Sunday, 10 September 2023
10h00 – 16h00
Continuing Education Courses (CEC)
CEC01: A hands-on introduction to applied artificial intelligence in toxicology
The application of Artificial Intelligence (AI) has experienced an upsurge in almost all scientific disciplines. From physics and medicine to social sciences and biology, scientists have been increasingly applying advanced machine learning and deep learning techniques to solve problems that seemed unsolvable for a long time. Not only is AI changing the way we tackle scientific challenges, it is also revolutionizing the way we collaborate. More researchers than ever are using open-source software for computations and to write algorithms. Increasingly, this work is shared via publicly available repositories.
In this research Continued Education Course, we aim to organize a number of hands-on demonstrations on how to apply programming to develop machine learning approaches to address toxicological challenges. Because both programming languages R and Python are popular tools to do this, we chose to organize two tracks with a shared start and ending. The demonstrations in the R track will address building a machine learning and deep learning model to apply these in the context of classification and read-across QSARs. The Python track will focus on applying deep learning in toxicology.
The course also focuses on sharing good practices for collaborating on code and publishing your data science products in a reproducible manner. We will close the course with a demonstration on how to effectively organize your work as a researcher involved in data science activities.
For this course, you will need to bring a laptop. There will be an online cloud computing instance that participants can use to run all the code examples and get access to the course materials. All materials will be made available to the participants during the course.
This course is aimed at researchers that are familiar with or just starting with programming for AI applications in the toxicological domain. If you have no experience at all, you can also participate but we recommend some self-paced study in advance. If you are in doubt, please reach out to the course organizer.
Thomas Hartung (John’s Hopkins University, USA)
Introducing Artificial Intelligence in Toxicology (keynote 1 – track A)
Marc Teunis (University of Applied Sciences, NL)
Machine learning with R (hands-on 1 – track A)
Thomas Luechtefeld (Toxtrack/ JHU, USA)
Read across QSAR for probabilistic risk assessment; A hands on demo in R // (hands-on 2 -track A
Djork-Arne Clever (Bayer Pharmaceuticals, DE)
An introduction to Machine Learning in Python (hands-on 1 – Track B)
Priyanka Banerjee (Charite, DE)
Advanced Deep Learning for Toxicology (hands-on 2 -track B)
Giulia Callegaro (Leiden University, NL)
Toxicogenomics data and analysis workflow // (hands-on 3 -track A) Good coding practices
Alyanne De Haan (University of Applied Sciences, NL)
Publishing your work and code -collaboration // hands-on 4 – track A and B)
CEC02: Characterizing, validating, and reporting physiologically-based kinetic models – hands on training on the new PBK model OECD guidance
Physiologically Based Kinetic (PBK) modelling is a scientifically-sound tool for predicting internal dose metrics by describing the critical physiological, physicochemical, and biochemical processes that determines the disposition of a chemical in an organism. Traditionally, the calibration of parameters in a PBK model and the validation of its predictive capability rely heavily on comparing model simulations with in vivo data. The availability of in vivo data is limited to a few well-studied chemicals, which impedes the broader applications of PBK models by regulatory agencies. As increasing emphasis is being placed on using non-animal data to assess health risks posed by chemical exposures, PBK models plays a critical role in converting in vitro points of departure to exposure levels. In this case, PBK models also need to rely on non-animal data to inform kinetic parameters. In 2017, an OECD project has initiated to develop a guidance on characterising, validating, and reporting PBK models without the use of animal data. This guidance document highlights non-animal approaches that can be used to parameterise PBK models, and recommends modelling assessment framework and tools for evaluating the credibility of these models for their intended purposes. The goal for this guidance document is to promote the acceptance and use of PBK models in a regulatory context. This CEC is intended to support such effort by providing training on the use of this guidance document. The first half of the CEC will involve six presentations to give an overview of the different sections in the guidance document, including a PBK modelling workflow and non-animal approaches for model parameterisation, and PBK modelling assessment framework and model evaluation toolbox. A case study will also be presented to demonstrate how to use the guidance document to construct and evaluate a PBK model. The second half of the CEC will involve two role-playing trainings for participants to apply the knowledge they learned in the first half of the CEC as PBK modellers and model reviewers. Through these presentations and exercises, the participants will gain deeper understanding of the principles in development and evaluation of PBK models without using animal data.
Magda Sachana (OECD, FR)
An international effort to promote the regulatory use of PBK models based on non-animal data
Alicia Paini (esqLABs GmbH, DE)
PBK modelling workflow and in vitro methods for model parameterisation
Iain Gardner (Certara UK Limited, Simcyp Division, UK)
PBK modelling platforms and in silico methods for model parameterisation
Cecilia Tan (US EPA, USA)
PBK modelling assessment framework – PBK model evaluation toolbox
George Loizou (HSE Science and Research Centre, UK)
PBK modelling assessment – uncertainty and sentivity analysis characterization
Jean-Lou Dorne (EFSA, IT)
Demonstration of PBK model evaluation – fish and farm animals case study
CEC03: Building a NAM-based IATA for chemical risk assessment
Chemical risk assessment relies mostly on in vivo animal toxicity data, using traditional endpoint measurements. However, much investment and progress has been made in the development and regulatory application of new methodologies and tools, the so-called New Approach Methodologies or NAMs. In the EU, projects such as EU-TOXRISK and RISK-HUNT3R have paved much of the way to support the evolution towards the application of these new tools to chemical risk assessment. However, even though the new methods are becoming sufficiently mature for regulatory considerations, challenges remain, often linked to a lack of confidence in their use for decision making. Therefore, it has become urgent to address the lack of confidence through targeted educational and training events.
This CEC has been developed for this exact purpose. Through interactive sessions, the key problems such as NAMs identification and their integration into IATAs to meet regulatory acceptability will be addressed. The CEC will also include issues like uncertainty and how to submit a NAM-based IATA into IUCLID to meet data format requirements.
Costanza Rovida (CAAT-Europe, DE)
Set the stage (Theoretical lecture)
Magdalini Sachana (OECD, FR)
Introduction to the IATA structure (Theoretical lecture)
Sylvia Escher (ITEM Fraunhofer, DE)
Examples of a NAM-IATA for repeated dose toxicity (Theoretical lecture)
George Kass (EFSA, IT)
Building a IATA, piece by piece (Hands-on activity)
Susanne Fitzpatrick (US FDA, USA)
Acceptability issues: How to select the most suitable NAM and Regulatory perspectives (Theoretical lecture)
Salomon Sand (Swedish Food Agency, SE)
Guidance on Uncertainty Analysis in Scientific Assessments (Theoretical lecture)
Costanza Rovida (CAAT-Europe, DE)
Submission of NAM-based IATA into IUCLID (Hands-on activity)
CEC04: Risk perception and risk communication of chemical substances
Existing chemical risks (e.g., PFAS, household chemicals, pesticides) or the public outrage over perceived risks (e.g., Aspartame, MSG) highlight the importance and complexity of effective risk communication. Communicating risks and related uncertainties is part of our work as toxicologists. However, toxicologists perceive risks differently than lay people. Toxicologists assess risks based on hazard and exposure but lay judgement is based on an interaction of values, beliefs and expectations (‘intuitive toxicology’). Therefore, risk communication based on scientific information alone does not align with lay perspectives and information needs and reinforces misperceptions. Toxicologists need to better understand how different risk perceptions come about, but they have little training in risk communication. This workshop, jointly organised by the Swiss Centre for Applied Human Toxicology (SCAHT and EFSA), introduces key principles of public risk perception and shows their relevance for (risk) communication within topical and applied use cases. This will help us in developing targeted risk communication approaches with different stakeholders, to strengthen trust in science and create broad agreement on risk-reducing measures.
Tom Jansen will discuss some distinct factors that contribute to misperception and miscommunication between toxicologists and the general public and Domagoj Vrbos will present key insights from Eurobarometer research on chemical risk perception and present implications and appraoches from EFSA’s work in risk communication.
The psychological principles introduced will then be discussed in light of four specific use cases. Ellise Suffill and Nadja Contzen will present current research on risk communication and risk perception in the field of PFAS (Suffill) and pesticides (Contzen). Angela Bearth will introduce key findings on laypeople’s use of risk labels on chemical products and their adherence to safety instructions, and Annalise Richmond and Gerard Stihntjes will talk about factors contributing to unintended poisoning of infants in the home and the role of educational communication and product packaging design as a means to help mitigate risk through behavioural change from the perspective of the industry.
The workshop will close with an interactive session, where participants can introduce their own questions and challenges and discuss them with the speakers.
Tom Jansen (National Institute for Public Health and the Environment (RIVM), NL)
Misperception and miscommunication. Barriers and opportunities for effective communication about risks from chemical substances.
Domagoj Vrbos (European Food Safety Authority (EFSA), IT)
Perception of chemical substances > insights from social research at EU level in the area of food safety (based on EFSA Eurobarometer and EU insight studies).
Ellise Suffill (University of Vienna Environmnetal psychology, AU)
Expert and lay perspectives on the health risks, ‘essentiality’, and substitutability’ of Per- and Polyflouroalkyl Substances (PFAS) in everyday products.
Nadja Contzen (Eawag: Swiss Federal Institute of Aquatic Science and Technology, CH)
Risk perception of pesticides.
Angela Bearth (ETH Zürich, CH)
Household chemicals, their packaging and labelling: implications for consumers’ risk perception and adherence to safety instructions.
Anna Richmond (Procter & Gamble (P&G), BE)
Unintended interactions with Liquid Laundry Capsules – A case study to showcase how a unique partnership between Toxicology and Behaviorial Science changed a pack to reduce the risk of infant accidents in the home.
Gerard Stijntjes (Procter & Gamble (P&G), BE)
Unintended interactions with Liquid Laundry Capsules – A case study to showcase how a unique partnership between Toxicology and Behaviorial Science changed a pack to reduce the risk of infant accidents in the home.
CEC05: Particle and fiber toxicology
This Education Course is intended for toxicologists who would like to keep up to date on the latest developments in the field of particle and fibre toxicology. Particles and fibres affect human health as a function of their properties such as chemical composition, size and shape but also depending on complex interactions in an organism that occur at various levels between particle uptake and target organ responses. While particulate pollution is one of the leading contributors to the global burden of disease, particles are also increasingly used for medical purposes. Over the past decades we have gained considerable experience in how particle properties and particle-bio interactions are linked to human health. This insight is useful for improved risk management in the case of unwanted health effects but also for developing novel medical therapies. The concepts that help us better understand particles’ and fibres’ risks include the fate of particles in the body; exposure, dosimetry and dose-metrics and the 5 Bs: bioavailability, biopersistence, bioprocessing, biomodification and bioclearance of (nano)particles. This course will address all these aspect with examples from occupational toxicology, air pollution, nanomaterials and micriplastics. The course will also touch upon Integrated Approaches to Testing and Assessment (IATAs) to streamline hazard testing and Safe-by-Design, focusing on the testing for safety of compounds/materials during the development process and what critical aspects of particles and fibres need to be considered when designing new materials.
Flemming Cassee (Utrecht University, NL)
From exposure to dose and biodistribution upon inhalation
Paul Borm (Nanoconsult, NL)
Occupational toxicology of particles and fibres
Roel Schins (IUF – Leibniz Research Institute for Environmental Medicine, DE)
a) Oral exposure b) Neurodegenation
Mark Miller (Centre for Cardiovascular Science at the University of Edinburgh, UK)
Systemic effects due to nano-size particles
Vicki Stone (Heriot Watt University, UK)
IATAs, grouping and read-across for solid particles
CEC06: Recent perspectives for the safe use of pesticides in agriculture
This one-day tutorial with five lectures and two exercise sessions will address the main contemporary topics in the safe use of pesticides in agriculture, with emphasis to state-of-the-art knowledge on its main facets. Especially prepared tutorials from international experts will address a wide array of knowledge and recent trends in research. Key lectures will topic the size and urgency of the problem (epidemiology); the different tiered approaches to the authorization pathway for new and renewal of authorization for existing products in the EU; tools for prevention of risk and protection of workers performing different tasks, with presentation of tiered personal protective equipment; strategies for protection of the general population. In particular, the tutorial course will present the main computer-based tools currently available for risk assessment of occupational exposure, with emphasis on their modelling basis and hands-on guided practice of several available web-based and stand-alone software resources. Tutorials will also include discussion of recent cases, around which suitable occasion for guided discussion is reserved and encouraged. A Take-Home Message session will summarize lecture, exercise and discussion outcomes among participants. Lectures are tailored both to an audience of specialists seeking update and to newcomers to the field who will be introduced to key players for further discussion and to practicing colleagues to further contacts among EU-and-outside-EU professionals working on the topics.
Claudio Colosio (Università degli Studi di Milano, IT)
Introduction – Pesticides old risks and new scenarios
Angelo Moretto (Università di Padova, IT)
Registration, authorization, renewal of pesticides; how the system works in EU and what it offers to the post marketing risk assessment at the workplace
Isabelle Baldi (University of Bordeaux, FR)
Epidemiology of pesticides: recent data
Antonio Hernandez (University of Grenada, ES)
Integration of epidemiology with other lines of scientific evidence into pesticide occupational risk Assessment
Aris Tsatsakis (University of Crete, GR)
Examples of pesticide occupational exposure monitoring in the field
Alain Garrigou (University of Bordeaux, FR)
The use of personal Protective Equipment
Tanja Fatur (National Institute of Public Health, SI)
Practical exercise concerning pesticides with RA of plant protection products for operators, workers, bystanders and residents.
Bolcic Tavcar Mateja (National Institute of Public Health, SI)
Practical exercise concerning pesticides with RA of plant protection products for operators, workers, bystanders and residents.
Federico Maria Rubino (Università degli Studi di Milano, IT)
Practical case-solving with the integrated use of available tools for pesticide risk assessment.
Claudio Colosio (Università degli Studi di Milano, IT)
Guided discussion & take-home messages
Monday, 11 September 2023
08h30 – 09h30
EUROTOX LECTURE AWARD
09h30 – 10h00
Coffee Break and Poster Viewing 1
10h00 – 12h00
S01: Human biomonitoring – a view to the future based on current achievements
Human Biomonitoring (HBM) is a tool for determination and surveillance of chemical exposure in human matrices, such as fluids, cells, tissues and biochemical processes resulting from exposure to chemicals. HBM serves for the assessment of exposure, effects and susceptibility, enables risk assessment based on human data, and provides for risk management a follow-up tool to evaluate risk reduction measures. HBM of exposure is determination of concentrations of exogenous chemicals in body fluids and tissues and has become an increasingly important tool in exposure assessment from all routes of exposure and a variety of sources. Besides the recent developments in determining and refining biomarkers of exposure to a wide range of chemicals (bisphenols, metals, mycotoxins, pesticides, phthalates and their substitutes, perfluoro chemicals, persistent organic chemicals, triclosan, volatile organic chemicals) and/or their metabolites in classical matrices such as urine, blood, serum, human milk etc., a special presentation will be devoted to deciduous teeth. The skeletal compartment is an important chemical repository, making calcified tissues important for measuring exposure. Teeth have been used to estimate long-term cumulative exposure to various chemicals thus opening possibilities of insights into a retrospective temporal exposome. HBM of effects measures biochemical, physiologic, behavioural, or other alteration in humans that are associated with an established or possible health impairment or disease while HBM of susceptibility assesses congenital and acquired capacities of an organism to respond to chemical exposure. The combination of established effect markers and omics biomarkers may represent the strongest approach, especially if based on knowledge of mechanistic principles. A selection of recently developed effect biomarkers associated with, for example, oxidative stress, target organ damage, immunotoxicity, carcinogenicity, together with their validity and applicability will be presented. HBM-guidance values (GVs) are toxicologically and epidemiologically derived health-based GVs that correspond to internal exposure levels at which there is no appreciable risks and are instrumental in assessing risks based on HBM data. A presentation on recently developed HBM GVs for selected chemicals will conclude the symposium.
Marike Kolossa-Gehring (German Federal Environmental Agency, DE)
Crucial achievements in developing new human biomonitoring methods for assessing exposure to chemicals of concern
Janja Jan (Division of Dental Medicine, Faculty of Medicine, University of Ljubljana, SI)
Deciduous teeth as a matrix for determining human biomonitoring markers of exposure
Mariana Fátima Fernández (University of Granada, Centre for Biomedical Research, ES)
Human biomonitoring markers of early health effects
Ovnair Sepai (UK Health Security Agency, UK)
Development of human biomonitoring health based guidance values
S02: Implementation of new approach methods into regulatory risk assessment using case studies
Risk assessment is currently undergoing a paradigm change towards the use of more mechanistic approaches, which heavily rely on the testing and integration of human in vitro models and modelling approaches. This so called next generation risk assessment (NGRA) will also have to develop new concepts to integrate and assess data from different models and tools. One challenge for the implementation of these new concepts is the lack of experience and thus confidence into these new tools and models.
The development of new approach methods is an area of intensive research and progressing very rapidly. These findings together with the need of implementation ask for alternative ways to gain confidence into NGRA and to develop guidance on how to use these.
This session will display utility case studies on different areas of NAM (new approach method) development.
Thomas Sobanski (ECHA, FI)
APCRA Prospective Study- Chemical screening and assesment using and developing New Approach Methodologies (NAMs)
Carsten Kneuer (BfR, DE)
Case studies used to build AOP like networks from the AI4NAM project
Andrea Terron (ECHA, IT)
The DNT in vitro battery used in IATA case studies fostering regulatory up-take
Sylvia Escher (Fraunhofer ITEM, DE)
Read-across case studies to implement new approaches for hazard assessment
S03: Current and future perspectives about the extended one-generation reproductive toxicity study (EOGRTS)
The hallmark of the EOGRTS (OECD test guideline 443) is that based on certain criteria or triggers, selected offspring are assigned at weaning to different cohorts for further investigation of sexual maturation, reproductive organ integrity and function as well as developmental neurotoxicity (DNT) and/or developmental immunotoxicity (DIT). The triggers allow for a more customizable design based directly on the data, minimizing animal usage resulting in more efficient utilization of the F1 generation. The first presentation of the symposium will introduce the different study designs and share experience on designing and conducting EOGRTS under REACH.
Recently, ECHA and volunteering Member States conducted the analysis of 55 studies (during 2021 and 2022) to assess how the EOGRTS were performed with reference to the OECD technical guideline and the ECHA guidance. Based on this project, tangible recommendations were provided on how to improve future studies. Available guidance helps to design and conduct reliable studies, which meet the regulatory requirements and support effectively the hazard assessment.
As introduced earlier, if DNT and/or DIT are triggered evaluation is performed within EOGRTS. Recently, international efforts have led to the development of the DNT In Vitro Battery (DNT IVB) of assays which covers mechanisms directly involved in DNT using human cell-based assays. The on-going DNT project under the umbrella of the OECD and in close collaboration with EFSA and US EPA & FDA that aims to finalize the OECD Guidance Document on the DNT IVB of assays application and data interpretation will be presented.
Similarly to DNT, methods for assessing DIT have been included in the EOGRTS (OECD Test Guideline 443); however, they are still insufficient as a tool to screen for agents that may affect the developing immune system. New approach methodologies (NAMs) are desperately needed to evaluate the impact of exogenous agents on DIT, but they are lagging behind NAMs for other toxicological screens. This presentation will address existing NAMs for DIT and barriers to the development of additional NAMs for DIT.
Manon Beekhuijzen (Charles River Laboratories, NL)
The design and conduct of Extended One-Generation Reproductive Toxicity studies (EOGRTS)
Virve Sihvola (European Chemicals Agency (ECHA), FI)
Extended One-Generation Reproductive Toxicity studies (EOGRTS) in the EU regulatory context
Anna Bal-Price (European Commission, Joint Research Centre (EC JRC), IT)
New approach methodologies (NAMs) for developmental neurotoxicity evaluation (DNT) and their use for regulatory purposes
Jamie DeWitt (North Carolina State University, USA)
Will new approach methodologies (NAMs) ever work for developmental immunotoxicological outcomes?
12h00 – 13h00
Lunch Break and Poster Viewing 1
13h00 – 14h00
14h00 – 15h30
S04: Safety aspects of cannabidiol (CBD) applications
Cannabidiol (CBD) is a non-psychoactive cannabinoid which has been approved by the Food and Drug Administration of the United States in 2018 for the treatment of two epilepsy disorders. CBD is widely marketed as nutritional supplements in a continuously increasing spectrum of products for various applications. It is advertised for claimed effects such as decreased anxiety, fear memory extinction, anti-inflammatory properties, relief of pain, and especially for post-exercise recovery in sports. Recently, the European Food Safety Authority (EFSA) considered that the safety of cannabidiol (CBD) as a novel food can not be established and highlighted the need to address important knowledge gaps. In sports, the World Anti-Doping Agency (WADA) excluded CBD from its list of prohibited substances. However, caution is currently advised for athletes intending to use CBD-containing products, as these, particularly non-medicinal so-called full spectrum cannabis extracts, frequently contain significant levels of psychoactive tetrahydrocannabinol (THC), potentially leading to positive doping tests. More than 30% of CBD products on the German market were shown to contain levels that would lead to a THC intake > 2,5 mg/day, which may result in adverse effects on cognition. Besides contamination with THC, the safety profile of CBD itself is controversially discussed. This session summarizes the regulatory status of CBD in the EU and highlights safety concerns as well as potential therapeutic benefits, focusing on the complex situation in public and elite sports and doping.
Patrick Diel (Deutsche Sporthochschule Köln, DE)
CBD in public, professional sports and doping
Chiara Laezza (Institute of Endocrinology and Experimental Oncology, IT)
CBD Pharmacology and therapeutic applications
Barbara Engeli (Federal Food Safety and Veterinary Office, CH)
CBD Regulatory and safety aspects
S05: Consideration of the endogenous exposome in risk assessment
In modern risk assessment, deriving accurate exposure estimates can present serious challenges and uncertainties. This originates in part from the fact that today’s consumer exposure is multifactorial, encompassing exogenous environmental, occupational and food related sources. In addition, there is increasing awareness that in some cases endogenous exposure may add to the aggregate exposure. This is especially true for certain process related contaminants (PRC) formed in foods but also generated endogenously as components of physiological metabolism. This workshop aims to provide an overview of the state-of-the-art dosimetry informing about the contribution of endogenous exposure to the overall exposure and to highlight the associated challenges in case studies with selected PRC. Whereas exogenous exposure in most cases is supported by direct PRC analysis in foods, endogenous exposure in general has to rely on dosimetry of biomarkers of exposure since the relevant pathways may only be partially elucidated and influenced by the physiological homeostasis reflecting individual health-, age- and gender related parameters. Nevertheless, in cases where endogenous exposure appears to add substantially to the exposome, it becomes essential to better understand the contribution of the endogenous exposome to overall exposure to arrive at a comprehensive risk assessment. By the same token, an adequately explored, endogenous exposome may become an established reference point (point of departure) against which to evaluate exogenous exposure in human health risk assessment.
Gerhard Eisenbrand (University of Kaiserslautern (Retired), Food Chemistry & Toxicology, DE)
Acrylamide, acrolein and N-nitrosamines: three cases to discuss challenges concerning dosimetry and risk assessment of endogenous vs. exogenous exposure
Angela Mally (Department of Toxicology, University of Würzburg, DE)
Biomarker based dosimetry of endogenous vs. exogenous exposure to acetaldehyde, furan, and glycation compounds
Ivonne Rietjens (Wageningen University, AFSG/Division of Toxicology, NL)
Implications of endogenous exposure for risk assessment
S06: Chemical emergencies – public health management and the role of poison centers
A chemical emergency can be defined as an unexpected and unusual event caused by a toxic substance that consistutes a public health risk and potentially requires a coordinated response. Management of public health in chemical incidents requires collaboration among many stakeholders to assess exposure and risk and to provide advice to authorities and to the general public. This symposium will focus on the specific role of poison centres in the management of chemical incidents. The first presentation covers the diverse nature of chemical incidents and the challenges for public health authorities when faced with exposure to hazardous chemicals as a result of industrial accidents, natural disasters, chemicals in products, conflicts or deliberate use of chemicals. The second presentation describes how poison centres can contribute to each stage of the disaster management cycle with specific reference to the WHO Guidelines for establishing a poison centre. The third presentation is a case study of the preparedness, involvement and support provided by the medical services, including the local poison centre, following an explosion in a chemicals factory in Slovenia in 2022 in which six people were killed.
Raquel Duarte-Davidson (UK Health Security Agency, UK)
Public Health management of chemical incidents
Irina Zastenskaya (WHO European Centre for Environment and Health, DE)
Chemical emergencies, the International Health Regulations and poison centres – importance of toxicological data
Lucija Šarc (Centre for Clinical Toxicology and Clinical Pharmacology, SI)
Preparedness of the medical sector to chemical emergencies – the Slovenian experience
S07: Involvement of mitochondria in adverse drug reactions
Mitochondria play a central role in mechanisms of hepatic cell death and survival after an acute paracetamol overdose. Alkylation of mitochondrial proteins by an electrophilic metabolite of the drug initiates a mitochondrial oxidative stress which triggers activation of a mitogen-activated protein kinase cascade ultimately activating c-jun N-terminal kinase (JNK). Phospho-JNK translocates to the mitochondria and substantially amplifies superoxide and peroxynitrite formation within the mitochondrial matrix, which triggers the mitochondrial membrane permeability transition pore opening. Despite this severe cellular stress, adaptive mechanisms such as removal of damaged mitochondria by mitophagy and replacement by mitochondrial biogenesis may rescue the cell. However, if these defense mechanisms are overwhelmed, extensive nuclear DNA fragmentation occurs, which is generally considered the point-of-no-return in the signaling events leading to cell death (programmed necrosis). Because peroxynitrite also causes loss of mitochondrial DNA as part of the pathophysiology, comparative data on nuclear and mitochondrial DNA damage upon paracetamol overdose will be discussed. The session will also deal with xenobiotic-induced mitochondrial toxicity as a mechanism of steatosis and steatohepatitis. Two different clinical forms of steatosis will be addressed, namely microvesicular steatosis (“Reye-like syndrome“), a severe form of liver lesion that can be associated with liver failure and severe hypoglycemia and macrovacuolar steatosis, which is benign in the short term but can evolve in the long-term to steatohepatitis and cirrhosis. While severe inhibition of mitochondrial fatty acid oxidation is involved in microvesicular steatosis, milder mitochondrial dysfunction can lead to macrovacuolar steatosis, along with other metabolic disturbances such as inhibition of VLDL secretion and increased de novo lipogenesis. Nevertheless, xenobiotics that are more likely to cause steatohepatitis could be those that alter the respiratory chain activity, thereby reducing mitochondrial FAO and increasing the generation of reactive oxygen species.
Hartmut Jaeschke (KUMC, USA)
The central role of mitochondria in acetaminophen-induced programmed necrosis and liver recovery
Hilmi Orhan (EGE UNIVERSITY, TR)
Comparative mitochondrial and nuclear DNA damage by paracetamol
Bernard Fromenty (INSERM, FR)
Mitochondrial toxicity as a mechanism of steatosis and steatohepatitis
S08: Skills for the early career toxicologist
Heather Wallace (Univeristy of Aberdeen, UK)
Making an impression – networking and influencing
Ruth Roberts (ApconiX, UK)
Building a career
Angela Mally (University of Würzburg, DE)
Writing for publication
Martin Wilks (Swiss Centre for Applied Human Toxicology, CH)
Handling difficult questions in toxicology
15h30 – 16h00
Coffee Break and Poster Viewing 1
16h00 – 18h00
S09: Current use of NAMS/alternatives in DART testing
The greatest revolution in toxicity testing is the shift from black-box driven animal experiments towards tailor-made mechanistic approaches by intelligent and pragmatic testing using computational, molecular, and in vitro tools. This change will apply for all type of compounds and is for pharmaceuticals in line with the recent update of the ICH S5 guideline. Especially for industrial chemicals there is currently a high demand of Developmental and Reproductive Toxicology (DART) studies due to REACH, which increases the need for grouping of chemicals and thereby reducing the use of high numbers of animals. However, most stakeholders still lack confidence to change the standard methods. A critical need exists, therefore, to build confidence in the new approach methodologies (NAMs) and alternatives as a reliable and human-relevant paradigm.
With this symposium, we would like to provide an overview of the current ways to use NAMs and alternatives in DART testing. We will present approaches that successfully reduced the number DART studies necessary in the regulatory arena.
The first presentation will introduce this field, provide background and introduce the rest of the speakers and there topics. The second talk will present a human-based animal-free approach towards innovating risk assessment, based on a virtual model of human physiology, AOP networks extracted from that physiology, in vitro and in silico tools as a test battery selected based on the AOP network, and an integrating in silico model translating test battery results to human risk assessment. The talk will address opportunities and challenges and compare the innovative approach with the current animal-based regulatory risk assessment strategy. The third presentation will cover the use of alternative assays for pharmaceutical products in lieu of a second species. The fourth talk will share how in vivo data in one species, a QSAR generated from the historical database of testing in two species and predicted exposures from a chemical’s registered uses have been integrated to guide decisions on the need to conduct a study in a second species under the REACH regulation. Successes, challenges and opportunities toward gaining greater acceptance of such approaches under REACH will be shared.
Manon Beekhuijzen (Charles River Laboratories, NL)
Introduction on current use of NAMS/alternatives in DART
Aldert Piersma (RIVM, NL)
The road to a human-based animal-free safety assessment strategy based on in vitro and in silico approaches
Nicola Powles-Glover (AstraZeneca, UK)
ICHS5(3) Alternatives use in pharmaceutical development
Ming Kung (ExxonMobil Biomedical Sciences, Inc., USA)
Integrating exposure and a historical database into decision-making for DART testing in a second species under REACH
S10: Pathology and adverse outcome pathways
An Adverse Outcome Pathway (AOP) is a sequence of key events linking a molecular initiating event (MIE) to an adverse outcome (AO) through different levels of biological organisation. AOPs span multiple levels of biological organisation, and the AO can be at the level of the individual organism, population or ecosystem. Each AOP is a set of chemical, biochemical, cellular or physiological responses, which characterise the biological effects cascade resulting from a particular exposure. The key events in an AOP should be definable and should make sense from a physiological or biochemical perspective. AOPs are the central element of a toxicological knowledge framework being built to support chemical risk assessment based on mechanistic reasoning. The objective of this symposium is to show that a pathology can be associated with a AOP supportted by different tests that can be integrated into ‘Integrated Approaches to Testing and Evaluation’ (IATA).
Maurice Whelan (European Commission DG Joint Research Centre, IT)
Liver fibrosis and AOP
Ellen Fritsche (IUF , DE)
Neurotoxicity and AOP
Dominique Lison (LTAP, BE)
Lung toxicity and AOP
Saadia Kerdine-Römer (Université Paris-Saclay, FR)
Allergy and AOP
S11: Contact allergen potency: the missing piece in the huge puzzle of alternative methods
Several regulations in EU, such as REACH and Cosmetic Regulation, require the assessment of skin sensitization potential. There remains an important need to understand the hazard and the risk associated with exposure to chemicals that have the potential to cause skin sensitization in the induction phase. For hazard identification there are available validated in vivo and in vitro methods while is the assessment of the risk of skin sensitization based on potency information is still lacking. Knowledge of the Adverse Outcome Pathways (AOPs) of the skin sensitization allowed the development of in silico, in chemico and in vitro methods addressing specific key events (KEs). Information generated by these alternative methods can contribute to the assessment of hazard identification and potency classification of chemicals when used as information sources within defined approaches (APs) and Integrated Approaches to Testing and Assessment (IATA). Also, the Quantitative Risk Assessment (QRA) approach, based on the general toxicology principle that the risk is the product of hazard and exposure, and some important additional features like safety factors and NESIL, provide a basis for accurate assessment of risk of inducing skin sensitization. Finally, the aspect of potency related to a chemical sensitizer can be also take into consideration starting from a mechanistic point of view able to support in vitro potency information, necessary for full replacement of animals in the broader perspective of classification and labeling of potential sensitizers.
Laura Rossi (WIL Research Europe , FI)
A regulatory perspective: hazard identification and potency classification
David Basketter (DABMEB Consultancy Ltd, , UK)
Quantitative Risk Assessment and potency in skin sensitization: what about
Silvia Casati (European Commission, Joint Research Centre (EC JRC), IT)
IATA and definded approaches (DAs): state of the art in skin sensitization and potency issue
Valentina Galbiati (Università degli Studi di Milano, IT)
Contact allergen potency: a mechanistic point of view
S12: Finding synergies for 3Rs – Toxicokinetics, Physiologically-Based Kinetic (PBK) Models and Read-Across
Read-across, the process by which a specific piece of information from known (source) chemical(s) is used to infer the same information of unknown (target) chemical(s), is an important tool for chemical safety assessment across multiple industrial sectors, such as food, drugs, pesticides, household products, cosmetics. Read across provides a means to support the 3Rs philosophy, which is replacement, reduction, and refinement of animal testing. Among the various purposes, internal decision-making, research and development or in regulatory submissions, regulatory applications are subjected to the most scrutiny when determining the extent of justification required or level of uncertainty that is acceptable for the prediction. When predicting a target chemical’s potential to elicit a biological response, the read-across approach can be considerably strengthened by considering both the intrinsic activity and toxicokinetic properties of the source and target chemicals. Toxicokinetic properties determine a chemical’s ability to reach the site of action in sufficient concentration to elicit biological responses in an organism. Toxicokinetic properties involve the absorption, distribution, metabolism and elimination (ADME) of chemicals, and ideally, their time-dependent profiles, when available, should be considered in read-across hypothesis. This symposium will provide an overview of the need for, and potential resources of, ADME properties and time-dependent toxicokinetic data for use in read-across. It will also include the introduction of physiologically based kinetic (PBK) modeling, which is a predictive tool that integrates ADME properties and predicts internal dose metrics. The audiences will learn about the outcome of a systematic review of existing PBK models, and recommendations of using these existing models to support read-across. Industrial and regulatory perspectives will also be shared on incorporating toxicokinetics, PBK models and read-across to support more rapid human health risk assessment. Finally, we will introduce the OECD effort to promote the regulatory use of PBK models based on non-animal data with an assessment of model predictive capacity by using a read-across approach.
Judith Madden (Liverpool John Mooree University , UK)
Physiologically-Based Kinetic (PBK) Models and Applications In Read-Across
Corie Ellison (P&G, USA)
Toxicokinetics, PBK models and read-across prespective from industry
Cecilia Tan (US EPA, USA)
Toxicokinetics, PBK models and read-across prespective from regulatory
Andrew Worth (EC JRC, IT)
An assessment framework for PBK models including read-across approach – an international effort
18h30 – 19h30
Specialty Section Meetings
Tuesday, 12 September 2023
08h30 – 09h30
SOT MERIT AWARD LECTURE
09h30 – 10h00
Coffee Break and Poster Viewing 2
10h00 – 12h00
S13: Acceptance and use of in vitro methods: a perspective from various chemical sectors
Evaluation of human safety is a prerequisite prior introduction of new chemicals onto the market. Historically, animal testing has formed the basis for such safety assessment exercises. However, driven by ethical, societal and scientific constraints, starting a number of decades ago, there is a clear tendency worldwide to increasingly address animal-free methods for this purpose. This has been reinforced in the past few years by a number of legislative changes, imposing a ban on animal testing for particular groups of chemicals. Accordingly, the scientific community has been urged to develop animal-free methodology for evaluating the safety of chemicals, including in vitro assays. For most acute and/or local toxicological endpoints, a variety of non-animal methods have been implemented and many of those have been formally validated. For chronic and/or systemic toxicological endpoints, however, validated methods are not available today. This symposium will give a state-of-the-art overview of the acceptance and application of in vitro methods in various chemical areas, including the cosmetics, food additives, pharmaceutical and plant protection regulatory sectors.
Vera Rogiers (Vrije Universiteit Brussel, BE)
How far are we with the implementation of the Next Generation Risk Assessment for cosmetics?
Ans Punt (Wageningen Food Safety, NL)
Drivers and barriers that influence the acceptance of non-animal approaches in food safety evaluations
Freddy Van Goethem (Janssen Pharmaceutica, BE)
Non-animal safety assessment in pharmaceutical research and development
Martin Wilks (University of Basel, CH)
Use of non-animal methods as part of integrated approaches for testing and assessment of plant protection products
S14: NAM mechanistic information for the risk assessment of chemical mixtures
Human health assessment of combined exposure to multiple chemicals (‘chemical mixtures’) is a challenging topic for scientists, risk assessors and risk managers alike due to the complexity of the problem formulation, the large number of chemicals potentially involved, their toxicological profiles and human exposure patterns to these chemicals. The capacity for conducting in vivo animal bioassays to address these challenges is limited and the number of possible permutations that can be considered real-life chemical mixtures is large. Moreover, realistic exposure scenarios can be extremely complex. For these reasons, the use of NAMs has been advocated. High-throughput and high content testing in vitro approaches not only allow to test large numbers of chemical mixtures but can also provide invaluable mechanistic information to support the grouping of multiple chemicals and the development of AOP networks. NAMs can support (i) comparison of modes of actions and potency estimations (ii) predictions of the interaction between chemicals and their molecular targets, (iii) predictions of toxicological endpoints. This symposium was designed to discuss the opportunities and solutions provided by the different in vitro approaches, from simple cellular models to microphysiological systems to full small organisms, to support a risk assessment of chemical mixtures, in the context of food safety and hypothesis driven Next Generation Risk Assessments.
Christer Hogstrand (King’s College London, UK)
Regulatory risk assessment of chemical mixtures: EFSA’s approach
Jose Tarazona (Spanish National Environmental Health, ES)
Human in vitro models to support the risk assessment of chemical mixtures: Building a new paradigm.
Robyn L. Tanguay (Oregon State University, USA)
Full organism in vitro approaches to support the risk assessment of chemical mixtures
Susanne Fitzpatrick (US FDA, USA)
Microphysiological systems to assess the system of mixtures
S15: Next generation risk assessment of food chemicals, environmental contaminants and pharmaceuticals using open-source modelling platforms: Perspectives from regulatory agencies, academia and industry
Over the last decade, a number of regulatory agencies have been developing tools to integrate new approach methodologies (NAMs) including open source in silico tools such as biologically based and physiologically-based models for humans, animals and species of ecological relevance to support risk assessment. These models provide a quantitative means to link exposure assessment, internal dose and toxicological data to derive 1.safe levels of chemicals on an internal dose (forward dosimetry), 2.perform quantitative in vitro to in vivo extrapolations, 3.recalculate exposure using biomonitoring data (reverse dosimetry) and ultimately support the reduction of animal testing. These methodologies and tools address four major scientific, ethical and legislative needs: 1. achieve a mechanistic understanding of toxicity for hazard assessment (e.g. mode of action/AOPs); 2. reducing animal testing under the 3Rs principles (reduce, replace, refine); 3. assessing thousands of chemicals; and 4. optimise the use of risk assessment capacity. Predictive approaches reveal and exploit mechanistic understanding of why a chemical might be toxic to an organism under certain conditions, opening the door to more tailored, substance‐specific approaches. Embracing this new toxicity-testing paradigm offers considerable benefits to society including improved assessment of more chemicals, simplified cross‐sector legislation based on harmonised assessment approaches, and higher levels of protection for sensitive populations. The main objective of this session is to describe these open-source platforms developed by scientific advisory bodies, academia and industry. Available modelling tools will be described and case studies applied to food and feed chemicals, environmental contaminants, veterinary dugs and pharmaceuticals will illustrate their use for the human health, animal health and ecological risk assessment areas. Finally, associated benefits, limitations and current research needs will be foster a discussion to identify future research and developmental needs to fully implement these tools in routine risk assessment.
John Wambaugh (US Environmental Protection Agency, USA)
Modelling kinetics and dynamics of chemicals at the US-EPA using the httk open source platform
Jean Lou Dorne (EFSA, IT)
EFSA Modelling tools for human health, animal health and ecological risk assessment
Stephan Schaller (esqLABS, DE)
PK-Sim as a open source simulation tool for human risk assessment of pharmaceuticals: an industry perspective
Leonie Lautz (Wageningen Food Safety Research, NL)
Relevance of inter-species comparisons in kinetics to animal health risk assessment
S16: Organ-on-a-Chip and the Developing Role in Early Drug Development
With the increasing number of new drug modalities, pre-clinical development of Novel therapies is becoming increasingly challenging for the pharmaceutical industry utilising animal models. Organ-on-a-Chip (OOAC) systems are ever growing in complexity and rapidly increasing in value in response to such challenges. These are enabling basic disease modelling for greater prediction of adverse clinical outcomes prior to First In Human (FIH) clinical trials. This series of talks will detail and share background of advances in OOAC models to answer these critical questions. The first talk will discuss the modernization of drug development via the medium of OOAC. This seminar will showcase the Emulate platform and will present the findings of the first of its kind OOAC study which utilized the pharmaceutical consortium Innovation and Quality (IQ) roadmap for developing in vitro liver models for the prediction of drug-induced liver injury. The seminar will complete with an overview on how such a tool can be implemented into drug discovery workflows whilst providing organizations with significant productivity gains. The second talk focuses on a collaboration between Labcorp and MIMETAS regarding the development and validation of a novel fully autologous blood vessel on a chip system, designed for the greater hazard prediction of antibody & cell therapy induced cytokine release. Next, a talk outlining a kidney-on-a-chip system, co-developed between Labcorp and Emulate, where the speaker will delve into its role in understanding drug-drug interaction and the metabolism of small molecule drugs. The final talk from scientific experts at Sanofi will open with a Liver-on-a-Chip system where the speaker will delve into its role in studying drug induced liver injury (DILI). The talk will outline an in vitro microfluidic 3D human immune-liver model which cultures together liver cell types with peripheral blood mononuclear cells (PBMCs). This complex model allows the direct measurement of a number of key biochemical endpoints for the evaluation of biological molecules and small molecule therapeutics.
Lorna Ewart (Emulate Bio, UK/USA)
Modernizing Drug Discovery and Development with Organ-Chip Technology
Daniel Thwaites (Labcorp Drug Development, UK)
Novel Autologus Vessel & Vascularised Tissue-on-a-Chip Technology for the Hazard Identificantion of Drug Induced CRS
Don McKenzie (Labcorp Drug Development, USA)
Kidney-on-a-Chip Model for the Understanding of Transporter Mediated Drug-Drug Interaction
Karissa Adkins (Sanofi, USA)
A Microfluidic Immunocompetent Liver-on-a-Chip Model: A New Tool that Enables Translational Safety Assessment
12h00 – 13h00
Lunch Break and Poster Viewing 2
13h00 – 14h00
HESI CITE LECTURE
14h00 – 15h30
S17: Critical organs and exposure windows for developmental immunotoxicity assessment
In utero and early-life exposures to xenobiotics, including chemical, biological, or physical factors, can alter the developing immune system. Developmental immunotoxicity may elicit immunosuppression, hyperactivation, or dysregulation of immune responses, resulting in (long-term) alterations in host resistance to pathogens, allergic and autoimmune diseases, inflammatory diseases and cancer later in life. However, the mechanisms for this are still poorly understood, and potential interventions or remedies are generally lacking. Therefore, it is important to examine the evidence pointing to windows of exposure as well as sites of susceptibility. Gestation and the early years of development constitute critical windows of enhanced immune system susceptibility to xenobiotics, as experimental and clinical studies indicate that adverse effects may occur at lower doses and immunomodulation may be more persistent or delayed. The placenta plays a critical role at the interface of maternal-fetal exposures and is therefore an important organ to consider for developmental immunotoxicity assessment. The developing immune system is also highly receptive to endocrine signals and the impact of this immune–endocrine cross talk becomes clear when assessing developmental immunotoxicity from a sex-specific perspective.
The goal of this workshop is to provide an overview of the current knowledge on the critical organs and windows for developmental immunotoxicity assessment. General considerations on the maternal-fetal interface, dose- and sex-specific differences, endocrine regulation of the developing immune system and the relationship between endocrine disruption and the developing immune system, as well as outcomes later in life will be discussed. To achieve this, we will bring experts together to discuss the role of the placenta as a critical organ to be considered for developmental immunotoxicity assessments, as well as the dose- and gender-specific effects of in utero / early-life exposures and the impact of such exposure windows on the susceptibility to immune-mediated diseases. This workshop will provide a better understanding of the critical organs and windows during immune development that are vulnerable to toxic exposures, the effect of dose, sex / gender and endocrine regulation on the impacts of in utero / early life exposures, as well as data gaps and challenges for developmental immunotoxicity assessment and human translatability.
Andre Schmidt (Universitats Klinikum Jena, Department of Obstetrics, DE)
The placenta: critical for developmental immunotoxicity assessment
Fenna Sillé (Johns Hopkins University, Bloomberg School of Public Health, Department of Environmental Health & Engineering, USA)
The long-term impact of perinatal exposures on susceptibility to immune-mediated diseases
S18: Uncertainty in chemical risk assessment – identifying, evaluating, reducing
Uncertainty analysis has long been considered an integral part of chemical risk assessment. Traditional sources of uncertainty have included inter- and intra-species extrapolation, extrapolating subchronic to long-term exposure scenarios, and database deficiencies. New approach methodologies, such as human cell-based assays and computational methods, offer numerous advantages, including more human relevance, mechanistic information, throughput, and feasibility, recognizing new potential sources of uncertainty, with some easier to quantify than others. To make decisions, risk managers need quantifiable information on the sources of uncertainty and their magnitude, and must understand and communicate the strengths, weaknesses, and overall confidence of the assessment. It is therefore desirable to have clear methods to identify and evaluate uncertainties, and to reduce uncertainties, where possible.
This workshop will present key considerations around uncertainty analysis, and the use numerical factors to account for them, including their anticipated evolution in the context of next generation risk assessments. The use of evidence-based methodology to strengthen the identification and characterization of uncertainties in risk assessments will be a particular focus of the workshop. The overall aim of the workshop will be to present the state of the science for addressing uncertainties in chemical risk assessments, to explore the evolution of techniques to evaluate a broader range of evidence and strengthen the identification and characterization of the uncertainties, to ultimately reduce uncertainty and increase confidence in decision-making for human health risk assessment.
Heather Wallace (University of Aberdeen, UK)
Approaches to uncertainty in chemical assessments
Paul Whaley (University of Lancaster, UK)
How evaluating uncertainty in systematic review could apply to the context of chemical risk assessment
Virunya Bhat (Independent consultant, USA)
Evolution and increasing utility of Chemical Specific Adjustment Factors to reduce uncertainty
S19: Micro-and nano-plastics in our environment: presence and potential impact
During the last years micro- and nano-plastics (MNP) are repeatedly being discovered in aquatic, soil and marine environments including human consumer products increasing the potential of human exposure. Knowing the presence, distribution and fate of these ubiquitous pollutants as well as understanding their potential threat to environment and human is important to direct our future research priorities and political actions. Although a considerable amount of research is being performed to understand the risks associated with MNP exposure, the available studies with particles in the low micro- and nano range are scarce. Nano-plastics are believed to have an even deeper interaction with biota, but analytical hindrances have so far prevented advancing knowledge in this area. This symposium aims to bring together experts on MNP environmental monitoring and hazard assessment to review and discuss the current understanding of the environmental presence and impacts posed by MNP. Top-scientists in the field will present their view on the MNP issue in agricultural soils, marine environment and freshwater habitats. Focus will be to discuss: the sources and fate of MNP in environment, environmental weathering of MNP and potential contribution to hazard, address new and improved methods for accurate sampling, detection and quantification of MNP, hazard posed by MNP alone and combined with other environmental contaminants, hazard of chemical additives released by MNPs, and novel approaches to tackle an issue of MNP remediation. This session will provide an important and timely outlet for emerging research on MNP pollution.
Illaria Corsi (Università degli Studi di Siena, IT)
From macroplastic to nanodimension: a hidden threat to marine life
Dana Kuehnel (Helmholtz Centre for Environmental Research, DE)
Plastic pollution in aquatic environments: impact of weathering on fate and impacts.
Kalčikova Gabriela (University of Ljubljana, Faculty of Chemistry and Chemical technology, SI)
The reduction of microplastic pollution – from sources to sinks: An environmental engineering perspective
15h30 – 16h00
Coffee Break and Poster Viewing 2
16h00 – 18h00
S20: Are diseases and conditions related to hormone imbalance really increasing?
The incidence and prevalence of several diseases and conditions potentially related to the endocrine system have been reported increasing in European and North American high-income countries. Exposure to endocrine active compounds has been proposed as a possible explanation for these trends. However, it is still not clear whether trends from 2000 onwards are really increasing, and, in case, whether these increases are true or are due to artefacts in data, such as changes in diagnostic criteria over time, improved recording and registration, patients’ awareness, improved survival of high risk individuals, or changes in diagnostic practices, including the introduction of population screening.
Furthermore, major changes in exposure to several risk factors for these conditions have also occurred in the past in high-income countries. For example, several human reproductive factors have been associated to some of these diseases, and average maternal and paternal age has increased, particularly at first child; family size has decreased, thus proportionally the number of firstborn children has increased; and survival of very low birth weight infants has increased. Exposure to several other risk factors has been changing over time as well.
Incidence/prevalence trends of selected hormone-related diseases and conditions from 2000 onwards in selected high-income countries from Europe and North America will be presented. Potential artefacts that may have influenced trends will be discussed. These include, among others, changes in exposure to risk factors such as chemicals that may have effects on reproductive parameters. The application and integration of epidemiological data with toxicological information and exposure data are key in understanding whether there changes in trends are or might be related to such chemical exposures.
These issues will be discussed by an epidemiologist, and regulatory toxicologists from a regulatory body and from industry.
Eva Negri (University of Bologna, IT)
Trends in hormone related diseases and conditions: an epidemiological analysis
Andrea Terron (EFSA, IT)
Link the adverse outcomes t theo endocrine activity in the context of the regulation of endocrine disruption chemicals
Stephanie Melching-Kollmuss (BASF, DE)
Relevance of endocrine disruption testing and assessment using animal and mechanistic studies for humans
S21: Environmental chemical mixtures and cancer hallmarks – new developments and open questions
Ten years ago, more than 100 cancer researchers from around the world initiated the Halifax Project, focusing on the carcinogenic effects of environmental chemical mixtures and on a new integrative design for cancer prevention and therapy. One of the most innovative aspect of the Halifax Project was the use of cancer hallmarks, as previously described, to mark the key steps in chemical carcinogenesis, trying to understand additive or antagonists effects that environmental mixtures, containing chemicals with different mechanisms or mode of action, can exert on crucial biological processes (Goodson et al., 2015). The Halifax Project paved the way to further initiatives to refine the concept of the role of chemicals in multistep carcinogenesis and to better understand the early steps in the process of human cancer (Jacobs et al, 2016, Smith et al, 2016, Guyton, 2018, Jacobs et al, 2020). Ten years later, a more advanced knowledge of tumor formation and progression raises the question whether tumor conceptualization based on cancer hallmarks is still a valid approach, and if other biological processes or enabling characteristics, should be considered in order to address the complexity of chemically-induced cancer. These include multiple processes, such as tumor plasticity and the role of epithelial-to-mesenchymal transition, the immune-mediated inflammation, which sustains the transition from adaptive to maladaptive response, or the role of differentiation, transdifferentiation and senescence (Hanahan, 2022). All of these characteristics seem to be the preferential targets for environmental chemicals. Even if little is (still) known about the cumulative and aggregate effects from exposures to multiple chemicals, accumulating evidence seem to suggest that chemical interaction at molecular and cellular level enables a row of common events strictly related to some enabling characteristics that should be considered as new additions to cancer hallmarks.
This session aims at reviewing the current knowledge on cancer hallmarks and tumor enabling characteristics as key targets for environmental factors and stressors playing a role in the action of human carcinogens.
Sasi Senga (Ludwig Cancer Research, University of Oxford, UK)
Cancer hallmarks – new dimensions
William Bisson (OHSU Knight Cancer Institute, USA)
The Halifax Project 10 years later: what we are still missing about the cumulative carcinogenic effects of environmental mixtures?
Jonas Fuxe (Karolinska Institutet, SE)
Epithelio-mesenchymal transition (EMT) and tumor plasticity – links with environmental carcinogens?
S22: Role of immunity and contribution of immunotoxicity in the identification of non-genotoxic carcinogens
Many chemical carcinogens act by inducing DNA damage and are called ‘genotoxic’ in their carcinogenic mode of action. Notwithstanding, a group of carcinogens named non-genotoxic carcinogens (NGTxC), that induce cancer in a non-genotoxic manner, exists. Different modes of action have been identified, among which NGTxC have been shown to act as tumor promoters, endocrine-modifiers, and immunosuppressants to mention some. The diversity of modes of action, together with the lack of genotoxicity makes predicting the carcinogenic potential of NGTxC extremely challenging. Here, with the intent of better understanding the applicability of immunotoxicological assays in chemical carcinogenicity assessment, we focus on the contribution of immunotoxicology in the characterization of chemical-induced immunosuppression and immune evasion, as one of the key characteristics of carcinogens. Starting from a current assessment of immunotoxicity, the in vitro opportunities will be discussed and their applicability to NGTxC assessment are discussed. With immunosuppression being a hallmark of cancer, and considering the in vitro opportunities available, the investigation of the immunosuppressive potential of NGTxC is practicable and should be included in IATA assay combinations. This workshop aims to provide knowledge and perspective in the identification of NGTxC for the better protection of public health.
Anna Maria Colacci (Regional Agency for Prevention, Environment and Energy of Emilia-Romagna (ARPAE), IT)
Tumor immunology and mechanisms of evasion
Emanuela Corsini (University of Milan, IT)
In vitro assessment of immunotoxicity with a focus on immunosuppression
Miriam Jacobs (Department of Toxicology, Centre for Radiation, Chemical and Environmental Hazards UK Health Security Agency, UK)
The way forward in the identification of NGTxC
19h30 – 24h00
Wednesday, 13 September 2023
08h30 – 09h30
09h30 – 11h30
S23: Towards quantitative adverse outcome pathway networks
Adverse outcome pathways (AOPs) are designed to provide a simplified mechanistic representation of critical toxicological effects that propagate over different levels of biological organization from the initial interaction of a chemical with a molecular target to an adverse outcome at the individual or population level. AOPs are currently gaining momentum, especially in view of their many potential applications as pragmatic tools in the fields of human toxicology and ecotoxicology, including the establishment of (quantitative) structure-activity relationships, the development of novel in vitro toxicity tests and the elaboration of prioritization strategies. In recent years, increasing attention has been paid to the development of AOP networks, which arise from combining single AOPs that share at least one key event. Compared to single AOPs, AOP networks provide a better reflection of the complexity of in vivo toxicity and, hence, can be used for real-life applications. A prerequisite for their implementation in contemporary risk assessment includes quantification. A number of different strategies are currently used for quantification of AOPs and their networks, including dose-response modelling, Bayesian network calibration and systems biology modelling. This symposium will give a state-of-the-art overview of the development and use of quantitative AOP networks.
Andrew Worth (European Commission, Joint Research Centre, IT)
Introduction to quantitative AOP models and their utility in toxicology and risk assessment
Elias Zgheib (Certara UK Limited, Simcyp division, FR)
A Bayesian view on quantitative AOPs: lessons learned from the EU-ToxRisk project
Stephan Schaller (esqLABS GmbH, DE)
A qualified open-source framework for precision toxicology by integration of PBK with mechanism-based quantification of AOPs
Mark Cronin (Liverpool John Moores University, UK)
Making quantitative AOPs networks into usable tools for risk assessment
S24: Toxicogenomics: breaking barriers for regulatory implementation
The assessment of an increasing number of chemicals in a way that better protects human health requires a paradigm shift in the safety assessment of chemicals. It should involve an interdisciplinary approach that integrates different types of knowledge and data. Toxicogenomics, a mature technology, can provide a broad and mechanistic estimation of chemical-induced perturbations of biology. Within the agricultural, chemical, and pharmaceutical sectors, the primary use of toxicogenomic information has recently been to better understand mechanisms of toxicity and human relevance. In this session, we will showcase recent developments in approaches supported by toxicogenomics and the current status of their implementation in industrial sectors and regulatory agencies.
Translation across species of mechanisms informative of adverse response is pivotal to transition to non-animal-based approaches and to gain confidence for regulatory purposes. We will discuss how toxicogenomics combined with Artificial Intelligence can help in replacing traditional animal testing by determining conserved responses in non-traditional test species. In addition, we will present how gene network analysis approaches applied to and cross animal and non-animal test systems can identify conserved mechanisms associated with adversity in vivo.
Ultimately, uptake from industrial sectors and regulators in determining the success of these approaches. We will share the recent approach and opinion of the European Food Safety Authority and the major limits to regulatory implementations of toxicogenomics. Finally, industrial practices, benefits, and limitations will be shared from the chemical and cosmetic sectors. This series of presentations will provide a comprehensive overview of the recent advancements of toxicogenomics and the status of its regulatory application.
Joseph Shaw (Indiana University, USA)
Evolutionary conserved transcriptomics responses to support holistic chemical safety assessment
Giulia Callegaro (CERTARA, NL)
Gene network approaches predictive of adverse outcomes
George Kass (EFSA, IT)
Regulatory implementations of toxicogenomics: opportunities and challenges
Andrew White (Unilever, UK)
Toxicogenomics use in chemical and cosmetic industry
S25: Re-emerging concerns associated with Phytotoxins
Toxins are poisonous chemicals of natural origin produced by plants, animals and microorganisms. The proposed symposium will concentrate on recent challenges from exposure to plant toxins in herbal medicines, food supplements or as food contaminants. Besides their generally well characterized acute effects, plant toxins may cause chronic toxicity, may be endocrine active, genotoxic, teratogenic or carcinogenic. As herbal medicines they may cause a range of adverse effects due to their pharmacologically active ingredients (coumarine, hydrastine, hypericine, indole, isoquinoline, lobeline, piperidine, polyciclic diterpenoids, pyridine, pyrrolizidine alkaloids, quinolizidine, sparteine, tropane alakaloids etc), as well as due to their interactions with pharmaceuticals. Globalization presents an additional challenge as previously unknown combinations of herbal mixtures with poorly characterized toxicological properties have appeared on the market. Globally, the most abundant plant toxins are pyrrolizidine alkaloids (PA). They appear in approximately 6000 plant species from various plant families, such as Boraginacae, Compositae, Leguminosae etc. In European populations exposure to PAs is mainly due to ingestion of herbal products and honey. Specific hepatotoxicity and pulmonary toxicity of PAs have been recognized for a long time. More recent studies revealed their genotoxic and carcinogenic properties calling for additional regulation. Tropane alkaloids (TA) are another group of plant toxins which have been used as medicines and poisons since times immemorial. TAs have attracted attention in recent years as contaminants of food and consequent mass poisonings with typical anticholinergic syndrome. In 2019, mass poisoning with 5 deaths and over 300 hospitalized people occurred in Uganda following consumption of a “Super Cereal” (a fortified blended food) that was contaminated by tropane alkaloids, specifically scopolamine and hyoscyamine, from Datura stramonium. A Joint FAO/WHO Expert Meeting on Tropane Alkaloids assessed the available information in order to provide guidance for the development of operational limits for hyoscyamine and scopolamine in World Food Programme products. A Margin of Exposure approach based on pharmacological effects in humans and acute dietary exposures were used in the risk characterisation. At the proposed symposium the analyses of pharmakokinetic data from human volunteers, not available to the joint FAO /WHO Meeting, will also be presented to encourage a further refinement of the present FAO/WHO opinion.
Samo Kreft (University of Ljubljana, SI)
Adverse effects of herbal drugs and their interactions with pharmaceuticals
Heidi Foth (Martin Luther University Halle-Wittenberg, Faculty of Medicine, Institute for Environmental Toxicology, DE)
Genotoxicity and carcinogenicity of pyrrolizidine alkaloid
Susan Barlow (Independent Consultant in Toxicology and Risk Assessment, UK)
WHO/FAO development of limits for tropane alkaloids in foods
Katarina Černe (Institute of Pharmacology and Experimental Toxicology, Faculty of Medice, University of Ljubljana, SI)
Pharmakokinetics of atropine and scopoloamine as food contaminants in human volunteers
S26: Translational Advanced Platforms
To this day, animal testing provides a substantial share of the data required for regulatory safety assessment of chemical and pharmaceutical substances. If the safety margin between the intended therapeutic and toxic dose is not reached, programs will very often be stopped without further mitigation efforts leading to a loss of promising, innovative therapeutic concepts. As species differences may skew the effective potential for drug-induced liver injury in humans, additional translational tools are needed. Ethical concerns, embodied in the Replacement, Refinement and Reduction (3Rs) principles, as well as an increasing amount of evidence for the limited predictive power of animal models spur the advancement of animal free testing. In the last decade, the advancement of systems including 3D culture models and microphysiological systems (MPS) delineated a promising route to human-relevant in vitro testing by emulating biology in single- or multi-organ systems as a basis for fit-for-purpose assays. To enhance regulatory acceptance of these advanced non-animal test systems, it is necessary to increase the scientific credibility and confidence in the data generated. Standards are perfect tools to support technological reliability and biological relevance, encouraging implementation and use by the industry. Standardization can play a key role in ensuring a proper characterization of systems and their expected performances, benchmarking against reference elements and aiding efficient communication among stakeholders.
This session will first demonstrate case studies supporting i) the transferability and robustness of MPS as an essential basis for confidence ii) the capacity to support read across for different application scenarios based on comparative assessment of metabolite profiles and tissue responses iii) the potential benefit within a tiered Next Generation Risk Assessment. In the next talk, we propose a platform for a tired-testing strategy for species-specific drug effects, based on organotypic 3D liver microtissues from rat, dog, cynomolgus monkey and human to confirm or disproof liver adversities observed in regulatory animal studies. The outcome of a cross-species platform validation study performed by a pre-competitive industry consortium and its regulatory context will be discussed. The following talk will provide an overview of the standardization state of play for MPS while the last talk will concentrate on assessment of the MPS generated data for regulatory use.
Jochen Kühnl (Beiersdorf AG, DE)
Case studies to evaluate the use of MPS in a tiered next generation risk assessment for cosmetic compounds
Armin Wolf (InSphero AG, CH)
Translation of DILI from regulatory animals to man using 3D liver microtissues – Results of the international cross-species DILI validation consortium
Monica Piergiovanni (European Comission Joint Research Centre, IT)
Standards to enhance the scientific credibility of MPS: towards regulatory acceptance
Suzanne Fitzpatrick (U.S. FDA – Center for Food Safety and Applied Nutrition, USA)
Establishing Confidence in MPS Data for Regulatory Use
11h30 – 12h00
12h00 – 13h30
S27: Ontologies as translational tools in toxicology
An ontology is defined as an area of knowledge that is formalised such that the individual terms or concepts can be delineated by a set of assertions that connect them to other terms. In a biological context, ontologies are used as a way to classify terms, how they relate to broader concepts and their interrelationships. As such, ontologies provide a means to deal with knowledge in a structured manner in view of data integration. Ontologies have many applications, including genome annotation, interpretation of omics findings, knowledge integration across species and biological levels of organisation, information retrieval and semantic computing. In the field of toxicology, ontologies can help to (i) predict and explain which chemicals are likely to induce specific types of toxicity, (ii) overcome some of the limitations of current safety testing by exploiting the state-of-the-art of science and the increasing amounts of data that can inform about mechanisms leading to adverse outcomes, (iii) enable the design of more informative and predictive models and assessment strategies for toxicity of chemicals, (iv) improve public health protection through increased relevance and accuracy of testing, (v) facilitate the design of chemicals so that they are unlikely to have the potential for inducing toxicity in humans, and (vi) save resources and animals. This symposium will give an introduction to the basics of ontologies and their use in toxicology with focus on aspects relevant for the areas of in vitro and in silico toxicology.
Aldert Piersma (The Netherlands National Institute for Public Health (RIVM), NL)
Setting the scene: what are ontologies and how can they be used in toxicology?
Mathieu Vinken (Vrije Universiteit Brussel (VUB), BE)
Ontologies as the basis for setting up in vitro test strategies
Thomas Knudsen (US Environmental Protection Agency (EPA), USA)
Ontologies as the basis for in silico reconstruction of tissue dynamics
S29: Current issues concerning air pollution
EU legislation has led to improvements in air quality. The percentage of urban citizens exposed to pollutant levels above EU legal standards set to protect human health fell between 2000 and 2020, in particular for PM2.5 and NO2, partly due to road transport emissions reductions in 2020 caused by Covid-19-related lockdown measures. For these pollutants, less than 1% of citizens were exposed to levels above EU legal standards in 2020. However, poor air quality remains a problem: in 2020, 12% of citizens were exposed to O3 and 11% to PM10 levels above EU standards. A state of the science situation in Europe will be presented.
Indoor air pollution arises from the infiltration of outdoor air and from indoor emissions, as a result of human occupancy, cooking, cleaning, heating, tobacco smoking, building and furniture materials, electrical and electronic devices, leading to exposure to CO2, CO, NO, NO2, polycyclic aromatic hydrocarbons, volatile organic compounds, aldehydes, metals, volatile organic chemicals, polychlorinated biphenyls, brominated flame retardants, oxidized fragrances etc. Sources, physico-chemical and toxicological properties of air pollution and its health impact will be presented, followed by a lecture devoted to toxicity of combustion products from flame-retarded and non-flame-retarded furnishings.
State of the science of air pollution in Europe
Juana Maria Delgado-Saborit (Universitat Jaume, ES)
Sources, physico-chemical and toxiclogical properties of indoor air pollution and its health impact
Thomas G. Osimitz (Science Strategies, LLC, US)
The toxicity of combustion products from flame-retarded and non-flame-retarded furnishings in large chambers.
13h30 – 14h00
Closing Ceremony and Awards Presentation