International Efforts to Ensure Global Food Safety: Incorporating Advanced Toxicological Sciences in Food Risk Assessment
Room: CC 316
Chairpersons: Angelika Tritscher, World Health Organization; and Yongxiang Fan, China National Centre for Food Safety Risk Assessment.
Science-based food standards are essential to protecting public health and facilitating international food trade. To assist the Codex Alimentarius Commission to establish international standards for food additives, chemical contaminants, veterinary drug residues and pesticide residues, the Food and Agriculture Organization of the United Nations (FAO) and World Health Organization (WHO) regularly convene joint expert committees on Food Additives (JECFA) and joint meetings on pesticide residues (JMPR) to assess the health risk of exposures to these chemicals from food. Another important element of this work is the update and harmonization of risk assessment methods and principles as science evolves, and the development of interactive tools and databases to assist food chemical risk assessment and management globally. In this symposium, WHO and experts involved in this international work will present recent efforts and new developments initiated by JECFA and JMPR that reflect the implementing of current science. Toxicologists who have served on these international committees will give their perspectives and share examples that showcase how advances in toxicological sciences improve the quality and rigor of food chemical risk assessments. This symposium intends to enhance awareness, share knowledge and encourage participation among the international toxicology and risk assessment community.
Risk Assessment Methodologies As Applied by JECFA and JMPR. Angelika Tritscher, World Health Organization, Switzerland.
Applications of Evolving Science in Assessing the Safety of Food Additives and Chemical Contaminants by JECFA. Yu Janet Zang, US Food and Drug Administration, The United States of America.
Incorporation of Duration of Exposure into The Risk Assessment of Residues of Pesticides and Veterinary Drugs in Food. Alan Boobis, Imperial College London, United Kingdom.
Updated WHO Guidance on the Evaluation of Genotoxicity of Compounds in Food. Virunya Bhat, NSF International, The United States of America.
Lysosomes: Key Regulators of Inflammation and Life or Death of a Cell
Room: CC 313
Chairpersons: Andrij Holian, The University of Montana; and Srikanth Nadadur, National Institute of Environmental Health Sciences.
Lysosomes are important organelles involved in the maintenance of cellular homeostasis and degrading extracellular pathogens and antigen presentation. It is now recognized that lysosomes also play a critical role in fundamental cellular processes, such as protein secretion, endocytic receptor recycling, energy metabolism, and cell signaling. Lysosomes are also involved in the degradation of cellular components through the process of autophagy as homeostatic pathways for normal cells. The lysosomal membrane is protected from the acidic hydrolases by lysosome specific expression of membrane proteins such as Lamp-1 and Lamp-2. However, in response to certain toxic stimuli, lysosomal membrane permeabilization (LMP) may occur causing NLRP3 inflammasome activation, alteration of normal autophagy, etc., leading to the initiation of intracellular pathways resulting in inflammation, fibrosis and cancer. Therefore, an understanding of the regulation of lysosomal membrane integrity is therefore essential in preventing the release of hydrolytic enzymes to the cytosol which would affect normal cell function and likely involved in a number of chronic diseases. This symposium will review current information on the role of this important organelle in normal cellular function, as well as, potential mechanisms leading to LMP resulting in cell death and inflammation.
Mechanistic Insights in Lysosome-Mediated Cell Death. Karin Öllinger, Linköping University, Sweden.
Lysosomal Alterations in Health and Disease. Patricia Boya, Centro de Investigaciones Biologicas, CIB-CSIC, Spain.
Impact of Lipids and Particles on Lysosomal Membrane Permeability (LMP). Andrij Holian, University of Montana, The United States of America.
Why Lysosomal Membrane Permeabilization (LMP) Could Be Considered a Key Event (KE) in Adverse Outcome Pathway (AOP) to Particle-Induced Inflammation and Fibrosis of the Lung. Mary Gulumian, Toxicology Resaerch Projects NIOH, South Africa.
Emerging Mechanisms of Chemical Teratogenesis
Room: CC 312
Chairpersons: Peter G. Wells, University of Toronto; and Neil Vargesson, University of Aberdeen.
By age 5, 12–14% of children show problems of developmental origin (teratogenesis) including structural malformations, infant mortality and functional deficits like neurodevelopmental disorders. In utero exposure to drugs and environmental chemicals (xenobiotics) is estimated to cause about 5% of malformations detected at birth, and a higher percentage of postnatal functional disorders. Current associations are likely underestimates due to detection limitations and dependence upon interactions with genetic/epigenetic factors. This symposium presents emerging data from animal models and humans revealing mechanisms that underlie these disorders and determine individual risk. The first speaker will discuss the involvement of reactive oxygen species, DNA oxidation and repair in neurodevelopmental deficits initiated by fetal exposure to methamphetamine and alcohol (ethanol). The second speaker will discuss the role of stress response signaling pathways, and particularly the P53 pathway, in abnormal embryonic development caused by cyclophosphamide and hydroxyurea. The third speaker will focus upon epigenetic mechanisms, and particularly microRNAs (miRNAs), in humans and human trophoblast cell lines, in ethanol teratogenesis. The final speaker will discuss the vascular basis of teratogenesis exemplified by thalidomide. Insights from these studies may facilitate the development of diagnostic biomarkers for high-risk individuals, and novel strategies for therapeutic mitigation.
Oxidative DNA Damage and Repair in Teratogenesis. Peter G. Wells, University of Toronto, Canada.
Stress-Response Signaling Pathways in the Organogenesis-Stage Embryo. Barbara F. Hales, McGill University, Canada.
Assessing the Function of Endocrine miRNAs in Pregnant Women That Predict FASD Infant Outcomes. Rajesh C. Miranda, Texas A&M Health Science Center, The United States of America.
Vascular Basis of Teratogenesis. Neil Vargesson, University of Aberdeen, United Kingdom.
Systemic and Functional Impacts of Maternal Pulmonary Nanomaterial Exposures on the Offspring
Room: CC 315
Chairpersons: Phoebe Stapleton, Rutgers University; and Karin Sørig Hougaard, National Research Centre for the Working Environment.
Toxicological exposures during gestation often results in outward teratogenicity, malformations, and fetal death. Recently xenobiotic exposures have been found to induce subtle teratogenic responses in the fetus and long lasting effects in the offspring. The effects of nanomaterial exposure are still poorly understood, and even more so for the shaping of fetal physiology. Recent studies point towards fetal multi-organ sensitivity to maternal particle exposure during pregnancy. This symposium will focus on how xenobiotic engineered nanomaterial exposures during susceptible gestational time points can affect the health of the developing offspring. These presentations will demonstrate exposure to engineered nanomaterials during gestation may compromise the in utero environment. Fetal impairments may be associated with particle translocation and direct placental toxicity. Maternal exposures have led to severe consequences on the fetal and adult physiological function of the pulmonary, neurological, reproductive, and cardiovascular systems. Lastly, maternal exposures can lead to epigenetic alterations in the fetal genome leading to modifications of gene expression. In summary, this symposium seeks to address the significant threats that engineered nanomaterial exposure during gestation may impose to alter fetal developmental trajectory towards suboptimal physiological phenotypes and identify how future research may enlighten our insight within the field of developmental nanotoxicology.
Inhalation of Nanomaterials Can Result in Systemic Effects Leading to Pre- and Postnatal Effects. Flemming R. Cassee, National Institute for Public Health and the Environment (RIVM), The Netherlands.
Deposition of Nanomaterials at the Feto-Maternal Interphase and Their Effects on the Fetus. Luisa Campagnolo, University of Rome “Tor Vergata”, Italy.
Effects of Maternal Lung Exposure to Nanomaterials on the Nervous and Male Reproductive Systems. Karin Sørig Hougaard, National Research Centre for the Working Environment, Denmark.
Cardiovascular, Metabolic, and Epigenetic Susceptibility in Offspring after Maternal Engineered Nanomaterial Exposure. Phoebe Stapleton, Rutgers University, The United States of America.
New Approach Methodologies: A Global Perspective
Room: CC 316
Chairpersons: Charu Chandrasekera, Canadian Centre for Alternatives to Animal Methods/Validation of Alternative Methods (CaCVAM); and Nicole Kleinstreuer, The National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods.
From the Americas to the Far East, countries across the globe have established national Centers for the Validation of Alternatives Methods (CVAMs) dedicated to the development, validation, and promotion of non-animal alternative methods that can reduce and replace the current—predominantly animal based—modes of toxicological risk assessment. These integrative new approach methodologies offer rapid, human-relevant predictions, enabling research and regulatory enterprises to streamline safety and risk assessment. Promising new technologies across the spectrum—from molecular and cellular in vitro alternatives to microphysiological systems to systems biology and computational toxicology—are poised to improve the reliability, reproducibility, sensitivity, and human relevance of assessing both toxicity and efficacy. In keeping with the theme for IUTOX 2019—to create diverse sessions highlighting excellence in science and toxicology from across the globe—here we present the latest 21st century toxicology and regulatory testing efforts from three continents: Americas (USA and Canada), European Union, and Asia (Japan). These members of the International Cooperation on Alternative Test Methods (ICATM) representing academic, government, and regulatory sectors will discuss their respective strategies, projects, and global harmonization efforts.
Beyond the Silver Anniversary: The Next 25 Years of Alternatives in the European Union. Maurice Whelan, European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM), European Commission Joint Research Centre, Italy.
Adopting New Approach Methodologies: The US Strategic Roadmap and Implementation Activities. Nicole Kleinstreuer, The National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, The United States of America.
21st Century Toxicology and Regulatory Testing: An Update from East Asia. Hajime Kojima, Japanese Center for the Validation of Alternative Methods (JaCVAM), National Institute of Health Sciences, Japan.
O Canada: A Strategic Vision toward Replacement in the True North. Charu Chandrasekera, Canadian Centre for Alternatives to Animal Methods/Validation of Alternative Methods (CaCVAM), Canada.
Emerging CRISPR Applications in Environmental Health Sciences and Toxicology
Room: CC 313
Chairpersons: Luoping Zhang, University of California, Berkeley; and Chris Vulpe, University of Florida.
Advanced genome editing technology, most notably the CRISPR-Cas system, has been rapidly applied to numerous fields, including gene-therapy for treatment of human diseases, drug screening and development, and plant engineering to improve food security. Contrary to its widespread interdisciplinary use, CRISPR application in environmental health science and toxicology has remained limited. Similar to drug screens, toxicity of environmental chemicals can be readily tested in a cell-based assay and their mechanistic pathways can be further elucidated through genome-wide functional testing. Previously, this approach was applied in a yeast screening system, and findings were validated in human cells in vitro and in population studies. To date, the novel CRISPR technology, including genome-wide CRISPRi (interference, loss-of-function) and CRISPRa (activation, gain-of-function) can be employed to fully examine genomic responses to a tested chemical. Recently, a targeted approach, Tox-CRISPR, is developed to focus on testing genes frequently involved in toxicity caused by environmental exposures. Applying both genome-wide and targeted approaches, we can harness the power and flexibility of the CRISPR functional screening to gain mechanistic insight in modern toxicology for an unprecedented protection of human and environmental health. This symposium aims to guild and encourage ICT community to apply CRISPR in environmental health research.
Genome-Wide and Targeted CRISPR Screening to Understand Gene-Environment Interactions. Chris Vulpe, University of Florida, The United States of America.
CRISPR Screening to Identify Suppressors of Cellular Stress Response to Proteo-Toxicants. Quan Lu, School of Public Health, Harvard University, The United States of America.
CRISPR Application to Uncover Redox Biology. Navdeep Chandel, School of Medicine, Northwestrn University, The United States of America.
A Vision for CRISPR Applications in Toxicology and Environmental Health. Luoping Zhang, School of Public Health, University of California, Berkeley, The United States of America.
Epigenetic Biomarkers of Exposure to Environmental Carcinogens
Room: CC 312
Chairpersons: Igor Pogribny, National Center for Toxicological Research; and Shuk-mei Ho, Cincinnati Cancer Center, University of Cincinnati Medical Center.
Cancer development in humans is determined by the interaction of two key etiological factors, genetics and environmental exposures. There is increasing evidence, however, that genetic factors might not be the principal cause of cancer development, but that exposure to natural and man-made chemical and physical carcinogens may have a more profound impact. Extensive and constantly growing data indicate that epigenome is a major target for environmental carcinogens and is greatly affected by their exposure. This suggests that carcinogen-induced epigenetic changes might be useful in safety assessment of carcinogens, including pharmaceutical products and food additives and contaminants. Furthermore, the transition from using epigenetic signatures of exposure as potential biomarkers only to identifying their mechanistic role in cancer development allows for better characterization and fundamental understanding of the biology of how environmental insults are involved in the carcinogenic process. This symposium will present current knowledge on the linkages among exposure, genome, epigenome and cutting-edge research on the role of the epigenome as a central component linking environmental exposures to cancer development. Additionally, it will illustrate that the evaluation of carcinogen-induced epigenomic alterations may not only enhance the carcinogen assessment process but also provide opportunity for the development of better cancer preventive strategies.
Epigenomics, Stem Cells, and Environmental Carcinogens. Shuk-Mei Ho, Cincinnati Cancer Center, University of Cincinnati Medical Center, The United States of America.
Epigenomics and Drug-Induced Carcinogenicity. Jonathan Moggs, Novartis Institutes for BioMedical Research, Switzerland.
Corrections of Epigenetic Abnormalities as Prevention of Chemical-Induced Carcinogenesis. Fernando Salvador Moreno, University of São Paulo, Brazil.
The Role of Epigenetic Science in Carcinogen Detection. Igor Pogribny, National Center for Toxicological Research, The United States of America.
Concerns of Herbal Product-Induced Toxicity
Room: CC 315
Chairpersons: Nan Mei, US FDA, National Center for Toxicological Research; and Amy C. Brown, John A. Burns School of Medicine, University of Hawaii at Manoa.
Global interest in botanicals or derivative products is growing because people often believe that “natural” sources may be beneficial to health. Herbal products made from botanicals are usually used to maintain or improve health. A group of chemicals can be isolated from a botanical and sold as a botanical dietary supplement. Thousands of herbal products are sold in many forms and millions of people worldwide regularly consume herbal products. Herbal products are expected to be safe, effective, and of appropriate quality. However, the complex chemical nature of herbal products makes it difficult for efficacy and safety evaluation. Herbal products often exhibit great variability in quality because of problems in authentication, adulteration and substitution, along with numerous variable factors during growth, harvest, and postharvest processing. Reported adverse effects have raised public health risk concerns regarding the concentration, composition, and individual contaminants of dietary supplements. Recently, the IARC has assessed the carcinogenicity of some herbal products, and part of them are classified as Group 2B (volume 108 of the IARC Monographs). Herbal products also have been recognized in certain cases of drug-induced liver injury. Therefore, testing of herbal products for efficacy and safety is important and needs to be conducted scientifically.
Safety Evaluation of Herbal Products: Current Standards to a Proposed More Comprehensive Evaluation. Ahmet Aydın, Yeditepe University, Turkey.
Hepatotoxicity of Usnic Acid and Its Mechanisms. Si Chen, National Center for Toxicological Research (NCTR), US Food and Drug Administration (FDA), The United States of America.
Neurotoxicity of Ginkgo biloba Seeds and Its Mechanisms. Daisuke Kobayashi, Health Sciences University of Hokkaido, Japan.
Cardiotoxicity of Aconitum Plants and Its Mechanisms. Xianju Huang, South-Central University for Nationalities, China.
Clinical and Mechanistic Aspects of Drug-Induced Liver Injury
Room: CC 316
Chairpersons: José E. Manautou, University of Connecticut; and Ann Daly, Institute of Cellular Medicine.
Drug-induced liver injury (DILI) continues to be prominent problem in drug development and patient care. Although our knowledge of DILI mechanisms is incomplete, multiple cellular events and their molecular mediators contributing to DILI have been defined. Despite multiple efforts, preclinical animal models do not always predict liver injury in humans. This has prompted investigators to develop new and better screening tools and to identify new genetic determinants of DILI earlier in the drug discovery process. This symposium will cover the various DILI risk factors relating to immune response, including HLA alleles, followed by the impact of drug transporters on compensatory hepatocellular regeneration following liver injury and the establishment of new animal models to study DILI by acyl glucuronide intermediates. We will conclude the symposium with a description of efforts by world-wide registries and multicenter networks in identifying mechanistic-based DILI biomarkers and the use of ‘omics approaches to the study DILI.
Genetic Aspects of DILI: Recent Advances on Predicting Risk. Ann K. Daly, Institute of Cellular Medicine, Newcastle University, United Kingdom.
Application of Circulating MicroRNA to Diagnose Early Stage of Liver Injury and Its Pathogenesis in Rat DILI Model. Tsuyoshi Yokoi, Nagoya University Graduate School of Medicine, Japan.
Impact of Multidrug Resistance Protein 4 (MRP4/ABCC4) Function in Compensatory Hepatocellular Proliferation. José E. Manautou, University of Connecticut, The United States of America.
Clinical and Mechanistic Aspects of Drug-Induced Liver Injury. Fernando Bessone, University of Rosario School of Medicine, Argentina.
Effects of Environmental Mixture Exposure on Brain Development and Function Based on Epidemiological, In Vivo, and In Vitro Studies
Room: CC 313
Chairpersons: Anna Bal-Price, European Commission Joint Research Centre (JRC); and Oddvar Myhre, Norwegian Institute of Public Health, Department of Toxicology and Risk Assessment.
Epidemiological and experimental data suggest that pre- and postnatal exposure towards chemical mixtures affects brain development. In addition to genetic factors, such exposure might be causally linked to the recently increased prevalence of neurodevelopmental disorders (NDDs) like attention deficit/hyperactivity disorder, autism spectrum disorders and learning disabilities. Yet, there is a profound knowledge gap in understanding the chemical-related pathogenesis of NDDs. Therefore, novel approaches in human exposure assessment, in vitro and in vivo studies are needed to identify such causative factors. Speakers of this session will present from the scientific and regulatory point of views the most recent approaches (a) on evaluation and description of an alternative developmental neurotoxicity testing battery permitting (b) evaluation of an impact of mixture exposure on brain development using in vitro approaches, driven by key events identified in relevant adverse outcome pathways, as well as (c) a mixture risk assessment of combined human exposures to PBDEs and (d) identification of possible mechanisms of chemical mixtures as risk factors for NDDs based on epidemiological and in vivo studies. As NDDs have profound consequences for families and society, the identification of preventable risk factors such as environmental pollution exposure should be of high priority.
Methods for Stage-Specific Developmental Neurotoxicity Testing with Human Stem-/Progenitor Cell-Based Models for Mixture Evaluation. Ellen Fritsche, IUF, Leibniz Research Institute for Environmental Medicine, Germany.
Adverse Outcome Pathways (AOPs)-Driven Evaluation of Developmental Neurotoxicity Induced by Mixture of Environmental Chemicals. Anna Bal-Price, European Commission Joint Research Centre (JRC), Italy.
Mechanisms of Environmental Pollutants Mixtures As Risk Factor for Attention Deficit/Hyperactivity Disorder and Autism Pathophysiology Based on Epidemiological and In Vivo Studies. Oddvar Myhre, Norwegian Institute of Public Health, Department of Toxicology and Risk Assessment, Norway.
A Human Mixture Risk Assessment for Neurodevelopmental Toxicity Associated with Polybrominated Diphenyl Ethers Used as Flame Retardants. Andreas Kortenkamp, Brunel University London, Department of Life Sciences, College of Health and Life Sciences, United Kingdom.
Immunotoxicity Associated with Exposure to Nanomaterials
Room: CC 312
Chairpersons: Carolyn Vickers, World Health Organization; and Henk van Loveren, Maastricht University.
Due to their properties, nanomaterials have a propensity to interact with components of the immune system. In addition to direct effects on the immune system, interaction with the immune system may be relevant in the facilitation of cancer. The World Health Organization in 2018 released a new Environmental Health Criteria Document, titled Principles and methods for assessing the risk of immunotoxicity associated with exposure to nanomaterials. The symposium will present the WHO document, and review information on the mechanisms of immunotoxicity due to exposure to nanomaterials. Information on carbon nanotubes in a range of products will be provided as examples.
WHO Principles and Methods for Assessing the Risk of Immunotoxicity Associated with Exposure to Nanomaterials. Henk Van Loveren, Maastricht University, The Netherlands.
Occurrence of TiO2 in Food, Supplements and Toothpaste, Resulting Exposure and Toxicokinetics. Minne Heringa, Centre for Safety of Substances and Products (VSP), The Netherlands.
Mechanisms and Consequences of Immune Interactions of Graphene-Based Materials. Bengt Fadeel, Karolinska Institutet, Sweden.
Immunotoxicity and Susceptibility Issues following Pulmonary Exposure to Carbon Nanotubes. James Bonner, North Carolina State University, The United States of America.
The Carcinogenicity of Hexavalent Chromium: A Global Public and Environmental Health Concern
Room: CC 315
Chairpersons: John Pierce Wise Sr., University of Louisville; and Kazuya Kondo, Tokushima University.
Hexavalent chromium [Cr(VI)] is a global environmental pollutant and a major public health concern. It is an established human lung carcinogen, particularly after inhalation exposure, and lung cancer remains the leading cause of cancer death around the world. It is clear that, while cigarette smoking is the most familiar cause of lung cancer, other agents cause a significant amount of the disease. For example, in the United States, of those diagnosed with lung cancer, 1 in 5 women and 1 in 12 men will never have smoked. Thus, understanding how agents other than cigarettes cause lung cancer is a significant need and a key aspect to combating the disease. While Cr(VI) has been known to cause lung cancer for decades, its carcinogenic mechanisms are still poorly understood. Impacts on DNA repair, chromosome structure and number, cellular metabolism, inflammation, apoptosis, cell signaling, centrosome amplification, among others have all been implicated in its carcinogenicity along with epigenetic, mutagenic and aneugenic changes. This symposium will present current perspectives that provide deeper understanding of Cr(VI) carcinogenesis and directions towards solutions with presentations spanning a spectrum of ideas ranging from clinical to laboratory to risk assessment-based paradigms in order to better understand this important carcinogen.
Genetic and Epigenetic Alterations of Lung Cancer in Workers with Chromate Exposure. Kazuya Kondo, Tokushima University, Japan.
Inflammation-Driven Cancer Stem Cells Formation as Promoter of Hexavalent Chromium Carcinogenesis. Carmen Alpoim, University of Coimbra, Portugal.
Mechanisms of Hexavalent Chromium-Induced Genomic Instability: How a Lung Carcinogen Breaks DNA and Inhibits Repair. John Pierce Wise Sr., University of Louisville, The United States of America.
Using the Latest Science in Cancer Risk Assessment for Hexavalent Chromium: Is It Time to Step Away from the Default Regulatory Approaches? Deborah Proctor, ToxStrategies, Inc., The United States of America.
Out of the Box: Contribution of the Immune System to Organ Toxicity
Room: CC 316
Chairpersons: Emanuela Corsini, Università degli Studi di Milano, Milan, Lombardy, Italy; and Nurşsen Başaran, Hacettepe University.
Inflammation is known to play a prominent role in several human diseases and is a common response to many stressors, including chemicals. Under normal conditions, inflammation is an adaptive process that contrast infections and is involved in tissue damage repair. However, chemicals can elicit prolonged, severe, and inappropriate inflammatory responses that play a central role in a variety of target organ toxicities. The purpose of this symposium is to link immunotoxicity to target organ toxicity, showing the Janus face of the inflammatory reaction and of the immune system.
Early-Life Exposure to Immunotoxic Compounds and Later-in-Life Diseases. Rodney Reynolds Dietert, Cornell University, The United States of America.
Role of the Immune System in Drug-Induced Liver Injury. Tsuyoshi Yokoi, Nagoya University Graduate School of Medicine, Japan.
Role of Inflammation in Chemical-Induced Kidney Damage. David J. Nikolic Paterson, Department of Nephrology, Australia.
Particles, Fibres, and Lung Toxicity: Effects Beyond the Lung. Flemming R. Cassee, Institute for Risk Assessment Sciences, Utrecht University, The Netherlands.
Acute, Chronic, and Long-Term Pesticide Effects: Mechanisms of Actions, Epidemiological Data, Priority Areas for Research
Room: CC 313
Chairpersons: Aristidis Tsatsakis, University Crete; and Emanuela Corsini, University of Milano.
Pesticides have been, wrongly or reasonably, associated with increased prevalence of several pathological conditions. Among these, behaviour, dementia and Parkinson’s disease, and cancer, represent particularly relevant public health issues and specific group of pesticide, in particular organ chlorinated compounds, are considered as high concern group. Acute pesticide poisoning still remain an outstanding issue, but data collection, evaluation and interpretation is quite difficult due to a significant underreporting. This workshop aims at critically evaluating the existing evidence on these issues and at identifying priority areas and approaches for research. Each speaker will develop a systematic review on the assigned topic, will show the results and will highlight evidence and doubts. A 15-minute slot at the end of the symposium will be addressed at the discussion of the presentations. The Authors have committed themselves to prepare a paper on these topics, to be published in an international journal.
Pesticide Exposure, Human Behavior, Parkinson’s Disease and Dementia: Evidences, Uncertainties, Open Points. Claudio Colosio, Department of Health Sciences of the University of Milano and International Centre for Rural Health of the San Paolo Hospital of Milano, Italy.
Pesticides and Cancer: Current Knowledge and Epidemiological Evidence. Martin Wilks, Swiss Centre for Applied Human Toxicology, Switzerland.
Persistent Organochlorinated Pesticides and Mechanisms of Their Toxicity: An Updating. Ezra Mrema, Muhimbili University of Health and Allied Sciences, United Republic of Tanzania.
Acute Pesticide Poisoning and the Effect of Pesticide Regulation. Won Jin Lee, Korea University College of Medicine, The Republic of Korea.
Collaborative Approaches to Proactively Advance 3Rs in Nonclinical Drug Development
Room: CC 312
Chairpersons: Thomas Monticello, Amgen; and Ian Pyrah, Seattle Genetics.
Animal toxicology studies are conducted during drug development to ensure human safety, identify potential organs of toxicity and aid in establishing a clinical starting dose. The conduct of animal toxicology studies is based on historical precedence and regulatory guidance, centered on the assumption that the animal model of choice and the toxicology study provide value in identifying potential human hazards and help ensure patient safety. The 3R approaches are designed to advocate for the replacement of animals with alternative models, the reduction of animal use by improvements in study designs that minimize animal numbers and optimize the information gained per animal, and refinement to minimize distress or harm in situations where the use of animal testing is unavoidable. This session will present proactive considerations of implementing the 3Rs in nonclinical safety assessment that will begin with the overview of the current state of the predictive value of animal studies, including safety pharmacology studies. Opportunities to optimize study designs to incorporate other regulatory mandated endpoints, considerations in species selection and inclusion of recovery animals, approaches to an ‘animal free’ drug development, and finally, opportunities to replace animal testing by implementing microphysiological system technologies (aka ‘organ on a chip’), will also be presented.
Setting the Bar for Positive and Negative Animal Predictive Values: The IQ Translational Database. Thomas Monticello, Amgen, The United States of America.
Applying the 3Rs within Regulatory Toxicology Studies in Drug Development. Helen Prior, National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), United Kingdom.
Animal-Free INDs and CTAs: A Reality or Dream? Michael W. Leach, Pfizer, The United States of America.
Strategic Application of Microphysiological Systems in Safety Assessment to Decrease Dependence on Animal Studies. Brian Berridge, National Toxicology Program, National Institute of Environmental Health Sciences, The United States of America.
Empowering Toxicology and Environmental Health Research to Address Disasters and Emerging Threats
Room: CC 315
Chairpersons: Scott Masten, National Institute of Environmental Health Sciences; and Shoji F. Nakayama, National Institute for Environmental Studies.
Disasters including the World Trade Center attack, Great Eastern Japan Earthquake, Gulf Oil Spill, and recent tropical storms, wildfires and volcanic eruptions have revealed the dire need for improved ability to perform rapid data collection and research to address health-related concerns. The collection of human exposure and health data in the immediate aftermath of public health emergencies and disasters is essential for ensuring situational awareness, shaping the public health response, identifying health research needs, supporting recovery efforts and enhancing future preparedness. Yet the initiation of public health research and response is often delayed by a host of long-standing logistical, process, and regulatory barriers. This session will provide an overview of the critical importance and need for timely toxicology and environmental health research in response to disasters. Speakers will discuss challenges in understanding human health implications and addressing public concerns for recent disasters, highlight research responses to specific large-scale disasters and describe evolving programs to develop improved disaster research response capacity. The session will encourage discussion of the challenges and potential strategies that will enable the conduct of time-critical human health assessments to support decision-making.
Addressing Toxicology and Human Health Concerns with the NIH Disaster Research Response (DR2) Program. Linda Birnbaum, National Institute of Environmental Health Sciences (NIEHS) and National Toxicology Program, The United States of America.
Disaster Response Research Development in Japan. Shoji F. Nakayama, National Institute for Environmental Studies, Japan.
When Disaster Strikes: Response, Research, and Recovery. Sharon Petronella Croisant, University of Texas Medical Branch at Galveston, The United States of America.
Addressing Public Health Hazards Arising from Recent Threats and Disasters in California. Lauren Zeise, Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, The United States of America.
Applying the Key Characteristics Paradigm in Hazard Identification and Risk Assessment
Room: CC 313
Chairpersons: Martyn Smith, University of California at Berkeley; and Kathryn Guyton, Monographs Programme, International Agency for Research on Cancer, World Health Organization.
This symposium will highlight the potential application of the key characteristics paradigm to the identification of human carcinogens and other health risks from chemical exposures and to suggest consensus solutions and new approaches. Smith et al. (Env. Health Perspect. 124: 713, 2016) identified 10 key characteristics, one or more of which are commonly exhibited by established human carcinogens. The key characteristics are distinct from the hallmarks of cancer, which are the properties of tumors. The key characteristics instead reflect the properties of a cancer-causing agent, such as ‘is genotoxic’, ‘is immunosuppressive’ or ‘modulates receptor-mediated effects’. In the cancer hazard identification process, the key characteristics have been used to guide a systematic literature search focused on relevant end points. Further, the National Academy of Sciences recently suggested development of key characteristics for other hazards, such as cardiovascular and reproductive toxicity. The presentations will first describe the scientific basis of key characteristics of carcinogens, discuss how biomarkers of the key characteristics and new assays for their measurement could be applied to assess human cancer risk in drug development, and describe solutions based on the key characteristics to advance cancer research and hazard identification as being applied in national and international settings.
The Key Characteristics of Carcinogens. Martyn T. Smith, University of California at Berkeley, The United States of America.
Applying the Key Characteristics of Carcinogens to Assess Human Cancer Risk in Drug Development. Mark Fielden, Amgen Inc, Comparative Biology and Safety Sciences, The United States of America.
Air Pollution Exhibits Multiple Key Characteristics of Carcinogens. Hideko Sone, Yokohama University of Pharmacy, National Institute for Environmental Studies, Japan.
Application of the Key Characteristics in the IARC Monographs Programme. Kathryn Guyton, Monographs Programme, International Agency for Research on Cancer, World Health Organization, France.
Biomarker Qualification: Accelerating Drug Development by Enabling the Use of Novel Diagnostic and Safety Biomarkers
Room: CC 312
Chairpersons: Jiri Aubrecht, Takeda; and John-Michael Sauer, Critical Path Institute.
The application of novel biomarkers in drug development is needed to accelerate the approval of new therapeutic modalities and improve diagnosis of diseases in clinical practice. However, the development and qualification of biomarkers is a costly and time-consuming process. Therefore, new innovative scientific approaches and analytical technologies, as well as access to appropriate human samples for biomarker qualification and assay validation, are required. Recently consortia including Critical Path Institute, the Predicative Safety Testing Consortium (PSTC), Innovative Medicines Initiative Safer and Faster Evidence Based Translation Consortium (IMI SAFE-T), International Life Sciences Institute Health and Environmental Sciences Institute (ILSI HESI), and Foundations for the National Institutes of Health Biomarker Consortium (FNIH BC), have identified several promising advances to support biomarker development including scientific advances in analysis and quantification of circulating microRNA and toxicogenomics. In addition, the recent progress in defining the scientific and regulatory expectations for biomarker qualification, led by C-Path and FNIH BC, provides a blueprint for the conduct of regulatory qualification of biomarkers. This symposium will provide insights into innovative approaches and state-of-the-art science involved in the development and world-wide regulatory acceptance of biomarkers for use in drug development, environmental risk assessment, and diagnosis of disease.
How Much Evidence Is Enough to Accept a Biomarker for Regulatory Decision-Making? Development of Evidentiary Considerations. John-Michael Sauer, Critical Path Institute, The United States of America.
GLDH as an Example of Regulatory Biomarker Qualification: A Liver-Specific Biomarker of Liver Injury in Drug Development and Medical Care. Jiri Aubrecht, Takeda, The United States of America.
Case Studies on Integration of Toxicogenomic Biomarkers in Genetic Toxicology Assessment. Carole Yauk, Health Canada, Environmental Health Centre, Canada.
Serum MicroRNA Signatures as “Liquid Biopsies” for Interrogating Hepatotoxic Mechanisms and Liver Pathogenesis in Human. Julian Krauskopf, University of Maastricht, The Netherlands.
Recent Trends in Research on Arsenic Toxicity
Room: CC 315
Chairpersons: Yoshito Kumagai, University of Tsukuba; and Jin-Ho Chung, Seoul National University, Gwanak-gu.
Arsenic is ubiquitously distributed in nature throughout Earth’s crust is also reported to modulate a variety of cellular signal transduction pathways. Speakers in the symposium will introduce recent findings found by each laboratory on the basis of molecular biology or chemical biology. For example, Prof. Zhang introduces disruption of formation of the STX17-SNAP29-VAMP8 SNARE complex, leading to inhibition of the autophagy pathway. Prof. Pi introduces importance of Nrf2/1 in β-cells and adipocytes and provide insight into the effects of inorganic arsenic exposure on insulin secretion and action. Prof. Kumagai introduces (E)-2-alkenals with an α,β-unsaturated aldehyde moiety, which is a common substituent in phytochemicals isolated from C. sativum leaves, activate the Keap1/Nrf2 pathway associated with cellular protection against arsenic. Prof. Chung introduces prometastastic effects of arsenic exposure can indeed contribute to cancer-related mortality.
Arsenic in Oxidative Stress vs. Proteotoxic Stress. Donna Zhang, University of Arizona, The United States of America.
Paradoxical Roles of CNC-bZIP Proteins NRF2 and NRF1 in Arsenic-Induced Dysfunction in Pancreatic β-Cells and Adipocytes. Jingbo Pi, China Medical University, China.
Activation of Nrf2 through Covalent Modification of Keap1 by 2-alkenal Group of Aliphatic Electrophiles in Coriandrum sativum L. Diminishes Arsenic-Mediated Cytotoxicity. Yoshito Kumagai, University of Tsukuba, Japan.
Arsenic May Act As a Pro-Metastatic Carcinogen through Promoting Tumor Cell-Platelet Aggregation. Jin-Ho Chung, Seoul National University, The Republic of Korea.
Leveraging Zebrafish to Support Global Toxicology Challenges
Room: CC 316
Chairpersons: Jennifer Freeman, School of Health Sciences, Purdue University; and David Volz, Department of Environmental Sciences, University of California, Riverside.
Over the past 20 years, adoption and integration of the application of zebrafish as a toxicological model system has magnified in most areas of toxicology-based research. As a well-recognized biomedical research model, zebrafish presents numerous strengths that have been leveraged in many toxicity studies. Rapid ex vivo development of a small, near-transparent singular embryo permits ease for assessing chemical perturbations at all stages of early development as well as use in high-throughput chemical screens and automated phenotyping. In addition, a complete genome sequence, array of tools for manipulating gene function, and availability of several thousand mutant and transgenic lines provides, similar to mouse models, readily available resources for comprehensive mechanistic studies of toxicity. Furthermore, maturation at three months of age and a shorter lifespan allow for multi- and transgenerational studies and efficient identification and evaluation of developmental origins of health and disease. As researchers continue to expand the use of the zebrafish in toxicology, limitations of this animal model are also being identified. In this session, speakers will highlight what has been learned from over two decades of using zebrafish as a model for toxicology, spanning mechanistic studies to current applications in high-throughput screening of chemicals and chemical mixtures.
Transcriptomics Coupled with High-Throughput Phenotypic Screening to Accelerate Discovery of Toxicity Pathways. Robert Tanguay, Department of Environmental and Molecular Toxicology, Oregon State University, The United States of America.
Methylmercury-Induced Epigenetic Transgenerational Inheritance of Abnormal Neurobehavior Is Correlated with Sperm Epimutations in Zebrafish. Michael Carvan, School of Freshwater Sciences, University of Wisconsin-Milwaukee, The United States of America.
Lessons Learned on the Toxicokinetics upon Waterborne Chemical Exposure in Zebrafish Larvae. Krishna Tulasi Kirla, Department of Forensic Pharmacology and Toxicology, Eawag, Switzerland.
The Fish Embryo Model: Update and Challenges for Its Potential Regulatory Applications. Marc Léonard, L’OREAL Research and Innovation, Environmental Research Department, France.