicokinetics of chemical substances. In addition, toxicological responses can be variable due to differences in the biological programs that drive adverse responses. While environmental and life-style factors contribute to the overall variability, in the healthy population genetic polymorphisms in genes directly controlling toxicokinetics and toxicodynamic responses are likely causative factors for the human interindividual variability. In this session we will address recent advances in our understanding of the interindividual variability in toxicokinetics and toxicodynamics and how they compare to the toxicokinetics and toxicodynamic uncertainty factors of 3.2 that are traditionally used in chemical risk assessment to account for human variability. We will focus on the known genetic polymorphisms in both transporters and drug metabolism enzymes that contribute to the variability in toxicokinetics and the overall consequences for this variability for the safety factor related to toxicokinetics. Subsequently we will discuss the variability in toxicodynamics based on transcriptional profiling observed in a large panel of primary human liver hepatocyte donors as well as primary human peripheral blood monocyte donors in relation to activation of diverse chemical substances that activate specific toxicity pathways and how this impacts on the understanding of safety factors related to toxicodynamics. Finally, we will discuss real life examples from clinical studies on how systematic evaluation of genetic variability in critical polymorphisms related to drug metabolism has direct impact on personalized medicine and can prevent drug-induced adverse responses in a clinical setting. This symposium will provide scientific understanding of underlying mechanisms of interindividual variability of adverse responses and show how novel insights can contribute to a scientific underpinning of safety factors that are used in chemical risk assessment.
Georges Kass (European Food Safety Authority (EFSA), IT)
Toxicokinetic and toxicodynamic uncertainties in chemical safety assessment.
Emanuela Testai (Istituto Superioro di Sanita, IT)
Human interindividual variability of toxicokinetics.
Bob van de Water (Leiden University, NL)
Population variability of toxicodynamics driving adverse responses.
Henk-Jan Guchelaar (Leiden University Medical Center, NL)
Pharmacogenetics monitoring in personalized medicine to prevent drug-induced adversities.
S28: HOT TOPIC: How to build trust in Artificial Intelligence for Toxicology?
Session Chair(s): tba
Science is producing data in exponentially increasing amounts, and scientists are rapidly and increasingly turning towards artificial intelligence (AI) and machine learning (ML) based tools to manage the data, identify patterns, or to otherwise exploit this information. In addition, generative AI provides the option to automate or at least facilitate time consuming tasks such as report generation using large language models (LLMs), releasing resources that can be better spent elsewhere. Recent advances in computing have also greatly improved access to and performance of these tools.
Yet, despite its power, implementation of AI also comes with challenges and risks. Examples of failures leading to unreliable results as a result of incorrect use by scientists who are unfamiliar with the details, or the use of inadequately trained models or unsuitable input data sets have been documented extensively. Mitigating potential harm and addressing legal as well as ethical challenges from the use of AI therefore becomes a pre-requisite for its implementation.
The aim of this session is to discuss the risks of AI, the impact these could have for toxicology and chemical risk assessment and the mitigation steps that are available to scientists.
Shelley Stall (AGU, USA)
Garbage in, garbage out: How to mitigate risks and maximise benefits of AI.
Carsten Kneuer (BfR, DE)
AI and ML in chemical risk assessment: opportunities, challenges, solutions
Karim Jebari (Institute for Future Studies, SE)
Ethics and AI: what does the EU AI Act bring?
S29: Integration of developmental neurotoxicity data across adverse outcomes for improved safety assessment of chemicals
Session Chair(s): Yue Ge (US Environmental Protection Agency (EPA), US), Anna Bal-Price (European Commission, Joint Research Centre, IT)
Due to the extreme molecular and cellular heterogeneity of the developing nervous system in different species, defining the complicated neuronal development processes and extrapolating developmental neurotoxicity (DNT) using currently available molecular targets, indicators or biomarkers is challenging, and a high priority need is the ability to extrapolate DNT data from in vitro to in vivo in a predictive manner. Although several human stem cell-based models have shown promise when used for in vitro DNT testing, development of information to link these assays and the events measured by these assays to adverse outcomes (AOs) in vivo has lagged behind assay development. There is a clear need to identify molecular targets, signatures, and biomarkers that can directly, accurately, and efficiently facilitate in vitro to in vivo extrapolation and aid in development of novel approach and methodologies (NAMS) for DNT assessment. The major goal of this session is to present the most recent research, in vitro, in vivo, and in silico, on the identification of molecular targets, signatures, and biomarkers linked to adverse outcome pathways (AOPs) that can be translated to in vivo toxicity and effective bioassays for risk assessment of the chemicals.
The session will cover:
•Identification of novel molecular targets, signatures, and biomarkers of genes, proteins and metabolites that reflect both molecular initiating events (MIEs) and neuronal development stages, using in vitro human cell culture systems and in vivo model organisms exposed to environmental and pharmaceutical chemicals
•Development of AOPs that link molecular changes of gene, proteins, and metabolites from in vitro to in vivo and AOs either by comparison of the in vitro and in vivo changes after treatment with chemicals or by focused in vivo testing to examine AOs indicated by alterations in the AOPs
•Application of molecular targets, signatures, and biomarkers linking DNT Data and AOP to the development of innovative bioassays for high throughput screening of environmental chemicals, pharmaceuticals, and materials
Yue Ge (US Environmental Protection Agency (EPA), US)
Novel molecular and cellular approaches for linking developmental neurontoxicity data to adverse outcomes to support risk assessment of neurotoxicant
Anna Bal-Price (European Commission, Joint Research Centre, IT)
Assessment of developmental neurotoxicity induced by chemical mixtures using an adverse outcome pathway concept
Nicoleta Spînu (Liverpool John Moores University, UK)
Prediction of the neurotoxic potential of chemicals based on modelling of molecular initiating events upstream of the adverse outcome pathways of neurotoxicity
OS04: Oral session 4
13h30 – 14h00
Closing Ceremony and Awards Presentation
14h00 – 17h00
Workshop: Dose level selection for Developmental and Reproductive Toxicology (DART) studies
15h00 – 20h00
ASPIS Open Symposium