Monday, September 19, 2022
10:00 AM - 12:00 PM
Chairperson(s): Sylvia Escher (Fraunhofer ITEM, DE), Nynke Kramer (WUR, NL)
Next-generation risk assessment (NGRA) is an exposure led, hypothesis driven approach to risk assessment moving away from reliance on data generated in animal studies in line with the 3Rs of reduction, refinement, and replacement. The replacement of animal studies with in silico and in vitro new-approach methodologies (NAMs) presents opportunities for more human relevant risk assessment, but challenges in promoting confidence and ultimately regulatory acceptance of data generated through such methods. The range of NAMs available necessitates multi-disciplinary collaboration, bringing together expertise from computational modellers, chemists, kinetic experts, in vitro biologists, toxicologists and risk assessors.
In vitro to in vivo extrapolation (IVIVE)-linked physiologically-based kinetic (PBK) modelling and simulation are ideally suited to the prediction of internal exposures without the need for animal data. However, as with all computational models, IVIVE-PBK models are data driven and their parameterization and interpretation requires knowledge of the in vitro data requirements as well as the assumptions of the model itself. In vitro absorption, distribution, metabolism and elimination (ADME) assays providing parameters for a range of exposure and metabolic routes have been developed. However, these have largely been established in the context of the pharmaceuticals and while they can be applied, consideration must be given their application in a broader chemical space. As part of a robust IVIVE coupled approach consideration must be given to distribution kinetics in the respective in vitro assays accounting for the specifics of the in vitro assay set-up and the physicochemical properties of test compounds.
A multi-disciplinary panel will summarise the critical considerations in the application of IVIVE-PBK, their parametrisation, the importance of kinetics in the interpretation of in vitro data, and how these components come together to inform NGRA.
Sylvia Escher (Fraunhofer ITEM, DE):
Integration of PBK, in vitro kinetics, and NAMs into chemical risk assessment – challenges observed for inhalation exposure
Per Artursson (Uppsala University, SE):
In vitro ADME assays to inform IVIVE-PBK modelling and simulation
Nynke Kramer (WUR, NL):
Integrating in vitro distribution kinetics analysis in IVIVE-PBK
Heeseung Jo (Certara – Simcyp Division, UK):
Parametrisation and Interpretation of IVIVE-PBK in Risk Assessment
Chairperson(s): Martyn Smith (University of California – Berkeley, USA), Federica Madia (European Commission, Joint Research Centre (JRC), IT)
The concept of ‘key characteristics’, properties of chemicals and other agents that confer potential human health hazard, was first developed for carcinogens and was based on the data for known human carcinogens as classified by the International Agency for Research on Cancer (IARC). These key characteristics of carcinogens were first applied as the basis for the evaluation of mechanistic data by the IARC Monographs Programme and have since become part of the IARC Monographs process. Key characteristics of carcinogens are now widely used as a unifying principle to systematize multi-dimensional mechanistic data by a number of authoritative bodies, such as the National Toxicology Program Report on Carcinogens, the U.S. EPA, the California EPA, and the Joint Research Center of the European Commission. The value of the “key characteristic” approach to adverse health endpoints other than cancer has been recognized and recent efforts by a number of expert panels focused on defining key characteristics for other “-icities”. This symposium will pick up where the ICT 2019 session on “key characteristics” left off – the examples of how this concept is contributing to translation of basic and mechanistic research to decision-making. Then, four recent examples of key characteristics will be described. Key characteristics of endocrine-disrupting chemicals and obesogens, hepatotoxicants, and cardiovascular toxicants. Finally, the example of how key characteristics facilitate integration of data across toxicity endpoints for improved safety assessment of chemicals will be presented.
Martyn Smith (University of California – Berkeley, USA):
Key characteristics of human toxicants: A unifying concept for human chemical hazard evaluations
Michele La Merrill (University of California – Davis, USA):
Key characteristics of endocrine-disrupting chemicals and obesogens
Ivan Rusyn (Texas A&M University, USA):
Key characteristics of human hepatotoxicants
Lars Lind (University of Uppsala, SE):
Key characteristics of cardiovascular toxicants
Federica Madia (European Commission, Joint Research Centre (JRC), IT):
Integration of data across toxicity endpoints for improved safety assessment of chemicals: Key characteristics and other approaches to cancer hazard evaluation
Chairperson(s): William Slikker Jr (US FDA/NCTR, USA), tba.
Human exposures to drugs, chemicals, or chemical mixtures often cause nervous system dysfunction (dizziness, fatigue, cognitive changes, etc.), yet broadly applicable screening methods to predict and assess neurotoxicity in animal models are lacking. Thus, there is a need for more sensitive and specific biomarkers that can help diagnose and predict neurotoxicity, are relevant across animal models and are translatable to the clinic. Fluidâbased biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF), and imaging-based biomarkers which utilize MRI-based identification have great potential due to the relative ease of sampling. At present, data on expression and translation of these potential biomarkers are lacking or inconsistent. This symposium will highlight findings from collaborative nonclinical studies focused on the search for minimally invasive biomarkers of neurotoxicity and their translation to clinical applications. The symposium will offer its target audience a a detailed assessment of possible neurotoxicity endpoints within the context of biomarker development. Such assessments can be valuable in regulatory guidelines as well as in basic mechanistic studies of neurotoxicants or pharmacological development of therapeutic candidates. Capturing the latest developments and scientific breakthroughs in this fast-paced research area, the symposium will provide state-of-the-art information of interest to risk assessors, neurobiologists, clinicians and neurotoxicologists.
Ruth Roberts (Chair and Director of Drug Discovery, University of Birmingham, UK):
Overview of Fluidic Biomarkers of CNS toxicity – The HESI Consortium Approach
Serguei Liachenko (Division of Neurotoxicology, US FDA/NCTR, USA):
Development of T2 MRI Biomarker of Neurotoxicity as a Non-invasive Quantitative Approach
Greet Teuns (Janssen Pharmaceutical Research & Development, BE):
Clinical Evaluations and Qualification of Blood-based Biomarkers of Drug-induced Neurotoxicity: An IMI TransBioLine Approach
Syed Imam (Division of Neurotoxicology, US FDA/NCTR, USA):
Update on Fluidic Biomarkers of CNS toxicity – Current Approach and Development
Chairperson(s): Margaret-Anne Craig (Newcells Biotech, UK), Yasunari Kanda (National Institute of Health Sciences, JP)
The ability to generate 3D organoids or “mini-organs” that more closely mimic native tissue function has great potential for various applications including drug development and chemical safety assessment. The novel 3D models have been designed to bridge the gap between conventional in vivo models and 2D cell cultures. To date, many methods have been employed to create human relevant structures with functionality through stem cell biology, developmental process, self-guided assembly, and bioengineering. These efforts have resulted in the development of organ-specific human relevant 3D models, such as heart, brain, lung, and retina from human iPS cells. As these systems closely resemble in vivo tissues, they could help predict drug responses early in development and offer vast possibilities for modeling many diseases. These in vitro 3D organoids highlight the future toxicity testing with high predictivity in human. However, practical application and effective implementation of these advanced 3D models requires an understanding of their advantages and limitations. For example, it is necessary to understand the added values of 3D models, compared with 2D cells. In addition, there are some critical issues to consider reproducibility and reliability, the availability of the biomaterials, and when and how we can use these advanced models for toxicity. Here, we bring together top scientists from regulatory, academia and industry to discuss the exciting challenges for engineering complexity into organ-like systems, good cell culture practice for stem cells and implementation, and future perspectives to make 3D models increasingly reliable, reproducible, and accessible to a wider audience.
Yasunari Kanda (National Institute of Health Sciences, JP):
Current status and future perspectives of toxicity testing using stem cell-derived 3D models
Kareen Coulombe (Brown University, USA):
In Vitro Pro-arrhythmic Toxicity Assessment Using 3D Human iPSC-derived Cardiac Microtissues
David Pamies (University of Lausanne, CH):
BrainSpheres: applications and future
Lyle Armstrong (University of Newcastle, UK):
Retinal organoids for disease modelling and toxicity studies
Chairperson(s): Flemming R. Cassee (National Institute for Public Health and the Environment – RIVM, NL), Mary Gulumian (University of the Witwatersrand, ZA)
Within the components of SbD process, the hazardous aspect of nanomaterials is of great relevance. There is however concern that the data produced in the assessment of the hazard of nanomaterials may heavily rely on tests conducted using those that are shown to be interfered by nanomaterials tested. Moreover, that the tests conducted measure short term toxicity and ignore the long-term effects of nanomaterials. It is therefore of great relevance to use approaches to reliably predict the interactions of nanomaterial with biological (sub) systems to support the subsequent SbD processes.
Charlene Andraos (NIOH, ZA):
Safe materials and products by design: Designing nanomaterials through hazard assessment to humans and the environment early in the development stage of development process.
Vicki Stone (Heriot Watt University, UK):
How can Grouping and Read-Across support Safe(r)-by-design of Nanomaterials and Advanced Materials? GRACIOUS
Thomas Kuhlbusch (BAuA, DE):
Safe industrial production: Controlling manufacturing process to ensure the protection of workers and reduce exposure through reduction in release of hazardous nanomaterials to the workplace and the outdoor environment.
Nienke Ruijter (National Institute for Public Health and the Environment – RIVM, NL):
Oxidative potential and oxidative stress as key markers in an early-stage hazard assessment strategy for safe by design – SAbyNA
Andrew Nelson (University of Leeds, UK):
An innovative approach to dealing with the Safety-by-Design issue – SABYDOMA
3:30 PM - 5:30 PM
Chairperson(s): Weida Tong (Division of Bioinformatics and Biostatistics, FDA/NCTR, USA), Nicole Kleinstreuer (NICEATM, NIH/NIEHS, USA)
Increasingly, 21st century toxicology and risk assessment rely upon new data streams (e.g., image, graphic and omics data) from emerging technologies and New Approaches Methodologies (NAM). These types of data tend to be complex and multi-dimensional, and from efforts to automate digitization of legacy reference studies, necessitating integrative strategies. Meanwhile, Artificial Intelligence (AI) approaches to synthesize, interpret, and leverage data have demonstrated significant impact across a broad range of scientific disciplines, including computational toxicology. Data connectivity, FAIR (Findable, Accessible, Interoperable and Reusable) computational resources, and new/advanced algorithms fuel the rise of AI, providing new insight into underlying mechanisms of human health and disease and their susceptibility to exogenous perturbations. Some new AI methodologies such as deep learning can accurately extract complex patterns from these new data streams and formats, thus are playing a growing role in many facets of regulatory decision making. AI consists of two application categories, predictive and generative; both are critical to risk assessment and toxicology. Predictive algorithms learn from existing data/information to predict future outcomes, while generative algorithms produce new data with AI-driven study design; both represent unique opportunities for replacing animal models. This session will discuss the current state-of-the-art practice and on-going efforts in applying both predictive and generative features of AI in toxicology and risk assessment with a specific focus on real-world examples in the area of environmental chemical and drug safety.
Weida Tong (Division of Bioinformatics and Biostatistics, FDA/NCTR, USA):
ToxGAN: An AI Approach Alternative to Animal Studies
Nicole Kleinstreuer (NICEATM, NIH/NIEHS, USA):
AI on the CompTox Continuum: Applications in Environmental Chemical Assessment
Igor Tetko (Helmholtz Zentrum München, Russian Academy of Sciences, DE/RU):
A Snapshot of AI in Predictive Toxicology: Explainable AI
Cesare Furlanello (HK3Lab, IT):
PathologAI: An AI Framework to Support Preclinical Digital Pathology
Chairperson(s): Bengt Fadeel (Karolinska Institutet, SE), Phil Demokritou (Harvard University, USA)
There has been a considerable interest in two-dimensional (2D) materials since the discovery of graphene. Since that time, several other families of 2D materials including the transition metal dichalcogenides (TMDs) and transition metal carbides and nitrides (so-called MXenes) have been produced with applications in numerous sectors ranging from energy storage, electronics, environmental remediation, and medicine. It is therefore of great importance to evaluate the potential impact of these materials on human health and the environment. Indeed, the fact that these materials display novel and desirable properties may also yield new and unexpected effects on biological systems. Considerable efforts have already been invested in the hazard assessment of graphene-based materials (GBMs) not least in the frame of the European Commission-funded Graphene Flagship project [Fadeel, B. et al. ACS-Nano. 2018;12(11):10582-620]. However, less is known about other 2D materials including transition metal-based materials such as MoS2 and WS2. In this symposium, leading experts from the United States, Asia, and Europe, along with accomplished early career scientists, will present novel findings on the biological behavior of 2D materials using a host of analytical tools ranging from RNA-sequencing to high-dimensional immune profiling. The presentations in this session will cover the biotransformation of 2D materials using both in vitro and in vivo models as well as the environmental biodegradation of 2D materials.
Bengt Fadeel (Karolinska Institutet, SE):
Two-dimensional (2D) materials in a three-dimensional (3D) world: an introduction
Chunying Chen (Chinese Academy of Sciences, CN):
Biodistribution and biological activity of 2D nanomaterials: role of the protein corona
Phil Demokritou (Harvard University, USA):
Biotransformation and biological activity of 2D nanomaterials in the gastrointestinal tract
Lucia Delogu (University of Padua, IT):
High-dimensional approaches for immune profiling of 2D materials: towards safe-by-design
Fabio Candotto (University of Trieste, IT):
Environmental degradation of graphene-based materials: a case study with saprotrophic fungi
Chairperson(s): Martin Wilks (Swiss Centre for Applied Human Toxicology, University of Basel, CH), Stephanie Melching-Kollmuss (BASF SE, DE)
Human clinical evidence indicates a link between altered serum levels of thyroxine (T4) and/or thyroid stimulating hormone (TSH) in pregnant mothers and child neurodevelopmental outcomes. Rodent toxicity studies have shown that substances identified to disrupt the thyroid system are often liver enzyme inducers, that lead, via increased thyroid hormone glucuronidation, to increased thyroid hormone clearance. One of the major scientific and regulatory uncertainties is to establish whether there is a concern for neurodevelopmental impairment in humans arising from maternal UGT-induced increased thyroid hormone clearance and alterations of the thyroid gland, as seen in rodents. The development of a robust experimental approach to clarify the underlying uncertainties is urgently required in order to assess any neurodevelopmental concern in humans arising from rodent thyroid toxicity, following the mentioned sequence of key events. This is also crucial to identify or rebut compounds as endocrine disruptors in line with the criteria laid out in Regulations EC 2017/2100 (biocides) and 2018/605 (pesticides). The first speaker will present available human clinical evidence for how child neurodevelopment may be affected by altered T4 and/or TSH levels in pregnant mothers and where there are similarities or differences between humans and rats. The second speaker will present outcomes of a perinatal rat study, with a liver enzyme inducer, with the attempt to derive a quantitative an Adverse outcome pathway (AOP). The third speaker will present a PBPK model to estimate serum thyroid hormone concentrations in adult humans and rats in an euthyroid situation and after exposure to a liver enzyme inducer. The fourth speaker will present a testing scheme to investigate and assess compounds affecting the thyroid in rat in order to conclude on thyroid (hormone) disruption in context of the endocrine disruption criteria (EC 2018/605, 2100/2017, ECHA/EFSA Guidance on Endocrine Disruption).
Peter Taylor (Thyroid Research Group Cardiff University, UK):
Thyroid hormones, pregnancy and offspring development in humans and correlation to animals
Aldert Piersma (National Institute for Public Health and the Environment, NL):
Developing a quantitative AOP for liver-mediated thyroid modulation after prenatal exposure to a xenobiotic compound in the rat
Rebecca Clewell (21st Century Tox Consulting, USA):
Model development of a THM in adult rat versus human rat thyroid hormone concentrations in serum
Stephanie Melching-Kollmuss (BASF SE, DE):
How can a testing strategy to identify a human-relevant thyroid hormone disruptor look like
This session is supported by
Chairperson(s): Fenna Sillé (Johns Hopkins Bloomberg School of Public Health, USA), Unni Cecilie Nygaard (Norwegian Institute of Public Health, NO)
Developmental immunotoxicity (DIT) occurs following in utero exposure to xenobiotics, including chemical, biological, or physical factors, able to alter immune system development. It is generally believed that development constitutes a period of increased immune system susceptibility to xenobiotics, as several experimental and clinical studies indicate, adverse effects may occur at lower doses and/or immunomodulation may be more persistent. DIT may elicit suppression, hyperactivation, or dysregulation of immune responses, resulting in altered resistance to pathogens, allergic and autoimmune diseases, inflammatory diseases and cancer later in life. When evaluating DIT in an animal model, specific endpoints are assessed, which can reveal the potential for a risk factor to altered immune responses. The goal of this session is to provide an overview of the current status as well as a future outlook on DIT. General considerations on endocrine regulation of the immune system and the possible relationship between endocrine disruption and development of the immune system, will be also discussed. To achieve this, we will bring experts together to discuss the historic perspective as well as current and future challenges and innovations in the field of DIT. Workshop will provide better understanding of the regulatory needs, data gaps and challenges for developmental immunotoxicity testing and human translatability, with a perspective on future innovations.
Sebastian Medina (Dept. of Biology, New Mexico Highlands University, USA):
Basic and Translational Aspects of Developmental Immunotoxicity Testing
Rubhana Raqib (ICCDR, Infectious Disease Division, International Centre for Diarrhoeal Disease Research, BD):
Effect of Prenatal Exposure to Arsenic on T Cell Development in Children
Unni Cecilie Nygaard (Norwegian Institute of Public Health, NO):
Current State of Developmental Immunotoxicity Testing & Knowledge Gaps
Fenna Sillé (Johns Hopkins Bloomberg School of Public Health, USA):
Future Perspectives of Alternatives to Developmental Immunotoxicity Testing
Chairperson(s): Lawrence Segal (CEPI, ES)
The Covid pandemic took the world by surprise in late 2019 and the need for rapid development of vaccines became paramount. The challenge was how to reduce standard vaccine development times as much as possible. With knowledge of the genetic code of SARsCOV2, vaccine manufacturers throuhgout the world have risen to the challenge and several new vaccines were rapidly developed for emergency use. In March 2020, global Regulatory Authorities met to consider how to start early clinical trials and accept rolling submissions. Before use in clincial trials or in mass vaccination campaigns, the safety and quality, including nonclincial toxicology studies, were required as an important part of vaccine safety evaluation. The extent of the toxicology evaluation prior to the start of clinical trials depended on several factors, including: the type of product; information already available; and the use of supportive data, such as immunogenicity studies. For vaccine candidates with pre-existing data, this would save valuable time whilst a full toxicology evaluation was completed in parallel. For vaccines with more limited data, toxicology data was required before clincial development could start. Now that several vaccines are reaching the market, the question is how to manage the new variants and what further toxicology studies will be needed. Will covid variants be managed like seasonal flu or will a full toxicology package be required for each new variant?
This workshop will examine the nonclinical toxicology studies for new Covid vaccines from the perspectives of:
- Vaccine manufacturers with different vaccine technologies, managing global regulatory submissions/responses;
- CROs, managing the urgency of conducting and reporting studies and supporting new players in the vaccine world; and
- Regulatory Authorities, in supporting the review process, juggling the need for safety and quality with mounting pressure to approve vaccines.
Sarah Gould (Charles River, FR):
Covid19 Vaccine Toxicology: Introduction and CRO Experience/Perspectives
Claudia Wrzesinski (FDA Center for Biologics Evaluation and Research, USA):
Regulatory considerations for non-clinical studies for COVID-19 vaccines: US FDA perspective
Richard Stebbings (AstraZeneca, UK):
Accelerated Timelines for Non-Clinical Studies to Support COVID-19 Vaccine (AZD1222, ChAdOx1-nCov19)
Christina Neske (CureVac AG, DE):
Rapid Development of Vaccines in Challenging Times
Tuesday, September 20, 2022
10:00 AM - 12:00 PM
Chairperson(s): Richard Currie (Syngenta Ltd., UK), Patience Browne (OECD, FR)
To meet the combined challenges of sustainably feeding a growing global population, reducing the impact of agriculture on greenhouse gas emissions and improving the environment through regenerative agriculture there is a need to speed the introduction of new innovative technologies whilst maintaining high levels of protection to human and environmental health. The development of new crop protection solutions takes considerable time and currently require the use of OECD guideline vertebrate studies to help understand safe uses. At the same time there is considerable pressure to reduce animal use by the development of new approach methods (NAMs). The development of NAMs that rely on the wealth of existing data on crop protection chemicals and modern hypothesis-based scientific approaches offers the possibility that the assessment of new crop protection chemical technologies can be accelerated whilst maintaining human and environmental health. This workshop explores the potential and the challenges of using the wealth of existing data to reliably predict exposures and human and ecotoxicological effects.
Elaine Freeman (Exponent, Inc, USA):
Using Existing Knowledge for the Risk Evaluation of Crop Protection Products to Guide Exposure Driven Data Generation Strategies
Mark Viant (School of Biosciences, UK):
Importance of Public Databases and Data Transparency
David Dreier (Syngenta Crop Protection, USA):
Predictive Risk assessments for Eco and Human Health
Patience Browne (OECD, FR):
The changing testing paradigm and its potential impact on regulatory science
Chairperson(s): Keiko Taguchi (Tohoku University, JP), Ian Copple (University of Liverpool, UK)
The transcription factor Nrf2 coordinates the expression of hundreds of genes that contribute to the maintenance of cellular homeostasis under conditions of chemical and oxidative stress. As a result, Nrf2 plays an important role in protecting cells against a wide range of toxicological insults, and is emerging as a promising therapeutic target in several disease areas. In this symposium, the five speakers will highlight recent advances in our understanding of the toxicological roles of Nrf2, including in detoxication, carcinogenesis and development, using different in vivo and in vitro models. The goal is to foster knowledge exchange and support new research interactions that will ultimately contribute to an enhanced understanding of the cellular response to environmental hazards and an improvement in human health.
Keiko Taguchi (Tohoku University, JP):
Role of Nrf2 in tissue construction
Ian Copple (University of Liverpool, UK):
Role of Nrf2 in drug-induced toxicity
Amedeo Columbano (University of Cagliari, IT):
Role of Nrf2 in chemical carcinogenesis
Alicia Timme-Laragy (University of Massachusetts Amherst, USA):
Redox stress and Nrf2 in the zebrafish embryo
Pi Jingbo (China Medical University, CN):
Nrf2 in environmental stress and toxicity testing
Chairperson(s): Paul Fowler (University of Aberdeen, UK), Pauliina Damdimopoulou (Karolinska Institutet, SE)
While in vitro studies using human cell lines and animal models can inject key knowledge on causal toxicological mechanisms, translation between species and model systems is challenging. Human fetal and placental tissues provide the most valuable data to unravel human development and what goes wrong. Toxicologists, biologists, endocrinologists, and epidemiologists lean on these gold standard studies to understand what molecules are produced, in which tissues and when in development. Historically, such studies used low dimensional approaches. Now data are generated from fetal and placental tissues using high dimensional approaches. Fetal sex differentiation exemplifies developmental processes primarily described by measuring single hormones. High throughput transcriptomics confirm some original knowledge, challenge some and add new discoveries. Large epidemiological datasets, with maternal screening, offer powerful insights into associations between maternal exposures and potential adverse outcomes. Divergences between real-life data and narrow confines of toxicological studies using animals, highlights a chasm in comprehension that toxicology needs to bridge. 9/10 toxicology studies only consider whether a compound crosses the placenta, with toxicologic effects presumed as direct. Human fetal/placental tissue biomarker and exposome studies offer insights into placental mediation of chemical exposure effects on fetal development. New evidence for key placental roles in human developmental processes, such as masculinisation, highlight the weakness of current toxicological over-simplification.
The symposium aims to share insights gained by generating data from early pregnancy fetal and placental tissues to understand harmful effects of chemical exposures on human development. Each talk will report findings and take a bigger picture view benefits to toxicology and environmental epidemiology more broadly.
Majorie Van Duursen (Vrije Universiteit Amsterdam, NL):
Challenges of using animal and in vitro models to understand human developmental toxicology
Jennifer Adibi (University of Pittsburgh, USA):
Discordant findings on phthalate effects on human chorionic gonadotropin when phthalate metabolites are measured in maternal urine vs. placental tissue: which one is the gold standard?
Linn Mamsen (University Hospital of Copenhagen, DK):
Prenatal exposures to environmental toxins are more pronounced in human male fetuses
Severine Mazaud-Guittot (Institut de recherche en santé, environnement et travail, Inserm U1085, FR):
Knowledge gaps: case studies from human fetal ovary and adrenal gland
Chairperson(s): Ryuichi Ono (National Institute of Health Sciences (NIHS), JP)
DNA double strand break (DSB) is the most serious DNA damage to cells, and DSB in fertilized eggs is a life-threatening problem. On the other hand, it has become possible to introduce DSB at any position on the gene using the CRISPR / Cas9 system, and it is at the stage where clinical application to gene therapy using genome editing and application to genetically modified foods are being considered. However, the off-target effect in which gene mutations unintentionally occur at positions other than the target site has been a major issue.
We found that when genome editing was performed in fertilized mouse eggs to induce DSB, insertion of long DNA exceeding 100 bp occurred at approximately 10% of DSB sites (on-target). Many of these unintended sequences were retrotransposons, endogenous retroviruses, endogenous genes, and vectors used for genome editing. The occurrence of fusion genes of these unintentional sequences and endogenous genes can be a new risk event in clinical application using genome editing and application to genetically modified foods, namely “on-target risk”. (Ryuichi Ono)
The insertion of a retrotransposon may also lead to the acquisition of new functional genes and the risk that the insertion of a retrotransposon may change the epigenetic state of the neighboring genome.
In this workshop, we report that Peg10 and Rtl1 derived from the puffer fish Sushi-ichi retrotransposon inserted in the past and Syncytin derived from the endogenous retrovirus were acquired as new functional genes in the process of mammalian evolution. (David Simmons/Neil Youngson)
We also report on the importance of epigenetic regulations, such as diet-induced epigenetic remodelling and transcriptional changes in fatty liver disease (Neil Youngson) and epigenomic modulations in germ cells, aging and neurodegeneration (Shau-Ping Lin).
Shau-Ping Lin (National Taiwan University, TW):
Epigenomic Modulations in Germ Cells, Aging and Neurodegeneration
Neil Youngson (University of New South Wales, AU):
The relationships between retrotransposons and local and genome-wide epigenetic state
David Simmons (University of Queensland, AU):
Endogenous Retroviral Envelope Genes in Placentation
Ryuichi Ono (National Institute of Health Sciences (NIHS), JP):
Horizontal Gene transfer mediated by exosomes: a possible new risk for genome editing
Chairperson(s): Richard Brown (World Health Organization, CH)
Public concern regarding the potential health effects of environmental contaminants in water, food and air is increasing. This symposium will present recent reports from the World Health Organization on the potential health effects of nano- and microplastic particles. The challenges of generating and evaluating robust data for microplastics will also be described. Other talks will present different schemes used to prioritize chemical contaminants for possible assessment in food and drinking-water, including for an update to the WHO Guidelines for drinking-water quality.
Todd Gouin (Independent consultant, UK):
Dietary and inhalation exposure to nano- and microplastic particles: Potential implications for human health.
Lauren Robin (U.S. Food and Drug Administration, USA):
Prioritization of contaminants for evaluation in food by WHO/FAO expert committees
Georges Kass (ESFA, IT):
Screening for potential emerging chemical risks in the food chain associated with substances registered under REACH – a case study on a predictive approach
Richard Brown (World Health Organization, CH):
Updating the WHO Guidelines for drinking-water quality – how are chemicals prioritized?
3:30 PM - 5:30 PM
Chairperson(s): Richard Brown (World Health Organization, CH)
Assessing chemical hazards often requires the evaluation of different types of evidence. Evidence may be obtained from toxicology studies, from human epidemiological studies, from exposure studies or exposure modelling and from investigations of biological mechanisms. Successful risk assessment requires the integration of evidence from these different evidence streams. However, scientists from different disciplines may work with different assumptions on issues such as causality and the treatment of uncertainty. All scientific disciplines may use an element of expert judgement, which introduces a degree of subjectivity. Transdisciplinary approaches means different disciplines working jointly towards a common framework to address a problem, as opposed to different disciplines each working from their own perspectives in the hope that their results can later be combined to address a problem. This symposium will explore the issues of working across disciplines with different evidence streams, through a number of examples and case studies. The importance of pre-defined frameworks and systematic approaches will be described. The talks will present some of the guidance which is available on systematic approaches, integration of evidence and frameworks for reaching decisions.
Alan Boobis (Imperial College London, UK):
Synthesis and integration of epidemiological and toxicological evidence
Mary Schubauer-Berigan (International Agency for Research on Cancer, FR):
Fifty years of IARC Monographs leading to a modernized approach for synthesizing epidemiological and experimental data on carcinogenicity
Brandiese Beverly (National Institute of Environmental Health Sciences/National Toxicology Program, USA):
Integrating evidence streams for risk assessment, including systematic approaches.
Thorhallur Halldórsson (Faculty of Food Science and Nutrition, University of Iceland, IS):
Toxicology and Epidemiology: Reflections on a transdisciplinary approach to risk assessment based on selected case studies
Chairperson(s): Xiaobo Zhong (University of Connecticut, USA), Baitang Ning (National Center for Toxicological Research/U.S.FDA, USA)
Long non-coding RNAs (lncRNAs) are a group of non-coding RNAs with more than 200 nucleotides in length and are mainly transcribed with tissue specificity in the mammalian genomes. Existing studies show that lncRNAs can exert transcriptional control in a cis– or trans– manner and regulate gene expression and functions. Interacting with DNA, RNA, and protein molecules, lncRNAs are involved in the regulation of various cellular activities with diverse molecular mechanisms, such as molecular decoys to sequester miRNAs from mRNAs or DNA-binding proteins from response elements, as guides for RNA binding proteins to their promoters and enhancers, and as scaffolds to affect chromatin remodeling. Increasing evidence in both human and animal models shows that lncRNAs play an important role in critical cellular events in response to xenobiotic stimuli and toxicological conditions. Dysregulation of lncRNAs has been affected by exposures to various xenobiotics, including chemical pollutants (e.g. aromatic hydrocarbons, benzene, cadmium, bisphenol A, and phenols) and drugs (e.g. acetaminophen, cisplatin and doxorubicin). On the other hand, molecule mechanisms underlying the role of lncRNAs in the toxicological responses to various xenobiotics, and xenobiotic-induced toxicity have been investigated and reported. This symposium will highlight the studies focusing on the interaction between lncRNAs and xenobiotic exposures and will address the fundamental questions of molecular mechanisms of lncRNAs in xenobiotic-induced toxicity.
Xiaobo Zhong (University of Connecticut, USA):
Roles of lncRNAs HNF1A-AS1 and HNF4A-AS1 in drug metabolism and drug-induced toxicity
Yiguo Jiang (Guangzhou Medical University, CN):
Epigenetic toxicity of fine particulate matter mediated by lncRNAs
Verónica Miguel (Programme of Physiological and Pathological Processes, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), ES):
Role of lncRNAs in response to environmental stressors and consequences on human health
Baitang Ning (National Center for Toxicological Research/U.S.FDA, USA):
Cross-talking among lncRNAs, miRNAs and ribonucleoproteins in acetaminophen-induced hepatotoxicity.
Chairperson(s): Catherine Verfaillie (Stem Cell Institute Leuven, BE), Costanza Rovida (CAAT-Europe, DE)
Risk assessment requires a detailed analysis of the risk derived from the exposure to a specific chemical substance. The decision on the threshold that has the minimum probability to cause harm to workers or consumers is traditionally based on the response of in vivo studies. This session highlights current developments of advanced in vitro models within the European ‘Flagship’ Programme EU-ToxRisk. The first talk centres around iPSC-derived 3D-neurospheres which, depending on their differentiation stage, can be used for the assessment of developmental neurotoxicity. Another presentation is going to highlight complex 3D liver models encompassing all major liver cell types, produced from primary from iPS-cells harbouring reporters for AOP relevant MIEs or KEs, cultured in a tuneable, functionalized hydrogel. The third talk will present the integration of standalone advanced in vitro models into a PBPK-compliant human four-organ chip for ADME profiling, systemic multi-organ toxicity evaluation and risk assessment at repeated dose exposures. The physiology-based chip harbours a functional intestinal barrier model and a kidney barrier equivalent with fluidic connection to the described 3D liver and neuronal models. The four-organ chip has been exposed to specific tool compounds, well-known to be metabolised both in human liver and kidney and causing multi-organ toxicity. We report the results of systemic repeated dose exposure regimens with focus on substance PK and systemic changes. In future, acceptability of such advanced in vitro systems for regulatory purposes will largely depend on high performance quality, good reproducibility and accuracy as well as their potential to reduce animal testing at affordable costs. The last talk will share some insights into the potential use of microphysiological systems (MPS) in the context of risk assessment and alignment strategies with current and future regulatory requirements.
Andras Dinnyes (BioTalentum Ltd., HU):
Human iPSC-based 3D-Neurosphere Assays for the detection of Developmental Neurotoxicity
Manoj Kumar (Stem Cell Institute, KULeuven, BE):
An all iPSC liver model for advanced risk assessment
Beren Atac (Tissuse GmbH, DE):
Towards an ADME-competent human 4-organ chip for risk assessment
Costanza Rovida (CAAT-Europe, DE):
Advanced in vitro model integration for risk assessment
Chairperson(s): Bernard Robaire (McGill University, CA), Tara Barton-Maclaren (Healthy Environments and Consumer Safety Branch, Health Canada, CA)
Numerous chemicals are now recognized as acting as disruptors of the endocrine system, with adverse effects on human health and on many animal species. These chemicals include plasticizers, such as phthalates, epoxy resins, such as bisphenol A, and flame retardants, such as polybrominated diphenyl ethers. As individual chemicals become regulated or are voluntarily withdrawn because of demonstrated or suspected toxicity, a market gap develops, and replacement chemicals are introduced. However, there are limited requirements for manufacturers to test these chemicals; there is no requirement to determine whether replacements have endocrine disrupting effects that are similar to those of the legacy compounds that they replace. This symposium will highlight approaches to address this issue. After an introduction by the Chair, speakers will discuss: 1) the current status of human biomonitoring/exposure assessment, 2) the development of an automated workflow to enhance screening and identification of substances with endocrine activity for the purpose of setting risk assessment priorities, 3) a comparison of the effects of legacy and emerging replacement chemicals on phenotypic endpoints in cell and organ cultures, and 4) the development for policies to ensure that the choice of alternative chemicals is responsible.
Greet Schoeters (Flemish Institute for Technological Research (VITO), BE):
Human biomonitoring of exposure to legacy and replacement Endocrine Disrupting Chemicals
Tara Barton-Maclaren (Emerging Approaches Unit, Healthy Environments and Consumer Safety Branch, Health Canada, CA):
The screening and identification of substances with endocrine activity following an IATA workflow model
Barbara Hales (Department of Pharmacology & Therapeutics, McGill University, CA):
A comparison of the effects of legacy endocrine disrupting chemicals and their emerging replacements on phenotypic endpoints in cell and organ cultures
Cristina De-Avila (EU Commission, Circular Economy and Green Growth, Sustainable Chemicals, BE):
The commitments in the European Union’s Chemicals Strategy for Sustainability to address endocrine disruptors
Generally, pesticides are considered toxic if they produce an identified adverse reaction in the organism, their offspring, or an ecosystem. Dose-response toxicological relationships are considered in some countries and endpoints are expressed as No Observed Effect Concentration (NOEC) and LC50/LD50 for key sentinel species1. Almost all countries require these acute toxicity studies but fewer require chronic toxicity on key species to be assessed. As post-registration monitoring for unexpected toxicity is not required, nor routinely performed, there is little chance of capturing unexpected sublethal effects of pesticides on bystander species and an ecosystem until independent research highlights a potential problem. This has been the case for the neonicotinoids, where detrimental effects on bees were reported in France. These findings stimulated the research community and once a substantial body of evidence of harm from neonicotinoids amassed, the key neonicotinoids were banned within the EU. This was after 20 years of their unrestricted use.
In this symposium, we present the impact of neonicotinoids on beneficial insects to demonstrate how other indicators of risk may be assimilated into the current safety testing regimen. We will present evidence of bioactive neonicotinoid reaching the bee brain following oral exposure of field-relevant doses and how this correlates with evidence of harm to individual bees, to detrimental behavioural effects on whole colonies and deficits in transgenerational fitness.
The removal of the neonicotinoids in the EU does not solve the problem of the loss of abundance and diversity of insects across the globe. However, it does highlight the caveats in our current approach to assess pesticide safety. Together, we will present a case for the use of other indicators of stress in the safety testing of all pesticides and identify a role for pharmacological principles to work alongside those of toxicology in providing a more robust indication of risk. Importantly, pharmacology provides mechanisms to extrapolate our knowledge obtained from key sentinel species to other species based on molecular pharmacological principles such as the relative affinity of the chemical for its target site in related species.
Michael Spedding (FR):
Pharmacological principles applied to environmental science, pesticides and pollutants
Chris Connolly (UK):
Pharmacological responses of bees to neonicotinoids
Penelope Whitehorn (DE):
The sub-lethal impacts of chronic exposure to neonicotinoids on non-target species
Lars Straub (CH):
The impact of neonicotinoids on transgenerational fitness as an indicator of ecotoxicology risk assessment
Wednesday, September 21, 2022
9:30 AM - 11:30 AM
Chairperson(s): Douglas Wolf (Syngenta, USA), Michelle Embry (Health and Environmental Sciences Institute (HESI)
The rapidly growing human population, in parallel with increasing pressures due to a changing world and climate, are increasing the demands on the agrochemical industry, and heightening the needs for safe and effective crop protection products. Although the existing agrochemical safety evaluation paradigm is well established, and anchored in trusted test guidelines, based on classical toxicology methods, it is unlikely to meet the emerging challenges of a developing and ever-expanding sustainable agriculture.
The science underpinning chemical testing methods is advancing at a remarkable pace, and the ability to implement the most modern tools in assessing safe uses and risks of crop protection chemicals has dramatically increased. Therefore, it is critical to consider how to incorporate the advancements that have occurred to better inform human health and environmental risk assessment decisions for agrochemicals.
This session will provide an overview of a transformative vision for the evaluation of agrochemicals, and how this new, fit-for-purpose approach relies on the integration of state-of-the-art scientific methods, technologies, and data sources, to inform risk decisions, and adapt them to evolving local and global needs. Presentations will identify existing barriers to change in the current paradigm, and how to overcome them, as well as opportunities to realize the potential for developing science to improve the risk assessment of agrochemicals. Speakers will illustrate how new approach methods can help efficiently generate robust data for human and ecological safety assessment, while decreasing animal use. They will also emphasize the importance of transparency and data sharing to leverage existing knowledge, and minimize the needs for testing.
Sandrine Deglin (HESI, USA):
Paving to the way to transform the evaluation of agro-chemicals
Raffaella Corvi (European Commission Joint Research Centre, IT):
NAMs, regulatory use and future opportunities
Marco Corvaro (Corteva, IT):
From tick-the-box to out-of-the-box: an industry perspective on changing human health assessment paradigms for agrochemicals.
Jean-Lou Dorne (European Food Safety Authority (EFSA), IT):
Breaking down silos using toxicokinetic information: A One Health Perspective
Chairperson(s): Jorrit Hornberg (Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, SE), Philip Hewitt (Merck Healthcare KGaA, DE)
Investigative Toxicology drives safety assessment from being descriptive to providing mechanistic understanding and improve human translation. In drug discovery, its aim is to reduce clinical attrition by the identification of the most promising drug candidates with an acceptable Benefit / Risk ratio. In drug development, it aims to facilitate successful drug progression and approval by elucidating pre-clinical and clinical safety signals enabling optimal risk management and mitigation. Often these early predictions are supported by new in silico and in vitro technologies. While such novel methods hold many promises, there is also a potential for dead-end roads and wasted investments. Therefore, in line with the conference theme, the Investigative Toxicology Leaders Forum (ITLF) aims to improve exchange of expertise and knowledge within the investigative toxicology community on such new technologies/platforms. ITLF is a pre-competitive discussion forum consisting of European-based investigative toxicology leaders from the pharmaceutical industry. The objectives of the group:
to jointly elaborate robust, reliable and accepted Investigative Toxicology concepts for decision making for early safety-related attrition, de-risking, and mechanistic elucidation of safety-related effects, to increase the understanding and improve the translation of in vitro to in vivo mechanistic data, and enhance the adoption of new technologies/platforms into the drug discovery back-bone, to increase knowledge and awareness of Investigative Toxicology as a discipline (eg through publications, meetings and conferences). In this symposium, we bring together a set of topics that highlight several cutting-edge methods and technologies and innovative approaches to investigative toxicology, and how they can be applied to the discovery and development of novel drugs.
Anna Ollerstam (AstraZeneca, SE):
Innovative toxicology approaches to predict safety of inhaled candidate drugs
Philip Hewitt (Merck Healthcare KGaA, DE):
That Gut Feeling: Comparison of advanced intestinal cell models for early safety assessment
Diana Karwelat (Bayer AG, DE):
Fit-for-Purpose qualification of a two-organ MPS – a case example
Karen Dernick (Roche Innovation Center, CH):
Novel in vitro models to address toxicity in the eye and brain
Chairperson(s): Chris Goldring (University of Liverpool, UK), Theo de Kok (Maastricht University, NL)
It is widely acknowledged that the accurate prediction of Adverse Drug Reactions (ADRs) is poor, particularly at early stages in the drug development process. As a consequence, the risk of such events remains a major complication in the development of new, safe and effective therapies. In order to advance our ability to predict ADRs, it is essential to improve our understanding of their mechanistic basis of and to make predictions in a quantitative rather than just a qualitative sense. In the context of the Innovative Medicines Initiative (IMI), pharmaceutical industry and academia unite together to address this challenge in the TransQST project (Translational quantitative systems toxicology to improve the understanding of the safety of medicines). The main strategy is to develop systems modelling approaches for liver, kidney, cardiovascular and gastrointestinal-immune system that can be implemented in the drug development process. Existing data from the public domain as well as unpublished data from industry have been gathered from different sources. Additionally, crucial data gaps have been identified and new experimental data, both human and rodent in vitro and in vivo data, have been generated to feed into the developed models. An important element in the TransQST philosophy is to build on existing pharmacokinetic-pharmacodynamic models that have a physiological basis and define systemic as well as specific organ or cell exposure to drug and metabolites in a holistic fashion. In this symposium, the overall strategy of the project will be presented, and the approaches on how to develop translational quantitative systems-based toxicological models that can integrate different types of kinetic, molecular and phenotypic data will be discussed. Various innovative methodologies and software tools for systems toxicology modelling will be presented and various use cases will be given on how such models can be implemented in practice to support risk assessment.
Laura Furlong (Hospital del Mar Research Institute (IMIM), ES):
The TransQST concept and approach: supporting the implementation of QST models
Steven Kunnen (Leiden Academic Centre for Drug Research, Leiden University, NL):
Gene co-expression network analysis of toxicogenomic data linked to histopathology provides quantitative mode-of-action assessment and prediction of drug-induced organ toxicity
Carmen Pin (AstraZenica, UK):
Multiscale models, integrating several data types, applied to predict clinical pharmacological adverse events in early stages of drug development
Hennig Hermjacob (European Bioinformatics Institute, European Molecular Biology Laboratory (EMBL-EBI), UK):
Reproducibility in Systems Biology Modelling — Sometimes
Chairperson(s): Yoshiro Saito (Tohoku University, JP), Michael Davies (Panum Institute, University of Copenhagen, DK)
Biological responses and biomolecular modifications evoked by electrophiles have been received much attention and are induced by a variety of exogenous and endogenous chemicals such as environmental pollutants and lipid peroxidation products. The response system for electrophiles, represented by the KEAP1-NRF2 system, demonstrates the sophistication of defense against electrophiles. An antioxidant system, to remove reactive oxygen species and to prevent oxidative stress, functions for the deletion of toxic effects of electrophiles. In this symposium, the cutting-edge researchers in this field focus on the molecular mechanism of the biological response to electrophiles and lecture on the relationship between oxidative stress-related diseases and exogenous and endogenous electrophiles. Prof. Saito from Japan will lecture on the interaction between methylmercury, an environmental pollutant with electrophilicity, and a selenium-containing protein. Prof. Dinkova-Kostova from the UK will present the mechanism of action of Nrf2 inducers. Prof. Yin from China will talk about lipid oxidation products as covalent adduction agents. Prof. Spickett from the UK will present the effects of reactive oxidized lipid adducts on metabolic regulation. Finally, Prof. Davies from Denmark will talk about the adduction of quinone and alpha,beta-unsaturated aldehydes to protein. Through this international symposium, we will discuss the effects of environmental factors surrounding us on living organisms from the characteristics of electrophiles.
Yoshiro Saito (Tohoku University, JP):
Methylmercury-induced modification of selenocysteine in selenoprotein P- Implication to its physiological function
Albena Dinkova-Kostova (University of Dundee, UK):
Huiyong Yin (Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences, CN): Lipid oxidation products as covalent adduction agents characterized by LC-MS in the context of atherosclerosis
Corinne Spickett (College of Health and Life Sciences, Aston University, UK):
Structure-function studies of the effects of reactive oxidized lipid adducts on metabolic regulation
Michael Davies (Department of Biomedical Sciences, Panum Institute, University of Copenhagen, DK):
Adduction reactions of alpha,beta-unsaturated aldehydes to proteins
12:00 PM - 2:00 PM
Chairperson(s): Michelle Embry (Health and Environmental Sciences Institute (HESI), USA), Jos Bessems (VITO, BE)
Next generation risk assessment increasingly demands reduction of animal use. However, in many contexts, fit-for-purpose animal-based toxicity testing, such as long-term repeat-dose testing, is expected to remain in the foreseeable future. Such tests provide unique data that, to date, cannot be gained sufficiently via alternative methods, including systemic exposure, cross-scale endpoint responses, dose-response relationships, and insight into the role of toxicokinetics and potential mechanisms of toxic action. While recognizing the value in conducting these animal studies, it is crucially important to optimize the study design of long-term, repeat-dose studies by leveraging complementary data with a mindset of minimizing animal use and suffering to support the 3Rs principles (reduction, refinement, and replacement) in animal testing.
Study design is best optimized by collectively assessing the available body of knowledge to achieve a science-based recommendation on the uncertainties and knowledge gaps. Many in vitro, in silico, and targeted in vivo approaches can be integrated to help inform animal study design, including dose selection and measurement of additional endpoints without increasing animal use. Identification and monitoring of biomarkers associated with early key events can aid in the prediction of apical adverse outcomes in 28 day and 90 day studies that would emerge only in 2 year or targeted studies (carcinogenicity, reproductive and developmental toxicity). This symposium is composed of a series of interrelated presentations exploring the lines of evidence, or pieces of the puzzle, that when pulled together, can dramatically improve the design, relevance and informative power of repeat-dose animal toxicity studies for human health risk assessment. Speakers will highlight the use of in silico tools, in vitro studies, short-term in vivo studies with integrated endpoints, MOA/AOP hypotheses, and PBPK modeling to inform long term study design.
Nynke Kramer (Wageningen University, NL):
In Vitro and In Silico Tools for Estimating Chemical-Specific Kinetic Processes
Cecilia Tan (United States Environmental Protection Agency, USA):
Applying Physiologically Based Pharmacokinetic (PBPK) Modeling to Design and Optimize Animal Toxicity Studies
Alicia Paini (European Commission, Joint Research Centre, IT):
Using Adverse Outcome Pathways (AOPs) to Support Tiered-Testing Strategies for Toxicity Assessment
Jeanne Domoradzki (Corteva Agriscience, USA):
Putting the puzzle together: Integrated Weight of Evidence (WoE) Approach to Optimize Animal Toxicity Studies
Chairperson(s): Frans Russel (Radboud University Medical Center, NL), Tom Schirris (Radboud University Medical Center, NL)
Mitochondria produce the majority of cellular ATP and are a central hub for many metabolic pathways. They act as major regulators of cell death and innate immune responses. Consequently, their dysfunction is associated with numerous inherited and common diseases as well as a steadily increasing number of adverse effects of commonly prescribed drugs, including cholesterol-lowering and anti-diabetic drugs, antibiotics, chemotherapeutics and immunosuppressants. The relevance of drug-induced mitochondrial dysfunction is exemplified by the observation that it is associated with approximately 50 percent of all FDA black box warnings. In addition, various environmental chemicals, like pesticides, have been linked to neurodegenerative diseases such as Parkinson’s through mitochondrial impairment. This session will provide insight into the state-of-the-art methods to reveal mitochondrial drug off-targets, including the use of pathway analysis to illustrate metabolic rewiring and the association with inter-individual differences in adverse drug effects and toxicity. A potentially even more challenging pursuit is whether in vitro mitochondrial dysfunction will translate into clinically relevant toxicity. The latter represents another contemporary topic of discussion in the field, which will be reflected on both from an academic as well as an industry point-of-view. The various topics will all address model systems ranging from cellular in vitro studies to the use of advanced in vivo models up to how to assess mitochondrial toxicity in patients. A comprehensive overview will be given into the detection and eventually amelioration of mitochondrial adverse effects of various xenobiotics.
Tom Schirris (Radboud University Medical Center, NL):
The role of mitochondrial carriers in mitochondrial toxicity and drug disposition
Jon Lyon (GlaxoSmithKline, Safety Assessment, UK):
Assessing the Risk of Mitochondrially Active Compounds in Medicines Development
Kendal Wallace (University of Minnesota, Department of Biomedical Sciences, USA):
Silencing Mitochondrial Toxicity; An Age-Old Problem
Joel Meyer (DNicholas School of the Environment, Duke University, USA):
Caenorhabditis elegans as a model for investigating pollutant, genetic, and environmental contributors to mitochondrial dysfunction and neurodegeneration
Chairperson(s): Douglas Wolf (Syngenta, USA), Gina Hilton (PETA Science Consortium International e.V., DE)
Over the past five decades, much has been learned about chemical carcinogenicity and thus the ongoing necessity of the rodent cancer bioassay may no longer have a regulatory need to be performed for human health safety assessment. Taking advantage of fit-for-purpose new approach methods (NAMs) to modernize safety assessment, a multi-stakeholder expert workgroup formed the Rethinking Carcinogenicity Assessment for Agrochemicals Project (ReCAAP) to examine whether cancer hazard and risk assessment for agrochemicals can be performed without conducting rodent cancer bioassays. The ReCAAP workgroup developed a framework to provide a structured approach for weight of evidence (WOE)-based carcinogenicity assessment, which includes information on agrochemical use pattern(s), exposure scenario(s), pesticidal mode-of-action, physiochemical properties, metabolism and toxicokinetics, toxicological data including mechanistic data, and chemical read-across. This session will provide an overview of the development of the WOE-based reporting framework, followed by technical case studies illustrating utility of the framework to organize a WOE assessment to support a food-use pesticide for regulatory submission. The session will highlight integration of NAMs into a WOE approach through the Organisation for Economic Co-operation and Development (OECD) Integrated Approaches to Testing and Assessment (IATA) Case Studies Project that will provide greater mechanistic insight to evaluate human-relevance of a mode of action. The session will also showcase ongoing initiatives from the European Partnership for Alternative Approaches to Animal Testing (EPAA) to identify the most relevant MOA and key events to be considered in a WOE-based carcinogenicity assessment of agrochemicals.
Gina Hilton (PETA Science Consortium International e.V., DE):
Rethinking Carcinogenicity Assessment for Agrochemicals Project (ReCAAP) – Overview of a WOE-based framework
Amber Goetz (Syngenta Crop Protection LLC, USA):
An agrochemical case study for assessing human carcinogenicity risk using the WOE-based ReCAAP framework
Patience Browne (Organisation for Economic Co-operation and Development, FR):
Integrated testing approaches to support a WOE-based assessment in place of the rodent cancer bioassay
Mirjam Luijten (Center for Health Protection, National Institute for Public Health and the Environment (RIVM), NL):
Mode of action and key events to support a weight-of-evidence carcinogenicity assessment of agrochemicals
Chairperson(s): Juliette Legler (Utrecht University, NL), Jane Muncke (Food Packaging Forum, CH)
The use of plastics for food packaging and many other useful applications is increasing globally and, as a consequence, so is human and environmental exposure to micro- and nanoplastics (MNPs). But the human health effects of NP exposures are not well understood. In this session, we will introduce the topic and highlight what is known, where the most pertinent knowledge gaps are, and what scientific developments are essential to overcome the current hindrance of proper risk assessment.
This scientific session will touch upon:
- Assessing human exposure to MNPs and identifying the exposure sources
- Overview of human health impacts of MNPs
- Lessons learned from environmental sciences research on MNPs
- Lessons learned from research on nanoparticles as starting point for nanoplastics research
- First results of novel scientific research projects on human health impacts of MNPs that started in early 2021 (e.g. H2020 AURORA, H2020 POLYRISK, ZonMw MOMENTUM)
Juliette Legler (Utrecht University, NL):
Setting the Scene: Human health impacts of micro- and nanoplastics (MNPs)
Marja Lamoree (Vrije Universiteit Amsterdam, NL):
Chemical analysis of micro and nanoplastic – evidence of plastic particle pollution in human blood
Julien Gigault (CNRS/ Université Laval, TAKUVIK Laboratory, CA/FR):
Microplastics vs Nanoplastics: a scale problem for human health
Hanna Dusza (Utrecht University, NL):
Studying the early life human health impacts of MNPs
Chairperson(s): Gisela de Aragão Umbuzeiro (University of Campinas, BR), P. David Josephy (Molecular and Cellular Biology, University of Guelph, CA)
Synthetic dyes are ubiquitous. Worldwide, more than 1 billion kg of azo dyes (the largest synthetic dye class) are produced annually, for colouring textiles, paints, papers, plastics, cosmetics, etc. Releases of synthetic dyes from manufacturing and processing operations have resulted in notorious cases of river-water pollution. The use of synthetic dyes in pharmaceuticals, cosmetics, and food (including illicit use) is of particular human health concern. Thousands of different dyes are commercially available but few have been tested adequately(or at all) for possible toxicity. Surprisingly little is known about the metabolism of synthetic dyes, but ingested azo dyes can undergo reductive metabolism in the human gut, releasing aromatic amines and other mutagens/ carcinogens. Chemical remediation of dye wastes is often carried out with the goal of decolourization (“out of sight, out of mind”), but the products, although colourless, may be even more toxic than the dyes themselves. The concept of replacing chemical synthesis of dyes by “green” biosynthetic processes (for example, using engineered microorganisms as factories) is quickly moving from the laboratory to commercialization. In this Scientific Session, the toxicology of dyes will be examined from a range of perspectives: basic chemistry and biochemistry; industrial use; engineering; regulation; human and experimental toxicology.
Gisela de Aragão Umbuzeiro (University of Campinas, BR):
Mutagenicity of dyes: a call to fill the knowledge gaps and improve our predictive ability
P. David Josephy (Molecular and Cellular Biology, University of Guelph, CA):
Characterization and toxicology of azo dye metabolites
Hui Peng (Chemistry, University of Toronto, CA):
Halogenated azo dyes in the indoor environment: detection, occurrence, and toxicokinetic
Riikka Räisänen (BioColour Research Consortium, University of Helsinki, FI):
Developing safe biocolourants for consumer applications