Continuing Education Program

Separate registration required.

Course Book

Room 313

Chairperson(s): Angelika Tritscher, World Health Organization; and Yu Janet Zang, US Food and Drug Administration.

With changing climate and agricultural practices, continuous growth of international food trade and increasing integration of Global Economy Country List, food standards are of critical importance for global food security, public health and economy. There is urgent need to promote the understanding of food risk assessment and standard development process among toxicologists and risk assessment professionals from different geographic and economic regions of the world. This basic-level training course provides essential knowledge on food chemical risk assessment methodologies used by Food and Agriculture Organization of the United Nations (FAO) and World Health Organization (WHO) in assessing health risks and recommending safe exposure levels as basis for global food standards for pesticides, additives and contaminants. The training will give a short overview of the review process applied by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Joint FAO/WHO Meeting on Pesticide Residues (JMPR), followed by lectures that elaborate hazard identification, hazard characterization including dose-response analysis, and exposure assessment. Case examples will be provided, including a hands-on exercise to apply the risk assessment procedures.

Risk Assessment of Food Additives and Chemical Contaminants. Gordon Shephard, Cape Peninsula University of Technology, South Africa.

Risk Assessment of Veterinary Drug and Pesticide Residues in Food. Alan Boobis, Imperial College London, United Kingdom.

The Key to Risk Assessment: Dose-Response Analysis. Matthew Wheeler, Centers for Disease Control and Prevention, The United States of America.

Dietary Exposure Assessment of Chemicals in Food. Peter Cressey, Institute of Environmental Science and Research Limited, New Zealand.

Separate registration required.

Course Book

Room 312

Chairperson(s): Dori Germolec, NIEHS; and Emanuela Corsini, Università degli Studi di Milano.

Significant progress has been made regarding the use of in vitro assessments to evaluate immunotoxicity. This session will focus on current strategies that may transform immunotoxicity assessments from a system based on animal testing to one founded primarily on in vitro methods that evaluate changes in immunologic processes using primary cells, cell lines, or cellular components. The human whole-blood cytokine release assay measures the chemical induced modulation of interleukin (IL)-1β and IL-4 release in human blood samples in response to lipopolysaccharide (LPS) or staphylococcal enterotoxin B (SEB). The Multi-ImmunoTox assay, which uses reporter cell lines derived from Jurkat and THP-1 cells to examine cytokine changes following chemical treatment, has shown promising results in early validation efforts. Machine learning analyses suggest that various integrated approaches based on the adverse outcome pathway for skin sensitization are more accurate in identifying potential skin sensitizers than in vitro, in chemico, or in silico methods by themselves, and can show a high degree of accuracy in predicting known human skin sensitizers. In vitro methods that assess signaling pathways associated with immune function allow the ability to explore indirect mechanisms of immunosuppression. Each of these tools contribute to the identification of compounds that modify immune function.

Approaches and Challenges for Assessing Unintended Cytokine Release by Novel Protein Therapeutics. Madeline Fort, Amgen Inc., The United States of America.

Immunotoxicological Profiling of Chemicals Using Novel In Vitro Assays. Setsuya Aiba, Tohoku University Graduate School of Medicine, Japan.

NTP Approaches to In Vitro Assessment of Dermal Hypersensitivity. Dori Germolec, NIEHS, The United States of America.

Indirect Immunotoxicity: In Vitro Opportunities. Emanuela Corsini, Università degli Studi di Milano, Italy.

Separate registration required.

Course Book

Room 315

Chairperson(s): Abby Li, Exponent, Inc.; and Kristen Ryan, National Toxicology Program, National Institute of Environmental Health Sciences.

New efforts have been made to improve conduct and evaluation of adult and developmental neurotoxicity (DNT) studies for regulatory assessment. In 2017, Health Canada and US EPA published the North American Fair Trade Agreement (NAFTA) internal guidance document for regulatory evaluators on how data from OECD and EPA DNT studies should be reviewed. This, plus new recommendations recognized by Society of Toxicologic Pathology on brain processing and quantitative analysis have relevance for adult and DNT studies. Additionally, adverse outcome pathways (AOP) relevant to adult and developmental neurotoxicity have been published for potential use in regulatory frameworks by the European Food Safety Authority. This continuing education (CE) course will provide participants with basic understanding of state-of-the art approaches for conduct, analysis, reporting and synthesis of neurotoxicology data. The course will begin with a review of current global guideline studies for adult and developmental neurotoxicology, followed by review of recent recommendations on evaluation and reporting of behavioral and neuropathology data. The third speaker will illustrate synthesis of toxicokinetic, neuropharmacologic, additional histological, and stereology approaches that are not required but recommended for further investigation by EPA and OECD guidelines. The final speaker will describe the potential use of in vitro neurotoxicity studies in regulatory frameworks and critical areas for consideration such as biological/human relevance, assay validation, and systematic review.

Introduction to Adult and Developmental Neurotoxicity Testing: History, Guidelines, and Use in Risk Assessment. Hiroaki Aoyama, The Institute of Environmental Toxicology, Japan.

Neurotoxicity Testing: From Benchtop to Regulatory Evaluation. Abby Li, Exponent, Inc., The United States of America.

Integrated Approaches to Testing and Assessment: Aggregating Lines of Evidence from Toxicokinetics and Advanced In Vivo Neuropathology and Neurochemistry Studies. Daniel Minnema, Syngenta Crop Protection, LLC, The United States of America.

Introduction to and Quality Criteria for In Vitro Neurotoxicity Assays and Alternative Methods for Use in Regulatory Frameworks. Kristen Ryan, National Toxicology Program, National Institute of Environmental Health Sciences, The United States of America.

Separate registration required.

Course Book

Room 316

Chairperson(s): Vishal Vaidya, Pfizer, Inc.; and Warren Glaab, Merck and Co.

Biomarkers can serve as variety of functions, such as monitoring safety, provide quantitative measures of chemical exposures and biologically effective doses, predict outcome in a patient with disease, and identify who will respond to an intervention and whether the intervention is working. This course will provide an overview of biomarker science that goes from discovery to evaluation and qualification of biomarkers for safety assessment. After a brief introduction to the pipeline of biomarker development and qualification, the first talk will present past successes and currents state of biomarkers for early detection of kidney injury in nonclinical and clinical studies. Lack of reliable biomarkers for detection of pancreatic as well as skeletal muscle damage remains to be unmet medical need and will be the focus of the next two talks. The fourth talk will describe the significant progress that has been made towards identification of mechanistic biomarkers for liver damage at the interface of novel proteins and microRNAs. Amongst several consortia working on advancing biomarker science the Innovative Medicines Initiative has devoted significant resources towards biomarker discovery and qualification. The final talk will not only summarize learning’s from past initiatives but also discuss opportunities around their latest initiative called TransBioLine.

Clinical Biomarkers for Skeletal Muscle Injury and Neuromuscular Diseases. Vishal Vaidya, Pfizer, Inc., The United States of America.

Translational Biomarkers of Kidney Damage. Mira Pavkovic, Bayer AG, Germany.

Advancing Biomarkers for Pancreatic Toxicity and Pancreatitis. Warren Glaab, Merck and Co., The United States of America.

Translational and Mechanistic Biomarkers of Liver Injury. Chris Goldring, MRC Centre for Drug Safety Science, University of Liverpool, United Kingdom.

Separate registration required.

Course Book

Room 315

Chairperson(s): Weida Tong, US FDA, National Center for Toxicological Research; and Richard Paules, NTP/NIEHS.

Toxicology in the 21st century is marked with increasing incorporation of high throughput technologies to improve our molecular-level understanding of toxicity, moving towards a data-driven regulatory decision-making paradigm. These technologies generate vast amounts of data, representing a truly big data scenario in modern toxicology. Efforts in this field include the Tox21 and ToxCast programs in US, and several EU-based projects motivated by the EU REACH regulation and guided by the 3Rs principle (Replacement, Reduction and Refinement) of animal use. The lack of advanced data mining and knowledge discovery tools powered by big data analytics threatens progress in this new approach to toxicological science. Thus, this era is characterized by significant focus on computational and automational approaches to extract useful information from big toxicology data. This session will introduce some big data methodologies for analysis of large toxicogenomics data sets, particularly by considering designs involving dose-response and time-dependent features that are essential for advancing toxicology. In addition, the read-across of integrating chemical structure information and in vitro data will be also discussed. The focus will be on the analytics to turn data into knowledge, which is the next innovation cycle in this area of big data science.

Transcriptional Responses to Chemicals in Hepatocytes In Vivo and In Vitro. Benjamin Haibe-Kains, Princess Margaret Cancer Centre and University of Toronto, Canada.

Assessing the Potential Liver Toxicity of Compounds Using TG-GATEs Database: A Connectivity Map Approach. Xiaohui Fan, College of Pharmaceutical Sciences, Zhejiang University, China.

Genomic Dose Response Analysis: Identifying Biological Potency at a Genomic Level. Scott Auerbach, Division of the National Toxicology Program at NIEHS, The United States of America.

Transitioning towards Objective Read-Across Approaches: Landscape, Research, and Practical Application. Grace Patlewicz, National Center for Computational Toxicology, US EPA, The United States of America.

Separate registration required.

Course Book

Room 316

Chairperson(s): Aline de Conti, US Food and Drug Administration, National Center for Toxicological Research; and Alexandra Antunes, ULisboa, Instituto Superior Técnico.

Recently epigenetics has become one of the fastest-growing areas of science and due its impact on global, environmental and personal health it is also rapidly expanding in the toxicology field. This course will provide an overview of the current knowledge and a variety of perspectives, challenges and application of epigenetics in toxicological sciences. Initially, the course will cover the basic concepts of epigenetics and its practical application in toxicology. The following presentations will provide recent discoveries on how epigenetic mechanisms are related to adverse health outcomes caused by toxicant exposures early in life or to development of noncommunicable diseases, as cancer. Moreover, the course will bring information on the potential application of epigenetic biomarkers for safety assessment, as well as, the development of epigenetic therapies. The basic concepts will be always be accompanied by studies illustrating the key role of epigenetics for toxicology and safety assessment. The course will also emphasize the experimental methodologies used for epigenetics analysis providing to participants an overall idea of the more accurate experimental methodologies to assess epigenetic modifications. Participants can expect to have an understanding of the role of epigenetics events in toxicology and the specific methodologies used in epigenetic studies.

Epigenetics Overview and Advances. Aline de Conti, National Center for Toxicological Research, US Food and Drug Administration, The United States of America.

Longitudinal Effects of Developmental Exposures on Age-Related DNA Methylation and Hydroxymethylation. Dana C. Dolinoy, University of Michigan School of Public Health, The United States of America.

Epigenetics and Environmental Origins of Cancer. Zdenko Herceg, International Agency for Research on Cancer (IARC), France.

Importance of Investigating Epigenetic Alterations for Industry and Regulators. Jonathan Moggs, Novartis Institutes for BioMedical Research, Switzerland.

Separate registration required.

Course Book

Room 312

Chairperson(s): Barbara F. Hales, McGill University; and Thomas Hartung, Center for Alternative Animal Testing (CAAT), Johns Hopkins University.

New advances in the area of reproductive and developmental toxicology require updated educational opportunities for both current experts in the field as well as new graduate students. The purpose of this educational session will be to share these updates within an international context. Emphasis on in vitro models for both reproductive as well as developmental toxicology endpoints will be presented. Methods of integrating in vivo (rodent and human) with in vitro output will be presented and linkage with quantitative values. The first speaker will illustrate how in silico, in vitro and in vivo assessments of developmental neurotoxicity can be integrated in Adverse Outcome Pathways (AOPs). The second speaker will use case studies to demonstrate how high-throughput screening data, based on embryonic stem cell assays, and developmentally conserved cell signaling pathways, in simulations with agent-based models, contribute to the risk assessment for environmental chemicals. The third speaker will use the plasticizer diethylhexyl phthalate (DEHP) as an example to present a four-step approach for the design, characterization and toxicological assessment of alternative responsible replacements for chemicals with endocrine disrupting effects. The fourth speaker will describe new in vitro approaches based on the evaluation of specific androgen based endpoints and 3D cultures for use in the early identification of chemicals with an adverse impact on male reproductive outcomes. The experts chosen for this session are from a variety of agencies and organizations and have global experience.

Alternative Approaches for Developmental Neurotoxicity (DNT) Evaluations. Anna Bal-Price, European Commission–DG Joint Research Centre (JRC), Italy.

Computational Systems Biology: Translational Tools for Data Integration and Modeling. Thomas B. Knudsen, National Center for Computational Toxicology (NCCT), US Environmental Protection Agency, The United States of America.

Developing a Responsible Approach for Replacing Endocrine Disrupting Chemicals. Bernard Robaire, McGill University, Canada.

Linking In Vivo and In Vitro Male Reproductive Toxicity Risk Assessment. Elaine M. Faustman, University of Washington, The United States of America.

Separate registration required.

Course Book

Room 313

Chairperson(s): Maria Lucia Zaidan Dagli, University of São Paulo, School of Veterinary Medicine and Animal Science; and Robert R. Maronpot, Maronpot Consulting, LLC.

Defining adversity is a central question in toxicology. Regulatory agencies require information on adverse effects from animal toxicological studies to approve the release of commercial products destined for the human population. Establishing what is adverse contributes substantially to risk/safety assessment, helping to define the hazard and allowable exposures to a particular substance (‘no-observed-adverse-effect-level’ (NOAEL) and margin of exposure) and other toxicological parameters. The definition of “adverse” depends on the complete pathological evaluation and interpretation of findings in animal studies. That is why it is important to define whether the relevant pathological alterations are related to the test material, are adaptive and reversible, relevant and translatable to humans. In current toxicology practice, it is often challenging to reliably determine if a particular pathological alteration qualifies as an adverse effect. This course aims to present the most important tools to help toxicologists to define adversity in risk/safety assessments. General pathology and toxicologic pathology concepts will be presented and the audience will learn from specific examples, including theoretical and practical aspects of adverse effects on the liver, endocrine (thyroid) and immune/lymphoid systems.

Defining Adverse, Non-Adverse, and Adaptive Responses in Safety/Risk Assessments. Robert R. Maronpot, Maronpot Consulting, LLC, The United States of America.

Importance of Defining Adverse Effects for Toxicologic Evaluations Risk/Safety Assessment: The Case of Octamethylcyclotetrasiloxane and Decamethylcyclopentasiloxane. Wolfgang Dekant, University of Wuerzburg, Germany.

The Application of Adversity and Adverse Outcome Pathway Analysis to Rodent Thyroid Hormone Perturbation. John R. Foster, ToxPath Sciences Ltd, United Kingdom.

Fundamental Concepts to Understand Adverse Effects in the Immune/Lymphoid System. Maria Lucia Zaidan Dagli, University of São Paulo, School of Veterinary Medicine and Animal Science, Brazil.