Continuing Education Courses (CEC)

Sunday, September 18, 2022

Full day and half day courses with coffee & lunch breaks

10:30 AM - 4:00 PM

Chairperson(s): Emanuela Corsini (Università degli Studi di Milano, IT), Marc Pallardy (Université Paris-Sud, FR)

This Education Course is part of the CE identified by the Education Subcommittee at EUROTOX. Vaccines are an important topic in light of new infections, think of the Corona virus 2019-n-CoV or the Sars between 2002 and 2003, or that of Mers between 2012 and 2019. This topic has never been addressed in education course at EUROTOX. The course will focus on vaccines from design, to efficacy and regulatory requirements. The course includes three lectures followed by an intense group work in the afternoon in order to stimulate the participation of learners as much as possible. The course participants will be divided into three groups which, led by the teachers, will deepen aspects such as the design of a new vaccine, the factors that influence the response to a vaccine, side effects and ethical issues related to the use of animals in vaccine testing.

Presentations:

Emanuela Corsini (UniversitĂ  degli Studi di Milano, IT):
Introduction to the course and working group assignment

Rino Rappuoli (GSK, IT/UK):
The principle of vaccination

David Lewis (Imperial College, UK):
Evaluation of efficacy: the clinincal experience

Marc Pallardy (Université Paris-Sud, FR):
Evaluation of safety: regulatory requirements

Chairperson(s): Johanna Zilliacus (Karolinska Institute, SE)

The aim of the course is to give an introduction to regulatory toxicology. The course will start by introducing concepts and describing the different steps in risk assessment (hazard identification, hazard characterisation, exposure assessment, risk characterisation). The role of health risk assessment for different regulatory systems will be introduced. The second presentation will describe how risk assessment is applied to derive health based guidance values in the context of a regulatory authority. Data requirements, methodological challenges and examples will be included. In the third presentation novel approaches in health risk assessment will be discussed, such as use of new approach methodologies and adverse outcome pathways. The last part of the course will be interactive, and the participants will have the opportunity to get practical exerience and discuss the topics of the course.

Presentations:

Anna Beronius (Karolinska Institute, SE):
Introduction to regulatory toxicology, different steps in risk assessment

Georges Kass (EFSA, IT):
Regulatory toxicology from an authority perspective

Andrew Worth (European Commission Joint Research Center, IT):
Novel approaches in health risk assessment

Johanna Zilliacus (Karolinska Institute, SE):
Workshop with active involvement of the participants

Chairperson(s): Mirjam Luijten (National Institute for Public Health and the Environment (RIVM), NL), Bette Meek (McLaughlin Centre for Risk Science, University of Ottawa, CA)

The Adverse Outcome Pathway (AOP) is a well-known concept that has gained wide acceptance in the toxicology community. It greatly facilitates systematic and transparent assembly of mechanistic information at different levels of biological organization to support regulatory decision making. The development, documentation and assessment of AOPs is supported by a program of the Organisation for Economic Co-operation and Development (OECD). An associated handbook guides users in the description and evaluation of AOPs in an official knowledge base of the program. This course builds on training developed within the OECD programme on principles of AOP development and best practices of documentation and assessment: It evolves content of an earlier course, by updating, refocussing and extending to quantitative modelling aspects and application. By combining lectures on theoretical aspects with practical demonstrations, the course focuses on descriptions of quantitative elements in the AOP wiki and links between weight of evidence evaluation and quantitation. Additionally, examples of regulatory application will be presented. The course is designed to provide students with an understanding of both qualitative and quantitative components of the development, evaluation and application of AOPs.

Presentations:

Mirjam Luijten (Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), NL):
Quantitative AOPs: Background and Principles

Clemens Wittwehr (European Commission, Joint Research Centre (JRC), IT):
AOP Knowledge Collection and Dissemination via the AOP-Wiki: Latest Developments and Live Demo

Bette Meek (McLaughlin Centre for Risk Science, University of Ottawa, CA):
Weight of Evidence Evaluation for AOPs and Link to Quantitation/Stressors

Stephen Edwards (RTI International, USA):
Quantitation of AOPs and Predictive Toxicology

Andrea Terron (European Food Safety Authority, IT):
The AOP programme at EFSA – Case studies on development and use; qualitative and quantitative aspects

Chairperson(s): Alistair Middleton (Unilever, UK), Logan Everett (U.S. Environmental Protection Agency, USA)

Next Generation Risk Assessment (NGRA) is an exposure-led, hypothesis-driven approach that uses new approach methodologies (NAMs) to ensure the safety of chemicals without the use of animal data. Several theoretical frameworks for NGRA have been described, and concrete examples of how to analyse, integrate and interpret NAMs to inform a safety decision are beginning to appear in the literature. However, many of the decision-making steps in NGRA are underpinned using computational models to analyse complex data sets or generate predictions. These approaches can often appear unfamiliar to non-specialists, limiting the extent to which industry and regulatory risk assessors can apply NGRA approaches with confidence. This course aims to give an overview of the various computational approaches used in NGRA. Importantly, the course is aimed to be accessible to the general ICT audience, and therefore no prior knowledge of computational toxicology will be necessary. The first session will give a broad introduction to the area, and then focus on how models can be used to estimate a point of departure from concentration-response data. The second session will discuss physiologically-based kinetic models and how they can be used to estimate internal chemical concentrations based on specific exposure scenarios. The third talk will look at the analysis of high-throughput data, such as transcriptomics, and how these such datasets can be used to characterise the hazard presented by chemicals. The fourth talk will focus on uncertainty quantification using Bayesian approaches, and showcase applications to liver- and cardio-toxicity predictions. The final session will provide a view on the acceptance and adoption of these approaches for risk assessment in regulatory applications. Disclaimer: the views expressed are those of the presenters and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency.

Presentations:

Alistair Middleton (Unilever, UK):
Using computational models to estimate points of departure from in vitro assay data

Ans Punt (Wageningen Food Safety Research, NL):
Development of physiologically based pharmacokinetic (PBPK) models for quantitative in vitro-in vivo extrapolations (QIVIVE)

Logan Everett (U.S. Environmental Protection Agency, USA):
Integration and analysis of high-throughput assays in Next Generation Risk Assessment (NGRA)

Elizaveta Semenova (Imperial College London and University of Oxford, UK):
Capturing uncertainty in toxicity profiling models

Carpi Donatella (European Commission, DG Joint Research Centre, IT):
Perspectives on acceptance and adoption of complex modelling approaches for risk assessment

9:30 AM - 12:30 PM

Chairperson(s): Kimberly McAllister (National Institute of Environmental Health Sciences, USA), Ivan Rusyn (Texas A&M University, USA)

Most human diseases result from a complex interplay of genome-associated (G) and environmental (E) factors, yet studies that combine these factors are difficult in human populations. In addition, quantitative estimation of the extent of human variability in potential adverse effects of chemicals, an important parameter for estimating safe exposure levels in a population, often relies on pharmacokinetic modeling alone, with pharmacodynamic variability impossible to measure. However, new genetically-diverse models have now been developed in the past two decades to better simulate the genetic diversity found in human populations through experimental means. This course will increase awareness of the toxicologist and environmental scientists about the importance of population-based model organisms research for understanding GxE interactions in complex human disease outcomes. First, this course will introduce the role that genetic susceptibility plays in both environmental science research and decision-making. Second, we will show how rodent population-based resources can be used to model environmental exposures and GxE interactions in human disease. Third, we will detail how human cell-based populations have been used in high throughput in vitro assays, toxicity screens, and functional validation experiments. Finally, we will describe a variety of other population-based non-vertebrate model organism systems that have also been developed in recent years and used in toxicology experiments. Overall, this course will combine the concepts of genetics with examples of the solutions that population-based models may offer for challenging issues in environmental health. Specifically, it will address conceptual and practical aspects of designing toxicology studies that incorporate genetic diversity such as choice of appropriate model system(s) and cohort structure, sample size, dosing, analysis methods, relevant outcome measures and translation of findings to the human context.

Presentations:

Kimberly McAllister (National Institute of Environmental Health Sciences, USA):
Overview of the role for studies of inter-individual variability in toxicology

Gary Churchill (The Jackson Laboratory, USA):
Rodent models for studies of genetic diversity and case studies of their use in toxicology

Ivan Rusyn (Texas A&M University, USA):
Human cell-based models of genetic diversity and case studies of their use in toxicology

Erik Andersen (Nortwestern University, USA):
Invertebrate models of genetic diversity and case studies of their use in toxicology

1:30 PM - 4:00 PM

Chairperson(s): Linda Roberts (NapaTox Consulting LLC, USA), Alan Hoberman (Charles River Laboratories, USA)

The majority of women work outside the home during their reproductive years, and a significant number continue to work during pregnancy. Although regulatory actions have led to improved hazard information and protections, there are still unique occupational toxicology challenges presented to ensuring a safe workplace during pregnancy. Occupational exposure limits (OELs), which essentially represent risk management decisions for exposures deemed protective for most employees, may be established with incomplete data relevant for pregnancy, and many chemicals do not have an OEL at all. Companies are tasked with the responsibility of ensuring that their site is safe for all workers, including the period of pregnancy. This course will cover historical context, data interpretation, exposure considerations, regulatory parameters, and practical approaches to risk management for pregnant workers. The course may illustrate complexities at each step through example agents.

Presentations:

Linda Roberts (NapaTox Consulting LLC, USA):
A framework for occupational risk management for pregnant workers

Alan Hoberman (Charles River Laboratories, USA):
Pregnancy and nonclinical developmental/reproductive toxicity testing and classification

Jason Hodgkiss (On Advice Limited, UK):
Exposure evaluation and control options

Salmaan Inayat Hussain (PETRONAS, MY):
Risk management in practice

Chairperson(s): Heli Miriam Hollnagel (Dow Europe GmbH, CH), Kristi L. Muldoon Jacobs (US FDA, USA)

Thresholds of Toxicological Concern is a concept for risk assessment of low oral exposures based on generic de minimis thresholds below which there is negligible concern for effects on human health. Initial ideas on the approach were developed in the 1960s, formalised in publications in the 1990s, and acknowledged by authoritative bodies such as the US FDA, EFSA and WHO some years later. As new toxicity data, mechanistical knowledge and assessment approaches become available, a scientific concept such as TTC should be updated to reflect those, and can also be expanded. A recent expansion is the generation of a multitude of clearance and intestinal absorption data for the use of PBPK modelling to derive internal TTC thresholds which can be applied to assess exposures by other than the oral route, or aggregate exposures via different routes. The carcinogen potency database used to derive the threshold for DNA-reactive structures was recently updated and reanalysed, paired with an analysis whether the Cramer Class thresholds are appropriate for non-DNA-reactive carcinogens, as assumed by the concept endorsed by WHO and EFSA. The US FDA has been working on updating and expanding the Cramer et al. Decision Tree to reflect the current state of science and make it applicable to a wide variaty of compouds with broad structural variation. Sources of uncertainty were identified and estimated for impact for both TTC and specific data – based hazard characterisation. All of those ongoing or recent projects will be presented to update attendees on those recent developments in TTC.

Presentations:

Heli Miriam Hollnagel (Dow Europe GmbH, CH):
Introduction to TTC – concept, databases, excluded substances and sources of uncertainty

Sylvia Escher (Fraunhofer ITEM, DE):
Recent advances: TTC values for (non)- DNA reactive carcinogens and TTC for airborne compounds

Abdulkarim Najjar (Beiersdorf AG, DE):
Towards internal threshold of toxicological concern (iTTC): Implementation of Pharmacokinetics (PK) in the safety assessment

Kristi L. Muldoon Jacobs (US FDA, USA):
TTC in regulatory processes and the US FDA Expanded Decision Tree